Close
Home
Collections
Login
USC Login
Register
0
Selected
Invert selection
Deselect all
Deselect all
Click here to refresh results
Click here to refresh results
USC
/
Digital Library
/
University of Southern California Dissertations and Theses
/
Impaired Learning Of Spatial And Passive Avoidance Habits With Lesions Of Precommissural And Postcommissural Fornix
(USC Thesis Other)
Impaired Learning Of Spatial And Passive Avoidance Habits With Lesions Of Precommissural And Postcommissural Fornix
PDF
Download
Share
Open document
Flip pages
Contact Us
Contact Us
Copy asset link
Request this asset
Transcript (if available)
Content
INFORMATION TO USERS This malarial was produoad from a microfilm copy of the original documant. Whila tha most advancad tachnological moans to photograph and raproduco this documant have boon usad, tha quality is haavily dapandant upon tha quality of tha original submittad. Tha following oxpianation of tachniquos is provided to help you understand markings or patterns which may appear on this reproduction. 1. The sign or "target" for pages apparently lacking from tha document photographed is "Missing Pags(s)". If it was possible to obtain the missing pago(s) or section, they arc spliced into the film along with adjacent pages. This may have necessitated cutting thru an image and duplicating adjacent pages to insure you complete continuity. 2. Whan an image on tha film is obi iterated with a large round black mark, it is an indication that tha photographer suspected that the copy may have moved during exposure and thus causa a blurred image. You will find a good image of tha page in the adjacent frame. 3. Whan a map, drawing or chart, etc., was part of the material being photographed the photographer followed a definite method in "sectioning" the material. It is customary to begin photoing at tha upper left hand comer of a large sheet and to continue photoing from left to right in equal sections with a small overlap. If necessary, sectioning is continued again — beginning below the first row and continuing on until complete. 4. The majority of users indicate that tha textual content is of greatest value, however, a somewhat higher quality reproduction could bo made from "photographs" if asaantial to the understanding of tha dissertation. Si Ivor prints of "photographs" may be ordered at additional charge by writing the Order Department, giving the catalog number, title, author and specific pagas you wish reproduced. 5. PLEASE NOTE: Some pegss may have indistinct print. Filmed as received. Xerox University Microfilms 900 North ZMb Hoad Am Aibor. Michigan 40106 HENDERSON, Judith Lynn, 1940- IMPAIRED LEARNING OF SPATIAL AND PASSIVE AVOIDANCE ' HABITS WITH LESIONS OF PRECOMMISSURAL AND POSTCOWIISS URAL FORNIX. University of Southorn California, Ph.D., 1974 Psychology, experimental Xerox University Microfilms, A nn A rb or, M ic h ig a n 4 $ io « THIS DISSERTATION HAS BEEN MICROFILMED EXACTLY AS RECEIVED. IMPAIRED LEARNING OP SPATIAL AND PASSIVE AVOIDANCE HABITS WITH LESIONS OF PRECOMMISSURAL AND POSTCOMMISSURAL FORNIX by Judith Lynn Henderson A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (Psychology) January 1975 UNIVERSITY O F SO U TH ER N CALIFORNIA T H t GRADUATE SCHOOL UNIVERSITY PARK LOS A NOELES. CA LIFORN IA # 0 0 0 7 This dissertation, written by J U D I T O . U M ^ ......... under the direction of h.ftT... Dissertation Com mittee, and approved by all its members, has been presented to and accepted by The Graduate School, in partial fulfillment of requirements of the degree of D O C T O R OF P H IL O S O P H Y IMITTEE ACKNOWLEDGMENTS Several people have helped me a great deal in achieving my educational goals. My committee members, Dr. James Walker and Dr. Eric Holmes, have contributed valuable time in assessing this research. I want to particularly thank four very Important men for making my completion of this doctoral program possible. My husband, Robert, has continuously offered much-needed encouragement during my college career. His enthusiastic support and assistance was the single most important factor in the completion of my graduate program. The extra work done by my sons, Jeffrey and Kenneth, has given me the time required to finish my research. Thank you Bob, Jeff and Ken. My committee chairman, Dr. Ernest Greene, has been extremely helpful to me throughout my graduate program. His valuable help in developing the techniques and analy sis used in this research is gratefully acknowledged and sincerely appreciated. Thank you, Dr. Greene. ii CONTENTS Page LIST OF TABLES..................................... iv LIST OF FIGURES................................... v INTRODUCTION ....................................... 1 Chapter I. ANATOMY OF THE HIPPOCAMPAL FORMATION AND ITS RELATIONSHIP WITH OTHER NUCLEI .... 4 II. THEORIES OF FUNCTION OF THE HIPPOCAMPUS, SEPTUM, MAMMILLARY BODIES AND THALAMUS . . 21 III. PURPOSE OF THIS RESEARCH................... 39 IV. METHODS.................................... 43 Subjects Apparatus Taming Surgery- Training and Testing Histology V. RESULTS.................................... 53 Behavioral Results Histological Results VI. DISCUSSION, CONCLUSIONS, AND SUMMARY .... 71 Discussion and Conclusions Summary REFERENCES......................................... 86 iii LIST OF TABLES Table Page 1. Summary of the Efferent Projections of the Fornix............................. 12 2. Pre- vs. Postcommissural Fornix............. 5^ iv LIST OF FIGURES Figure Page 1. Alternation errors of intact surgical groups ........................... 58 2. Alternation errors of selected surgical groups ........................... 59 3. Passive avoidance latencies ................. 62 4. Passive avoidance trials ................... 63 5. Illustrations of lesion placement ........... 69 v INTRODUCTION The hippocampal syndrome that results from lesion- ing the hippocampus consists of behavior that is persevera- tive, hyperactive, and may possibly involve loss of recent memory. Attempts to assess the role of the hippocampus physiologically have relied heavily on lesion or depression techniques, which involve the entire structure. Also, most theories attempting to explain hippocampal function have described behavioral impairment following hippocampal lesions in terms of the failure of a single mechanism. It is possible that the complexity of hippocampal anatomy may be reflected in independent and dissociable functional mechanisms. Although there are many unresolved and conflicting results in the anatomical literature, the past two decades of research have greatly expanded our knowledge of the connections within the limbic system. For example, the work of investigators at the University of Aarhus (Black- stad, 1956; HJorth-Simonsen & Jenue, 1971; HJorth-Simonsen, 1971, 1972) has clarified the relationships of the struc tures of the hippocampal gyrus with the hippocampus. Others, most notably Raisman, Cowan, T. P. S. Powell and E. W. Powell (Powell, Guillery, & Cowan, 1957; Powell, 1 1963; Raisman, Cowan, & Powell, 1 9 6 5* 1966; Ralsman, 1 9 6 6; Powell, 1966, 1973) have concentrated on connections pass ing to and from the hippocampus via the fornix. However, there has been very little clarification of the function served by these various connections. Although the activi ties of the hippocampus have been a matter of intensive study, few laboratories have conducted experiments designed to sever particular tracts to discover what role is played by each in mediating hippocampal function. One such approach has been to cut a major afferent and efferent hippocampal pathway, the fornix. Lesions of the entire fornix have been found to produce behavior that is perseverative (McCleary, 1 9 6 6; Hirsh & Segal, 1972; Greene, Stauff, & Walters, 1972), which is the same behav ioral deficit found in animals with lesions involving the entire hippocampus. Perseverative behavior is also pro duced by septal lesions (Douglas & Raphelson, 1 9 6 6; Neil- son, Mclver, & Boswell, 1 9 6 5; Hamilton, 1970) and by lesions of the diagonal band (Schwartzbaum & Donovick, 1968). When the fornix is severed, spatial learning abil ity, extinction, and passive avoidance are impaired (Greene & Stauff, 1974). Passive avoidance, but not spatial learn ing or extinction, are impaired when the posterior connec tions of the hippocampus are severed (i.e., a cut which severs the perforant fibers passing through the subiculum) (Greene & Stauff, 197*0- The purpose of this study is to further examine the communications of the hippocampus, using cuts which inter rupt postcommissural fornix connections (to anterior thala mus and mammillary bodies) and cuts which sever different parts of the precommissural fornix projection. Behavioral tasks used are those in which animals with hippocampal or septal lesions have shown deficiencies, namely activity in an open field, learning an original position habit, revers ing the position, single-alternation of position, extinc tion, and passive avoidance. CHAPTER I ANATOMY OP THE HIPPOCAMPAL FORMATION AND ITS RELATIONSHIP WITH OTHER NUCLEI The principal parts of the hippocampal formation are the fimbria, the sublculum, the hippocampus proper (Ammon's horn) and the dentate gyrus. The fimbria is continuous with the fornix, and contains hippocampal affer- ents and efferents. The subiculum is a transitional area from the entorhinal cortex to the hippocampus which is structurally and functionally poorly understood. Ammon's horn and the dentate gyrus are frequently considered together as the hippocampus. Closely associated with the hippocampal formation is the pyriform lobe. This is the cortex which extends, in rats, from the rhinal fissure to the hippocampus. The caudal part of the pyriform lobe is the entorhinal cortex, which is a major source of hippocampal afferents. Rostral to the entorhinal cortex are periamygdaloid cortex and prepyriform cortex. The hippocampus and dentate have a laminar appear ance which is partly due to the termination of afferent neurons at different levels in these structures. The two 4 5 primary sources of hippocampal afferents are the entor hinal cortex and the septum. The entorhinal cortex has a close association with a number of cortical areas, making it an interesting link between the neocortex and the limbic system. Orbito- frontal, prepyriform and ventral temporal cortical projec tions to the lateral entorhinal area have been examined in monkeys (Van Hoesen, Pandya, & Butters, 1972) and may explain some of the similar effects between hippocampal and orbitofrontal lesions. These cortical areas receive afferents from the major sensory systems. Therefore the hippocampus appears to have an indirect link to the various sensory systems through the perforant path from the entor hinal cortex (Van Hoesen et al., 1972). The pyriform cortex and the cingulate cortex also project to the entorhinal area, and the cingulate also projects to CA1 of the hippocampus (Alksne, Blackstad, Walberg, & White, 1 9 6 6). A second source of hippocampal afferents is from the medial septal and diagonal band nuclei through the fimbria to CA3 and the dentate gyrus (Cragg, 1961; Raisman, Cowan, & Powell, 1965). The septum appears to play a sig nificant role in regulating hippocampal electrical activ ity (Green & Arduinl, 195^). 6 The lateral preoptlc and lateral hypothalamic nuclei project to the presubiculum and CAl through the dorsal fornix (Raisman, Cowan, & Powell, 1 9 6 5). Terminations of these afferent neurons on the pyramidal cells of the hippocampus and the granule cells of the dentate contribute to the production of laminar sub divisions In the three major hippocampal layers. The outer layer of the hippocampus contains the stratum alveus and stratum oriens. The alveus contains axons of the major pyramidal cells which have transversed the oriens from the cell body on their way to the fimbria. The oriens contains the basal dendrites of the hippocampal pyramids as well as other cell types. Commissural fibers terminate here throughout the hippocampus (Blackstad, 1 9 5 6). Afferents from the medial septum terminate in CA3 and CA4 (Cragg & Hamlyn, 1957; Cragg, 1961; Raisman et al., 1 9 6 5) and in posterior CAl (Raisman et al., 1 9 6 5). The oriens layer is rich in acetylcholinesterase. Sectioning the fimbria, through which septal neurons travel, reduces the acetylcholinesterase level (Shute & Lewis, 1 9 6 6) indicating that the medial septum has a role in regulating neuronal activity in the hippocampus. The middle layer, stratum pyramidale, is named for the cell bodies located here. It has been divided into cellular areas based primarily on morphological differences in the cells. Classifications by Lorente de Nd and Cajal are both commonly used. Lorente de N6 (1934) divided the hippocampus into four cellular areas, while Cajal (1911) divided it into two regions. Lorente de N<5's CAl and CA2 correspond roughly to Cajal's regio superior, while CA3 and CA4 correspond to regio inferior. The largest pyramidal cells are in CA3. Cells in CA4 are in the fold of the dentate gyrus, and are contiguous with the polymorph layer of the dentate. Cells in CAl are much smaller than CA3 cells, and are in multiple layers. Those in CA2 blend into CAl, although the CA2 cells are larger, and the areas are particularly difficult to distinguish in the dorsal hippo campus. It has been suggested that there is no valid dis tinction between CA3 and CA2 (Blackstad, Brink, Hem, & Jeune, 1970), since the key distinction was based on the presence of mossy fibers in CA3 but not in CA2 which has recently been refuted. The inner layers of the hippocampus include four strata--the lucidum (in CA3 only), the radiatum, the lacunosum and the moleculare. Mossy fibers (axons of the granule cells from the dentate gyrus) terminate in the stratum lucidum, as well as in the oriens, of CA3 (Hamlyn, 1962). The stratum radiatum is composed of the primary shafts of the apical dendrites of the pyramidal cells. There are some afferent terminations in the radial layer of 8 CA3 and CA4 from the medial septal and diagonal band nuclei and commissural terminations in all cellular areas (Rais man et al., 1 9 6 5). The stratum lacunosum is a dense mass formed by the synapses of Schaffer collaterals from CA3 with the apical dendrites of CAl (Hamlyn, 1963; Raisman et al., 1 9 6 5). Longitudinal afferents from the entorhinal cortex terminate in the stratum moleculare, with the neu rons from the lateral entorhinal area terminating on the superficial apical dendrites of CA3, and those from the medial entorhinal cortex terminating deeper in the molecu lar layer on the apical dendrites of CA3. This projection is via the perforant path (HJorth-Simonsen, 1972). A projection from the medial entorhinal area to CAl (the alvear path) was proposed (Cajal, 1911; Raisman et al., 1 9 6 5) but has not been confirmed in recent studies (HJorth- Simonsen, 1972). Like the hippocampus, the dentate gyrus has a laminar structure determined by afferent neurons. The outer polymorph layer of the dentate gyrus is continuous with CA4 and contains the proximal portions of the mossy fibers. Septal afferents terminate here (Raisman et al., 1965). The granule layer contains the cell bodies whose mossy fibers form the efferent contact with CA3 of the hippocampus. The molecular layer contains the dendrites of the 9 granule cells. The distal parts of the granule cell den drites receive afferents from the entorhinal cortex via the perforant tract, with the afferents from the lateral entor hinal area terminating on the superficial third and those from the medial entorhinal cortex terminating on the middle third of the dendrites. Afferent fibers from the septum via the fornix end in the molecular layer (Raisman et al., 1965) and are apparently cholinergic fibers (Schute & Lewis, 1 9 6 6). Commissural fibers from the contralateral hippo campus may terminate on the proximal third of the basal dendrites (Blackstad, 1956). A proposed projection from CAl to the dentate (Raisman et al., 1 9 6 5) has not been verified (HJorth-Simonsen, 1973). Zimmer (1 9 7 2) found neurons projecting from CA3 and CA4 of the hippocampus to the ipsilateral commissural zone of the dentate. The dentate gyrus has no efferent projections except to CA3 and CA4 of the hippocampus via the mossy fibers. The dentate granule cells apparently have two feedback loops. One is via the Zimmer collaterals Just described, and the other involves mossy fiber collaterals synapsing with basket cells which surround the granule cell body. This is an inhibitory feedback loop (Zimmer, 1972). The fornix carries many of the hippocampal efferent fibers, but is not the sole source of hippocampal output as was once proposed (Brodal, 19^7; Raisman et al., 1 9 6 6). In 10 addition to the efferent fibers traveling through the fornix, there is an efferent