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Mapping multi-scale connectivity of the mouse posterior parietal cortex
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Mapping multi-scale connectivity of the mouse posterior parietal cortex
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Content
MAPPING MULTI-SCALE CONNECTIVITY
OF THE MOUSE
POSTERIOR PARIETAL CORTEX
by
Monica Ying Song
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(NEUROSCIENCE)
December 2023
Copyright 2023 Monica Ying Song
ii
Acknowledgements
First and foremost, I would like to express my deepest thanks to Dr. Hongwei Dong for
his many years of mentorship, encouragement, and guidance. I would not be here without his
support or his genuine enthusiasm for the research, and I am grateful for the opportunity to have
worked in his lab. I would also like to thank my committee members: Drs. Alan Watts (as Chair),
Larry Swanson, Li Zhang, Huizhong Tao, and Michael Bonaguidi, for their guidance and
insightful advice at different stages of my studies.
Thank you to all my labmates, colleagues, and NGP friends for sharing your passion for
science, for lending your technical expertise so generously, and for all the coffee breaks and
funny random conversations that helped me remember life outside the lab. My sincere
appreciation also goes to the Neuroscience Graduate Program administrators, faculty, and staff,
whose dedication and care for students has fostered a fun and supportive community that
makes our learning possible. I would also be remiss if I did not thank my therapist Christina for
her seeing and understanding, and staying so long to teach me the art of kintsugi.
Finally, I would like to thank my family: my brother Michael and stepmother Christine for
their years of bemused support and confidence in me; my parents, who are no longer here to
see me graduate, for all the sacrifices they made to give me opportunities to excel and for
shaping who I am today; my dog Argos for enforcing time outdoors with him and his grumpy,
steadfast company during my nighttime writing sessions, even when they went long past his
preferred bedtime; and finally my partner Alex, who has been at my side every step of the way.
Words don’t adequately describe how grateful I am for your love and patience with the student
life during all our years together. I look forward to sharing the future with you.
iii
Table of Contents
Acknowledgements ..................................................................................................... ii
List of Tables ................................................................................................................. iv
List of Figures ............................................................................................................... v
List of Abbreviations .................................................................................................... vi
Abstract .................................................................................................................. xi
Chapter 1: Introduction ................................................................................... 1
1.1. Introduction to Connectomics and Its Challenges ............................. 1
1.2. Introduction to Posterior Parietal Cortex ........................................... 3
Chapter 2: Subregional Differences in PTLp whole-brain connectivity .......... 6
2.1 Introduction ......................................................................................... 6
2.2 Materials and Methods ........................................................................ 7
2.2.1 Animals, stereotaxic injections, and tracers .................................... 7
2.2.2 Histology and Imaging in 2D ........................................................... 11
2.2.3 Informatics Processing for 2D Imaging Data ................................... 12
2.3 Results ................................................................................................ 23
2.3.1 Efferent Projections from PTLp ...................................................... 23
2.3.2 Afferent Projections to PTLp ........................................................... 32
2.4 Discussion ........................................................................................... 38
References .................................................................................................... 46
iv
List of Tables
Table 2.1 | Coinjection Sites .............................................................................................. 10
Table 2.2 | Brain-wide Proportions of Labeling Values: PTLp Afferents ............................. 20
Table 2.3 | Brain-wide Proportions of Labeling Values: PTLp Efferents ............................. 21
v
List of Figures
Figure 2.1 | PTLp Co-injection Locations in Coronal Views .......................................... 11
Figure 2.2 | 2D Workflow for Image Acquisition and Analysis ....................................... 14
Figure 2.3 | Representative Coinjections for PTLp Subregional Analyses .................... 16
Figure 2.4 | Summary Map of Brain-wide Projections from PTLp Subregions ............... 17
Figure 2.5 | Summary Map of Brain-wide Inputs to PTLp Subregions .......................... 18
Figure 2.6 | Bar Graph: Strongest Outputs of PTLp Subregions .................................. 24
Figure 2.7 | PTLp Connections with Cortical Areas have Bidirectional
Medial-Lateral Gradient Topography ................................................ 27
Figure 2.8 | PTLp Connections to the LP, LD, and PO Thalamic Areas ........................ 30
Figure 2.9 | Bar Graph: Strongest Inputs to PTLp Subregions ...................................... 34
Figure 2.10 | Flatmaps of PTLp Subregion Anterograde Tracing to Brain-wide ROIs ..... 39
Figure 2.11 | Flatmaps of PTLp Subregion Retrograde Tracing to Brain-wide ROIs ....... 40
Figure 2.12 | Strongest Proportional Connections by PTLp Subregion ............................ 44
vi
List of Abbreviations
TRACERS
AAV, Adeno-associated virus
CTB, Cholera toxin subunit B
FG, Fluorogold
PHAL, Phaseolus vulgaris leucoagglutinin
RVdG, G-deleted Rabies virus
BRAIN REGIONS
ACAd, Anterior cingulate area cortex, dorsal part
ACAv, Anterior cingulate area cortex, ventral part
AD, Anterodorsal nucleus, thalamus
AId, Agranular insular area, dorsal part
AIv, Agranular insular area, ventral part
AIp, Agranular insular area, posterior part
AMd, Anteromedial nucleus, dorsal part, thalamus
AMv, Anteromedial nucleus, ventral part, thalamus
APN, Anterior pretectal nucleus
AUDd, Auditory cortex, dorsal part
AUDp, Primary auditory cortex
AUDv, Auditory cortex, ventral part
AV, Anteroventral nucleus, thalamus
BLA, Basolateral amygdalar nucleus
BLAa, Basolateral amygdalar nucleus, anterior part
BLAp, Basolateral amygdalar nucleus, posterior part
BMA, Basomedial amygdalar nucleus
BMAa, Basomedial amygdalar nucleus, anterior part
BMAp, Basomedial amygdalar nucleus, posterior part
CA1, Field CA1, hippocampal formation
vii
CA3, Field CA3, hippocampal formation
CLA, Claustrum
CLI, Central linear nucleus raphe
CM, Centromedial nucleus, thalamus
CP, Caudate putamen
CPc.d, Caudate putamen, caudal, dorsal domain
CPi.dm.dm, intermediate Caudate putamen, dorsomedial community, dorsomedial
domain
CPi.dm.dl, intermediate Caudate putamen, dorsomedial community, dorsolateral
domain
CPi.dm.d, intermediate Caudate putamen, dorsomedial community, dorsal domain
CPr.imd, rostral Caudate putamen, intermediate dorsal domain
DG, Dentate gyrus
ECT, Ectorhinal cortex
ENT, Entorhinal cortex
ENTl, Entorhinal cortex, lateral part
ENTmv, Entorhinal cortex, medial ventral part
EPd, Endopiriform nucleus, dorsal part
GPe, Globus pallidus, external part
GU, Gustatory cortex
Hb, Habenula nucleus, thalamus
IAM, Interanteromedial nucleus, thalamus
ICc, Inferior colliculus, central nucleus
ILA, Infralimbic area cortex
IPL, Interpeduncular nucleus, lateral part
IRN, Intermediate reticular nucleus
LA, Lateral amygdalar area
LD, Laterodorsal nucleus, thalamus
LG, Lateral geniculate nucleus, thalamus
LGd, Lateral geniculate nucleus, thalamus, dorsal part
LGv, Lateral geniculate nucleus, thalamus, ventral part
viii
LHA, Lateral hypothalamic area
LP, Lateroposterior nucleus, thalamus
MARN, Magnocellular reticular nucleus
MD, Mediodorsal nucleus, thalamus
MDc, Mediodorsal nucleus of the thalamus, central part
MDl, Mediodorsal nucleus of the thalamus, lateral part
MDm, Mediodorsal nucleus of the thalamus, medial part
MM, Medial mammillary nucleus
MOp, Primary motor cortex
MOs, Secondary motor cortex
MOs-fef, Secondary motor cortex, frontal eye field
MRN, Midbrain reticular nucleus
mPFC, Medial prefrontal cortex
MPT, Midbrain pretectal region
NDB, Diagonal band nucleus
NOT, Nucleus of the optic tract
NPC, Nucleus of the posterior commissure
NTB, Nucleus of the trapezoid body
OP, Olivary pretectal nucleus
ORBl, Orbitofrontal area cortex, lateral part
ORBm, Orbitofrontal area cortex, medial part
ORBvl, Orbitofrontal area cortex, ventrolateral part
PAG, Periaquaductal gray nucleus
PAG.dl, Periaquaductal gray nucleus, dorsolateral column
PAG.l, Periaquaductal gray nucleus, lateral column
PAG.vl, Periaquaductal gray nucleus, ventrolateral column
PAR, Parasubiculum
PARN, Parvicellular reticular nucleus
PBG, Parabigeminal nucleus
PCG, Pontine central gray
ix
PERI, Perirhinal area cortex
PF, Parafascicular nucleus
PG, Pontine gray
PH, Posterior hypothalamic nucleus
PIR, Piriform area
PL, Prelimbic area cortex
PP, Peripenduncular nucleus
PPC, Posterior parietal cortex (primates)
PPN, Pedunculopontine nucleus
PPT, Posterior pretectal nucleus
PO, Posterior complex, thalamus
POR, Superior olivary complex, periolivary region
POST, Postsubiculum
PRE, Presubiculum
PRNc, Pontine reticular nucleus, caudal part
PRNr, Pontine reticular nucleus, rostral part
PTLp, Posterior parietal cortex
PTLp-rl, Posterior parietal cortex, rostrolateral part
PTLp-rm, Posterior parietal cortex, rostromedial part
PTLp-mid, Posterior parietal cortex, middle part
PTLp-mid-m, Posterior parietal cortex, middle-medial part
PTLp-mid-l, Posterior parietal cortex, middle-lateral part
PTLp-cl, Posterior parietal cortex, caudolateral part
PTLp-cl, Posterior parietal cortex, caudomedial part
PtP, Posterior parietal cortex, posterior tail part
RE, Reuniens nucleus, thalamus
RSP, Retrosplenial area
RSPagl, Retrosplenial area, agranular part
RSPd, Retrosplenial are, dorsal part
RSPv, Retrosplenial area, ventral part
x
RT, Reticular nucleus, thalamus
SC, Superior colliculus
