Sex and Pubertal Status Influence Dendritic Spine Density on Frontal Corticostriatal Projection Neurons in Mice

Abstract In humans, nonhuman primates, and rodents, the frontal cortices exhibit grey matter thinning and dendritic spine pruning that extends into adolescence. This maturation is believed to support higher cognition but may also confer psychiatric vulnerability during adolescence. Currently, little is known about how specific cell types in the frontal cortex mature or whether puberty plays a role in the maturation of some cell types but not others. Here, we used mice to characterize the spatial topography and adolescent development of cross-corticostriatal (cSTR) neurons that project through the corpus collosum to the dorsomedial striatum. We found that apical spine density on cSTR neurons in the medial prefrontal cortex decreased significantly between late juvenile (P29) and young adult time points (P60), with females exhibiting higher spine density than males at both ages. Adult males castrated prior to puberty onset had higher spine density compared to sham controls. Adult females ovariectomized before puberty onset showed greater variance in spine density measures on cSTR cells compared to controls, but their mean spine density did not significantly differ from sham controls. Our findings reveal that these cSTR neurons, a subtype of the broader class of intratelencephalic-type neurons, exhibit significant sex differences and suggest that spine pruning on cSTR neurons is regulated by puberty in male mice.

Download Full-text

Sex and pubertal status influence dendritic spine density onto frontal corticostriatal projection neurons

10.1101/787408 ◽

2019 ◽

Cited By ~ 1

Author(s):

Kristen Delevich ◽

Nana J. Okada ◽

Ameet Rahane ◽

Zicheng Zhang ◽

Christopher D. Hall ◽

...

Keyword(s):

Adolescent Development ◽

Dendritic Spine ◽

Cell Types ◽

Projection Neurons ◽

Spine Density ◽

Adult Males ◽

Puberty Onset ◽

Spatial Topography ◽

Different Cell Types ◽

Spine Pruning

In humans, nonhuman primates, and rodents, the frontal cortices exhibit grey matter thinning and dendritic spine pruning that extends late into adolescence. This protracted maturation is believed to support higher cognition but may also confer psychiatric vulnerability during adolescence. Currently, little is known about how different cell types in the frontal cortex mature or whether puberty plays a role. Here, we used mice to characterize the spatial topography and adolescent development of cross-corticostriatal (cSTR) neurons that project to the dorsomedial striatum (DMS). We found that apical spine density on cSTR neurons in the medial prefrontal cortex decreased significantly between late juvenile (P29) and young adult time points (P60), with females exhibiting higher spine density than males at both ages. Adult males castrated prior to puberty onset had higher spine density compared to sham controls. Adult females ovariectomized before puberty onset showed greater variance in spine density measures on cSTR cells compared to controls, but their mean spine density did not significantly differ from sham controls. Our findings reveal that these cSTR neurons, a subtype of the broader class of intratelencephalic-type neurons, exhibit significant sex differences and suggest that spine pruning on cSTR neurons is regulated by puberty in males.

Download Full-text

Vertebrate retinal ganglion cells are selected from competent progenitors by the action of Notch

Development ◽

10.1242/dev.121.11.3637 ◽

1995 ◽

Vol 121 (11) ◽

pp. 3637-3650 ◽

Cited By ~ 33

Author(s):

C.P. Austin ◽

D.E. Feldman ◽

J.A. Ida ◽

C.L. Cepko

Keyword(s):

Cell Fate ◽

Ganglion Cells ◽

Notch Pathway ◽

Cell Types ◽

Projection Neurons ◽

Specific Cell ◽

Vitro Assay ◽

Notch Activity

The first cells generated during development of the vertebrate retina are the ganglion cells, the projection neurons of the retina. Although they are one of the most intensively studied cell types within the central nervous system, little is known of the mechanisms that determine ganglion cell fate. We demonstrate that ganglion cells are selected from a large group of competent progenitors that comprise the majority of the early embryonic retina and that differentiation within this group is regulated by Notch. Notch activity in vivo was diminished using antisense oligonucleotides or augmented using a retrovirally transduced constitutively active allele of Notch. The number of ganglion cells produced was inversely related to the level of Notch activity. In addition, the Notch ligand Delta inhibited retinal progenitors from differentiating as ganglion cells to the same degree as did activated Notch in an in vitro assay. These results suggest a conserved strategy for neurogenesis in the retina and describe a versatile in vitro and in vivo system with which to examine the action of the Notch pathway in a specific cell fate decision in a vertebrate.

Download Full-text

Single-cell genomics identifies cell type–specific molecular changes in autism

Science ◽

10.1126/science.aav8130 ◽

2019 ◽

Vol 364 (6441) ◽

pp. 685-689 ◽

Cited By ~ 134

Author(s):

Dmitry Velmeshev ◽

Lucas Schirmer ◽

Diane Jung ◽

Maximilian Haeussler ◽

Yonatan Perez ◽

...