projection from the hippo campus via the subiculum to the entorhinal cortex which was determined in an electrophysiological study to contain about half of the hippocampal efferents (Poletti, Sujata- nond, & Sweet, 1972). The posterior ventral part of CA3 projects to layer IV of the medial entorhinal cortex (HJorth-Simonsen, 1971). A lesion which severs this subicular-entorhinal connection has been found to have no effect on the performance of rats on a group of tasks on which hippocampally lesioned rats are impaired. These tasks are the ones chosen for this study: exploration of the open field, straight alley, position habit, reversal of the position habit, learned alternation and extinction of alternation. A passive avoidance task will also be used, and this is the only task of the group Just men tioned in which animals with subicular lesions were found to be impaired (Greene & Stauff, 197*0- Analysis of the possible functions of a brain structure is frequently based on lesioning or other manipu lation of the entire structure. Structures in the limbic system are anatomically complex, and data supporting various global theories about their functions frequently conflict. Recently, experimenters have begun to analyze brain struc tures by cutting the fiber tracts that connect them. This 11 technique is applicable to the study of the hippocampus, because of the anatomy of the fornix. Fornix fibers are described as being precommissural if they project rostral to the anterior commissure, and postcommissural if they turn in a ventral direction and do not project rostral to the anterior commissure. Pre- and postcommissural fibers have different target structures, and some difference in points of origin. Approximately half of the fornix fibers project through the precommissural fornix and half through the postcommissural fornix (Powell, Guillery & Cowan, 1957). Precommissural fibers project to the septal nuclei, nucleus of the diagonal band, accumbens, preoptic area and bed nucleus of the anterior commissure (Nauta, 1956), while postcommissural fibers project to the anterior thalamus, mammillary bodies, hypothalamus and midbrain (Raisman et al., 1 9 6 6). Table 1 summarizes the relationship between the hippocampal cellular areas and the nuclei to which the pre- and postcommissural fornix fibers project. The rela tionship between the hippocampus and the septum is of particular interest, because lesions of these structures produce similar behavioral impairments. The principal divisions of the septum are the medial and lateral septal nuclei, the nucleus of the diago nal band, and, in the caudal third of the septum, the septofimbrial and triangular septal nuclei. The bed 12 TABLE 1 SUM4ABX OF THE EFFERENT PROJECTIONS OF THE FORNIX Precommissural Pyramidal Field Theory6 Anterior CAl: Posterior CAl: CA3: Dorsal-ventral Theory^ Dorsal hippocampus: Ventral hippocampus: Postcommissural Pyramidal Field Theory6 Anterior CAl: Posterior CAl: CA3: Dorsal-ventral Theory Dorsal hippocampus: Ventral hippocampus: Medial septum, diagonal band of Broca, and possibly to the preoptic area Junction of medial and lateral septum, ventral parts of the lateral septum, dorsal parts of the septofimbrial nucleus, diagonal band and accumbens Dorsal parts of the lateral septum, septofimbrial nucleus, diagonal band and accumbens Medial septum, ventral nucleus of diagonal band Lateral septum and accumbens, minor projection to medial septum and ventral nucleus of diagonal band, ventrolateral preoptic area Anteromedial and anteroventral thalamic nuclei, dorsal parts of the mammillary bodies (especially pars posterior) Anteromedial and anteroventral thalamic nuclei, ventral parts of the mammillary bodies None Pars lateral medial mammillary body Pars posterior medial mammillary body Pars lateral medial mammillary body Pars posterior medial mammillary body Summarized from Raisman, Cowan, and Powell, 1966. ^Summarized from Siegel and Tassoni, 1971a, 1971b• 13 nucleus of stria termanalis, ventral and lateral to the septofimbrial and triangular nuclei, may be considered either as part of the septum or part of the preoptic area (Raisman, 1966). The major telencephalic source of septal afferent fibers is the hippocampus. Other telencephalic afferents to the septum are from the pyriform cortex to the diagonal band, and the olfactory tubercle (Raisman, 1966). The stria terminalis is a major efferent path for the corti- comedial amygdala, and projects to the bed nucleus in the septum surrounding the anterior commissure (Miller & Mogen- son, 1 9 7 2). Prom the diencephalon, the septum receives affer ents from the hypothalamus and midbrain through the medial forebrain bundle (Raisman, 1 9 6 6). Raisman and his associates (Raisman, Cowan, & Powell, 1965; Raisman, 1966) have reported anatomical evi dence from rats that the relationship between hippocampal pyramidal fields and septal nuclei is specific. Precom missural efferent fibers from anterior CAl project to the medial septum and diagonal band and preoptic nuclei. Pre commissural efferent fibers from the remainder of the hippocampus (posterior CAl, CA3 and CA4) project to the lateral septum, septofimbrial nucleus, accumbens and medial forebrain bundle (Raisman et al., 1 9 6 6). This is the 14 functional relationship outlined in Table 1. These pro jections to the septum are ordered, with posterior CAl projecting Just lateral to the anterior CAl projection, and CA3 and CA4 projecting bilaterally to the lateral septum (Raisman et al., 1966). The reciprocal projections from the septum to the hippocampus are reported to be equally specific with regard to the hippocampal cellular areas. Efferent fibers from the medial septum have been traced to the hippocampal areas CAl, CA3 and CA4 (Raisman, 1965* 196 6). No substan tial septum to dorsal fornix (CAl) projection was found (Raisman, 1 9 6 6; Daitz & Powell, 1954). Other investigators, working with cats (Siegel & Tassoni, 1971a) and rats (Siegel & Edinger, 1973) report that the various hippocampal pyramidal fields do not pro ject differentially. Instead, these investigators con cluded that the ordered relationships are between ventral vs. dorsal hippocampus and the septal nuclei. Fibers were traced from ventral hippocampus through the precommissural fornix to the lateral septal nucleus and nucleus accumbens. Not all of the efferent projections from the ventral hippo campus were limited to the lateral septum. Some fibers were traced through the medial septum to the ventral nucle us of the diagonal band and olfactory tubercle; a few terminated in the ventrolateral preoptic area (Siegel & Tassoni, 1971a). I I I I 15 In an animal in which lesions of the ventral hippo campus were placed more posteriorly, degeneration in the lateral septum was slightly medial to the degeneration found in the more anteriorly placed lesions described above, supporting the idea of anterior-posterior as well as ventral-dorsal topography (Siegel & Tassoni, 1971a). Fibers from the dorsal hippocampus were traced through the precommissural fornix to the medial septal nucleus (Siegel & Tassoni, 1971a). Again, termination of the fibers was not limited to the major target nucleus. Some fibers were traced to the ventral nucleus of the diagonal band. Lesions placed in the dorsal hippocampus produced no degeneration in the lateral nucleus of the septum (Siegel & Tassoni, 1971a). The projection from the dorsal hippocampus to the medial septum is quantitatively much smaller than the massive projection from the ventral hippocampus to the lateral septal nucleus (Siegel & Tas soni, 1971b). The ventral hippocampus-to-lateral septum and dorsal hippocampus-to-medial septum relationships described above appear to be reciprocal (Siegel & Tassoni, 1970; Siegel & Tassoni, 1971b; Brust-Carmona, Alvarez- Leefmans, & Arditti, 1973). Efferent septal fibers were traced from the lateral septal nucleus through the lateral part of the fornix to the fimbria, then into the ventral 16 hippocampus ipsilateral to the side of the lesion. The septal efferents appeared to terminate equally in each of the hippocampal pyramidal fields (Siegel & Tassoni, 1971b). Prom the medial septal nucleus, septal efferents were traced through the medial fornix to the dorsal fornix and into the dorsal hippocampus. Again, there was no sys tematic difference in the pyramidal fields in which the medial septal efferents terminated (Siegel & Tassoni, 1971b). The theory that the relationship between the hippo campus and the septum is organized on the basis of the ventral-dorsal rather than pyramidal field differentiation in the hippocampus is supported by single unit studies made in several species, including cats and rats (Edinger, Siegel, & Troiano, 1973). These investigators stimulated dorsal hippocampal efferents and recorded short-latency neuronal driving in the medial septum. When the ventral hippocampal area was stimulated, short-latency driving was recorded in the lateral septum. In contrast to the topo graphic organization of excitatory efferents from the hippocampus, inhibition in both the medial and lateral septal nucleus is produced by stimulation of either the dorsal or ventral hippocampus (Edinger et al., 1973) probably because of diffuse interneurons on the system. DeFrance, Shimono and Kitai (I97l)> using an evoked 17 potential technique, produced excitation in the medial part of the lateral septal nucleus by stimulating the fornix, and excited the entire lateral septum by stimulating the fimbria. Edinger et al. (1973) suggested that this may be because fibers from the ventral hippocampus travel in the fimbria, while fibers from the dorsal hippocampus travel in the dorsal fornix. The precommissural fornix pathway from the hippo campus through the septum is an indirect route by which the hippocampus can influence diencephalic brain struc tures (Raisman, 1 9 6 6). A direct route is through the post commissural fornix (Raisman, 1 9 6 6; Nauta, 1956). Postcom missural fornix fibers project mainly from CAl through the dorsal fornix to the mammillary bodies, anteroventral and anteromedial thalamus, hypothalamus, subiculum, and rostral midbrain (Raisman et al., 196 6). While as many as 50 percent of the fornix fibers go through the postcommissural fornix, less than half of them reach the mammillary bodies (Powell, Guillery, & Cowan, 1957). The fibers which do not reach the mammillary bodies are apparently projecting to the anterior thalamic nuc lei. There are two afferent tracts to the mammillary bodies: the fornix and the tract through the mammillary peduncle. The fibers from the hippocampus which end in 18 the mammillary nuclei come from the dorsal fold of the alveus, travel in the dorsal fornix, and go to the pars lateralis and pars posterior of the medial mammillary nucleus (Guillery, 1956). According to Siegel and Tassoni (1971a), the dorsal hippocampus contributes more efferents to the mammillary bodies than does the ventral part of the hippocampus. The pars lateralis projects to the antero- dorsal thalamus and the pars posterior projects to the anteroventral thalamus (Guillery, 1956; Powell et al., 1957)- The ventromedial two-thirds of the pars medialis projects to the anteromedial thalamic nucleus. Some input into the lateral medial mammillary nucleus is from the midbrain, specifically from the mammillary peduncle (Powell et al., 1 9 5 7). A direct hippocampal-thalamic projection was described as early as 1 8 8 1. The existence of a direct route was debated for many years, and was established by Nauta (1956) and Guillery (1956). Fibers from the hippo campus leave the anterior third of the postcommissural fornix and go to the anteroventral and anteromedial thalamic nuclei, according to Nauta (1956) and Guillery (1956). However one group of investigators (Siegel & Tassoni, 1971b) reported that the anteroventral nucleus is the only thalamic recipient of hippocampal efferents. According to Guillery (1956), fibers to the anteroventral 19 nucleus of the thalamus come directly from the hippocampus, while hippocampal fibers to the anterodorsal nucleus of the thalamus have been relayed in the pars lateralis of the medial mammillary nucleus. The anteromedial nucleus of the thalamus receives a direct hippocampal projection, and also a projection from pars medialis of the medial mammil lary nucleus and the mammillary peduncle (Powell et al., 1957). Thus the anteromedial nucleus of the thalamus might be influenced heavily by the midbrain (Powell et al., 1957). The anterior thalamic nuclei project to the cingu- late cortex (Rose & Woolsey, 1948). The anteriomedial nucleus of the thalamus is larger in the monkey than in the rat, but the mammillary peduncle is very small in primates. Powell et al. (1957) concluded, therefore, that the anteri or cingulate cortex may be more directly influenced by the hippocampus in primates than in rats. Anteromedial and anteroventral thalamic nuclei receive some septal afferent fibers, in addition to the hippocampal afferents, through the descending columns of the fornix (Powell, 1966). The major portion of the septal fibers to the thalamic nuclei pass through the stria medul- laris rather than through the fornix (Powell, 1 9 6 6; Powell et al., 1 9 5 7). In addition to the postcommissural fornix fibers that go to the thalamic nuclei and mammillary bodies, there 20 is a small group that goes to the hypothalamus in the rat, and probably in other species (Powell et al., 1957). The major projection to the anterior part of the lateral hypo thalamus comes from ventral hippocampus, while more effer ent fibers from dorsal hippocampus terminate in the poste rior lateral hypothalamus (Siegel & Tassoni, 1971a). Raisman (1965) has suggested that these hypothalamic affer ent s are from the subiculum. There is also a hippocampal-hypothalamic projection fi'om the fimbria to the supra-chiasmatic nucleus and the periventricular region of the anterior hypothalamus (Nauta, 1956; Guillery, 1956). CHAPTER II- THEORIES OF FUNCTION OF THE HIPPOCAMPUS, SEPTUM, MAMMILLARY BODIES AND THALAMUS A number of both specific and general functions have been suggested for the hippocampus. Thus far, there is no overwhelming evidence that compels the acceptance or rejection of any theory except that the hippocampus does not appear to function as a simple "center" for olfaction (Swann, 193^; Allen, 1940). Another early idea is that the hippocampus may have a role in mediating emotional behavior, as suggested by its position in the circuit proposed by Papez (1937). Temporal lobe lesions in monkeys produced emotional changes (Kluver & Bucy, 1 9 3 9), but these changes occur even when the hippocampus is spared (Douglas, 1 9 6 7). The possibility that the hippocampus has a very significant role in memory storage was suggested by the investigations of hippocampal lesions in humans (Scoville & Milner, 1957; Penfield & Milner, 1958). An enormous amount of animal research was generated by this work, from which conclusions regarding the role of the hippocampus in learn ing and memory must remain tentative. A review of the 21 22 lesion studies by Douglas (1 9 6 7) concludes that hippocampal lesions do not impair learning in general. The impairment is found in specific types of tasks only. Therefore, postulated memory deficits must be restricted to deficits in memory of body orientation in space (spatial mapping) and possibly of aversive stimulation under specific condi tions . The functional role of the septum, which interacts with the hippocampus through the precommissural fornix fibers, is as illusive as that of the hippocampus itself. The medial septum apparently has an important role in pacing the hippocampal theta rhythm, the characteristic slow (4-7 cps.) wave EEG that appears in the hippocampus in response to stimuli which produce neocortical EEG arousal, or desynchronization (Green & Arduinl, 1954; Petsche, Stumpf, & Gogalak, 1 9 6 2). Theta input to the septum appears to come from the brain stem and reticular forma tion, and to carry emotional or motivational information (Green & Arduini, 1954). Electrical stimulation of the midbrain reticular formation, septum, or hypothalamus evokes theta in the hippocampus, but direct stimulation of the hippocampus does not (Green, i9 6 0). Hippocampal activ ity is commonly desynchronized when cortical activity is synchronized. Little is known about the functional roles of some 23 of the nuclei which receive hippocampal efferents through the postcommissural fornix. Postcommissural target struc tures are the anterior thalamic nuclei, the mammillary bodies, the hypothalamus and the rostral mldbrain. Qer- brandt (1965) produced a passive avoidance impairment with anteromedial thalamic lesions. The Impairment produced by lesions of the mammillary bodies Is In active avoidance (Plogg & MacLean, 1963; Krieckhaus, 1964; Thomas, Hostetter, & Barker, 