SCm, Superior colliculus, motor-related (intermediate & deep layers)
SCig-a, Superior colliculus, intermediate grey, a layer
SCig-b, Superior colliculus, intermediate grey, b layer
SCig-c, Superior colliculus, intermediate grey, c layer
SI, Substantia innominate
SGN, Suprageniculate nucleus
SNc, Substantia nigra pars compacta
SNr, Substantia nigra pars reticulata
SPFp, Subparafascicular nucleus, parvicellular part
SSp, Primary somatosensory cortex
SSp-bfd, Somatosensory cortex primary, barrel field
SSp-ll, Somatosensory cortex primary, lower limb
SSp-m, Somatosensory cortex primary, mouth
SSp-n, Somatosensory cortex primary, nose
SSp-tr, Somatosensory cortex primary, trunk
SSp-ul, Somatosensory cortex primary, upper limb
SSp-un, Somatosensory cortex primary, undefined
SSs, Somatosensory cortex, supplementary
STN, Subthalamic nucleus
SUB, Subiculum
SUBd, Subiculum dorsal
SUBv, Subiculum ventral
ProSUB, Prosubiculum
TEa, Temporal association area
TRN, Tegmental reticular nucleus
TTd, Taenia tectum, dorsal part
VAL, Ventral anterior-lateral nucleus, thalamus
VISC, Visceral cortex
xi
VIS, Visual cortex
VISal, Visual cortex, anterolateral part
VISam, Visual cortex, anteromedial part
VISl, Visual cortex, lateral part
VISp, Primary visual cortex
VISpl, Visual cortex, posterolateral part
VISpm, Visual cortex, posteromedial part
VM, Ventromedial nucleus of the thalamus
vmPFC, Ventromedial prefrontal cortex
VPL, Ventral posterolateral nucleus, thalamus
VPM, Ventral posteromedial nucleus, thalamus
VPLpc, Ventral posterolateral nucleus, thalamus, parvicellular part
VTA, Ventral tegmental area
ZI, Zona incerta
ZI.r, Zona incerta, rostral part
ZI.d, Zona incerta, dorsal sheet
ZI.v, Zona incerta, ventral sheet
ZI.c, Zona incerta, caudal part
xii
Abstract
Integrating multimodal sensory cues and internal physiological cues to form a cohesive
embodied "whole" is an essential part of understanding and navigating the environment for any
animal. Yet, to date it remains unclear how the brain processes a constant flux of sensory
inputs, motor feedback, and internal states to subsequently produce and orchestrate
appropriate behavioral and physiological responses.
The Mouse Connectome Project's research goal is to assemble a comprehensive wiring map (a
connectome) of the mouse brain. Similarities in neurobiology, anatomical organization, and
ubiquity in behavioral responses suggest that any general principles of organization found in
mammalian brain models will hold relevance for understanding the human neurological
condition in health and in disease. By systematically mapping all the mouse brain’s connections,
the MCP hopes to identify the guiding principles of organization in such a complex and ordered
system. A complete connectome map does not exist yet for the mouse, in large part because
previous mapping tools could not investigate the brain at the vast differences in scale at which
individual neurons, circuits, and behavioral networks concurrently operate. Recent leaps in
progress in neuroanatomical and informatics tools allow the MCP to use these tools in varying
combinations to investigate neuronal connections at greater resolution and simultaneously over
a larger brain area than ever before.
Across organisms, certain regions in the brain have been repeatedly identified as key
anatomical/network hubs for integration of multimodal sensory data. The neuroanatomical
mapping studies presented in this thesis focus on one such brain region, the posterior parietal
cortex (PTLp), which directly contributes to the MCP’s efforts.
xiii
Chapter 1 describes the structure-function frameworks underlying current understandings of
brain architecture and organization of neural circuits. This background facilitates an
understanding of concepts and key terminology described in the remainder of the manuscript
and discusses the importance of anatomical & network structure as it begets and informs neural
function. I further elaborate on how the field of connectomics addresses certain issues that arise
during the pursuit of comprehensive mapping of the brain’s connectivity, such as how to define
an all-inclusive strategy for classifying neuron cell types, how to best adapt new tracing and
genetic tools that conceptually allow for higher resolution in probing neural circuitry, and how
these brand-new informatics and molecular tools present their own challenges at every stage of
data collection, storage, and analysis.
Chapter 2 focuses on the mesoscale (subregional) organization of the mouse posterior parietal
cortex (PTLp). We constructed a comprehensive map of PTLp’s anterograde and retrograde
projections and identified three new gradient parietal subregions: the rostromedial (PTLp-rm),
middle (PTLp-mid), and caudolateral (PTLp-cl). We delineated each subnetwork’s brainwide
inputs and outputs to reveal their subnetwork organization, showing that while network
connections are similar among subregions, each subregion has a differential weighting of their
specific inputs and outputs. Overall, our results provide a structural framework for understanding
how the PTLp integrates different sensory modalities into a coordinated spatial map for directing
downstream goal-directed behavior.
Chapter 1
Introduction
1.1 Introduction to Connectomics and its Challenges
Creating comprehensive maps of an organism’s neuronal connections is the goal of the
field of connectomics. The human cerebral cortex is thought to have one to two hundred billion
neurons (10
11
) linked by at least several hundred trillion synaptic connections (10
14
) that
communicate in complex networks to generate the vast range of sensory integration and motor
behaviors that comprise the human experience
1,2
. Knowing how these networks are
anatomically connected is fundamental to understanding how the functional patterns of the brain
are generated, yet a comprehensive structural model of vertebrate neuronal connectivity does
not exist and is proving difficult to construct.
This task is made difficult firstly by the extraordinary diversity of neurons, which are all
slightly unique in morphology and function, and whose arrangement is so variable from one
region to another that no single area of the brain can reliably serve as a wiring guide for
anything but itself
3,4
. A second challenge facing connectomics is a technical need for imaging at
small and large distance scales simultaneously: a neuron’s soma is not very large, but its
dendrites often spread through a wide volume, while its axonal branches may extend enormous
distances to span the brain’s hemispheres or reach the body itself (cm to m). Yet a cell
distributes its synapses all along its axons and dendrites, forming fine nanoscale structures
(tens of nm). Imaging a single neuron and its direct connectivity partners thus requires a method
capable of sampling very large volumes of tissue at very high resolution. As there is a general
tradeoff between resolution and volume in light microscopy, researchers have been limited (until
very recently) to studying connectivity at a single level of analysis at a time. Neuronal
connections can be considered at three different levels: the macro-, meso-, and microscale. The
2
macroscale connectome focuses on long-range connections between different gray-matter
regions, while microscale connectomes focus on the nanoscopic connections between
individual cells. The mesoscale focuses on connections between different cell types (both within
and between gray-matter regions), and thus maps both local and long-range connections
5
.
It has also been a major goal of neuroscience to experimentally target and manipulate
specific cell types in a neural circuit or network. If individual network components can be
identified and probed, then establishing their roles in a given task or behavior becomes
possible. The development of new transgenic viral tract-tracing techniques provide a powerful
means to selectively identify neural pathways
6-9
. Neurotropic viruses such as rabies (RV) or
adeno-associated virus (AAV) are exploited to infect neurons through axon terminals, before
replicating new virions which then spread transneuronally through synaptic contacts. Viruses
are both labeled and restricted in their infection via genetic engineering: for instance, the rabies
virus EnvA-RV-ΔG-mCherry has transsynaptic transport that requires excised genes to be
reintroduced using complementary helper viruses for expression. This type of multi-virus
approach allows for the anatomical dissection of monosynaptic connections from genetically
defined neuronal subpopulations.
Managing the ever-increasing complexity of connectivity data sets (among other things)
is the aim of neuroinformatics, an interdisciplinary field for the collection, organization, analysis,
and sharing of neuroscience data. Neuroinformatics is usually used to facilitate one of three
avenues of approach
4,7
: (1) the development of tools and databases for data sharing and
management, (2) development of tools for data analysis and modeling, and (3) the development
of computational models of neural system function(s). Therefore, progression towards
connectomics objectives requires a solid understanding of neurons at different levels of scale,
an up-to-date grasp of currently available genetic- and molecular- tools for circuit manipulation,
and a plan for efficient, well-managed database organization and shared standards for data
3
collection. As all three fields are still rapidly evolving, there is no consensus on best or standard
practices for achieving a comprehensive connectome.
1.2 Introduction to Posterior Parietal Cortex
Animals need to process a wide range of sensory cues and internal states to
successfully navigate, orient, and interact with their environment. The posterior parietal cortex
(PTLp) is a major association area in the cortex, implicated by cross-species research to play a
key role in a variety of higher-order spatially related functions including navigation
11,12
, motor
planning
13
, visuospatial attention
14,15
, working memory
16
, decision making
17-19
, and even abstract
spatial reasoning like numerical calculations
16,19-21
. PTLp is also a site of massive multimodal
integration, known to receive inputs from the visual, auditory, and somatosensory cortices –
three senses that localize the body and external objects in space – and additionally connects
densely to cortical regions involved in cognition and goal-directed behavior
22-24
. Together, this
evidence suggests PTLp mediates sensorimotor transformations between egocentric and
allocentric spatial coordinates for behavior
25,26
.