Keyword(s):

Cell Types ◽

Molecular State ◽

Clinical Severity ◽

Projection Neurons ◽

Specific Cell ◽

Cortical Projection ◽

Molecular Changes ◽

Single Nucleus ◽

Gene Expression Studies ◽

Transcriptomic Changes

Despite the clinical and genetic heterogeneity of autism, bulk gene expression studies show that changes in the neocortex of autism patients converge on common genes and pathways. However, direct assessment of specific cell types in the brain affected by autism has not been feasible until recently. We used single-nucleus RNA sequencing of cortical tissue from patients with autism to identify autism-associated transcriptomic changes in specific cell types. We found that synaptic signaling of upper-layer excitatory neurons and the molecular state of microglia are preferentially affected in autism. Moreover, our results show that dysregulation of specific groups of genes in cortico-cortical projection neurons correlates with clinical severity of autism. These findings suggest that molecular changes in upper-layer cortical circuits are linked to behavioral manifestations of autism.

Download Full-text

WAVE1 in neurons expressing the D1 dopamine receptor regulates cellular and behavioral actions of cocaine

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1621185114 ◽

2017 ◽

Vol 114 (6) ◽

pp. 1395-1400 ◽

Cited By ~ 5

Author(s):

Ilaria Ceglia ◽

Ko-Woon Lee ◽

Michael E. Cahill ◽

Steven M. Graves ◽

David Dietz ◽

...

Keyword(s):

Dopamine Receptor ◽

Dendritic Spine ◽

Actin Polymerization ◽

Feedback Regulation ◽

Projection Neurons ◽

Spine Density ◽

Cocaine Exposure ◽

Chronic Cocaine ◽

D1 Dopamine Receptor ◽

Nmda Glutamate Receptor Antagonist

Wiskott-Aldrich syndrome protein (WASP) family verprolin homologous protein 1 (WAVE1) regulates actin-related protein 2/3 (Arp2/3) complex-mediated actin polymerization. Our previous studies have found WAVE1 to be inhibited by Cdk5-mediated phosphorylation in brain and to play a role in the regulation of dendritic spine morphology. Here we report that mice in which WAVE1 was knocked out (KO) in neurons expressing the D1 dopamine receptor (D1-KO), but not mice where WAVE1 was knocked out in neurons expressing the D2 dopamine receptor (D2-KO), exhibited a significant decrease in place preference associated with cocaine. In contrast to wild-type (WT) and WAVE1 D2-KO mice, cocaine-induced sensitized locomotor behavior was not maintained in WAVE1 D1-KO mice. After chronic cocaine administration and following withdrawal, an acute cocaine challenge induced WAVE1 activation in striatum, which was assessed by dephosphorylation. The cocaine-induced WAVE1 dephosphorylation was attenuated by coadministration of either a D1 dopamine receptor or NMDA glutamate receptor antagonist. Upon an acute challenge of cocaine following chronic cocaine exposure and withdrawal, we also observed in WT, but not in WAVE1 D1-KO mice, a decrease in dendritic spine density and a decrease in the frequency of excitatory postsynaptic AMPA receptor currents in medium spiny projection neurons expressing the D1 dopamine receptor (D1-MSNs) in the nucleus accumbens. These results suggest that WAVE1 is involved selectively in D1-MSNs in cocaine-evoked neuronal activity-mediated feedback regulation of glutamatergic synapses.

Download Full-text

Hippocampal and thalamic afferents form distinct synaptic microcircuits in the mouse frontal cortex

10.1101/2021.03.12.435140 ◽

2021 ◽

Author(s):

Kourtney Graham ◽

Nelson Spruston ◽

Erik B. Bloss

Keyword(s):

Information Processing ◽

Frontal Cortex ◽

Cortical Neurons ◽

Basolateral Amygdala ◽

Cell Types ◽

Brain Regions ◽

Projection Neurons ◽

Specific Cell ◽

Nucleus Reuniens ◽

Level Information

AbstractNeural circuits within the frontal cortex support the flexible selection of goal-directed behaviors by integrating input from brain regions associated with sensory, emotional, episodic, and semantic memory functions. From a connectomics perspective, determining how these disparate afferent inputs target their synapses to specific cell types in the frontal cortex may prove crucial in understanding circuit-level information processing. Here, we used monosynaptic retrograde rabies mapping to examine the distribution of afferent neurons targeting four distinct classes of local inhibitory interneurons and four distinct classes of excitatory projection neurons in mouse infralimbic cortex. Interneurons expressing parvalbumin, somatostatin, or vasoactive intestinal peptide received a large proportion of inputs from hippocampal regions, while interneurons expressing neuron-derived neurotrophic factor received a large proportion of inputs from thalamic regions. A more moderate hippocampal-thalamic dichotomy was found among the inputs targeting excitatory neurons that project to the basolateral amygdala, lateral entorhinal cortex, nucleus reuniens of the thalamus, and the periaqueductal gray. Together, these results show a prominent bias among hippocampal and thalamic afferent systems in their targeting to genetically or anatomically defined sets of frontal cortical neurons. Moreover, they suggest the presence of two distinct local microcircuits that control how different inputs govern frontal cortical information processing.