1968). Impairment of reversal learning in a T maze is also produced by mammillary body lesions (Thomp son, Langer, & Rich, i9 6 0), and was equated by these inves tigators with the impairment produced by hippocampal lesions. The hypothalamic nuclei have been studied exten sively, and function in complex integration of endocrine, visceral and somatomotor functions (Miller & Mogenson, 1972). The hypothalamic nuclei are strongly influenced by limbic system structures, particularly the septum (McCleary, 1 9 6 6). Because animals with lesions of the hippocampus or of nuclei connected with the hippocampus through the pre- or postcommissural fornix behave differently than normal animals in spatial tasks (reversal of position, learned alternation) and passive avoidance tasks, demonstrating hyperactivity, perseveration, and possible lack of inhibi tion, these tasks were chosen for this research and will be 24 discussed in detail along with proposed theories which attempt to explain the deficits. Clearly, lesions that result in animals that are either hyper- or hypoactive will result in learning deficits on most tasks and facilitation on some tasks, so examination of spontaneous activity level following a lesion is important. Animals with hippocampal lesions have been found to be hyperactive compared to normals in the open field (Kimb-e, 1 9 6 3) and between trials in shuttle box avoidance (Qreen, Beatty, & Schwartzbaum, 1 9 6 7). Small hippocampal lesions Increase activity in a wheel, but larger ones do not (Douglas & Isaacson, 1964). Lesions which disrupt the septo-hippocampal connection through the fornix and fimbria, as well as medial septal, dorsal septal, and diagonal band lesions, increase inter-trial activity in a one-way shock avoidance, but lesions of the lateral septum do not (Dono- vick, 1 9 6 8). Behavior in the open field task by rats with septal lesions appears to depend on their familiarity with the field. Rats that were tested before lesloning and retested after the surgery showed a decrease in activity in the open field (Schwartzbaum & Gay, 1 9 6 6) but rats that were tested postoperatively only were more active than normal controls (Donovick & Wakeman, 1 9 6 9). Pried (1972) suggested that 25 septally lesloned animals are hyperactive only in situations that encourage exploration of an unfamiliar environment. Spontaneous activity levels appear to be mediated through the septum (Gotsick, 1 9 6 9). Increases in activity on various tasks appear to depend on hippocampal involvement, while decreases in activity seem to depend particularly on interaction of the medial septum with non-hippocampal structures (Pried, 1972). In addition to being hyperactive, animals with hippocampal or septal lesions display deficits on spatial tasks in which a learned behavior must be altered, such as position reversal, and in alternation learning in a T maze, as well as in extinction of a learned response. Deficits are also found in passive avoidance tasks, in which the correct response is lack of movement. Learning of a position habit is not impaired by hippocampal lesions (Douglas & Pribram, 1966; Kimble & Kimble, 19 6 5) or with septal lesions, regardless of the placement (Hamilton, 1970; Hamilton, Kelsey, & Grossman, 1970; Schwartzbaum & Donovick, 1 9 6 8; Zucker & McCleary, 1 9 6 7). However, if hippocampally lesioned animals are trained against an original position bias, Greene (1971) has noted an impairment in learning a position habit. When learning to reverse the original position habit, impairment is found in both hippocampals (Douglas & Pribram, 19 6 6; Kimble & Kimble, 1965; Niki, 1 9 6 6; Teitel- 26 baum, 1964; Thompson & Langer, 1963; Webster & Voneida, 1964) and septals (Hamilton, 1970; Hamilton, Kelsey, & Grossman, 1970; Schwartzbaum & Donovlck, 1 9 6 8). In rats with septal lesions, the impairment was greater when the medial septal nucleus was lesioned than when the damage was in the lateral septal nucleus (Hamilton et al., 1970). The impairment disappeared with repeated reversals (Dono vick, 1 9 6 8). Spatial alternation learning (i.e., in which an animal is required to choose one arm of a T maze and then the other) is impaired with hippocampal lesions (Gross, Chorover, & Cohen, 1965; Pribram, Wilson, & Connors, 1962; Racine & Kimble, 1 9 6 5; Rosvold & Schwarcbart, 1964) or with hippocampal spreading depression (Greene, 1971; Henderson, Henderson, & Greene, 1973) and with septal lesions (Schwartzbaum & Donovick, 1 9 6 8). The spatial alternation deficit as well as the reversal deficit appear to be a result of lesioning the medial septal nucleus (Donovick, 1 9 6 8; Thompson & Langer, 1 9 6 3). Hippocampally lesioned rats are more resistant to extinction than normal animals (Douglas & Pribram, 1966; Jarrad, Isaacson, & Douglas, 1966; Kimble, 1 9 6 8). Septally lesioned animals also display a greater resistance to extinction of learned behavior than controls (Raphelson, Isaacson, & Douglas, 1 9 6 6). 27 Hippocampal or septal damage does not simply pre vent an animal from learning, because learning is normal in many tasks. The primary deficits following hippocampal and septal damage, apparent in the tasks described, involve an inability to inhibit ongoing responses. Theories attempting to explain these deficits differ by emphasizing the importance of inhibitory or perseverative aspects of the behavior. Some investigators suggest that the deficits can be explained as indicative of memory impairment. Kimble (1 9 6 8) has suggested that the hippocampus is necessary to the development of internal inhibition, which develops as a stimulus is presented many times. Hip pocampal lesions may impair "behavioral flexibility" by disrupting the inhibition of previously learned response patterns (Kimble & Kimble, 1 9 6 5). Hippocampectomized ani mals may be impaired in their ability to change their "hypotheses" or "response sets" (Kimble, 1 9 6 8). In using the term perseveration to describe the behavior of rats following hippocampal lesions, Ellen and Wilson (1 9 6 3) suggested that hippocampal lesions prevent an animal from giving up old responses, but do not prevent him from learning new ones. In investigating septal lesions, one of these researchers concluded that septal damage results in "an inability to modify responses to postoperatively acquired proprioceptive cues" (Ellen & Butter, 1 9 6 9). This perseverative hypothesis is supported by the finding that hippocampally lesioned rats have no trouble learning a simultaneous discrimination (Kimble, 1 9 6 3) and rats with septal lesions easily learn both simultaneous discrimination and reversal of the simultane ous discrimination (Donovick & Schwartzbaum, 1 9 6 6). Unde termined is whether it is body turns or responses to stimuli in the maze that are perseverated. Dalland (1970) found by rotating the stem of his T maze 180°, septally lesioned rats perseverated their choices on the basis of maze stimuli rather than body position. Hippocampally lesioned rats appear to be perseverating body turns (Dal land, 1 9 7 1). With questionable logic, Carey (1 9 6 8) concluded that the loss of a multiple maze habit, learned prior to septal lesions and lost after the lesions, was due to a memory impairment because the deficit was in no way corre lated with Increased emotionality which is sometimes sug gested as the basis of the deficit. Spatial learning may be impaired by lesions of the mammillary bodies, as well as by hippocampal or septal lesions. Thompson, Langer, and Rick (i9 6 0) suggested a memory hypothesis to account for the reversal impairment found with mammillary lesions. These lesions impaired learning of reversal in a T maze when the trials were 30 minutes apart more than when they were only 30 seconds 29 apart, leading the authors to conclude that the poor rever sal learning was due to memory impairment caused by retro active Inhibition from the activity occurring between trials. They find this comparable to the data from humans with hippocampal lesions, in which the retention of new material is possible for several minutes if the patient's attention is not diverted (Penfield & Milner, 1958; Scoville & Milner, 1957). They suggested that the function of the limbic system is to "protect the memory trace from oblitera tion in the presence of those conditions responsible for retroactive effects" (Thompson et al., i9 6 0, p. 54l). Other investigators (Grastyan, Lissak, Madarasez, & Donhoffer, 1 9 5 9) have suggested also that the ascending sensory impulses from the brainstem will, if not inhibited, inter fere with the memory trace. However Krieckhaus and Randal (1 9 6 8) did not find a reversal or an alternation deficit following lesions of the mammillothalamic tract. Their lesions were much more precise, and they suggested that the impairment in spatial tasks with mammillothalamic lesions found by Thompson (1964) was due to mass action or destruc tion of specific structures near the mammillothalamic system. Reversal, alternation and extinction tasks are similar in that learning the correct response requires suppression of previously rewarded responses. The most 30 extensively studied task fitting into this response- inhibition paradigm is passive avoidance, where the previ ously rewarded response is punished. Hippocampal lesions produce obvious and repeatable deficits in passive avoidance (Isaacson & Wickelgren, 1962; Kimble, 1963; Teitelbaum & Isaacson, 1965; Kimura, 1958). A huge number of investiga tors have found deficits in passive avoidance learning following septal lesions (Pox, Kimble, & Llckey, 1964; Fried, 1 9 6 9, 1970, 1971; Gurowitz & Lubar, 1966; Hamilton, 1970; Hamilton et al., 1970; Hamilton, McCleary, & Gross man, 1 9 6 8; Harvey, Lints, & Jacobson, 1965; Kaada, Rasmus sen, & Kviem, 1962; Kasper, 1964; Kasper-Pandi, Schoel, & Zysman, 1 9 6 9; Lubar, 1964; McCleary, 1961; McCleary, Jones, & Ursin, 1965; McGowan, Garcia, Ervin, & Schwartz, 1 9 6 9; McNew & Thompson, 1 9 6 6; Middaugh & Lubar, 1970; Schwartz baum & Spieth, 1964; Slotnick & Brown, 1970; Slotnick & Jarvik, 1 9 6 6; Thomas et al., 1968; Ursin, Linck, & McCleary, 1969; Van Hoesen et al., 1969; Wishart & Mogenson, 1970; Zucker, 1965; Zucker & McCleary, 1964). Habit strength plays an important role in passive avoidance learning. Rats with septal lesions were able to learn to avoid as well as controls when the punished response was not previ ously reinforced (Blanchard & Pial, 1 9 6 8; Middaugh & Lubar, 1970; Winnocur & Mills, 1 9 6 9)• The passive avoidance deficit in septally lesioned rats was found to be posi tively correlated with the number of rewarded preshock 31 trials (Middaugh & Lubar, 1970; Schwartzbaum & Spleth, 1964). Passive avoidance learning was not Impaired more when both the septum and the hippocampus were lesioned than when either nucleus was lesioned alone (Glick, Marsanlco, & Greensteln, 1974). From the Illustrations presented, the septal lesions In this research appear to be limited to the medial septal nucleus. When lesions of the caudate nucleus were combined with lesions of either the septum or hippocampus, a greater passive avoidance impairment was produced than that produced by septal, hippocampal, or combined septal-hippocampal lesions. Glick et al. (1974) concluded that this suggests that the septum and hippo campus are part of the same system, Lubar and Numan's (1 9 7 3) septo-hippocampal system, and that the caudate may be part of a redundant back-up system (Glick et al., 1974). Using potassium-chloride induced spreading depres sion of the hippocampus, a number of investigators have found impairment of avoidance behavior and have concluded that it is due to retroactive amnesia (Avis & Carlton, 1968; Hughes, 1 9 6 9). Kapp and Schneider (1971) concluded that depression given 10 seconds after training interrupts consolidation, resulting in permanent memory loss. If the depression is given 24 hours after training, only retrieval is blocked, because the training loss is temporary. Other 32 j studies have suggested that the hippocampus has a role in storage but not in recall of learned information. Retrograde amnesia for aversive stimuli has been produced by electrical stimulation of the hippocampus and the amygdala (McDonough 5s Kesner, 1971). Because of the time periods involved, Kesner and Conner (1972) concluded that the midbrain reticular formation is involved in short term memory and the hippocampus is involved in long-term memory. Stimulation of the hippocampus approximately one minute after training did not produce a memory deficit; the deficit was produced when the hippocampus was stimulated approximately four minutes after training. The passive avoidance data particularly appear to support the response-inhibition hypothesis suggested by Qerbrandt (1 9 6 5) that the loss of response suppression (inhibition) allows behaviors that have been previously stabilized (i.e., running for a reward) to be released (Pried, 1972). In addition, Fried (1 9 6 9* 1970, 1971) and Zucker (1 9 6 5) suggested that septal lesions increase the strength of the response habit that follows reinforcement. Vanderwolf (1971) opposes the idea that the hippo campus has an inhibitory role in behavior. He suggested that disinhibition in hippocampally lesioned animals is due to removal of the dentate, not to removal of the hippo campus. Ablation procedures generally remove both hippo 33 campus proper and dentate. Stimulation of the dentate sup presses theta and arrests ongoing locomotor behavior such as running, Jumping, swimming, or barpressing, but does not suppress involuntary behavior (Bland & Vanderwolf, 1972). This suggests that the dentate may have an important role in passive avoidance conditioning, and that it might be separable from the role of the hippocampus proper. A currently popular area of research is that cen tering around the possible role of the hippocampus in directing attention to stimuli. Early in learning, animals orient toward the novel stimulus, and this orienting response is accompanied by hippocampal theta and neocortical desynchronization (Grastyan, Lissak, Madarasz, & Donhoffer, 1959). During conditioning, the hippocampus may suppress the orienting reflex by inhibiting the ascending reticular activating system (Grastyan et al., 1959)> because both theta and orienting disappear as the stimulus becomes fami liar. Grastyan et al. (1959) found that cats with hippo campal lesions were unable to habituate to stimuli. Kaada (1 9 5 3) found that stimulation of the hippocampus produced orientation to the contralateral side. Because hippocampal afferents come primarily from two separate areas, the septum and the entorhinal cortex, which themselves have completely different input, theories have arisen which suggest that hippocampal involvement in 34 attention or learning varies with this input. Input to the septum is essentially subcortical, while input to the entor- hinal cortex is cortical. Both Meissner (196 6) and Douglas and Pribram (Douglas, 1967) have suggested that input over the septo- hippocampal (SH) path might subserve the emotional state of the animal and produce general arousal. The Douglas- Pribram gating model of attention suggests that "nonspecific gating" occurs in the hippocampus when it is stimulated over the SH path, and that this is similar to Pavlov's external inhibition and modulates the Judged Importance of a stimu lus. Input over the temperoammonic (TA) tract from the entorhinal area induces "specific gating" in the hippo campus, in which the reception of stimuli that have been associated with nonreinforcement is inhibited. Meissner (1 9 6 6) suggested that as learning progresses, control over the hippocampus shifts from input over the SH tract to input over the TA tract. Using a change of handedness task and a radioactive labeling technique, Yanagihara and Hyden (1971) conducted a study to test Meissner's (1 9 6 6) hypothesis. They suggested that the dentate gyrus and the hippocampal areas CA3 and CA4 would be labeled early in learning, because of their SH tract input, while CA1 would show a later increase in syn thesis because of its entorhinal (TA) tract input. Early 35 incorporation of label was found in CA4, with steady incor poration in CA3 throughout the learning task. The expected late labeling of CA1 was not found. One of the problems with this test of the SH-TA shift theory is that the entorhinal-CA1 path (the alvear path) found by Cajal (1911) and Raisman et al. (1 9 6 5) may not exist (HJorth-Simonsen, 1972). Recently, investigators have begun to consider the dorsal and ventral areas of the hippocampus, rather than the pyramidal cellular areas, as functionally different. Electrophysiological response differences between dorsal and ventral hippocampus were reported (in the antomy sec tion) when their relationship to the septal nuclei was being discussed. When examining exploration and activity level in hippocampectomized rats, Nadel (1 9 6 8) found that both dorsal and ventral lesions produced the traditional hyper activity, but that rats with dorsal lesions habituated to the environment at the same rate as normal rats, while those with ventral hippocampal lesions habituated faster than normals. In a passive avoidance task, total hippocampal lesions were required to produce impairment. Lesions limited to either dorsal or ventral hippocampus did not impair passive avoidance responding (Corscina & Lash, 1 9 6 9). 