Most of what is known about PTLp’s connectivity was studied using classic
neuroanatomical tracing or microelectrode recordings in non-human primates, which show that
posterior parietal cortex in primate species (PPC in primate nomenclature) is “functionally
specific,” meaning divisible into anatomical regions representing separate functions (e.g.,
reaching, grasping) with distinct, correlated patterns of body region-specific connectivity.
Anatomical
22,24,27-29
and physiological
16,20,22, 30-41
studies in the rodent PTLp suggest it performs
an analogous role in spatial processing compared to primate PPC, and its relative anatomical
location is similarly at the intersection of multiple sensory cortices (Figure 1.1) for which it acts
as a network hub. PTLp neurons are likewise responsive to multimodal stimulation
28,29
and
weigh inputs from different modalities flexibly, depending on task and context
15,19,30-32
.
4
Responses to damage or inactivation of PTLp in rodents, primates, and humans produces
comparable symptoms, such as multimodal hemispatial neglect and navigation deficits
21,33-39
.
Based on these similarities in structure and function, rodent PTLp can reasonably be
hypothesized to be organized into subdomains with distinctive connectivity and behavioral
involvement like the primate PPC
24,40-44
.
Connectivity in the rodent PTLp has yet to be studied comprehensively at high
resolution. Investigations of the long-range connectivity and organization of rodent PTLp have
largely been conducted in rats
22,24,25,28,45,47
, with far fewer in the mouse
29,48,49
. Many previous
studies of PTLp also did not consider possible differences in intra-PTLp connectivity and
cytoarchitecture, likely because its smaller size in rodents made its discrete targeting with tract
tracers difficult. Available rat studies have observed changes in connectivity densities across a
mediolateral gradient
45,46
; but limited their exploration to only a subset of PTLp connections
(e.g., corticocortical, thalamocortical) and used non-quantitative methods with limited spatial
resolution. The few recent investigations of subregional connectivity or anatomical subdivisions
in mouse PTLp
29,48,49
were similarly limited to a subset of PTLp connections or by large
injections that label more than the intended subregion. Mouse cortical connectome studies
50-52
did not search for potential intra-region variations within PTLp. Taken together, the extent to
which the mouse PTLp is divisible into subregions with functionally distinct roles and
connectivity is still uncertain. Yet understanding the organization of the mouse PTLp is
particularly important as the plethora of molecular tools and genetic manipulation available in
the mouse makes it an attractive model system for understanding organizing principles of
multimodal integration.
It is also probable that PTLp organization in the mouse does not occur at the subdomain
level, but at the level of cell-types and individual neurons. Neurons can be classified as different
cell-types based on multiple characteristics, including connectivity, genetic identity,
electrophysiological properties, anatomical location, and morphology. These properties have
5
been shown to often correlate with a neuron’s long-range projection targets and roles in distinct
behavioral networks
53-56
, so there is extensive interest in categorizing the properties of PTLp
neurons and evaluating how distinct neuron types might differentially contribute to PTLp’s
engagement in various functional roles. A few functional cell-types have been found in PTLp
thus far: head direction cells
56-59
, egocentric cells
60-63
, and mirror neurons
64
. However,
electrophysiological evidence consistently shows that neurons in PTLp have highly plastic,
multimodal response properties that can be modulated in a task- and context-dependent
manner
16,20,65
. Other rodent studies have shown that different classes of functionally-defined
PTLp neurons appear heterogeneously intermixed at the single cell level
16,20,33,66
. Evaluating
the contribution of distinct cell types to PTLp’s multiplicity of behavioral roles cannot, therefore,
rely on identifying cell populations solely by physiological profile. Mapping PTLp neuronal cell
types and their connections is necessary for understanding the overall organization of the PTLp
and its role in integrating cognitive and sensorimotor inputs to produce goal-defined spatially
related behaviors.
In this thesis work, we attempt to characterize the structural connectome of PTLp and
projection neuron-types using the latest neural tracers, microscopes, and informatics tools in
combination to systematically quantify and map connectivity of the mouse PTLp at large scale
and high resolution. Although incomplete, we hope this comprehensive and quantitative analysis
of detailed connectivity of the PTLp will provide a framework for future exploration of PTLp cell-
type network functions and understanding of the organizational principles underlying multimodal
integration.
6
CHAPTER 2
SUBREGIONAL DIFFERENCES IN PTLP WHOLE-BRAIN
CONNECTIVITY
2.1 INTRODUCTION
Most of what is known about PTLp’s connectivity was studied using classic
neuroanatomical tracing or microelectrode recordings in non-human primates, which show that
posterior parietal cortex in primate species (referred to as primate PPC) is “functionally specific,”
meaning divisible into anatomical regions representing separate functions (e.g., reaching,
grasping) with distinct, correlated patterns of body region-specific connectivity. Connectivity in
the rodent PTLp, especially the mouse, has not yet been studied at such high resolution, likely
because its smaller absolute and relative size have made it difficult to accurately target in
tracing studies. So far, anatomical
22,24,27-29
and physiological
16,20,22, 30-41
studies in the rodent
PTLp support the notion it plays an analogous role in spatial processing and higher cognitive
functions when compared to primate PPC
67
.
However, most previous studies of rodent PTLp
long-range connectivity have been conducted in rats and did not consider possible variations in
rostrocaudal and/or mediolateral connectivity and cytoarchitecture. Recent investigations in the
rat have observed changes in connectivity densities across a mediolateral gradient
45,46
; but
these studies limited their exploration to certain subsets of PTLp connections (e.g.,
corticocortical, thalamocortical) and used non-quantitative methods with limited spatial
resolution. In the mouse, there are a few new investigations of subregional connectivity or
anatomical subdivisions in mouse PTLp
29,48,49
, but are similarly limited to some subsets of PTLp
projections or by using large injections that label more than the intended subregion.
7
Some recent mouse studies also view PTLp as a collection of visual areas rather than a
region with equivalent role to the primate posterior parietal cortex (PPC), based on earlier
functional mapping experiments of extrastriate areas
50
. Their a priori assumptions about PTLp
subregion boundaries further complicate the comparison of PTLp and investigation into putative
subregions across studies. Connectomics studies of the mouse cortex
50-53
have explored overall
PTLp connectivity but did not describe domain-specific or cell-type specific variations in PTLp
connectivity. To this day mouse PTLp is not coherently anatomically defined, nor is its
connectivity, which makes the wealth of new functional data difficult to interpret. The extent to
which the mouse PTLp is divisible into subregions with functionally distinct roles and
connectivity also remains unknown. We therefore set out to construct a comprehensive map of
PTLp inputs and outputs using discrete injections of different classic neural tracers to see if
differences between PTLp subdomains could be identified.
2.2 MATERIALS AND METHODS
2.2.1 Animals, Stereotaxic Injections, and Tracers
Animals
Data from 8-11-week old male C57/BL6 mice with body weight of 24 -31g (n=14;
Jackson Laboratories) were used in this study. Mice were group housed in a light- (12 hr light:
12 hr dark cycle), temperature- (21-22°C), and humidity-controlled (51%) room within the Zilkha
Neurogenetic Institute vivarium with ad libitum access to food and water. Mice were allowed at
least one week to acclimate to vivarium conditions before undergoing stereotaxic surgery for
delivering tracers. Animal care and experimental procedures were performed in accordance with
8
the guidelines set by the Institutional Animal Care and Use Committee at the University of
Southern California.
Stereotaxic surgery & tracer delivery
Stereotaxic injection of tracers to anatomically delineated brain regions were carried out
as previously described in Zingg et al. (2014)
52
and Hintiryan et al. (2021)
68
. Mice were initially
anesthetized in a small induction chamber containing a mix of oxygen and 5% isoflurane
(Hospira, Inc.), then transferred and mounted to a stereotaxic apparatus equipped with heating
pad. An anesthetic state was maintained throughout the surgery with a nosecone delivering
oxygen gas (1 L/min) mixed with vaporized isoflurane (Datex-Ohmeda) maintained at 1.75-2.0
percent of the gas mixture. Buprenorphine SR (1 mg/kg BW) was subcutaneously injected at the
beginning of the surgery to minimize pain and inflammation. The scalp was shaved and
disinfected with betadine and 70% ethanol and once dried, a small incision was made along the
midline to expose bregma and lambda on the skull dorsal surface. After leveling the skull in all
planes (M-L, D-V, A-P) using the stereotaxic apparatus, injection coordinates referencing the
2008 Allen Mouse Reference Atlas
70
were used to determine the precise locations on the skull
directly above the two target regions, where small holes were drilled. All injections were placed
in the right hemisphere of the brain.
Pulled glass micropipettes whose outside tip diameters measured 20-32 µm outer
diameter tip filled with tracer were lowered into the target regions and then tracer was delivered
via iontophoresis (+5µA, 7s alternating current pulses, 3-10 min infusion time; Stoelting Co.).
Injection parameters were based on preliminary experiments to reliably produce small, localized
tracer delivery sites. Following each injection, the micropipette was left in place for 3 minutes
before being withdrawn to minimize potential tracer leakage along the pipette tract. After
9
injections were completed, incisions were sutured closed. The animal was then moved to an
isolated heatpad to recover from anesthesia before being returned to their home cage.