Download Full-text

Cell-Type-Specific D1 Dopamine Receptor Modulation of Projection Neurons and Interneurons in the Prefrontal Cortex

Cerebral Cortex ◽

10.1093/cercor/bhy299 ◽

2018 ◽

Vol 29 (7) ◽

pp. 3224-3242 ◽

Cited By ~ 18

Author(s):

Paul G Anastasiades ◽

Christina Boada ◽

Adam G Carter

Keyword(s):

Prefrontal Cortex ◽

Pyramidal Cells ◽

Cell Types ◽

D1 Receptor ◽

Receptor Expression ◽

D1 Receptors ◽

Projection Neurons ◽

Specific Cell ◽

Action Potential Firing ◽

Receptor Modulation

Abstract Dopamine modulation in the prefrontal cortex (PFC) mediates diverse effects on neuronal physiology and function, but the expression of dopamine receptors at subpopulations of projection neurons and interneurons remains unresolved. Here, we examine D1 receptor expression and modulation at specific cell types and layers in the mouse prelimbic PFC. We first show that D1 receptors are enriched in pyramidal cells in both layers 5 and 6, and that these cells project to intratelencephalic targets including contralateral cortex, striatum, and claustrum rather than to extratelencephalic structures. We then find that D1 receptors are also present in interneurons and enriched in superficial layer VIP-positive (VIP+) interneurons that coexpresses calretinin but absent from parvalbumin-positive (PV+) and somatostatin-positive (SOM+) interneurons. Finally, we determine that D1 receptors strongly and selectively enhance action potential firing in only a subset of these corticocortical neurons and VIP+ interneurons. Our findings define several novel subpopulations of D1+ neurons, highlighting how modulation via D1 receptors can influence both excitatory and disinhibitory microcircuits in the PFC.

Download Full-text

Mechanosensory Lateral Line Nerve Projections to Auditory Neurons in the Dorsal Descending Octaval Nucleus in the Goldfish, Carassius auratus

Brain Behavior and Evolution ◽

10.1159/000447943 ◽

2016 ◽

Vol 88 (1) ◽

pp. 68-80 ◽

Cited By ~ 3

Author(s):

Catherine A. McCormick ◽

Shannon Gallagher ◽

Evan Cantu-Hertzler ◽

Scarlet Woodrick

Keyword(s):

Lateral Line ◽

Low Frequency ◽

Cell Types ◽

Auditory Pathway ◽

Projection Neurons ◽

Specific Cell ◽

Lateral Line Nerve ◽

First Order ◽

Goldfish Carassius Auratus ◽

Auditory Nucleus

The nucleus medialis is the main first-order target of the mechanosensory lateral line (LL) system. This report definitively demonstrates that mechanosensory LL inputs also terminate in the ipsilateral dorsal portion of the descending octaval nucleus (dDO) in the goldfish. The dDO, which is the main first-order auditory nucleus in bony fishes, includes neurons that receive direct input from the otolithic end organs of the inner ear and project to the auditory midbrain. There are two groups of such auditory projection neurons: medial and lateral. The medial and the lateral groups in turn contain several neuronal populations, each of which includes one or more morphological cell types. In goldfish, the exclusively mechanosensory anterior and posterior LL nerves terminate only on specific cell types of auditory projection neurons in the lateral dDO group. Single neurons in the lateral dDO group may receive input from both anterior and posterior LL nerves. It is possible that some of the lateral dDO neurons that receive LL input also receive input from one or more of the otolithic end organs. These results are consistent with functional studies demonstrating low frequency acoustic sensitivity of the mechanosensory LL in teleosts, and they reveal that the anatomical substrate for sensory integration of otolithic and LL inputs is present at the origin of the central ascending auditory pathway in an otophysine fish.

Download Full-text

Mapping Mesoscale Axonal Projections in the Mouse Brain Using A 3D Convolutional Network

10.1101/812644 ◽

2019 ◽

Cited By ~ 1

Author(s):

Drew Friedmann ◽

Albert Pun ◽

Eliza L Adams ◽

Jan H Lui ◽

Justus M Kebschull ◽

...