36 Conflicting results are reported regarding the effects of dorsal and ventral hippocampal lesions on com plex maze learning. Hughes (1965) found that dorsal hip pocampal lesions produced an impairment in complex maze learning, while ventral lesions produced no impairment. However Gross, Chorover, and Cohen (1 9 6 5) found a large impairment in complex maze learning in rats with ventral hippocampal lesions, and no impairment in rats with dorsal hippocampal lesions. In a series of experiments designed as an attempt to resolve the apparent conflicts in existing data, Stevens and Cowey (1973) found an impairment in the form of persev erated responses on a spontaneous alternation task with dorsal hippocampal lesions when the inter-trial interval was long (50 min.) but not when the inter-trial interval was short (50 sec.). Animals with ventral hippocampal lesions perseverated responses with a short inter-trial interval, but not with a long one. The learned alternation task used by Stevens and Cowey (1973) was lever-altemation rather than alley alternation. In this task, rats with ventral hippocampal lesions were impaired, but those with dorsal lesions were superior to cortical control animals. These investigators concluded that the differences in qual ity, rather than quantity, of behavior which they found support the theory that the hippocampus serves multiple functions, and that these functions are dissociable. They suggested that the Douglas-Pribram "sensory gating" model (Douglas, 1967) best explains the impairment of the dorsally lesioned rats in the spontaneous alternation task, who were not able to habituate during the long inter-trial interval. These same animals were superior to controls on a cued alternation task, where stimuli that were remote (and therefore harder to notice) were relevant. The impairment of the ventrally lesioned animals during the short inter trial interval is better explained by the Silveira and Kimble (1 9 6 8) "impoverished hypothesis" model.' Stevens and Cowey (1973) suggested that they stopped perseverating turns during the long inter-trial interval because the hypothesis (perseverate body turns) eroded. When no visual cues were present, these animals performed as well as con trols, but were impaired when remote visual cues were intro duced (were unable to develop a hypothesis). It is unlikely, in view of the wide range of im pairments following hippocampal damage and the prolifera tion of theories regarding its function, that the hippo campus plays only one role in behavior, or that it acts as a unitary structure. It may be critical to understanding the function of the hippocampus that its interaction with other structures be clarified. Fried (1972) concluded that the septum cannot be considered to act as a unitary structure, but that differ ent nuclei subserve different and separable functions. The research, only now beginning, which attempts to analyze the function of the hippocampus by mapping ana tomical or electrophysiological pathways within the hippo campus itself and to and from other structures should be particularly fruitful. CHAPTER III PURPOSE OP THIS RESEARCH The lesion method has been used extensively in an attempt to determine the function of the hippocampus and the structures closely associated with the hippocampus by anatomical connections. Some of the behavioral deficits found when the hippocampus is damaged are similar to those found when the septal nuclei, the mammillary bodies, or the anterior thalamic nuclei are lesioned. This suggests that these structures may be functioning in an Integrated manner, and that information necessary to normal learning is relayed from one of these structures to another. The performance of different behavioral tasks may be subserved by different combinations of brain structures. Therefore an approach in investigating the function of one structure in the system is to surgically interrupt its connections with the rest of the system. The hippocampus has two afferent and efferent path ways, one through the fornix and one through the subiculum. Previous research has indicated that cutting the pathway through the subiculum impairs passive avoidance behavior, while cutting the pathway through the fornix impairs spatial 39 40 learning (reversal and alternation), extinction, and passive avoidance (Greene & Stauff, 1974). The purpose of this research is to investigate further the relationship between the hippocampus and asso ciated nuclei by selectively cutting the neuronal tracts that connect them. The fornix is described as being "postcommissural" when it turns ventral and does not project rostral to the anterior commissure. The hippocampus interacts with the mammillary bodies and the anterior thalamic nuclei through this postcommissural fornix projection. When it does project rostral to the anterior com missure, the fornix is described as being "precommissural." The hippocampus interacts with the septal and diagonal band nuclei through this precommissural fornix projection. One group of investigators (Raisman et al., 1966) have concluded that the various pyramidal fields of the hippocampus project differentially, while another group (Siegel & Tassoni, 1971a, 1971b) suggested that it is a dorsal-ventral dichotomy within the hippocampus that is critical in understanding possible differential projections to associated nuclei. (These conflicting theories are out lined in Table 1.) The relationship between the septal nuclei and the hippocampus will be investigated by compar ing a cut which completely interrupts the precommissural 41 fornix to one which spares the medial precommissural fornix fibers. The postcommissural fornix will be completely cut to investigate the relationship of the hippocampus to the mammillary bodies and anterior thalamic nuclei. Because medial septal lesions produce hyperactivity (Donovick, 1968) it might be expected that the group in which the precommissural connections between the hippo campus and septum are completely cut (total precommissural group) would be more hyperactive, as evidenced by activity in the open field, than the group in which the connections between the hippocampus and medial septum are spared (lateral precommissural group). Regarding spatial habits, no impairment is expected in learning the original position habit. However in both the reversal and alternation tasks, the total precommissural group might be expected to show a greater impairment than the lateral precommissural group because lesions of the medial septum produce greater alternation and reversal impairment than do lateral septal lesions (Donovick, 1968; Thompson & Langer, 1963; Hamilton, 1970). The finding of this impairment in the total precom missural group would implicate either anterior CA1 (Raisman et al., 1 9 6 6) or the dorsal hippocampus (Siegel & Tassoni, 1971a, 1971b) as being necessary in acquiring these habits, because these hippocampal areas have been reported to pro ject to the medial septum. Similar impairments might be 42 expected in the group with postcommissural lesions, because the proposed major hippocampal-septal projection areas also project through the postcommissural fornix to the anterior thalamic and mammillary nuclei. Impairments on these tasks found in the lateral precommissural group would suggest only that CA3 (Raisman et al., 1 9 6 6) or the ventral hippocampus (Siegel & Tassoni, 1971a, 1971b) is the critical hippocampal area, since these are the areas which project to the lateral septum. CHAPTER IV METHODS Subjects The Sis were 48 Long-Evans male rats, 52 days old and weighing 180-225 gm. at the date of surgery. They were purchased from Simonsen Laboratories In Gilroy, California. They were housed in pairs until the time of surgery, and separately after surgery, In standard wire cages. Purina Rat Chow was available to the rats throughout the experi ment. Water was available until training began, at which time each £[ had free access to a water bottle for 20 min utes at the end of each training or testing period. Apparatus The open field was a white box, 36" x 36" x > with a red grid of 6" squares. The open top was covered with chicken wire in a wooden frame. The blue-grey straight alley, 30" x 5J" x 5^" was covered with a wire screen, and had two Plexiglas guillotine gates at 10" and 10" intervals dividing the alley into start, intermediate and goal boxes. The doors could be opened and closed simultaneously. The water reward was delivered in 0.3 cc. metered amounts to a plastic cup in 43 the goal box by a syringe pump outside the alley. The gray T maze had alleys 6" wide and 5£" deep, and was covered with Plexiglas. The start box was 10" long, separated from 11" of Intermediate alley by a Plexiglas gate. The goal arms were 12" long, separated from the intermediate alley by Plexiglas gates. All three gates could be opened and closed simultaneously. The goal boxes were equipped with the same water-dispensing mechanism used In the straight alley. The red passive avoidance straight alley measured 36" x 5" x 5£" and was covered with a wire top. The last 12" of the floor of the alley consisted of a bar grid through which a 0.5 ma. dc. shock could be delivered to the feet of the rat. The shock was produced and the grid scrambled by a Grason-Stadler Shock Generator and Operant Conditioning Apparatus (E1064Gs) powered by a Grason-Stadler Power Supply (E1100DA). A water bottle was located in the grid-end of the alley, with the spout extending in over the grid. Taming All were handled for 5 min. per day for 7 days prior to surgery, and for 6 days following surgery. On the seventh day after surgery, testing began. 45 Surgery Each of the 48 rats was arbitrarily assigned to one of the four treatment conditions: (a) the cut was position ed to sever fornix connections passing to and from the lateral septum along the rostro-caudal axis (Lateral Pre commissural); (b) the cut severed the fornix fibers passing through the lateral septum, and in addition severed fibers passing to and from medial septum and the bed nucleus of the diagonal band (Total Precommissural); (c) the cut was positioned to sever the descending columns of the fornix (Postcommlssural); and (d) animals received cuts which damaged neocortex, corpus callosum, and tissue adjacent to the fornix projections, but did not encroach upon these c onnec t i ons (Sham). For both the Total Precommissural fornix cut and the Lateral Precommissural fornix cut, scalpel blades were ground down to the proper size and shape. The approximate dimensions of the blades were 5 mm. x 2 mm., although the tips had nonsymmetrical shapes in order to achieve the desired lesion. The two blades had the same hemispheric shape, but the center of the blade used for the Lateral Precommissural Group was removed, producing a crescent- shaped cutting instrument. The cutting instrument for the Postcommlssural fornix lesion was made by bending a 30 gauge hypodermic 46 needle to form a tip which extended 1.7 mm. at a 80° angle from the rest of the needle shaft. Twenty minutes prior to surgery, each animal was given 0.2 mg. of atropine sulfate to reduce the possibility of respiratory complications. Under sodium pentobarbital anesthetic (50 mg./kg./IP) earbars were inserted and the rat was placed in a Kopf stereotaxic. A midline incision was made to expose the skull. For the Total Precommissural fornix cut, an 18 gauge needle was inserted in the Kopf carrier to mark the skull 0.3 mm. posterior to bregma and 1.5 mm. lateral to the midsagital suture. The cutting instrument replaced the needle in the carrier, and was zeroed on the marks. A hole was drilled, exposing the dura, from one mark to the other parallel to bregma across the midsagital suture. The dura was broken, and the cutting instrument was lowered to 6.1 mm. below the skull mark on the animal's right side. Then the cutting instrument was brought 3*0 mm. toward the midline, using the Kopf lateral drive. The instrument was returned the 3.0 mm. to the lateral starting position, and withdrawn. The procedure was repeated for the left side of the animal. Qelfoam powder was placed in the trephine hole in the skull, and the skin was sutured. For the three Total Precommissural Sham animals, the cutting instrument was lowered to the above coordinates but was not brought toward the midline. 47 The surgical procedure for the Lateral Precommis sural cut was identical to the procedure Just described for the Total Precommissural cut, except for a slight change in each of the coordinates made necessary by a slight differ ence in the shape of the two cutting instruments. The coordinates for this cut are 0.5 mm. posterior to bregma, 1.5 mm. lateral to the midsagital suture, and 6.4 mm. ventral to the surface of the skull. The cutting instru ment was brought 2.7 mm. toward the midline from each lateral position. For the three Lateral Precommissural Shams, the cutting instrument was lowered to the above co ordinates but was not brought toward the midline. To make the Postcommlssural fornix cuts, the needle was introduced into the brain at a compound angle with the tip aligned in the sagital plane, and at coordinates which positioned the needle and tip beside the descending columns of the fornix. The tip was then rotated so that the tip passed through the columns to sever them. Half of the sur geries were performed with the tip pointed in the posterior direction, and half with it pointing in an anterior direc tion as it was inserted to the target. The use of two approaches minimized the possibility that extraneous damage would be the cause of a behavioral deficit, since different brain structures would be damaged by each of the methods of penetration. 48 Coordinates for the postcommlssural lesion were measured from the tip of the needle. With the tip pointed rostrally, the coordinates were 0.6 mm. posterior to bregma, 3.3 mm. lateral, and with the angle of penetration being 20° lateral, and 10° rostral to the vertical position. The cut ting needle was inserted 7.0 mm. as measured along the axis of penetration, then rotated 100° toward the midline to sever the descending columns. To remove the instrument the steps were reversed, and the procedure was repeated on the opposite side. When the tip was pointed in the posterior direction, the angle was set at 20° lateral, and 10° caudal to the vertical position. As it happens, with these angles of penetration and using a needle with a 1.7 mm. tip, the same coordinates could be used with either approach (i.e., 0.6 mm. posterior, 3*3 mm. lateral, and J.O mm. deep). The six remaining Sham animals were given lesions using the same coordinates and angles of penetration (three rostral and three caudal), except that the tip was not rotated. Training and Testing Test Day 1 was on the seventh day after surgery, following a 6-day recovery period during which the animals were each handled 5 min. each day. Each animal was placed in the middle of the open field and allowed to explore for 10 minutes. Activity was measured by counting the number 49 of grid lines crossed by the front paws during the 10-minute period. All times were measured with a stopwatch. On Day 2, each animal was placed in the straight alley and was taught to run 10 trials for a reward of 0.3 cc. water. Each animal was allowed to finish his water before being removed from the goal. Latencies were re corded for each trial from the opening of the start box gate to the closing of the goal box gate, and mean laten cies were calculated for each day. The straight-alley training was repeated on Day 3. Training of the position habit in the T maze began on Day 4. Each animal was placed in the start box. The lid was closed, which simultaneously opened the start box gate and both alley gates. The S£ were free to choose either the right or the left goal arm at the choice point. Half of the animals were rewarded in the goal with 0.3 cc. water for turning right at the choice point, while the other half were rewarded for turning left. Each animal was run 10 trials/day until it reached a criterion of 9/10 correct choices on two consecutive days. Errors and laten cies were recorded. An error consisted of choosing the non-rewarded goal arm. The day after criterion was reached on the position habit, reversal training began. During reversal