Tracing Strategies
Anterograde tracers included Phaseolus vulgaris leucoagglutinin (PHAL; 2.5%; Vector
Laboratories) and adeno-associated viruses encoding tdTomato (AAV-RFP;
(AAV1.CAG.tdTomato.WPRE.SV40; Penn Vector Core; 4×10¹² vg/mL). Retrograde tracers used
were FluoroGold (FG, 1%, Fluorochrome) and cholera toxin subunit B–Alexa Fluor conjugate
647 (CTb; AlexaFluor conjugates, 0.2%; Invitrogen). Animals received two coinjections, where
each injection site was injected separately with an anterograde and a retrograde tracer into the
same stereotaxic coordinates (e.g., PHAL with CTb 647, or FG with AAV-RFP). To determine if
there were differences in connectivity profiles between subdivisions of PTLp, discrete
coinjections were made to systematically target small areas of PTLp across all cortical layers
without tracer spread into adjacent areas. Based on pilot studies to determine the smallest
consistently achievable injection site size, PTLp was preliminarily divided into 6 target “zones” of
roughly equal size: the rostral-medial (PTLp-rm), rostro-lateral (PTLp-rl), mid-medial (PTLp-
mm), middle-lateral (PTLp-ml), caudal-medial (PTLp-cm), and caudal-lateral (PTLp-cl) zones
(for complete list of coinjection sites, see Table 2.1). Zones were targeted a minimum of two
times each and injections used the same stereotaxic locations to reproduce and validate
individual labeling patterns, for a total of 14 coinjection cases that together covered the entire
extent of the PTLp structure without leakage to neighboring areas (see Figure 2.1).
No statistical methods were used to pre-determine sample sizes, but our sample sizes
are similar to those reported in previous publications
52,69
. In most cases, anterograde tracing
10
results were cross validated by retrograde labeling injections at the anterograde fiber terminal
fields and vice versa. Coinjections made into identical locations within PTLp in different mice
resulted in identical brain-wide projection patterns. Coinjections were further replicated across
different mice using different tracer combinations (PHAL/CTb or AAV-RFP/FG) to provide
controls against any inherent differences in neuron uptake and axonal transport of different
anterograde tracers.
Table 2.1 | Coinjection Sites.
Table of coinjection site coordinates and tracer info for all cases used in this study. Cases are identified by case
number, injection site (PTLp subregion), tracer, tracer type, injection site ARA level, and injection site coordinates
based on the ARA Coordinate Frame (2008). (n=14 mice with 38 total pathways)
11
2.2.2 Histology and Imaging
Tissue processing was done in accordance with standard MCP guidelines (describe in
Ch1?). Either one (PHAL, CTb, FG) or three (AAVs) weeks was allowed for tracer transport
post-surgery, after which animals were perfused and their brains were extracted. Animals were
anesthetized with an overdose injection of sodium pentobarbital (Euthasol, 5cc, ip) then
transcardially perfused with 0.9% saline solution followed by chilled 4% paraformaldehyde
(PFA, pH 9.5). Brains were extracted and postfixed in 4% PFA for 24-48 hours at 4° C. In
Figure 2.1 | PTLp Coinjection Locations in Coronal View
Center locations of PTLp coinjection sites were imaged and organized by atlas level and medial-lateral location
within the PTLp to confirm that the entire area was systematically targeted (n=14 subjects, total of 19 coinjections).
Only representative injections for each discrete target location were shown here. Coinjections are identified by
case number (white), tracers (colored), and injection site atlas level (black; ARA).
______________________________________________________________________________
12
preparation for sectioning, brains were embedded in 4.5% covalent agarose Type I-B agarose
(Sigma-Aldrich).
All brains were sectioned coronally at 50-µm thickness using a vibratome (VF-700 or VF-
300 model, Precisionary Instruments, Greenville, NC). For coinjection experiments, a 1-in-4
series of sections across the entire brain was prepared for immunofluorescence staining. Brain
sections were stained using the free-floating method at room temperature. Briefly, sections were
transferred to a blocking solution containing normal donkey serum (Vector Laboratories) and
Triton X-100 (VWR) for 1 h. Following three 5-minute rinses, sections were incubated in a KPBS
solution comprised of donkey serum, Triton, and the appropriate antibody [1:1000 rabbit anti-
PHAL antibody (Vector Laboratories, #AS-2300)] for 48–72 h at 4 °C. Sections were rinsed 3
times in KPBS and then soaked for 3 h in the secondary antibody solution, which contained
donkey serum, Triton, and a 1:500 concentration of anti-rabbit IgG conjugated with Alexa Fluor®
488 or 647 (Invitrogen, 488: #A-21206; 647: #A-31573) for PHAL staining. Sections were then
incubated in a KPBS solution containing Triton X-100 (VWR) for 10 minutes, followed by 3
KPBS rinses and then counterstaining with a fluorescent Nissl stain, NeuroTrace® 435/455 (NT;
1:500; Invitrogen, #N21479) for 3 hours. The sections were serially mounted and coverslipped
using 65% glycerol. Complete tissue sections were scanned at 10x magnification as high-
resolution virtual slide image (VSI) files using an Olympus VS120 slide scanning microscope,
with similar exposure parameters for each tracer across all cases.
2.2.3 INFORMATICS PROCESSING FOR 2D IMAGING DATA
Connection Lens Informatics Workflow
The lab’s in-house informatics software, Connection Lens, was developed to reliably
warp 2D images to match their corresponding ARA atlas template level
69
, allowing for inter-
subject normalization of imaging data, and offers a host of informatics tools and workflows for
13
subsequent annotation and reconstruction of labeled pathways in standardized images (Fig
2.2). All PTLp coinjection data was processed through Connection Lens to analyze and
compare brain-wide connectivity patterns.
Sections from each analyzed case were first manually assigned and registered to the
corresponding Allen Reference Atlas levels
70
. Notably, cutting angles variations during
sectioning can introduce the problem of atlas level mismatch within a single tissue section and
consequently, increase warping difficulty and annotation inaccuracy. This problem is not
currently addressable using Connection Lens, so we chose to exclude cases with a moderate or
severe cutting angle (for example, sections showing a 2-or-more ARA level discrepancy along
either the D-V or M-L axis) from quantitative analysis of whole brain labeling. In cases with small
cutting angle differences (up to 1 ARA level of difference along the D-V or M-L axis), however,
matching the brain regions containing labeling was prioritized during atlas level assignment so
that atlas levels best fitting the location of the labeling were chosen. Subsequent annotation
would then accurately reflect the anatomic location of any labeled cells or fibers.
After standardizing case data via image warping, threshold parameters for tracer
labeling were manually adjusted for each case and section to maximize labeling visibility and
reduce background to generate binarized threshold images for automatic annotation. Adobe
Photoshop was used to remove any remaining obvious artifacts in threshold output files.
Oversaturated areas at or surrounding injection sites were considered potentially false dense
label and were also filtered out at the thresholding stage for all PTLp coinjection cases. We
excluded intra-parietal connections from our quantitative analyses for this study due to difficulty
in assessing whether positive pixels near an injection site were true labeling or high background
levels. The binary thresholded images from each representative case were then run through
overlap processing to automatically generate spreadsheet files with annotated values for each
tracer and section across the whole brain– either ROI pixel density for anterograde tracers or
ROI cell counts for retrograde tracers.
14
Figure 2.2 | 2D Workflow for Image Acquisition and Analysis
A) Connection Lens software image warping to the best-fit corresponding atlas level for standardization of brain
shape and area among cases. B) Fully-warped images are automatically thresholded for maximum isolated tracer
signal before remaining artifacts and background are manually removed to create binarized label reconstructions
(shown pseudocolored green). C) Reconstructions from different cases registered and processed to the same atlas
level can be automatically overlaid to directly compare different labeling patterns.
______________________________________________________________________________
15
Defining and Differentiating PTLp Subregional Projections
Initial observations noted that PTLp’s connections appeared to shift along a gradient in
multiple brain areas corresponding to changes in co-injection location along the medial-lateral
plane of PTLp, and possibly corresponding to location change in the anterior-posterior plane of
PTLp as well. To verify that gradient differences in labeling were not potentially confounded by
inter-subject variability in tissue size and shape, the first part of the 2D methods workflow was
applied to the projection data from 14 discrete PTLp co-injections (see Table 1). Sections taken
across the rostrocaudal extent of the entire cortex (ARA levels 24 –102) from each case were
registered and warped to the atlas. Standardized post-warp images were then manually overlaid
on atlas templates for quick confirmation of the existence of labeling differences.
To identify the maximum differences between PTLp subregion connectivity patterns, we
chose three representative cases: the rostromedial (PTLp-rm; case SW180717-03B), middle
(PTLp-mid; case SW110906-03B), and caudolateral (PTLp-cl; case SW171108-03A) areas of
PTLp. These cases had discrete, localized injection sites with the least overlap and together
spanned the longest spatial axis across PTLp (Figure 2.3), allowing for the greatest segregation
of labeling to be exhibited (Figure 2.1).
Select tissue sections from each representative coinjection case were re-processed
using the Connection Lens software to fit them onto a standard set of 11 corresponding ARA
levels ranging from 32 to 92. Standardized images received automated thresholding for
maximum signal intensity and remaining imaging artifacts and noise were manually removed
with Photoshop. Completed threshold images were then pseudo-colored and overlaid onto atlas
template images to show whole-brain labeling patterns. The standard set from each case were
manually aggregated atop the same ARA template images for a directly mapped visualization of
PTLp subregional connectivity differences (see Figures 2.4 and 2.5).
16
Figure 2.3 | Representative Coinjections for PTLp Subregional Analyses
The coinjection sites for the 3 representative cases used for subregional analyses, in coronal view. Top right panel
shows the PTLp-rm coinjection (SW180717-03B, PHAL/CTb-647), middle right panel shows the PTLp-mid
coinjection (SW110906-03B, PHAL/CTb-647), and bottom right panel shows the coinjection for PTLp-cl
(SW171108-03A, AAV-tdTomato/FG). The ARA level for the center of each coinjection is shown in the respective
left panels.
_________________________________________________________________________________________
17
Figure 2.4 | Summary Map of Brain-wide Projections from PTLp Subregions
Overlapped axonal labeling reconstructions from 3 representative cases are shown on the same 11 standard atlas
level templates spanning the entire cortex. Projections from PTLp-rm are red, PTLp-mid are green, and PTLp-cl are
purple.