Keyword(s):

Mouse Brain ◽

Neural Circuit ◽

Cell Types ◽

Ease Of Use ◽

Projection Neurons ◽

Specific Cell ◽

Cortical Projection ◽

Convolutional Network ◽

Light Sheet Microscopy ◽

Axonal Projections

AbstractThe projection targets of a neuronal population are a key feature of its anatomical characterization. Historically, tissue sectioning, confocal microscopy, and manual scoring of specific regions of interest have been used to generate coarse summaries of mesoscale projectomes. We present here TrailMap, a 3D convolutional network for extracting axonal projections from intact cleared mouse brains imaged by light-sheet microscopy. TrailMap allows region-based quantification of total axon content in large and complex 3D structures after registration to a standard reference atlas. The identification of axonal structures as thin as one voxel benefits from data augmentation but also requires a loss function that tolerates errors in annotation. A network trained with volumes of serotonergic axons in all major brain regions can be generalized to map and quantify axons from thalamocortical, deep cerebellar, and cortical projection neurons, validating transfer learning as a tool to adapt the model to novel categories of axonal morphology. Speed of training, ease of use, and accuracy improve over existing tools without a need for specialized computing hardware. Given the recent emphasis on genetically and functionally defining cell types in neural circuit analysis, TrailMap will facilitate automated extraction and quantification of axons from these specific cell types at the scale of the entire mouse brain, an essential component of deciphering their connectivity.

Download Full-text

Modular output circuits of the fastigial nucleus mediate diverse motor and nonmotor functions of the cerebellar vermis

10.1101/2020.04.23.047100 ◽

2020 ◽

Cited By ~ 1

Author(s):

Hirofumi Fujita ◽

Takashi Kodama ◽

Sascha du Lac

Keyword(s):

Gene Expression ◽

Inferior Olive ◽

Cell Types ◽

Cerebellar Vermis ◽

Projection Neurons ◽

Specific Cell ◽

Synaptic Connections ◽

Cell Gene Expression ◽

Output Neurons ◽

Cell Gene

AbstractThe cerebellar vermis, long associated with axial motor control, has been implicated in a surprising range of neuropsychiatric disorders and cognitive and affective functions. Remarkably little is known, however, about the specific cell types and neural circuits responsible for these diverse functions. Here, using single-cell gene expression profiling and anatomical circuit analyses of vermis output neurons in the mouse fastigial (medial cerebellar) nucleus, we identify five major classes of glutamatergic projection neurons distinguished by gene expression, morphology, distribution, and input-output connectivity. Each fastigial cell type is connected with a specific set of Purkinje cells and inferior olive neurons and in turn innervates a distinct collection of downstream targets. Transsynaptic tracing indicates extensive disynaptic links with cognitive, affective, and motor forebrain circuits. These results indicate that diverse cerebellar vermis functions are mediated by modular synaptic connections of distinct fastigial cell types which differentially coordinate posturomotor, oromotor, positional-autonomic, orienting, and vigilance circuits.

Download Full-text

Mapping mesoscale axonal projections in the mouse brain using a 3D convolutional network

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1918465117 ◽

2020 ◽

Vol 117 (20) ◽

pp. 11068-11075 ◽

Cited By ~ 5

Author(s):

Drew Friedmann ◽

Albert Pun ◽

Eliza L. Adams ◽

Jan H. Lui ◽

Justus M. Kebschull ◽

...

Keyword(s):

Mouse Brain ◽

Neural Circuit ◽

Cell Types ◽

Ease Of Use ◽

Projection Neurons ◽

Specific Cell ◽

Cortical Projection ◽

Convolutional Network ◽

Light Sheet Microscopy ◽

Axonal Projections

The projection targets of a neuronal population are a key feature of its anatomical characteristics. Historically, tissue sectioning, confocal microscopy, and manual scoring of specific regions of interest have been used to generate coarse summaries of mesoscale projectomes. We present here TrailMap, a three-dimensional (3D) convolutional network for extracting axonal projections from intact cleared mouse brains imaged by light-sheet microscopy. TrailMap allows region-based quantification of total axon content in large and complex 3D structures after registration to a standard reference atlas. The identification of axonal structures as thin as one voxel benefits from data augmentation but also requires a loss function that tolerates errors in annotation. A network trained with volumes of serotonergic axons in all major brain regions can be generalized to map and quantify axons from thalamocortical, deep cerebellar, and cortical projection neurons, validating transfer learning as a tool to adapt the model to novel categories of axonal morphology. Speed of training, ease of use, and accuracy improve over existing tools without a need for specialized computing hardware. Given the recent emphasis on genetically and functionally defining cell types in neural circuit analysis, TrailMap will facilitate automated extraction and quantification of axons from these specific cell types at the scale of the entire mouse brain, an essential component of deciphering their connectivity.

Download Full-text