training, the rewarded goal arm was opposite to the goal arm in which 50 the animal was rewarded when it acquired the initial posi tion habit. If an animal learned the initial position habit in the left goal arm, then choosing the right goal arm was rewarded during reversal training. The animals were again run 10 trials/day to a criterion of 9/10 correct choices, where an error consisted of choosing the non rewarded goal arm. Total errors and latencies were recorded. Alternation training began on the day after the animal reached criterion on the reversal task. The first arm chosen was rewarded whether the animal turned right or left. Thereafter, the rat had to alternate choices (e.g., RLRLRL ....) in order to receive the 0.3 cc. water reward. An error was recorded if the animal chose the same arm successively, and the animal received no reward until it finally chose the opposite arm. Animals were detained in the goal box for 5 sec. after an error. Each rat ran 10 alternation trials/day either to a criterion of 9/10 correct choices or for 10 days (100 trials). Errors and latencies were recorded. To test extinction after reaching criterion in the alternation task, the animals were run in the T maze with out water reward until they refused to run. After a 1-minute refusal to enter a goal arm, the rat was removed and placed in the start box and run again until it had 51 either made three such refusals or the 3 0-minute test period had elapsed. Recorded were the total time it took the rat to make three refusals and the total number of trials run. Passive avoidance pretraining began on the day after extinction of the alternation habit. This day was designated as PA-Day 1. Each rat was placed in the passive avoidance straight alley at the end opposite the grid, and allowed to run to the grid (goal) end where it was allowed to lick the water bottle for 5 sec. before being removed and restarted. Each animal was allowed 10 trials, with the latency of each trial recorded. On the next day, PA-Day 2, the rat was placed in the alley and the latency for running the first trial was recorded. When the rat reached the water spout and started licking, the grid was electrified for one minute. The number of shocks the animal received during the 1-minute period was recorded. At the end of the minute, the rat was removed from the alley and returned to his home cage. On PA-Day 3* retention of the passive avoidance habit was tested. Each animal was again put into the pas sive avoidance alley. Latencies in the start end were recorded, with a 10-minute cut-off period. If the rat approached the goal and began drinking, it was allowed to drink for 3 sec. and was then returned to the start end 52 of the alley and the number of trials run In 10 min. was recorded as during pretraining. Histology At the end of the test sequence, the animals were sacrificed with an overdose of Nembutal, and perfused with a cold solution of 1 percent DMSO and 10 percent glycerol. The brains were then removed, frozen, and sectioned in an IEC cryostat to verify lesion placement. Slides were taken every 100 microns in the vicinity of the lesion. Sections were fixed for 48 hours in 4 percent formalin, then were washed and dehydrated through a sequence of ethyl alcohol and xylene, rehydrated, stained in 0.5 percent cresyl violet, refixed in acid formalin, and then were dehydrated and mounted with coverslips. The sites of the lesions were examined and diagrammed using a Bausch and Lomb dissection microscope, and a Zeiss microscope. CHAPTER V RESULTS Behavioral Results The behavior of the animals has been summarized and analyzed In two ways. In the upper portion of Table 2 are mean scores for each task for all the animals which were assigned to a particular surgical group, and which received the operations described above. The lower portion of Table 2 contains the mean scores of animals which were selected on the basis of histological criteria (discussed below). Standard errors of the mean are also presented, with the exception of the passive avoidance task which was evaluated using nonparametric statistics. Scores in the first column are the number of squares crossed in the open field test. Scores in the second, third and fourth columns are the errors to criterion in the original position, posi tion reversal, and position alternation tasks. The fifth column is cumulative daily running time during testing of these spatial learning tasks, and the sixth is the number of trials run under the extinction condition. The data in the last three columns are from the passive avoidance task, and reflect the number of shocks given on the training day, 53 ■ = r m o o r o ti 04 a o T 4 * lo i S o - > « r * * * » C | M H V I U T O* > « o ' W « ^ 0% m t i v t u So- >s 3n<u> ooob T O* > « * -< h o jt n q g «n • » I W « So* > « , oorodg 04 H t i o t t i t o ’ > 0 ! < n d noqg <n • / n w i M TO* J * « d M il * n r fg p n v « C <n • * n * r « T O * > « . ■ • n r « 4 ! TO* > d T I ' d m i l u « i | o% SO > « •<rwu» • A t W W TO* > d i ir d lA t f m Q l p « « M f ©* u n n x TO * > S * 4 m i> « % OJ • * u n « SO* > ar a« ^ 0% u n « T M TO* > * ! « v i d 8 0% SO > • , <n « T l » T « So > a i • J n o jf «vqp TO- > v - A i c i f twqg <n •AHVTM t o - *«4nax9 a jv d g po« n q g o* • A n * t “ TO* > « . • J W J (W M | » w o* « T i m i n i n i i i jo • im W jx a ta n « « n » p -*n fopa— n oiJo4i« toeiSutoifio J° two* Wi n o 1 * 4 9 * 1 * 0 * J ra w * 0 1 m y on*. *>t jo Jinn T ow n «tt - n o n t i n rp*in» *m 9 0 1 * 1 0 1 mamibm *m at non* oio m u 0 3 4 iifhi ‘ > 4 u»T noaj -*14*4 *0 jo JT»4 JnM- *41 o; tw-qi *» o*i9lA looiftnt* 4904m 43J noon *41 je wru.ro luopomo poo 000911 I9V1 0 r . t r : * a eg 0' 0 < 6t 8 ' 1 s - s «V«* VI VIT i « ' C 0V2T I S 8 9 T N* 2 S - O 1 * 1 1 1 9 9 |mun4»QJ 1 c« ? * T e - » o ' 1 C S ' 9 L ' t J l 8' % f S ' l C 6- e 1' S l 0 0 * 2 0 0 *9 « 95 H» t 9* I— P»IM< m T 0' ' , 4C c - « 0 ‘ ( e-w 6- C S 1 1 T " 9 ooe C - T C ' l t o s - o c - e 5 5 9 T T IM 2 9 * " iiwiinii»h i*»94* i Cl e- 6 0” r? O ' t e St t ' 9 ? ' Z i 9 - * 9 - C T 6 0 - 0Vl 9 1 on KJ J n«« . r i u i r r s m s g r r . . . JO, P » 4 3 0 T 9 P 91 Mflliy JO J UVtf 0 4 OQ 4 9« O’ T 6- 1 O'l* O'l 9 ' S C - 9 , S ' 9 C C ' X 9 - 9 T 0 2 - 8 •Ot’ K T 9 C 1 S T HO 2 n*i 1 N I —9IHI >»m a 9« n 0' 4 9*T M 0 ' 9 * *‘ 2 S ' O * C ' C ^•1 C 9 " l 9 * 9 T 3? Cl 0 9 MO 2 n c - s 6’ T 99 099 6* t S ' T T 6 ' 8 111 S - T V«X C O - < * • # S 8 9 0 1 N O X n* f im i* 9 iii« n xoo»*| 0 ' \ e- 6 e - t V9 c’ te C ' T T‘ 9 VX C - l T 9‘ * 9- C l « o - 09*1 9 1 on N O X X T — ioN muq * P W Tto Joj I W N (•JOO-N) m i iiw iiw t SV") aMBfVJ ■■H M T (*T»U1) aoi4a>nai C®«9) ■ to fc i— ■ (u o u a ) O O 14*0U »4T» •0111*41 (•mua) •nwi (u o u a ) noiiiooj T»»»M0 (onmnki) r m »•> •009* 55 the initial avoidance latency when retention was tested the following day, and the total number of trials run during the 10-minute retention test. A multivariate analysis of variance (MANOVA) pro gram, developed at the University of North Carolina and available at the USC Computing Center, was used to analyze the data in the first six columns of the table. This analysis showed significant treatment effects when calcu lated using the intact surgical groups (F = 3.06, p < .001), or when the computation was based on the histologically selected animals (F = 2.36, p < .009). Post hoc univariate analyses were computed for each of the tasks using the MANOVA program, and on tasks in which this analysis indi cated a significant treatment effect, a Newman-Keuls test was applied to determine which of the lesion groups was responsible for the difference. In open field activity, Postcommlssural animals were the most active, Total Precommissural animals were the least active, while the mean scores of Lateral Precommis sural animals were approximately the same as the mean of the Sham group. However, these differences did not prove to be significant either with the intact surgical group (F = 0.7^) nor among selected animals (F = 1.78). The univariate analysis of the original position habit indicated a significant treatment effect among the 56 animals in the intact surgical groups (P = 5.49, p < .003), and the Newman-Keuls test indicated that the significance was due to an impairment of animals with Postcommissural lesions (p < .01 relative to Shams or Total Precommissural animals, p < .05 relative to the Lateral Precommissural group). The same analyses when applied to the selected lesion group did not find any significant effect, but since the mean behavioral scores were about the same, the lack of significance was likely due to a reduction in statistical power by using fewer animals. The univariate analyses of reversal learning scores were not significant either for the intact surgical groups (P = 1.18) nor for the selected lesion animals (F = 0.40). The univariate analyses of alternation scores showed a significant treatment effect among intact groups (P = 10.88, p < .001) and among selected lesion animals (F = 8.83, p < .001). Newman-Keuls comparisons of scores in the intact surgical groups indicated that Lateral Precommis sural animals did not differ from Shams, but that animals with Total Precommissural lesions were significantly Impaired relative to Shams (p < .01) or relative to the Lateral Precommissural group (p <.0l). The Postcommis sural animals differed from Shams and Lateral Precommis sural animals (p < .01 for either comparison), but did not differ from animals with Total Precommissural cuts. The 57 same calculation applied to the animals selected on the basis of histological criteria yielded roughly comparable results (see Table 2 for the significance levels, and Figures 1 and 2 for graphs of the learning curves). Animals with precommissural lesions (lateral or total) were slightly slower than normal in running speed, and the postcommlssural animals were a bit quicker. How ever the univariate analyses did not find a significant treatment effect on this measure. For the extinction task the pattern of mean scores is consistent, but the statistical tests do not indicate the presence of a significant deficit. The univariate analysis did not prove significant when applied to the intact surgical groups (F = 1.93* P < .14), and although it was significant for the animals selected on the basis of histology (F = 3.20, p < .04) the Newman-Keuls compari sons did not find a significant difference among any of the treatment means. It can be seen in Table 1 that the extinction scores were substantially larger than normal for each of the fornix lesion groups, and that they were comparable in size. However, the standard error scores were also very large, indicating high variability among the animals and precluding the conclusion of a significant treatment effect. The amount of variability decreased among the animals selected for Total Precommissural damage, LATIRAL' TOTAL 4 3 « DIN OP TKAMMO p » T I1 . 7 • • M Fig. 1. Mean errors made by each intact surgical group on each day of alternation training. V J l 00 60 but among the Lateral Precommissural and Postcommlssural animals the variability actually Increased when the animals were selected on the basis of histological criteria. We assume that there are specific fibers which mediate the ability of animals to extinguish, and that we have not interrupted these connections in a consistent way. Among the animals of the present experiment, we have not been able to locate a site of damage which correlates with the impairment of extinction. There was truncation of scores on the measures of passive avoidance (especially in the control group), so the data were analyzed using the nonparametric Mann-Whitney U test. The fornix-lesioned and control groups were very similar in the number of shocks they received on the train ing day, and the statistical comparisons did not indicate any difference among the groups in terms of immediate retention of the avoidance response. Latency until the first approach, and number of approaches during 10 minutes of test, were used as measures of avoidance retention on the following day. Analysis of the latency measure in the intact surgical groups showed that Postcommlssural animals were impaired relative to Shams (U = 24.5, p < .05), as were animals with Total Pre commissural lesions (U = 19, p < .01), When the compari sons were made among animals selected on the basis of 61 lesion placement, the impairment was again seen for Post- commissural animals (U = 0, p < .001), and Total Precommis sural animals (U = 2, p < .01), and also among the animals with Lateral Precommissural lesions (U = 0, p < .001). Figure 3 Is a graphic representation of these behavioral differences for both the intact and the selected groups. Analysis of number of trials run during the 10 minutes of testing by the intact surgical groups indicated that the Postcommissural animals were impaired relative to Shams (U = 24, p < .05). The animals with Total Precommis sural lesions were impaired when compared either with Shauns (U = 18.5j P < .01), or with Lateral Precommissural animals (U = 29.5i P < .05). Comparison among animals with veri fied lesions again showed the Postcommissural group to be impaired relative to Shauns (U = 0.5* P < .01) or relative to the animals of the Lateral Precommissural group (U = 0, p < .05). The Total Precommissural group was impaired relative to the Shams (U = 4, p < .01), and in this case the Lateral Precommissural animals were also impaired relative to the Shams (U = 5.5* p < .05). Figure 4 is a graph of these results for both the intact and the selected groups. The pattern of deficits in the passive avoidance scores suggest that they may be reflecting different as pects of hippocampal function. When one examines the 62 SHAM LATHAL TOTAL SUMMCAL CONDITIONS D O S T Fig. 3- Mean passive avoidance latency for each surgical group. Solid bars represent the intact surgical groups; dashed bars represent the selected surgical groups. 7 N U M M ft O F T R IA L S 63 SHAM LATIRAL TOTAL ROST SUMMCAL CONDITIONS Fig. Ms an number of trials run by each surgical group during passive avoidance testing. Solid bars represent the intact surgical groups; dotted bars represent the selected surgical groups. 64 traditional indicators of avoidance (shocks), impairments among the various fornix groups are about equal. However, the latency number of trials the animal then runs is sub stantially larger among the animals with damage to post commissural fornix or with lateral total precommissural damage. The number of shocks received can be considered a test for immediate retention deficit, because this is a test conducted in the first post-training minute. The number of avoidance trials becomes a measure of learning, after the first no-shock trials. The latency score meas ures the retention deficit after 24 hours have passed. Histological Results Damage to the septum (when visible) was seen as reticulation of the tissue, ragged borders, or the complete absence of tissue in several sections through the plane of the cut. Postcommissural damage was indicated by a slight separation of the columns, or by a line of glial cells passing through the columns at right angles to their descent. However, in a number of animals there was virtu ally no sign of the damage inflicted by the cutting instru ments used in this study. We believe that even in the animals without visible lesions the precommissural and postcommlssural fibers were interrupted, since in several dozen pilot surgeries conducted to refine the placement 65 coordinates, the blood-tract consistently fell across the intended target structure. Furthermore, neocortical damage among the animals of this experiment was not always visible. In some cases the tissue would be absent or show reticula tion along the route of penetration, and in other cases the tissue looked intact and normal. The cellular tissue appears to suffer minimal damage by the insertion of the cutting Instruments, and it is unlikely that the deficits of the present experiment are due to cell loss. It is our belief that the intended fornix-connections were inter rupted in all the animals of the experiment. However, so that the conclusions of the study do not hinge upon that conviction, we have sorted the animals on the basis of visible damage, and the data presented in the lower half of Table 2 were from animals whose lesions are described below. Among the animals of the Precommissural groups, four were selected as having the clearest bilateral damage to the tissue of the lateral septum, and six as having the clearest bilateral damage extending into the medial septum. In several of the Lateral Precommissural animals which were discarded, the damage to the lateral septum was clearly visible on one side, but not on the other. The Precommissural lesions were approximately 3 mm. wide, extending acrojsp the midline between the lateral