______________________________________________________________________________
18
Figure 2.5 | Summary Map of Brain-wide Inputs to PTLp Subregions
Overlapped retrograde-cell labeling reconstructions from 3 representative cases are shown on the same 11
standard atlas level templates spanning the entire cortex. Projections from PTLp-rm are red, PTLp-mid are green,
and PTLp-cl are purple.
_____________________________________________________________________________
19
When considering overall patterns of PTLp connectivity, all three cases were overlapped
and viewed simultaneously; otherwise, each case was analyzed individually to represent its
specific division along both the medial-lateral and anterior-posterior axes of the PTLp. The
aggregate overlap spreadsheets mentioned previously sum up the total ROI labeling for all grey
matter regions across the entire brain of each representative case. These aggregated ROI
annotation values from each tracer pathway were normalized by conversion into proportions of
total tracer labeling across the brain, such that cases with different injection volumes or uptake
of tracer could be compared. Normalized anterograde or retrograde ROI labeling proportions
from each brain were then pooled together and used to generate ROI ranking values according
to maximum amounts of total labeling per brain, total ROI labeling across all 3 brains, and
maximum range of values in an individual ROI across three brains. An ROI was removed from
ranking consideration if there were not a minimum of two non-zero labeling values across
cases. PTLp itself was also removed from ranking consideration to avoid any accidental
inclusion of injection site oversaturation in tracer quantification. A spreadsheet of ROIs ranked
from greatest to least by proportion of labeling was produced for both summed anterograde and
retrograde pathways. While contralateral projections were included in labeling quantification,
they are not directly discussed in the following text, as ipsilateral connections make up the vast
majority of total projections.
Color-Coding and Ranked-Data Visualizations
The same color scheme for PTLp subregions was used for consistency of reference in
figures unless otherwise noted: PTLp-rostromedial (red), PTLp-middle (green), PTLp-
caudolateral (purple). Coinjection tracer data in the coronal-view mapping of brain-wide
connections with the PTLp (Figures 2.4 and 2.5) follows this color scheme, as do the stacked
bar graphs for comparing proportions of labeling in each ROI (y-axis) connected to each PTLp
20
subregion (x-axis). The stacked bar graphs solely display the approximately 35 ROIs with the
greatest proportions of brain-wide labeling for inter-case (subregional) comparison of either
efferents from (Figure 2.6), or afferents to, PTLp domains (Figure 2.09). Graphed values
represent normalized proportions of labeled pixel density or cell count for individual grey matter
ROIs across all scanned tissue sections in the brain. For this dataset, bar graphs offer an
overview representation of how PTLp subregion projections differentially target or receive long-
range input from other brain regions and how they compare across cortical subnetwork groups.
For complete listing of values for ROI- and case-specific proportions of labeling used to
generate the bar graphs, see Tables 2.2 and 2.3.
The normalized connectivity values were also used to generate annotated heatmap
visualizations of PTLp subregion connection strengths on a template mouse brain flatmap
71
, to
provide spatially localized representations of each subregion’s most significant anterograde and
retrograde connections and facilitate comparative analysis. ROIs were each assigned a value
on a scale of 1-7 based on where they fell in the total range of entered labeling data that was
divided into 7 equal bins. Each scale value corresponded to a color in a predetermined color key
that was programmatically mapped onto a template flatmap of the mouse brain using a lab
collaborator’s Python visualization tool
72
, creating an annotated heatmap representation of ROI
connection strength per PTLp subregion.
21
Table 2.2 | Brain-wide Proportions of Labeling Values: PTLp Afferents.
Table of labeling values for top ranked ROIs sending afferents to PTLp, grouped by CNS division and putative
subnetwork participation. Values represent the proportion of total cell count for the selected (grouped) ROI
distributed across the entire brain.
______________________________________________________________________________
22
Table 2.3 | Brain-wide Proportions of Labeling Values: PTLp Efferents.
Table of labeling values for top ranked ROIs receiving efferents from PTLp, grouped by CNS division and
putative subnetwork participation. Values represent the proportion of total pixel density for the selected
(grouped) ROI distributed across the entire brain.
______________________________________________________________________________
23
2.3 RESULTS
2.3.1 Efferent Projections from PTLp
Cortex
PTLP sends its projections most prominently to other cortical areas within the medial
cortical sub-network
52
: the retrosplenial (RSP), motor cortex (MO), anterior cingulate (ACA),
orbital cortex (ORB), and other higher-order associative areas, as well as the associated
sensory cortices for visual (VIS), auditory (AUD), and somatosensory (SSp) information (see
Figures 2.6, 2.7). Its strongest projections go to the RSPd, the MOp, the ACAd, and ORBvl.
Regions also receiving significant innervation are the AUDp, RSPv, PtP, VISam, VISal, SSp-tr,
MOs, SSP-ll, ACAv, ORbl, PL. The remaining named areas appear to receive light innervation
(AUDd, AUDv, TEa, VISpm, VISl, PERI, ORBm, ILA, VISp, ENTl, PAR, POST, CLA). Very
sparse or no projections were detected in the other sensory cortices (gustatory, visceral, and
insular), the secondary somatosensory area (SSs), the piriform area (PIR), other olfactory areas
(MOB, AOB, AON, COA, PAA), or in the amygdalar regions (LA, BLA, BMA, EP).
Intra-PTLp projections are also prominent, showing strong connections between the
different parts of PTLp. Each of the PTLp subregions also sends strong projections to the
trailing posterior “tail” of PTLp, or PtP (abbreviated here as PtP to borrow a more specific
naming convention from Franklin & Paxinos, 2007).
Figure 2.6 | Strongest Outputs from PTLp Subregions.
Bar graph visualization of the ROIs which PTLp subregions target most strongly, ranked by proportion of labeling.
Values have been normalized to show proportion of brain-wide labeling density present in the specific ROI.
Different colors represent different cases and their injection site location within the PTLp: PTLp-rm (red), middle
PTLp (green), and PTLp-cl (purple). All values shown here include labeling from both ipsilateral and contralateral
ROI. ROIs are grouped along the x-axis according to the CNS division and associated cortical subnetwork.
24
(Figure 2.6)
25
PtP has been defined as a long narrow strip of cortex extending from roughly ARA 81-94 (B -
2.78 to -4.08) that separates the lateral parts of the visual cortex (VISal & VISl) from the dorsal
auditory cortex AUDd and the caudal-most part of TEa in the caudal end of the cortex. In the
Allen atlas
70
and the Swanson rat BM4 atlas
73
, the PtP is parcellated with the rest of the PTLp,
and not separately parcellated into PTPr and PTPd subregions as it is in the Paxinos atlas
74
.
Although we wished to include the PtP in this study as another PTLp subregion with possible
connectivity profile differences, due to its small size we were unable to target it without
contaminating neighboring brain areas with labeling.
While overall projection patterns are generally similar between the different PTLp
subregions, projection strengths to a specific region do vary. PTLp projections appear to
innervate certain cortical areas in a roughly topographic way, where a shift from medial to lateral
corresponds to similar change in PTLp injection position along the medial-lateral plane. Small
differences corresponding to injection location movement along the anterior-posterior plane
were seen but not found to be significant, possibly due to unavoidable tracer spread from
injections in the narrow 500um strip PTLp occupies in the anterior-posterior direction. This
medial-lateral topography is most visible in the cortex within the extrastriate visual areas
(VISam, VISal) and the ACA & MO (see Figure 2.7).
A “mirrored” or reflected gradient pattern can be seen in the visual cortex, particularly in
the extrastriate areas VISam and VISal (Figs. 2.7e and 2.4, ARA 79-92). Medial PTLp shows a
strong narrow projection to the medial VISam and lateral VISal, with relatively stronger
projections to the medial half of rostral VISam than to the lateral half of rostral VISal which
borders on the PtP. Proceeding posteriorly in the cortex shifts this pattern laterally, such that
medial PTLp projects to the lateral halves of caudal VISpm and VISl. Lateral PTLp meanwhile
sends a relatively stronger projection to the lateral half of VISal than to lateral VISam, and these
patterns proceed further laterally so that in caudal VISam/VISpm receive -rm inputs on the
lateral boundary with VISp, and -rm inputs to caudal VISl are both in the ventral VISl and the
26
PtP. Meanwhile, the middle of PTLp (PTLp-mid) makes projections to the VISp preferentially to
layer 1, connecting the two “mirrored” gradients (Fig 2.7e, ARA 84 in Fig 2.4). Interestingly,
PTLp efferents to primary visual cortex are proportionally much sparser and less densely
clustered than to any extrastriate areas, and these connections are strongly layer-specific in
comparison to the narrower “columns” of labeling seen in VISam, VISal, VISpm, and VISl.
Secondary motor cortex (MOs) receives relatively more innervation than primary motor
(MOp) depends on which subregion of PTLp was injected: the PTLp-cl significantly innervates
the entire extent of MOS rostrocaudally while sending only light projections to MOp, while PTLp-
rm lightly projects to only more caudal portions of MOs and MOp, with denser projections to
MOp. PTLp-mid does send significant projections to MOs across its rostrocaudal extent similar
to PTLp-cl, but innervates MOp most intensely in its mid-to-caudal portions in a manner similar
to PTLp-rm. PTLp projections to ACA are made in a similarly gradient way from ventral to dorsal
when moving in the anterior-posterior direction: the rostral portions of ACAv (barring the frontal
pole region) receive significant projections from the PTLp-rm, while the PTLp-mid and PTLp-cl
concentrate their projections in the ACAd across its entire rostrocaudal extent.
27
Figure 2.7 | PTLp connections with cortical areas have bidirectional medial-lateral gradient
topography.