ventricles. The dorsal border of the lesion was the corpus 66 callosum; the ventral border was the anterior commissure, and the lateral borders were the lateral ventricles. In the Lateral Precommissurals, the medial border was the lateral edge of the medial septum. In the Total Precommis surals, the cut extended across the midline. Seven animals were discarded from the Lateral Pre commissural group (L3, L7, L9, L10, L1 5, L4l, L47) for insufficient damage to the lateral septum. In these ani mals, the damage to the lateral septum was often complete in one hemisphere but spared more than half of the tissue in the other hemisphere. Sparing always occurred on the medial and particularly the ventral aspects of the lateral septum. Six animals were discarded from the Total Precom missural group because sufficient damage to the medial septum could not be verified (T5, Til, Tl6, T25 and T48). As with the Lateral Precommissurals, sparing was in the medial and ventral aspects of the lesion. One animal (L20) was added to this group due to extensive medial septal damage. When making the Precommissural cuts, the blade was directed through the neocortex and into the lateral ventri cles at an angle chosen to avoid damage to the cingulum. The visible tract into the ventricles was usuallyj to £ mm. wide. The cingulum was unilaterally damaged in four Pre commissural animals (L3 6, L20, T2 and T24), and bilaterally 67 damaged in two animals, both from the Total Precommissural group (T29 and T37). The dorsal border of the Precommis sural lesions, the corpus callosum, sustained some damage to its ventral border in several animals. The corpus cal losum was completely destroyed between the lateral ventri cles in one animal (L12) and was destroyed for a distance of approximately ^ mm. to each side of the midline in one animal (L15). There was unilateral damage to the corpus callosum in two animals (T37 and T45). The anterior commissure formed the ventral border of the Precommissural lesions, and sustained no damage in any animals. In one animal (L12) the lesion entered the dorsal surface of bed nucleus of the stria termlnalis bilaterally and traveled ventrally about £ mm., but remained above the anterior commissure. The lateral ventricles formed the lateral border of the lesions, and were often distended but not torn on their lateral sides. There was slight encroachment into the caudate-putamen in one of the Total Precommissural animals (T37). For the Lateral Precommissural group, the medial boundary of the lesion was formed by the medial septum. None of the lesions intruded into this area. Total Pre commissural lesions extended completely across the midline. The bed nucleus of the stria termanilis appeared to be spared in all animals. 68 Generally, the lesions were located slightly (ca. 200 microns) rostral to the anterior commissure. All lesions were rostral to the septofimbrial nucleus. Two animals were discarded from the Total Precommissural group (T8 and T35) because they were too far posterior and dam aged the descending columns of the fornix. Three animals were discarded from the Postcommis- sural group due to extensive gliosis and degeneration of the main body of the fornix (P21, P3^, P40). The septum was badly reticulated in one of these animals. Three ani mals were not included in the reanalysis of the data because the damage to the descending columns was not clearly visible on both sides. The damage to descending columns and extraneous damage was very comparable among the five animals selected for r*eanalysis of the data, and two representative lesions are shown in Figure 5* The damage was usually visible as a fine line of glial cells, or a slight folding of the tissue along the line of the cut. The cutting instrument used to make the Postcommis sural cuts was a 30 gauge needle with a 1.7 mm. tip which formed an angle of approximately 80° with the shaft. On the surface of the cortex, the tip was positioned in the sagital plane lateral to the cingulum. The tip was pointed in the rostral direction in half of the animals and in the 69 Total Preco— 1 saural Shao Total Pmrn— laaural Po*tcoaBl««ural PoatcoaaiMural Poatcoaalaaural Sbaa Fig. 5• Maximal and minimal damage among Lateral Precommissural and Total Precommissural animals used in the reanalysis of data are shown In the upper portion of the figure. The Postcommissural animals had very similar lesions, and two which are representative are shown In the lower left of the figure. Likewise, damage among Sham animals did not vary much, and representative sections are shown to the right. caudal direction in the other half. When pointing ros- trally, there may have been some damage to cells in the medial septum and in the bed nucleus of stria terminalis as the needle was lowered into cutting position and as it was withdrawn, but this damage was not evident in stained sections. The tip clearly passed over the anterior commis sure without damaging it. Some damage to stria medularis was expected when entering with the tip rotated in the caudal direction, but again none was evident. Very little tissue damage was evident among the sham-lesioned animals, whether the lesion was inflicted using the Lateral Precommissural knife, the Total Precom missural knife, or with the bent wire used to inflict the Postcommissural lesion. Representative lesions are shown for each of these conditions in Figure 5. The damage usually consisted of a narrow tract through cortex and corpus callosum which disappeared into the lateral ventri cles in the Precommissural animals, and sometimes could be seen penetrating the ventral portion of the lateral septum in Postcommissural animals. A few animals had enlarged ventricles. Several animals (S43, S13> S44) had unilateral damage to the cingulum. One animal (S23) had signs of infection around the point of entry into the brain, but was retained in the study because the infection was limited to cortex and did not involve the anatomical areas under investigation. CHAPTER VI DISCUSSION, CONCLUSIONS, AND SUMMARY Discussion and Conclusions The possibility that the fornix plays an Important role In passive avoidance learning was recently Investi gated by this laboratory. Although previous reports Indi cated that animals with fornix lesions were not impaired on passive avoidance tasks (McCleary, 1 9 6 6; Van Hoesen, Wilson, MacDougall, & Mitchell, 1972), Greene and Stauff (1974) found a very significant passive avoidance with fornix lesions. By the time they were tested on the pas sive avoidance task, the animals used by Greene and Stauff (197* 0 > like the animals used in the present study, had very strong goal-approach habits because they had been run ning in the mazes daily for three to four weeks. The degree of passive avoidance impairment appears to be di rectly related to the amount of approach training (Isaacson, Olten, Bauer, & Stewart, 1 9 6 6). Hippocampal lesions do not produce impairments in passive avoidance if the approach response is not well trained. Kimble, Kirkby and Stein (1 9 6 6) and Riddell (1 9 7 2) found no impairment with hippocampal lesions on step-through or step-down tasks, but Isaacson and Wickel- 71 72 gren (1 9 6 2) did find an impairment in avoidance when the hippocampectomized animals had been trained to run for water. The fornix-lesioned animals used by Van Hoesen et al. (1 9 7 2) had been trained to approach the goal for 5 days, compared to the 3- to 4-week training received by the animals in the present study, so the concept that the degree of passive avoidance impairment is a function of the approach strength may explain the impairment found in our animals and lack of impairment found in the Van Hoesen et al. (1 9 7 2) animals. Formally, the precommissural cuts used in the cur rent study should be classified as "septal lesions." How ever, it should be emphasized that very little tissue dam age was inflicted to the septal groups, so the deficits seen in the present study are most likely due to interrup tion of communication passing to and from these nuclei. The results of the current study are consistent with the many reports, some of which were described ear lier, that damage to the septum produces an impairment in the animal's ability to learn passive avoidance (McCleary, 1961; Kaada, Rasmussen, & Kveim, 1962; Fox, Kimble, & Lickey, 1964; Schwartzbaum & Speith, 1964; Slotnick & Jarvlck, 1 9 6 6; Thomas, Hostetter, & Barker, 1 9 6 8). The avoidance impairment of the current study, however, does differ in one respect from the many reports 73 above in that a deficit was not seen during the period .immediately following the training shock. Differences in training conditions and shock parameters will not totally account for the result, since identical conditions used in a prior study in this laboratory produced an immediate retention deficit in animals with total fornix lesions (Greene & Stauff, 1974). It seems more likely that the selective cuts used in t'.ie present study have only par tially interrupted the functional connections, resulting in a milder impairment than that produced by a lesion which severs all parts of the fornix. Since the avoidance impairment produced by the Total Precommissural cut (i.e., lateral septum plus medial septum) was no greater than that produced by the Lateral Precommissural cut (lateran septum only), it seems reason able that the essential source of communication for the habit passes through the lateral septum. As discussed in the Introduction, Raisman and associates (Raisman et al., 1965; Raisman, 1 9 6 6), reported that in rats efferent fibers exclusively from the CA3 and CA4 fields pass into and through lateral septum, but this conclusion has been chal lenged by Seigel and Tassoni (1971a) in cats and Siegel and Edinger (1973) in rats. These investigators find that lateral septum receives fibers from ventral hippocampus, and that the various pyramidal fields (i.e., CA1-4) do not project differentially. These anatomical reports have been supported by evoked potential and single unit studies (DeFrance, 1971; Edinger et al., 1973). Furthermore, it appears that the connections are reciprocal, with medial septum projecting to dorsal hippocampus and lateral septum projecting to ventral hippocampus (Brust-Carmona et al., 1973; Siegel & Tassoni, 1970; Siegel & Tassoni, 1971b). Damage to ventral hippocampus appears to be espe cially effective in producing an impairment of passive avoidance (Kimura, 1958; Updyke, 1 9 6 8), and in a previous report out of this laboratory it was found that lesions which spared the posterior connections of ventral hippo campus tended also to spare the animal's ability to perform the avoidance habit (Greene & Stauff, 197^). Alternatively, the communication passing from hippocampus to or through the lateral septum may be involved. In particular, the ventral hippocampal efferents serve lateral septal neurons, and also pass forward and then caudally to Join the medial forebraln bundle. These fibers end predominately in the lateral preoptic area, and at anterior sites in lateral hypothalamus (Siegel & Tassoni, 1971a). The fact that the postcommissural cut also produced impairment of avoidance deserves some attention. Most of the fibers of this tract are from the hippocampus (Nauta, 1 9 5 6; Raisman et al., 1 9 6 6) and pass principally into the 75 anteromedial and anteroventral nuclei of the thalamus, and Into the nuclei of the mammillary bodies (which themselves relay heavily into anterior thalamus). However, the septum also connects with a number of nuclei of the thalamus, including anteromedial and anteroventral nuclei. Most of this influence passes through the stria medullaris (which was not interrupted in any of the postcommissural lesions), but some of the septal connections pass to the thalamus by way of the descending columns (Powell, 1 9 6 6). Therefore it is not possible at present to resolve with certainty whether the passive avoidance deficit was due to interrup tion of hippocampal output, or of fibers coming from the septum. Intuitively, the favored view is that the essen tial circuit involves communication passing from lateral septum into the hippocampus, and then from hippocampus into the anterior thalamus. A role of the thalamic site is sug gested by the report of Gerbrandt (1 9 6 5) that lesion of anteromedial nucleus impairs passive avoidance. Regarding the role of mammillary bodies, several investigators have reported impairments of avoidance learn ing with damage to the mammillaries, or to the mammillo- thalamic tract (Plogg & MacLean, 1963; Krickhaus, 1964; Thomas et al., 1 9 6 8). However, in each of these reports, the deficit was in active avoidance, and Thomas et al. (1 9 6 8) said that the animals are more inclined to freeze as 76 a result of the training conditions. Heightened freezing, of course, would tend to facilitate rather than impair passive avoidance. McCleary (1 9 6 6) further reported that sectioning the horizontal columns of the fornix did not impair passive avoidance learning in cats. This appears to be at odds with the present results, although the cut used by McCleary may not have damaged the fibers which pass into the anterior thalamus. Another possibility is that the mammillary bodies have an inhibitory role in relation to the thalamus, so that damage to these connections would interfere with active, but not passive avoidance. However, it is even more likely that there is no discrepancy at all, and that the problem is one of summary rather than a difference in observation. McCleary tests for passive avoidance ability during the period immediately following the training shock, while in this study the primary test is conducted the fol lowing day. If number of training shocks is used as the measure of immediate retention deficit, the results of the present study are consistent with his in that none of the lesioned animals showed an avoidance deficit during the minute following the first shock. Turning to the impairment of spatial learning seen in this study, such deficits have been observed consis tently with lesions of the hippocampus (Racine 8 c Kimble, 1965; Greene, 1971), lesion of the fornix (Greene, Stauff, 8s Walters, 1972; Hirsh 3s Segal, 1973; Greene 8s Stauff, 197*0 > or following blockage of hippocampal function (Greene, 1971; Greene 3s Lomax, 1970; Henderson, Henderson, 3s Greene, 1973)- Many of these reports of spatial learning deficits were discussed in the Introduction, as were the similar deficits which have been reported as a result of septal damage (Zucker, 1965; Zucker 8s McCleary, 1964). Spatial deficits were found as a result of damage to the mammillary bodies, mammillothalamic tract, or anterior thalamus by Thompson et al. (1964) and Thompson (1974), but not by Krieckhaus and Randal (1 9 6 8). Since the Lateral Precommissural cut did not affect spatial learning, but a cut which also passed into medial septum (Total Precommissural cut) did produce the impair ment, it seems reasonable to infer that the medial precom missural connections are important for this function. As discussed above, these connections provide reciprocal com munication between dorsal hippocampus and the neurons of the medial septum and bed nucleus of the diagonal band. In addition, fibers from the hippocampus pass forward and serve the accumbens, and others turn back to Join the medial forebrain bundle. The neurons of medial septum and diago nal band are centrally involved in regulation of hippo campal theta (Petsche et al., 1 9 6 2), especially the theta 78 activity of dorsal hippocampus (Brust-Carmona et al., 1973)> and Schwartzbaum and Donovick (1 9 6 8), and Donovick (1 9 6 8) have shown that lesions of the diagonal band and medial septum which block hippocampal theta also block performance in an alternation task. Therefore, the spatial learning deficit of animals with the Total Precommissural cut was probably caused by interruption of influence passing from these medial septal nuclei into the hippocampus. Interruption of fibers passing from the hippocampus through the postcommissural fornix also produced an impair ment of spatial learning, although some comment is needed on the particular pattern of impairments seen in the origi nal learning and reversal tasks. Investigators frequently do not find an impairment in original position learning with damage to the hippocampus, but do find an impairment of reversal or some variation of the reversal task. Pre sumably this is due in part to the simplicity of the origi nal task, so that even if an animal did have a deficiency in its ability to discriminate position, it would be lost among the many performance variables occurring at the start of training. In fact there is reason to believe that hip- pocampally damaged rats have abnormally strong initial response preferences (Douglas, 1 9 6 7), and Greene (1971) has observed that