(a-c) Anterograde/retrograde tracer coinjections into either the medial or lateral parts of rostral, middle, and
caudal PTLp are shown along with their corresponding projections to the ACA and MO areas (rows). Coinjection
sites with their atlas level, tracer types/colors listed (left panels) produced narrow columns of overlapping
anterogradely-labeled fibers and retrogradely-labeled cell bodies within the ACA/MO areas (right panels),
28
Nearly all of PTLp’s projections to the retrosplenial cortex are sent to the middle regions
(ARA 75-90) while rostral and caudal-most RSP receive only trace fibers. Again, PTLp
subregions innervate all RSP subdomains, but connection strengths vary considerably by
subregion. The PTLp-rm sends extremely dense and substantial input to the ventral RSP while
the dorsal and agranual retrosplenial areas receive similar strong (but proportionally much
smaller) amounts of input. In contrast, the PTLp-mid and -caudolateral subregions both send a
roughly equal, moderate amount of input to dorsal and ventral RSP, and their projection
patterns are less skewed towards a single RSP domain (see Figures 2.4 and 2.6). RSPv
receives the most overall PTLp input of any retrosplenial region and is the only one to be
targeted selectively by layer (L1, dorsal L3 and dorsal L5), while RSPagl receives the least
PTLp input in the restrosplenial cortex. Interestingly, the majority of PTLp inputs received by any
retrosplenial domain originate from the PTLp-rm, suggesting that the rostromedial part of PTLp
is preferentially involved in the medial cortico-cortical subnetworks.
revealing a matching bidirectional topography of connections between the PTLp and the ACA/MO. Coinjections
into medial PTLp produced a column of strongly labeled fibers and neurons in the more medial (or ventral) parts
of the ACA/MO, while coinjections in lateral PTLp at the same ARA level labeled a dense column of fibers and
neurons more laterally in the ACA/MO. This mediolateral topography in the ACA/MO is consistent across the
longitudinal axis of the PTLp (right panels). Note that labeling from injection sites does not discretely target
individual ROIs but shifts along the medial-lateral axis of the ACA/MO in gradient fashion. (d) Anterograde maps
showing PTLp-rm (red), PTLp-mid (green), and PTLp-cl (purple) neuron projections to the ACA/MO. Mediolateral
topography of projections with respect to injection location along the PTLp mediolateral axis is conserved across
the longitudinal extent of ACA/ MO. Note that projections both consistently overlap at their edges and shift from
ventral to more dorsal parts of the ACA/MO regions when moving from anterior to posterior, validating the
presence of a topographic connectivity “gradient”. (e) PTLp reciprocal connections to VIS form a “mirrored”
gradient connectivity, where medial PTLp connects reciprocally to the outer extrastriate visual areas (narrow
columns of fibers and neurons in both medial VISam and lateral VISal) and lateral PTLp connects to the middle of
VIS (more diffuse fibers/neurons across the VISp), as shown by the resulting labeling patterns produced by
coinjections made to the same ARA level in caudal PTLp (left panel), as well as by the representative coinjections
that span longitudinal PTLp used for brain-wide mapping in Figs 2.3 and 2.4. Together, the sets of connections
show a clear mediolateral gradient connectivity between the ACA/MO and the PTLp, along with a smaller, more
nebulous change to mediolateral location in the ACA/MO based on the anteroposterior location in PTLp. Grey
arrows demarcate different cortical regions, as defined by the ARA.
29
Primary somatosensory areas appear to be differentially innervated by PTLp subregions
and location along the longitudinal axis. The PTLp-rm sends very few inputs to SSp, so
innervation to the SSp-bfd, SSp-ll, SSp-tr, and SSp-undefined primarily comes from the middle
and caudolateral subregions of PTLp. Between those subregions, the PTLp-mid sends relatively
stronger projections to the trunk and lower limb parts (more rostral SSp domains) and the PTLp-
cl more strongly innervates the barrel-field and undefined (hypothesized to be tail-related)
subregions found in caudal SSp. The middle and lateral PTLp may be preferentially involved in
the sensory cortico-cortical subnetworks in a roughly topographic way.
Lastly, the dorsal and medial prefrontal cortex areas (ORBvl, ORBl, ILA, and PL) receive
most of their input from the rostromedial subregion and a proportionally smaller amount of
innervation from the middle of PTLp. The PTLp-cl, meanwhile, sends virtually no inputs to the
PFC at all, suggesting very little involvement in the medial subnetworks of the cortex.
Cerebral Nuclei
All PTLp subregions send strong projections to the dorsal medial CP across its
rostrocaudal extent (CP.r.imd, CP.i.dm.d/dm/dl, CP.c.d). Connection patterns between the three
subregions are very similar.
Thalamus
PTLp-rm makes strong connections to all associative thalamic nuclei (LP, PO, LD) but
sends its strongest projections to the LD in rostral thalamus, while targeting the majority of its
projections in caudal thalamus to the LP. Similar to the gradient projection pattern seen in the
extrastriate visual areas, PTLp subregions project in a unique topographic pattern to the
associative thalamic areas akin to a mirrored gradient, forming arch-like bands of axonal
labeling (see Figures 2.8 and 2.4, ARA 68 & 75). The PTLp-cl forms two small dense spots of
30
labeling at the medial- and lateral-most edges of the dorsal PO, adjacent to the border shared
with LP (Fig. 2.8b). The PTLp-rm projects densely either to a small middle spot in the
dorsomedial LD (visible at ARA 68, Fig. 2.4), or to the middle of ventral LP also adjacent to the
Figure 2.8 | PTLp Connections to the LP, LD, and PO Thalamic Areas.
(a) Double coinjections of PHAL/CTb in PTLp-rm and FG/AAV in PTLp-rl show the unique “mirrored” topographic
pattern of labeling in the associative thalamic nuclei. Cells (yellow) and fibers (red) from rostrolateral PTLp are
present in two dense clusters, one in the ventromedial LD/LP and the other in dorsolateral PO. Labeling from
rostromedial PTLp forms a strong band or “arch” of fibers (green) and cells (pink) that dorsally connects the PTLp-
rl dense labeling clusters. This mediolateral mirrored gradient pattern is conserved across the longitudinal extent
of the associative thalamic areas, though it is most striking at ARA 75. (b) Double coinjections of PHAL/CTb in
PTLp-cm and FG/AAV in PTLp-cl show very similar topographic labeling patterns in the associative thalamic nuclei
when compared to the rostral PTLp. Cells (yellow) and fibers (red) from caudolateral PTLp are arranged in two
dense, somewhat larger clusters, one in the ventromedial LD/LP and the other in dorsolateral PO. Labeling from
the caudomedial PTLp forms a very strong “arch” of fibers (green) and cells (pink) that extends mediolaterally
across the dorsal nuclei (LD/LP) and connects the two clusters of PTLp-cl labeling. Note that the entire PTLp is
strongly and reciprocally connected to all 3 associative thalamic nuclei.
______________________________________________________________________________
31
LP-PO border (ARA 75, Fig. 2.4 and Fig. 2.8a, middle panel), while the PTLp-mid sends
projections in an arch to bridge all three labeling clusters.
All PTLp subregions uniformly provide a moderate level of input to the VAL. The AMd
however receives a proportionally strong input from the PTLp-rm. Only the trunk-related regions
of the ventroposterior thalamic complex (VPM/VPL) receive relatively sparse, selectively
targeted PTLp projections and are predominantly innervated by the caudolateral and middle
subregions of PTLp.
Hypothalamus
All PTLp subregions send moderate projections to the lateral part of caudal ZI and
weakly innervate the remaining caudal ZI. Proportionally, PTLp-cl sends much more input to the
lateral ZI than the other subregions, and that input is concentrated densely in the caudal parts of
the region. On the other hand, PTLp-rm not only sends fewer of its projections to lateral ZI, but
those projections appear uniformly dispersed throughout the region. The PTLp-mid sends
proportionally smaller amounts of input to ZI, like the rostromedial subregion, but its projection
density pattern lies somewhere between the two: there are few sections of denser labeling like
with the caudolateral (see ARA 84 in Figure 2.4), but the remainder of its ZI inputs are
otherwise sparsely and uniformly target the lateral ZI. PTLp does not appear to send any other
projections to the hypothalamus besides a few sparse fibers to the PH.
Midbrain
Individual areas in the midbrain such as the SC, the APN, and PAG receive similar
proportions of innervation from PTLp in comparison to their cortical and thalamic counterparts,
while the midbrain as a region makes up a fraction of total PTLp input smaller than the cortex
but larger than the thalamus. The intermediate grey layers of SC, the APN, and the rostral NPC
are targeted by moderately strong projections from PTLp, while the ICc, SC deep layers, MRN,
NOT, PPT, and MPT all receive weak projections. PTLp projections to the PAG are weak but
32
tend to be confined most densely to its lateral column and somewhat less to the dorsomedial
column (note that PAG subdivisions are not included in the ARA
70
; see Swanson BM4 atlas
73
for
PAG column nomenclature and boundaries mentioned here). Projection patterns to the midbrain
do not vary significantly by PTLp subregion except in the smaller rostral nuclei of the pretectum
(MPT, PPT, OP), which are primarily innervated by the PTLp-rm, and in the superior colliculus.
The rostromedial subregion of PTLp appears to preferentially innervate the lateral half of SCig
most strongly while the caudolateral subregion sends relatively denser projections to the medial
SCig. Interestingly, the middle subregion of PTLp appears to send only half as much input
proportionally to the SCig as do either the rostral or caudal subregions (Fig. 2.4, ARA 84-92).
Brainstem
PTLp projections to the pons or medulla were very sparse, and no trace of projections
from the PTLp to the cerebellum were seen. Weak projections were noted in the TRN, PG and
POR. Even sparser fibers were also seen in the PRNc and the PCG. For the medulla, sparse
fibers were seen in the NTB and in the pyramids of the corticospinal tract.
2.3.2 Afferent Projections to PTLp
Cortex
Afferents sent to PTLp from isocortex make up an even larger proportion of its overall
connections than its cortical efferents do (see Figure 2.9). Intra-PTLp projections are very
strong and include moderate afferents from the PtP innervating the other three subregions,
matching the pattern of reciprocal efferents previously mentioned. Intra-PTLp projections will not
be discussed in greater detail here to avoid the chance of including false-positive labeling in the
results that may be caused by inadequate filtering of high-background saturation of signal
surrounding the injection sites.
33
No labeled cell bodies were detected in the main or accessory olfactory areas, while very few
labeled cells were observed in the gustatory, rostral visceral, and agranular insular cortices.
Light projections from ECT and TEA targeted different PTLp subregions at roughly comparable
levels. In the cortical subplate, very sparse retrograde labeling was found in the LA, BMAp, and
PIR, showing light projections from these areas to the PTLp-cl, while EPd makes an equally
light projection to the PTLp-mid. The entire rostrocaudal extent of the CLA sends moderate
projections to the PTLp without any noticeable subregion specificity, targeting different parts of
PTLp in equal amounts (Figure 2.5).
________________________________________________________________________
Figure 2.9 | Strongest Inputs to PTLp Subregions.
Bar graph visualization of the ROIs projecting to PTLp subregions most strongly, ranked by proportion of labeling.
Values have been normalized to show proportion of brain-wide labeling density present in the specific ROI. Different
colors represent different cases and their injection site location within PTLp: PTLp-rm (red), middle PTLp (green),
and PTLp-cl (purple). All values shown here include labeling from both the ipsilateral and contralateral ROI. ROIs
are grouped along the x-axis according to the CNS division and associated cortical subnetwork.
34
(Figure 2.9)
35
Generally, projections received by the PTLp differ from projections leaving the PTLp in a
few ways: the higher-order association areas in the medial prefrontal cortex send proportionally
lighter projections to PTLp than they receive (see labeled cells vs. fibers in right panels of Fig.
2.7a-c), while the primary somatosensory areas (SSp, SSp-bfd, SSp-ll, SSp-tr, SSp-un) and the
extrastriate visual areas (VISam, VISal) send much heavier inputs to PTLp than they get in
return (see Figures 2.6 and 2.9). In contrast, the proportion of projections originating from the
auditory areas (AUDd, AUDp, AUDv) to the PTLp is similar to the proportion sent back from the
PTLp. Other members of the medial cortical subnetworks preferentially target the PTLp-rm
instead of the other subregions. The preference for PTLp-rm is most significant for inputs from
the MOp, RSPv, and MOs, and ACAd. Areas that instead prefer to innervate the PTLp-mid
subregion are the SSp-tr, the VISam, and all auditory areas (AUDd, AUDp, AUDv), more
evidence for its involvement in somatic and auditory networks. The PTLp-cl receives its most
significant inputs from the visual areas, the SSp-bfd, and the SSp-un, suggesting it plays a
stronger role in the visual networks than do the other PTLp subregions.
Some preferential topography of projections and varying projection strengths to PTLp
subregions from other cortical areas is also evident. Retrogradely labeled cell bodies in the
ACA/MO form a mediolateral gradient, such that: the PTLp-rm receives projections from the
more ventral ACAv and ACAd, the PTLp-mid receives projections from the dorsal ACAd and
medial MOs, and the PTLp-cl receives inputs mostly from lateral MOs (see Figure 2.5, ARA 44-
59, Fig. 2.7a-c). However, PTLp afferents are a more intermixed population than the
corresponding PTLp efferents to the same structures, so the gradient is coarse and less
noticeable across the ACA and MO. No subregional differences in the laminar location of
labeled ACA or MO cells were discovered. RSPv sends most of its inputs to the PTLp
preferentially from cortical layers L3 and L5 (Figure 2.5, ARA 75-89), unlike the other cortical
afferents that typically span a narrow cortical column.
36
Cerebral Nuclei
No labeling was detected in striatal regions. From the pallidum, the caudolateral
subregion of PTLp alone receives an extremely weak projection from the GPe and the NDB.
Thalamus
The associative nuclei provide the strongest thalamic projections to PTLp. Although all
PTLp subregions receive associative thalamic inputs, PTLp-med receives the most inputs
proportionally of any subregion (see Figure 2.9). PTLp-rm receives most of its innervation from
the LP, PTLp-cl receives the majority of its associative inputs from the PO, and all three
subregions receive roughly proportional innervation from the LD. Notably, aside from their
projection strength, the associative nuclei also make projections to PTLp that are
topographically organized which is most evident near the shared borders of LP, PO and LD
(Figure 2.8). The associative nuclei show a rough medial-to-lateral topography in their
projections to PTLp, such that medial LP projects exclusively to PTLp-rm, LP and PO neurons in
a wide strip adjacent to the center of their shared border send significant projections to the
PTLp-mid, and neurons in the lateral corner of PO projects to the PTLp-cl (see ARA 75 in
Figure 2.5).
Rostral thalamic areas (AMd, VAL, AV) send moderate projections to the rostromedial
subregion of PTLp and somewhat less to the PTLp-mid, while excluding the PTLp-cl entirely.
Caudal thalamic nuclei innervating PTLp project to all subregions, though the PTLp-mid
receives a proportionally larger fraction of those innervations. MD domains send weak
projections to the entire PTLp regardless of subregion.
Interesting to note is a small, discrete dense cluster of neurons innervating the entire
PTLp that are localized in the dorsal-most part of VPL (the lateral edge of the cluster may also
stray across the border into adjacent dorsal VPM), as shown in Figure 2.5 (ARA 68) and Figure
2.8. This cluster is consistently labeled across almost all anterograde and retrograde injections
37
used for this study. Based on current knowledge of the ventroposterior nucleus’s somatotopic
organization
75,76
, this part of the VP can be inferred to represent the (upper) contralateral trunk
region of the body.
In caudal thalamus, the SGN and SPFp send weak inputs to the PTLp-cl. LGd is also
shown here to have a small, dense cluster of retrogradely-labeled cells sending inputs to PTLp-
cl, which is not present in either the PTLp-rm or PTLp-mid. LGd labeling is not observed in other
cases with a similarly placed coinjection (not shown in figures) that remains discretely in the
PTLp, so this result can likely be attributed to minor tracer leakage into the VIS areas
neighboring the injection site and should be removed from consideration.
Hypothalamus
PTLp does not receive any significant inputs from the hypothalamus. The LHA, ZI, and
MM areas each send extremely sparse projections to PTLp with no visible subregional
specificity.
Midbrain
PTLp only receives very weak projections from the midbrain which may not be
significant: retrograde injections in the rostral and middle subregions of PTLp produced sparsely
labeled cells in the SCig-b, contralateral PAG and VTA, and the CLI.
Brainstem
The PRNr of the pons sends a barely-detectable projection to the PTLp-rm which is
likely insignificant. Meanwhile, no projections from the medulla or cerebellum to the PTLp were
detected.
38
2.4 DISCUSSION
In this work, we provided a comprehensively collected and analyzed dataset on mouse
PTLp connectivity. We summarized the quantitative long-range connectivity to and from the
PTLp by using multiple discrete coinjections of anterograde and retrograde tracers to directly
label structural pathways of the PTLp and validate all findings. We generated an anatomical
map integrating all pathway data for the mouse PTLp in a stereotaxic framework, which
revealed a broadly divergent and non-parallel structural organization of subnetworks that each
form connections across the entirety of the PTLp (Figure 2.12a), but with preferential weight
given to each subnetwork in different regions in a gradient fashion. Subregions were identified
and all clearly showed multimodal connectivity but were still able to be compared based on their
unique connectivity characteristics and differences in connection strength. Differences in PTLp
subregion connectivity shown here offer a structural basis for differential engagement of PTLp
subregions. These findings may provide insight into the principles underlying PTLp organization
and help explain results from previous studies showing contradictory modulation of multisensory
processing in context-specific ways
16,17,20,34
. The mapped data further serves as a resource,
offering an anatomical framework for interrogation of PTLp subregional organization to better
understand how PTLp integrates convergent input from multiple areas for spatial and cognitive
processing. We propose some testable functional hypotheses for the three PTLp subregions
and their brain-wide subnetworks.
__________________________________________________________________________________________
Figure 2.10 | Flatmaps of PTLp-subregion Anterograde Tracing to Brain-wide ROIs.
The strongest outputs from the (a) PTLp-rm, (b) PTLp-mid, and (c) PTLp-cl subregions represented on a mouse
brain flatmap at the macroscopic level (individual gray matter regions). For each PTLp subregion, strength values
of detected anterograde connections were binned into 7 equal divisions. This relative connection strength is
qualititatively represented on each map by depth of color, from very weak (pale pink) to very strong (dark red).
Only the top 35 ROIs (as previously ranked and shown in Figure 2.6) Brain-wide were mapped, for better visual
representation of each PTLp subregion’s strongest outputs. (d) Longitudinal half of the entire CNS flatmap
showing orientation and major brain divisions. The color key for flatmap connection strength is also shown.