there is an original position learning 79 deficit when animals are taught against this preference. In the present study, the animals were assigned arbitrarily to right or left positions for the original habit. Pos sibly an inordinate number of animals in the postcommissur al group were assigned positions which were against their initial preference, and that while they learned this choice only with a great deal of difficulty they found it quite easy to "reverse" back to their preferred side. In any case there is no ambiguity about the severity of the spa tial learning impairment of this group, as reflected by their scores in the alternation task. A few basic ideas about the systems which mediate the response suppression and spatial learning skills can be mentioned, and they might provide some perspective on the results of this study. A working hypothesis is that the nuclei of the septum receive kinesthetic and proprioceptive information (i.e., Interoceptive cues) about the actions being per formed by the animal, and relay this information to the hippocampus. The hippocampus then serves as a memory register for what actions were performed, and integrates this information with external cues (passing through the subiculum) about external events, and in particular about the consequences of the act. As long as the action is to be continued, the hippocampus remains in a receiving mode 80 for the interoceptive cues (i.e., as indexed by theta), but shifts to a desynchronous mode of activity when the action is to be shifted or discontinued. In the case of spatial reversal, the activity may be transmitted to anterior cingulate cortex, since damage to this area also produces alternation deficits (Pribram et al., 195*0 > and it has been shown that in the rat this area contains tissue which is homologous to dorsolateral frontal cortex in higher mammals (Domesick, 1972; Leonard, 1972). In the case of passive avoidance, the results of Greene and Stauff (197^) suggested that the information may be passed via the cingulum to posterior cingulate cortex, since their cingulum-lesioned animals had a passive avoidance impairment. This view of septal function is consistent with the conclusions of several laboratories (Sodetz, 1971; Ellen & Butter, 1969; Ellen & Bate, 1 9 6 9) and in particular with the review by Caplan (1973) who suggested impairments in the way septally lesioned animals deal with exteroceptive (visual, auditory) and interoceptive (proprioceptive, kinesthetic) stimuli. In her review of septal lesion studies, Caplan (1973) suggested that septally lesioned animals are hyperreactive to exteroceptive stimuli, as evidenced by exaggerated unconditioned responses. Septal 81 lesions also make the reinforcing stimulus more effective. These effects of septal lesions will either impair or fa cilitate normal behavioral responses depending on what type of stimuli are used (Caplan, 1973)- Studies requiring an animal to make temporal dis criminations (fixed interval and DRL responding) show that septal lesions produce impairment (Ellen & Powell, 1964; Ellen, Wilson, & Powell, 1962). Sodetz (1 9 7 1) and Caplan (1 9 7 3) suggested that responses and reinforcements must occur very closely in time or the responses and response- produced, or proprioceptive, cues will not acquire any significance for an animal with septal lesions. This sug gestion is supported by evidence that animals impaired on a DRL schedule with no exteroceptive cues available improved when given an external stimulus which marked the reinforce ment interval (Ellen & Butter, 1 9 6 9)• In an experiment which required five responses on one bar before food became available with one press of a second bar, rats with septal lesions changed to the food bar too soon. Ellen and Keln- hofer (1 9 7 1) suggested that this impaired performance occurs because the septal lesions prevent "stimuli arising from the animal's own behavior from becoming discriminative cues for shifting to the food bar." Regarding maze learning, Ellen and Bate (1 9 6 9) found that septally lesioned rats were inclined to reach a 82 goal by a straight, peripheral path rather than a central, zigzag one, and concluded that the rats were impaired In their ability to use response produced cues (body turns) generated in the zigzag approach. This hypothesis is sup ported by the spontaneous alternation deficit found in septally lesioned animals (Douglas & Raphelson, 1 9 6 6). The view of hippocampal function proposed here is consistent with Vanderwolf's hypothesis (Vanderwolf, 1 9 6 9; Vanderwolf & Bland, 1972) that the hippocampal formation, particularly the dentate gyrus, is active in controlling voluntary behavior. It is also consistent with attentional views of hippocampal activity (Grastyan et al., 1959; Douglas, 1967; Bennett, 1 9 7 1), which are based on the find ing that orientation to novel stimuli is accompanied by hippocampal theta, and orientation and theta disappear during conditioning, possibly because during learning the hippocampus is suppressing the reticular activating system. The features of the proposed theory which are in greatest need of supplementary data are (l) that there is a differential output of response suppression and spatial learning activities to particular nuclei of the thalamus, mammillary bodies and cingulate cortex; and (2) that the hippocampus serves as a memory register for the kinesthetic and proprioceptive consequences of action. The results of Henderson, Henderson, and Greene (1973) lend support to the 83 latter notion, as does the work of Kesner and associates (McDonough & Kesner, 1971; Kesner & Conner, 1972). Summary Lesions which differentially sever parts of the precommissural or postcommissural fornix were compared to each other and to the effects of control lesions In behav ioral tasks In which hippocampal lesions produce deficits (spatial learning and passive avoidance tasks). Alternation learning was Impaired by postcommissural fornix lesions, which interrupt the connections between the hippocampus and the mammillary bodies and anterior thalamic nuclei. Alternation learning was also impaired by precom missural lesions which sever the connections between the hippocampus and medial septal nuclei. Precommissural le sions which spared the connections between the hippocampus and the medial septal nuclei did not impair spatial learn ing, leading to the conclusion that it is the input from the medial septum and diagonal band to the hippocampus which is important in spatial learning. This theory is supported by the fact that the medial septal nuclei regu late theta activity in the dorsal hippocampus (Brust- Carmona et al., 1973) and alternation learning is impaired when theta is blocked by septal lesions (Donovick, 1 9 6 8). Passive avoidance learning was impaired by postcom missural fornix lesions and by precommissural fornix 84 lesions. The impairment in animals with lesions which severed the connections between the hippocampus and both the lateral and medial septum was no greater than those with lesions which severed the connections to the lateral septal nuclei only, leading to the conclusion that the lateral septum, which communicates with the ventral hippo campus, plays an essential role in passive avoidance learn ing. This pattern of deficits, considered together with the anatomical relationships of the system, suggests a model in which the medial septum relays kinesthetic infor mation to the dorsal hippocampus, which in turn serves as a memory system in the performance of spatial habits. It is less clear what kind of information is relayed by the lateral septum, but it may communicate with the ventral hippocampus regarding the consequences of punishment, and thus serve as part of a system for defensive suppression of behavior. REFERENCES 85 REFERENCES Alksne, J. F., Blackstad, T. W., Walberg, T., & White, L. E. Electron microscopy of axon degeneration: A valuable tool in experimental neuroanatomy. Erbeg. Anat. Entwlck. Gersch., 1966, 22, 1-31. Allen, W. F. Effect of ablating the frontal lobes, hippo campus, and occipito-parieto-temporal (excepting pyri- form areas) lobes on positive and negative olfactory conditioned reflexes. Am. J. Psychol., 1940, 128, 745-771. Avis, H., & Carlton, P. Retrograde amnesia produced by hippocampal spreading depression. Science, 1968, l6l, 73-75. Bennett, T. L. Hippocampal theta activity and behavior— a review. Commun. Behav. Biol., 1971* 6, 37-48. Blackstad, T. W. Commissural connections of the hippo campal region in the rat, with special reference to their mode of termination. J. Comp. Neurol., 1956, 105, 417-537. Blackstad, T. W., Brink, K., Hem, J., & Jeune, B. Distri bution of hippocampal mossy fibers in the rat. An experimental study. J. Comp. Neurol., 1970, 138, 433- 450. Blanchard, R. J., & Fial, F. A. Effects of limbic lesions on passive avoidance and reactivity to shock. J. Comp. Physiol. Psychol., 1968, 66, 606-612. Bland, B., & Vanderwolf, C. H. Diencephalic and hippo campal mechanisms of motor activity in the rat: Effects of posterior hypothalamic stimulation on behavior and hippocampal slow wave activity. Brain Res., 1972, 43, 67-68. Brodal, A. The hippocampus and the sense of smell. Brain, 1947, 10, 179-222. 86 87 Brust-Carmona, H., Alvarez-Leefmans, P. J., & Ardltti, L. Differential projections of septal nuclei to ventral and dorsal hippocampus In rabbits. Exp. Neurol., 1973, 40* 553-566. Cajal, R. Y. Hlstologie du systfeme nerveux de l'homme et des vertdgrds. Vol. 2. Paris: A. Maioine, 1911. Caplan, M. An analysis of the effects of septal lesions on negatively reinforced behavior. Behav. Biol., 1973, £, 129-167. Carey, R. J. Impairment of maze retention resulting from septal injury. Physiol, and Behav., 1 9 6 8, 2., 495-497. Corscina, D. V., & Lash, L. The effects of differential hippocampal lesions on shock vs. shock conflict. Physiol. Behav., 1 9 6 9, 4, 227-233- Cragg, B. Olfactory and other afferent connections of the hippocampus in the rabbit, rat, and cat. Exp. Neurol., 1 9 6 1, 2, 588-600. Cragg, B. Q., & Hamlyn, L. H. Histologic connections and electrical and autonomic responses evoked by stimula tion of the dorsal fornix in the rabbit. Expl. Neurol., 1959, 1, 187-213. Daitz, H. M., & Powell, D. P. Studies of the connections of the fornix system. J. Neurol. Neurosurg. Psychlat., 1954, II, 75-81. Dalland, T. Response and stimulus perseveration in rats with septal and dorsal hippocampal lesions. J. Comp. Physiol. Psychol., 1970, 114-118. DeFrance, J. F., Shimono, T., & Kitai, S. T. Anatomical distribution of the hippocampal fibers afferent to the lateral septal nucleus. Brain Res., 1971, 34, 176-180. Domesick, V. B. Thalamic relationships of the medial cortex in the rat. Brain Behav. Evol., 1972, 6, 457- 483. Donovick, P. J. Effects of localized septal lesions on hippocampal EEG activity and behavior in rats. J. Comp. Physiol. Psychol., 1 9 6 8, 66, 569-578. 88 Donovick, P. D., & Schwartzbaum, J. S. Effects of low- level stimulation of the septal area on two types of discrimination reversal in the rat. Psychon. Sci., 1966, 6, 3-4. Donovick, P. J., & Wakeman, K. A. Open-field luminance and "septal hyper-emotionality." Animal Behav., 1969, 17> 186-190. Douglas, R. J. The hippocampus and behavior. Psychol. Bull., 19 6 7> 6£, 416-442. Douglas, R. J., & Isaacson, R. L. Hippocampal lesions and activity. Psychon. Sci., 1964, 1, 187-188. Douglas, R. J., & Pribram, K. H. Learning and limbic lesions. Neuropsychologla, 1 9 6 6, 4, 197-220. Douglas, R. J., & Raphelson, A. C. Septal lesions and activity. J. Comp. Physiol. Psychol., 1 9 6 6, 62, 465- 467. Edinger, H., Siegel, A., & Troiano, R. Single unit analy sis of the hippocampal projections to the septum in the cat. Exp. Neurol., 1973, 4l, 5 6 9-5 8 3. Ellen, P., & Bate, G. Qualitative differences in the maze performance of rats with septal lesions. Psychon. Sci., 1969, 1£, 5-6. Ellen, P., & Butter, J. External cue control of DRL per formance in rats with septal lesions. Physiol. Behav., 1969, 4, 1-6. Ellen, P., & Kelnhofer, M. Discrimination of response feedr- back following septal lesions. Psychon. Sci., 1971, 21, 94-95. Ellen, P., & Powell, E. W. Temporal discrimination in rats with rhinencephalic lesions. Exp. Neurol., 1962, 6, 538-547. Ellen, P., Wilson, A., & Powell, E. Septal inhibition and timing behavior in the rat. Exp. Neurol., 1 9 6 3, 16, 162-171. Fox, S. S., Kimble, D. P., & Lickey, M. E. Comparison of caudate nucleus and septal-area lesions on two types of avoidance behavior. J. Comp. Physiol. Psychol., 1964, 5 8, 3 8 0-3 8 6. 89 Fried, P. A. Effects of septal lesions on conflict resolu tion in rats. J. Comp. Physiol. Psychol., 1969, 69, 375-380. ---- Fried, P. A. Pre- and post-operative approach training and conflict resolution by septal and hippocampal lesioned rats. Physiol, and Behav., 1970, 975-979. Fried, P. A. Limbic system lesions in rats: Differential effects in an approach-avoidance task. J. Comp. Physiol. Psychol., 1971, Z4, 349-353. Fried, P. A. Septum and behavior: A review. Psychol. Bull., 1 9 7 2, 18(4), 292-310. Gerbrandt, L. K. The effects of anteromedial and dorso- medial thalamic lesions on passive avoidance and activ ity. Psychon. Sci., 1 9 6 5, 2, 39-40. Glick, S. D., Marsanico, R. G., & Greenstein, S. Differen tial recovery of function following caudate, hippo campal, and septal lesions in mice. J. Comp. Physiol. Psychol., 1974, 86(5), 787-792. Gotsick, J. E. Factors affecting spontaneous activity in rats with limbic system lesions. Physiol, and Behav., 1969, 4, 587-593. Grastyan, E., Lissak, K., Madarasz, I., & Donhoffer, H. Hippocampal electrical activity during the development of conditioned reflexes. Electroencephalogr. Clin. Neurophysiol., 1959, .11, 409-430. Green, J. D. The hippocampus. Handbook of physiology, Sec. I. In J. Field (Ed.), Neurophys1o1ogy. Vol. II. Washington, D.C.: Physiology Section, I960. Pp. 1373- 1389. Green, J. D., & Arduini, A. Hippocampal electrical activ ity in arousal. J. Neurophysiol., 1954, 533-557. Green, R. H., Beatty, W. W., & Schwartzbaum, J. S. Comparative effects of septohippocampal and caudate lesions on avoidance behavior in rats. J. Comp. Physiol. Psychol., 1 9 6 7, 64, 444-452. Greene, E. Comparison of hippocampal depression and hippo campal lesion. Exp. Neurol., 1971, 313-325. 90 Greene, E., & Lomax, P. Impairment of alternation- learning in rats following microinjection of corbachol into the hippocampus. Brain Res., 1970, 18, 355-359. Greene, E., & Stauff, C. Behavioral role of hippocampal connections via fornix and subiculum. Exp. Neurol., in press. Greene, E., Stauff, C., & Walters, J. Recovery of function with two-stage lesions of the fornix. Exp. Neurol., 1972, 22, 14-22. Gross, C. G., Chorover, S. L., & Cohen, S. M. Caudate, cortical, hippocampal, and dorsal thalamic lesions in rats: Alternation and Hebb-Williams maze performance. Neuropsychologla, 1 9 6 5> 2.* 53-68. Guillery, R. W. Degeneration in the hypothalamic connec tions of the albino rat. J. Anat. (London), 1956, 91> 91-115. Gurowitz, E. M., & Lubar, J. P. Changes in activity, food ingestion, and passive avoidance behavior following limbic-septal ablation in the cat. Proceedings of the 74th Annual Convention of the American Psychological Association. 1966. 1. 197-10&. (Summary) Hamilton, L. W. Behavioral effects of unilateral and bilateral septal lesions in rats. Physiol, and Behav., 1 9 7 0, 5, 855-859. Hamilton, L. W., Kelsey, J. E., & Grossman, S. P. Varia tion in behavioral inhibition following different septal lesions in rats. J. Comp. Physiol. Psychol., 1970, 10, 79-86. Hamilton, L. W., McCleary, R. A., & Grossman, S. P. Behavioral effects of cholinergic septal blockage in the cat. J. Comp. Physiol. Psychol., 1 9 6 8, 6 6, 563- 5 6 8. Hamlyn, L. H. The fine structure of the mossy fibre end ings in the hippocampus of the rabbit. J. Anat., 1 9 6 2, 26, 112-120. Harvey, J. A., Lints, C. E., & Jacobson, L. E. Effects of lesions in the septal area on conditioned fear and dis criminated instrumental punishment in the albino rat. J. Comp. Physiol. Psychol., 1 9 6 5* 5£* 37-48. 