39
(Figure 2.10)
40
(Figure 2.11)
41
PTLp-rm
Our data shows that PTLp-rm preferentially connects in a bidirectional manner to the
higher-order association areas (ORBvl, ACA, MOp/s, RSPv) (see Figs. 2.10a and 2.11a) that
participate in information processing
together in the cortico-cortical medial subnetworks
51,52
,
suggesting that this subregion plays a larger role in decision making and cognitive processing
than the others (Fig 2.12b). Corroborating this, PTLp-rm is the only subregion with
proportionally significant connections to orbital cortex and medial prefrontal cortex areas
(ORBvl, PL), as well as the subregion sending the strongest projections to the ACAd/v across its
longitudinal extent, regions also strongly implicated in visual processing and goal-directed
behavior
77-79
. PTLp-rm is also the only subregion to send a proportionally strong projection to
the LD, a thalamic nucleus implicated in higher order visual processing
80,81
, or to make
connections of appreciable strength with all subdomains of retrosplenial cortex, a region with a
pivotal role in spatially related cognition, learning and memory.
Furthermore, PTLp-rm has the greatest number of strong connections with subcortical
areas, in particular multiple areas implicated in visual attention: the SCig plays a critical role in
generating orienting responses and visually coordinating movements
82
, while the ZId and the
lateral PAG are both part of a network associated with choosing and generating different
aspects of defensive behaviors
83
. (Note that ZI and PAG are not delineated into subdomains in
Figure 2.11 | Flatmaps of PTLp subregion retrograde tracing to Brain-wide ROIs.
The strongest inputs from the (a) PTLp-rm, (b) PTLp-mid, and (c) PTLp-cl subregions represented on a mouse
brain flatmap at the macroscopic level (individual gray matter regions). For each PTLp subregion, strength values
of detected retrograde connections were binned into 7 equal divisions. This relative connection strength is
qualititatively represented on each map by depth of color, from very weak (pale pink) to very strong (dark red).
Only the top 35 ROIs (as ranked and shown in Figure 2.9) Brain-wide were mapped, for better visual
representation of each PTLp subregion’s strongest intputs. (d) Longitudinal half of the entire CNS flatmap
showing orientation and major brain divisions. The color key for flatmap connection strength is also shown.
_________________________________________________________________________________
42
the Allen Reference Atlas
70
. Boundary definitions for the subdomains mentioned can be found in
the Paxinos atlas
74
)
PTLp-cl
Though the rostromedial PTLp has the strongest connections to the visual cortical areas,
the PTLp-cl is the subregion that ultimately has the greatest focus on visual-related processing.
PTLp-cl has the fewest strong connections of any subregion, and specifically receives the least
inputs overall (only from visual cortex and primary somatosensory cortex) compared with the
other two subregions (see Figure 2.12d). It receives extremely strong inputs from the primary
and extrastriate visual cortices (VISp, VISam, VISal) (Figure 2.11c) and sends the majority of
the PTLp’s inputs back to the visual cortex (Figure 2.10c). Its connection weights to thalamic
areas support this bias, as PTLp-cl also sends the greatest thalamic inputs to the PO, a higher-
order nucleus strongly activated by complex, often bilateral patterns of vibrissal stimuli
84-88
and
sends strong inputs to LP as well, a nucleus considered the rodent homologue of the primate
pulvinar and correlated with visual attention behavior
89,90
. The caudolateral subregion also
makes the strongest bidirectional connections to the barrel field and undefined (hypothesized to
be the tail representation) parts of the primary somatosensory cortex. These two body regions
are most suitable for collecting somatosensory information about nearby space. Altogether,
these connection preferences imply PTLp-cl is the subregion primarily tasked with dealing with
visual information and external orientation of visuospatial attention.
PTLp-mid
PTLp-mid appears to send the fewest descending projections to subcortical areas of any
subregion, instead sending a majority of its inputs preferentially back to the cortex. These
cortical projections target sensorimotor areas such as SSP-tr, VISam, MOp, MOs (see Figs. 2.6
and 2.10b), and of course parts of the PTLp itself (see ARA 75 & 79 in Fig. 2.4). Our data
showed that the strongest projections from PTLp-mid are to the MOp and the dorsal CP
43
domains, suggesting a role in directing movement of the body. Meanwhile, somatic processing
areas similarly provide its strongest inputs (the PO, MOp, SSp-tr, VISam, VISal, VISpm, AUDd
and AUDp).
PTLp-mid is the only subregion to make strong connections with the auditory cortex at all
(Figure 2.11b). Since hearing is the sensory modality in rodents frequently allowing the farthest
detection of a threat’s location, the relevance of these projections in triggering innate defensive
behaviors lends additional insight to its main function. PTLp-mid is also the only subregion with
a strong bidirectional connection to the PO, an important modulating hub in the processing of
vibrissal sensorimotor information
84-88
generated during tactile exploration of the nearby
environment. Likewise, the trunk is the most relevant body region for determining overall body
posture and proprioception, so PTLp-mid’s strong bidirectional connection to the SSp-tr area is
another indication that this subregion plays a somatically focused role. Our data overall implies
that the primary role of the PTLp-mid is audio-spatial processing and internal awareness of body
position in space (Figure 2.12c). Numerous past findings in the rat also highlight the importance
of the PTLp in navigation and spatial reasoning behaviors, and some studies speculate its
ultimate role is the conversion of egocentric (internal body representation) coordinates to
allocentric (environmental) spatial coordinates
25,26,62
. Our findings suggest the PTLp-mid
subregion to be a likely candidate for exploring these particular behaviors.
44
__________________________________________________________________________________________
Figure 2.12 | Strongest Proportional Connections of Each PTLp Subregion.
(a) Summarized significant brain-wide connections of PTLp neurons overall (irrespective of PTLp subregion).
Summary diagrams of the strongest inputs and outputs for the (b) PTLp-rm (red ellipse), (c) PTLp-mid (green
ellipse), and (d) PTLp-cl (purple ellipse). Connection strength to an ROI was denoted visually by line thickness
and split into weak (thin) or strong (grey) according to the flatmap binned values previously shown in Figures
2.10 & 2.11. Directionality of the connection is denoted through color (black solid: PTLp outputs, grey dashed:
PTLp inputs), as are the major brain divisions of connected ROIs (blue: isocortex, purple: striatum, green:
hypothalamus, yellow: thalamus, pink: midbrain).
45
Conclusion
Understanding the organization of PTLp neural networks in a mouse model has clinical
significance in defining and treating the neurobiological basis of neurodevelopmental disorders
with attentional and spatial symptoms. Inactivation of PPC in humans leads to deficits in
sensory integration and movement planning without significantly affecting sensory perception
per se
91
. Abnormal structure and function of the inferior parietal lobule (IPL) and superior
parietal lobule (SPL) regions of human PPC have been implicated in autism and attention deficit
hyperactivity disorder (ADHD)
92-96
, as well as specific learning disorders like dyslexia and
dyscalculia
97,98
. Adults with ADHD were observed in an early MRI study to have selective
cortical thinning in the IPL of the non-dominant hemisphere
99
. Patients with dyslexia, too, show
structural differences and decreased activation of the non-dominant IPL
100-102
. Interestingly, all
these disorders are commonly comorbid with each other and come with secondary deficits in
working memory, fine motor skills, and balance impairments
103-106
. Symptomatic variation
despite involvement of the same area(s) suggests that distinct IPL cell-types and their differing
contributions to normal frontoparietal network function may be selectively impaired in each
disorder.
Our findings here offer some insight into the organizing principles underlying rodent
PTLp substructure and how differential engagement of PTLp subregions may explain its
previously seen modulation of multisensory processing in context-specific ways
16,17,20,34
. The
complex prioritization of certain connections among PTLp subregions can guide hypotheses
regarding the roles of particular neuron populations in circuits for spatial reasoning, movement
planning, and attention, and help target them more accurately in future studies. A systematic
connectivity map and any resulting cell-type profiles of mouse PTLp can thereby serve as a
valuable cross-species reference that may be generalizable to human PPC sub-areas.
46
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Abstract (if available)
Abstract
The cerebral cortex can be segregated into distinct neural networks that work synergistically to perform detailed sensory processing and generate complex motor behaviors. However, organizational principles connecting individual sensory, motor, and associational neuronal cell types are largely unknown, and thus many aspects of sensorimotor integration remain unclear. The goal of the Mouse Connectome Project (MCP) is to assemble a comprehensive wiring map of the entire mouse brain (a connectome), providing a public resource which may help identify these organizational principles and the neural mechanisms involved, in hopes that this may hold future relevance for human neurological health and disease.
Across organisms, certain regions in the brain have been repeatedly identified as key anatomical/network hubs for integration of multimodal sensory data. The neuroanatomical mapping studies presented in this thesis focus on one such brain region, the posterior parietal cortex (PTLp). To further investigate cortical cell types involved in multimodal integration and as a part of the MCP’s efforts, we examined mesoscale structural connectivity and neuronal morphology within the PTLp of the mouse. We defined three previously-unknown subregions in PTLp by identifying differences in connectivity to other brain regions along a topographic mediolateral gradient, corresponding to a similar gradient location within PTLp. Quantification and comparison of the PTLp subregional networks also discovered significant differences in specific connection strengths for each subregion, suggesting that each subregion prioritizes processing for different functional roles and participates uniquely from the others in the PTLp's various downstream networks.
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Song, Monica Ying
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Core Title
Mapping multi-scale connectivity of the mouse posterior parietal cortex
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College of Letters, Arts and Sciences
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Doctor of Philosophy
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Neuroscience
Degree Conferral Date
2023-12
Publication Date
09/11/2024
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09/11/2023
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brain mapping,connectome,connectomics,mouse brain,neural networks,neural tract tracing,neuroanatomy,neuroinformatics,Neuroscience,OAI-PMH Harvest,parietal cortex,posterior parietal cortex,sensorimotor integration
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), Dong, Hong-Wei (
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), Swanson, Larry (
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), Zhang, Li I. (
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monica.y.song@gmail.com,monicaso@usc.edu
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Tags
brain mapping
connectome
connectomics
mouse brain
neural networks
neural tract tracing
neuroanatomy
neuroinformatics
parietal cortex
posterior parietal cortex
sensorimotor integration