91 Henderson, J., Henderson, R., & Greene, E. Impairment of memory with administration of KC1 to the hippocampus. Behav. Biol., 1973, £, 655-670. Hirsh, R., & Segal, M. Complete transection of the fornix and reversal of position habit in the rat. Physiol. Behav., 1972, 8, 1051-1054. HJorth-Simonsen, A. Hippocampal efferents to the ipsi- lateral entorhinal area: An experimental study in the rat. J. Comp. Neurol., 1971, 142, 417-438. HJorth-Simonsen, A. Projection of the lateral part of the entorhinal area to the hippocampus and fascia dentata. J. Comp. Neurol., 1972, 146, 219-232. HJorth-Simonsen, A., & Jeune, B. Origin and termination of the hippocampal perforant path in the rat studied by silver impregnation. J. Comp. Neurol., 1971, 144, 215- 232. Hughes, K. R. Dorsal and ventral hippocampal lesions and maze learning: Influence of preoperative environment. Canad. J. Psychol., 1 9 6 5, 1£, 325-332. Hughes, R. Retrograde amnesia in rats produced by hippo campal injections of KC1. J. Comp. Physiol. Psychol., 1969, 68 , 637-644. ------------------------- Isaacson, R. L., Olton, D. S., Bauer, B., & Swart, P. The effect of the number of training trials on the deficit in passive avoidance behavior in the hippocampectomized rat. Paper read at Midwestern Psychological Associa tion, Chicago, 1 9 6 6. Isaacson, R. L., & Wickelgren, W. 0. Hippocampal ablation and passive avoidance. Science, 1962, 1 3 8, 1104-1106. Jarrard, L. E., Isaacson, R. L., & Douglas, R. J. Effects on hippocampal ablation and intertrial interval on runway acquisition and extinction. J. Comp. Physiol. Psychol., 1966, ££, 442-444. Kaada, B. K., Jansen, J. Jr., & Anderson, P. Stimulation of the hippocampus and medial cortical areas in unanes thetized cats. Neurology, 1953, 2., 844-857- 92 Kaada, B., Rasmussen, E., & Kvlem, 0. Impaired acquisition of passive avoidance behavior by subcallousal, septal, hypothalamic, and insular lesion in rats. J. Comp. Physiol. Psychol., 1 9 6 2, 661-670. Kapp, B. S., & Schneider, A. M. Selective recovery from retrograde amnesia produced by hippocampal spreading depression. Science, 1971, 173, 1149-1151. Kasper, P. Attenuation of passive avoidance by continuous septal stimulation. Psychon. Sci., 1964, _1, 219-220. Kasper-Pandi, P., Schoel, W. M., & Zysman, M. Modification and response strength in passive avoidance deficits in septal lesioned rat. Physiol, and Behav., 1 9 6 9, 4, 815-821. Kesner, R. P., & Conner, H. S. Independence of short- and long-term memory: A neural system analysis. Science, 1972, 176, 432-434. Kimble, D. P. The effects of bilateral hippocampal lesions in rats. J. Comp. Physiol. Psychol., 1963* 56, 273-283. Kimble, D. P. The hippocampus and Internal inhibition. Psychol. Bull., 1 9 6 8, jb, 285-295. Kimble, D. P., & Kimble, R. J. Hippocampectomy and response perseveration in the rat. J. Comp. Physiol. Psychol., 1965. 60, 474-476. Kimble, D. P., Kirkby, R. J., & Stein, D. G. Response perseveration interpretation of passive avoidance deficits in hippocampectomized rats. J. Comp. Physiol. Psychol., 1 9 6 6, 61, 141-143. Kimura, D. Effects of selective hippocampal damage on avoidance behavior and conditioned avoidance response in the rat. J. Nerv. Ment. Pis., 1958* 126, 57-63. Kimura, D. Effects of selective hippocampal damage on avoidance behavior in the rat. Canad. J. Psychol., 1958, 12, 213-218. Kluver, H., & Bucy, P. C. Preliminary analysis of func tions of the temporal lobes in monkeys. Arch. Neurol. & Psychlat., 1939* 42, 979-1000. Krieckhaus, E. E. Decrements in avoidance behavior follow ing mammillothalamic tractotomy in cats. J. Neuro- physlol., 1964, 2£, 753-767. 93 Leonard, C. M. The connections of the dorsomedial nuclei. Brain Behav. Evol., 1972, 6, 524-541. Lorente de N<5, R. Studies on the structure of the cerebral cortex. II. Continuation of the study of the ammonic system. J. Psychol. Neurol., 1934, 46, 113-177. Lubar, J. P. Effect of medial cortical lesions on the avoidance behavior of the cat. J. Comp. Physiol. Psychol., 1964, £8, 38-46. Lubar, J. F., & Numan, R. Behavioral and physiological studies of septal function and related medial cortical structures. Behav. Biol., 1973* 8, 1-25. McCleary, R. A. Response specificity in the behavioral effects of limbic system lesions in the cat. J. Comp. Physiol. Psychol., 1 9 6 1, 54, 605-613. McCleary, R. A. Response-modulating functions of the limbic system: Initiation and suppression. In E. Stel lar & J. M. Sprague (Eds.), Progress in physiological psychology. Vol. I. New York: Academic Press, 1966. McCleary, R. A., Jones, C., & Ursin, H. Avoidance and retention deficits in septal cats. Psychon. Sci., 1965* 2, 85-86. --------- McDonough, J. H., & Kesner, R. P. Amnesia produced by brief electrical stimulation of amygdala or dorsal hippocampus in cats. J. Comp. Physiol. Psychol., 1971* XL, 171-1 7 8. McGowan, B. K., Garcia, J., Ervin, P. R., & Schwartz, J. Effects of septal lesions on bait-shyness in the rat. Physio, and Behav., 19 6 9* 4* 907-909- McNew, J., & Thompson, R. Role of the limbic system in active and passive avoidance conditioning in the rat. J. Comp. Physiol. Psychol., 1966, 6jL, 173-180. Meisner, W. W. Hippocampal functions in learning. J. Psychlat. Res., 1966, 4, 235-304. Middaugh, L. D., S c Lubar, J. P. Interaction of septal lesions and experience on the suppression of punished responses. Physiol, and Behav., 1970, 5* 233-237- Miller, J. J., S t Mogenson, G. J. Projections of the septum to the lateral hypothalamus. Exp. Neurol., 1972, 34, 229-243. 94 Nadel, L. Dorsal and ventral hippocampal lesions and behavior. Physiol, and Behav., 1968, 891-900. Nauta, W. J. H. An experimental study of the fornix sys tem in the rat. J. Comp. Neurol., 1956, 104, 247-268. Nielson, H., Mclver, H., & Boswell, R. Effect of septal lesions on learning, emotionality, activity, and explor atory behavior in rats. Experi. Neurol., 1965* 11, 147-157. ~ Niki, H. Response perseveration following the hippocampal ablation in the rat. Japanese Psychol. Res., 1966, 8, 1-9. Papez, J. W. A proposed mechanism of emotion. Arch. Neurol. Psychlat., 1937, 2®, 725-743. Penfield, W. Studies of the cerebral cortex of man: A review and an interpretation. In J. P. Delafresnaye (Ed.), Brain mechanisms and consciousness. Spring field, Mass.: Thomas, 1954. Penfield, W., & Milner, B. Memory deficit produced by bilateral lesions in the hippocampal zone. Arch. Neurol. Psychlat., 1958, ££, 475-479. Petsche, H., Stumpf, C., & Gogolak, S. K. The significance of the rabbit's septum as a relay station between the midbraln and the hippocampus. I. The control of hippo campus arousal activity by the septum cells. Electro- encephol. Clin. Neurophysiol., 1962, 14, 202-2TT. Plogg, D. W., & MacLean, P. D. On functions of the mamil lary bodies in the squirrel monkey. Exp. Neurol., 1963, 1, 76-85. Poletti, S. D., Sujatanond, R., & Sweet, S. Hippocampal influence on unit activity of hypothalamus, preoptic region, and basal forebrain in awake, sitting squirrel monkeys. J. Neurophysiol., 1972, 3 6, 308-324. Powell, E. W. Septal efferents revealed by axonal degener ation in the rat. Exp. Neurol., 19 6 3, 8, 406-422. Powell, E. W. Septal efferents in the cat. Exp. Neurol., 196 6, 14, 328-337. Powell, E. W. Limbic projections to the thalamus. Exp. Brain Res., 1973, 394-401. 95 Powell, T. P. S., Guillery, R. W., & Cowan, W. M. A quan titative study of the fomix-mamillo-thalamic system. J. Anat. (London), 1957, 21, 419-437. Pribram, K. H., Wilson, W. A., & Conners, J. Effects of lesions of the medial forebraln on alternation behavior of rhesus monkeys. Exp. Neurol., 1962, 6, 36-47. Racine, R. J., & Kimble, D. P. Hippocampal lesions and delayed alternation In the rat. Psychon. Sci., 1965, i, 285-286. Ralsman, G. The connections of the septum. Brain, 1 9 6 6, 8£, 317-348. Ralsman, E., Cowan, W., & Powell, T. The extrinsic affer ent, commissural, and association fibers of the hippo campus. Brain, 1 9 6 5> 88, 963-996. Ralsman, G., Cowan, W., & Powell, T. An experimental analysis of the efferent projections of the hippocampus. Brain, 1 9 6 6, 8£, 83-108. Raphelson, A. C., Isaacson, R. L., & Douglas, R. J. The effect of limbic damage on the retention and perform ance of a runway response. Neuropsychologia, 1966, 4, 253-264. Riddell, R. Shift and retention deficits in hippocampec- tomized and neodecorticate rats. Physiol. Behav., 1973, 1 0, 8 6 9-8 7 8. Rose, J. E., & Woolsly, C. N. Structure and relations of limbic cortex and anterior thalamic nuclei in rabbit and cat. J. Comp. Neurol., 1948, 89> 279-348. Rosvold, H. E., & Schwarcbart, M. K. Neural structures involved in delayed-response performance. In J. M. Warren & K. Ackert (Eds.), The frontal granular cortex and behavior. New York: McGraw-Hill, 19&4. Pp. I-I5 . Schwartzbaum, J. S., & Donovick, P. J. Discrimination reversal and spatial alternation associated with septal and caudate dysfunction in rats. J. Comp. Physiol. Psychol., 1 9 6 8, 6£, 83-92. Schwartzbaum, J. S., & Gay, P. E. Interacting behavioral effects on septal and amygdaloid lesions in the rat. J. Comp. Physiol. Psychol., 1 9 6 6, 61^, 59-65. 96 Schwartzbaum, J. S., & Spieth, T. M. Analysis of the response inhibition concept of septal functions in "passive-avoidance" behavior. Psychon. Scl., 1964, 1, 145-146. Scoville, W. B., & Milner, B. Loss of recent memory after bilateral hippocampal lesions. J. Neurol. Neurosurg. Psych., 1957, 20, 11-24. Shute, C. C., & Lewis, P. R. The use of cholinesterase techniques combined with operative procedures to follow nervous pathways in the brain. Bibl. anat. (Basel), 1961, 1, 34-49. Siegel, A., & Edinger, H. A comparative neuroanatomical analysis of the differential projections of the hippo campus to the septum. Paper presented at the Third Annual Meeting of the Society for Neuroscience, San Diego, 1973. Siegel, A., & Tassoni, J. P. Projections from the lateral and medial septal nucleus of the cat. Anat. Rec., 1970, 166, 378. Siegel, A., & Tassoni, J. P. Differential efferent projec tions from the ventral and dorsal hippocampus of the cat. Brain Behav. Evol., 1971> 4, 185-200. (a) Siegel, A., & Tassoni, J. P. Differential efferent projec tions of the lateral and medial septal nuclei to the hippocampus in the cat. Brain Behav. Evol., 1971, 4, 201-219. (b) Silveira, J. M., & Kimble, D. P. Brightness discrimination and reversal in hippocampally lesioned rats. Physiol. Behav., 1 9 6 8, 625-630. Slotnick, B. M., & Brown, D. L. Fear conditioning and passive avoidance in mice with septal lesions. Physiol. Behav., 1970, £, 1255-1261. Slotnick, B. M., & Jarvik, M. E. Deficits in passive avoidance and fear conditioning in mice after septal lesions. Science, 1 9 6 6, 154, 1207-1208. Sodetz, F. J. Sidman avoidance performance and response suppression in rats with septal lesions. Paper pre sented at the Eastern Psychological Association, New York, April 1971. 97 Stevens, R., & Cowey, A. Effects of dorsal and ventral hippocampal lesions on spontaneous alternation, learned alternation, and probability learning In rats. Brain Res., 1973, £2, 203-224. Swann, H. G. The function of the brain in olfaction. II. The results of destruction of olfactory and other nervous structures upon the discrimination of odors. J. Comp. Neurol., 1934, ££, 175-201. Teitelbaum, H. A comparison of the effects of orbitofron- tal and hippocampal lesions upon discrimination learn ing and reversal in the cat. Exp. Neurol., 1964, 9, 452-462. -------- Teitelbaum, H., & Isaacson, R. L. Activity changes follow ing partial hippocampal lesions in rats. J. Comp. Physiol. Psychol., 1 9 6 5, 56, 284-289. Thomas, G. J., Hostetter, G., & Barker, D. J. Behavioral functions of the limbic system. In E. Stellar & J. M. Sprague (Eds.), Progress in physiological psychology. Vol. II. New York: Academic Press, 1968. Thompson, R. A note on cortical and subcortical injuries and avoidance learning by rats. In J. M. Warren & K. Akert (Eds.), The frontal granular cortex and behavior. New York: McGraw-Hill, 1964. Thompson, R., & Langer, S. K. Deficits in position reversal learning following lesions of the limbic system. J. Comp. Physiol. Psychol., 1 9 6 3, 56, 987-995. Thompson, R., Langer, S. K., & Rich, I. Lesions of the limbic system and short-term memory in albino rats. Brain, 1964, Qj_, 537-542. Updyke, B. Behavioral effects of selective hippocampal damage. Paper presented at the Western Psychological Association, San Diego, 1 9 6 8. Ursin, H., Linck, P., & McLeary, R. A. Spatial differen tiation of avoidance deficit following septal and cingulate lesions. J. Comp. Physiol. Psychol., 1 9 6 9, 68, 74. Van Hoesen, G., Wilson, L., MacDougall, J., & Mitchell, J. Selective hippocampal complex deafferentation and deefferentation and avoidance behavior in rats. Physiol. Behav., 1972, 8, 873-879. 98 Vanderwolf, C. H. Hippocampal electrical activity and voluntary movement in the rat. Electroencephalogr. Clin. Neurophysiol., 1969* 26, 407-418. Vanderwolf, C. H. Limbic-diencephalic mechanisms of voluntary movement. Psychol. Rev., 1971* 78, 83-113. Vanderwolf, C. H., Bland, B. H., & Whishaw, I. Z. Diencephalic, hippocampal and neocortical mechanisms in voluntary movement. In J. D. Maser (Ed.), Efferent organization and the integration of behavior. New York: Academic Press, 1973. Webster, D. B., & Voneida, T. J. Learning deficits follow ing hippocampal lesions in split-brain cats. Exp. Neurol., 1964, 10, 170-182. Winnocur, G., & Mills, J. A. Hippocampus and septum in response inhibition. J. Comp. Physiol. Psychol., 1969* §1, 352-357- Wishart, T., & Mogenson, G. Effects of lesions of the hippocampus and septum before and after passive avoid ance training. Physiol. Behav., 1970, ^3, 31-33* Yanagihara, T., & Hyden, H. Protein synthesis in various regions of the rat hippocampus during learning. Exp. Neurol., 1 9 6 1, £2, 151-164. Zimmer, J. Ipsilateral afferents to the commissural zone of the fascia dentata, demonstrated in decommissurated rats by silver impregnation. Comp. Neur., 1972, 142, 393-416. Zucker, I. Effect of lesions of the septal-limbic area on the behavior of cats. J. Comp. Physiol. Psychol., 1965, 60* 344-352. Zucker, I., & McCleary. R. A. Perseveration in septal cats. Psychon. Scl., 1964, 1 _ , 3 8 7-3 8 8.
Abstract (if available)
Linked assets
University of Southern California Dissertations and Theses
Conceptually similar
PDF
Sex Differences In The Organization Of Spatial Abilities In Older Men And Women
PDF
Differential effects of epinephrine and propranolol on shuttle box avoidance learning in rats of different ages
PDF
Protein synthesis in the hippocampus of rats during learning assessed by radioautography
PDF
Hemispheric asymmetries in maintaining vigilance for younger and older adults
PDF
Effects Of Physostigmine On Avoidance Conditioning And Retention In The Isolated Cockroach Ganglion
PDF
Influences Of Interoperative Experience And Age On Recovery Of Visual Function Following Two-Stage Lesions Of The Striate Cortex
PDF
Diagnostic indices of hyperactivity and an investigation of verbal mediation training as an alternative to pharmacotherapy
PDF
The Effects Of Variant Forms Of Competition On The Cognitive Learning Outcome Of An Educational Game Played By College Students In English Classes
PDF
Elaborative facilitation, learning, and cognitive abilities in children with and without learning difficulties
PDF
Hemispheric Differences In Visual Search Of Tachistoscopically Presented Nonunitizeable And Unitizeable Verbal Material
PDF
Monocular Acquisition And Interocular Transfer Of Two Types Of Discriminations In Normal And Corpus Callosally-Sectioned Guinea Pigs
PDF
Psychomotor Performance And Change In Cardiac Rate In Subjects Behaviorally Predisposed To Coronary Heart Disease
PDF
The Role Of Cerebellar Cortex In Classical Conditioning Of Discrete Motor Movements: Intracranial Electrical Stimulation Studies
PDF
Biofeedback Control Of The Eeg Alpha Rhythm And Its Effect On Reaction Time In The Young And Old
PDF
Some new perspectives on the issue of countercyclical, U.S. fertility
PDF
Age Differences In Primary And Secondary Memory Processes
PDF
Effects Of Media Presentation Mode And Learner Personality In The Teaching Of A Factual Learning Task
PDF
Decision Making: An Individually Parameterized Deterministic Model
PDF
Annulling Crimes: A Hegelian Theory Of Retribution
PDF
Changes In Memory As A Function Of Age
Asset Metadata
Creator
Henderson, Judith Lynn
(author)
Core Title
Impaired Learning Of Spatial And Passive Avoidance Habits With Lesions Of Precommissural And Postcommissural Fornix
Degree
Doctor of Philosophy
Degree Program
Psychology
Publisher
University of Southern California
(original),
University of Southern California. Libraries
(digital)
Tag
OAI-PMH Harvest,psychology, experimental
Language
English
Contributor
Digitized by ProQuest
(provenance)
Advisor
Greene, Ernst (
committee chair
), Walker, James Paul (
committee member
), Holmes, Eric (
committee member
)
Permanent Link (DOI)
https://doi.org/10.25549/usctheses-c20-532671
Unique identifier
UC11226046
Identifier
7515538.pdf (filename),usctheses-c20-532671 (legacy record id)
Legacy Identifier
7515538.pdf
Dmrecord
532671
Document Type
Dissertation
Rights
Henderson, Judith Lynn
Type
texts
Source
University of Southern California
(contributing entity),
University of Southern California Dissertations and Theses
(collection)
Access Conditions
The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the au...
Repository Name
University of Southern California Digital Library
Repository Location
USC Digital Library, University of Southern California, University Park Campus, Los Angeles, California 90089, USA
Tags
psychology, experimental