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Nature Neuroscience Aug 2019The medial prefrontal cortex (mPFC) contains populations of GABAergic interneurons that play different roles in cognition and emotion. Their local and long-range inputs...
The medial prefrontal cortex (mPFC) contains populations of GABAergic interneurons that play different roles in cognition and emotion. Their local and long-range inputs are incompletely understood. We used monosynaptic rabies viral tracers in combination with fluorescence micro-optical sectioning tomography to generate a whole-brain atlas of direct long-range inputs to GABAergic interneurons in the mPFC of male mice. We discovered that three subtypes of GABAergic interneurons in two areas of the mPFC are innervated by same upstream areas. Input from subcortical upstream areas includes cholinergic neurons from the basal forebrain and serotonergic neurons (which co-release glutamate) from the raphe nuclei. Reconstruction of single-neuron morphology revealed novel substantia innominata-anteromedial thalamic nucleus-mPFC and striatum-anteromedial thalamic nucleus-mPFC circuits. Based on the projection logic of individual neurons, we classified cortical and hippocampal input neurons into several types. This atlas provides the anatomical foundation for understanding the functional organization of the mPFC.
Topics: Animals; Brain Mapping; Cell Count; Hippocampus; Interneurons; Male; Mice; Mice, Inbred C57BL; Parasympathetic Nervous System; Prefrontal Cortex; Prosencephalon; Raphe Nuclei; Serotonergic Neurons; Thalamus; gamma-Aminobutyric Acid
PubMed: 31285615
DOI: 10.1038/s41593-019-0429-9 -
Nature Neuroscience Sep 2023Idiopathic autism spectrum disorder (ASD) is highly heterogeneous, and it remains unclear how convergent biological processes in affected individuals may give rise to...
Idiopathic autism spectrum disorder (ASD) is highly heterogeneous, and it remains unclear how convergent biological processes in affected individuals may give rise to symptoms. Here, using cortical organoids and single-cell transcriptomics, we modeled alterations in the forebrain development between boys with idiopathic ASD and their unaffected fathers in 13 families. Transcriptomic changes suggest that ASD pathogenesis in macrocephalic and normocephalic probands involves an opposite disruption of the balance between excitatory neurons of the dorsal cortical plate and other lineages such as early-generated neurons from the putative preplate. The imbalance stemmed from divergent expression of transcription factors driving cell fate during early cortical development. While we did not find genomic variants in probands that explained the observed transcriptomic alterations, a significant overlap between altered transcripts and reported ASD risk genes affected by rare variants suggests a degree of gene convergence between rare forms of ASD and the developmental transcriptome in idiopathic ASD.
Topics: Male; Humans; Autistic Disorder; Autism Spectrum Disorder; Neurons; Neurogenesis; Prosencephalon; Organoids
PubMed: 37563294
DOI: 10.1038/s41593-023-01399-0 -
Nature Apr 2024Timothy syndrome (TS) is a severe, multisystem disorder characterized by autism, epilepsy, long-QT syndrome and other neuropsychiatric conditions. TS type 1 (TS1) is...
Timothy syndrome (TS) is a severe, multisystem disorder characterized by autism, epilepsy, long-QT syndrome and other neuropsychiatric conditions. TS type 1 (TS1) is caused by a gain-of-function variant in the alternatively spliced and developmentally enriched CACNA1C exon 8A, as opposed to its counterpart exon 8. We previously uncovered several phenotypes in neurons derived from patients with TS1, including delayed channel inactivation, prolonged depolarization-induced calcium rise, impaired interneuron migration, activity-dependent dendrite retraction and an unanticipated persistent expression of exon 8A. We reasoned that switching CACNA1C exon utilization from 8A to 8 would represent a potential therapeutic strategy. Here we developed antisense oligonucleotides (ASOs) to effectively decrease the inclusion of exon 8A in human cells both in vitro and, following transplantation, in vivo. We discovered that the ASO-mediated switch from exon 8A to 8 robustly rescued defects in patient-derived cortical organoids and migration in forebrain assembloids. Leveraging a transplantation platform previously developed, we found that a single intrathecal ASO administration rescued calcium changes and in vivo dendrite retraction of patient neurons, suggesting that suppression of CACNA1C exon 8A expression is a potential treatment for TS1. Broadly, these experiments illustrate how a multilevel, in vivo and in vitro stem cell model-based approach can identify strategies to reverse disease-relevant neural pathophysiology.
Topics: Animals; Female; Humans; Male; Mice; Alternative Splicing; Autistic Disorder; Calcium; Calcium Channels, L-Type; Cell Movement; Dendrites; Exons; Long QT Syndrome; Neurons; Oligonucleotides, Antisense; Organoids; Prosencephalon; Syndactyly; Interneurons
PubMed: 38658687
DOI: 10.1038/s41586-024-07310-6 -
Neuropsychopharmacology : Official... Jan 2022Subdivisions of the prefrontal cortex (PFC) evolved at different times. Agranular parts of the PFC emerged in early mammals, and rodents, primates, and other modern... (Review)
Review
Subdivisions of the prefrontal cortex (PFC) evolved at different times. Agranular parts of the PFC emerged in early mammals, and rodents, primates, and other modern mammals share them by inheritance. These are limbic areas and include the agranular orbital cortex and agranular medial frontal cortex (areas 24, 32, and 25). Rodent research provides valuable insights into the structure, functions, and development of these shared areas, but it contributes less to parts of the PFC that are specific to primates, namely, the granular, isocortical PFC that dominates the frontal lobe in humans. The first granular PFC areas evolved either in early primates or in the last common ancestor of primates and tree shrews. Additional granular PFC areas emerged in the primate stem lineage, as represented by modern strepsirrhines. Other granular PFC areas evolved in simians, the group that includes apes, humans, and monkeys. In general, PFC accreted new areas along a roughly posterior to anterior trajectory during primate evolution. A major expansion of the granular PFC occurred in humans in concert with other association areas, with modifications of corticocortical connectivity and gene expression, although current evidence does not support the addition of a large number of new, human-specific PFC areas.
Topics: Animals; Cerebral Cortex; Frontal Lobe; Prefrontal Cortex
PubMed: 34363014
DOI: 10.1038/s41386-021-01076-5 -
Brain, Behavior and Evolution 2022The forebrain plays a critical role in a broad range of neural processes encompassing sensory integration and initiation/selection of behaviour. The forebrain functions... (Review)
Review
The forebrain plays a critical role in a broad range of neural processes encompassing sensory integration and initiation/selection of behaviour. The forebrain functions through an interaction between different cortical areas, the thalamus, the basal ganglia with the dopamine system, and the habenulae. The ambition here is to compare the mammalian forebrain with that of the lamprey representing the oldest now living group of vertebrates, by a review of earlier studies. We show that the lamprey dorsal pallium has a motor, a somatosensory, and a visual area with retinotopic representation. The lamprey pallium was previously thought to be largely olfactory. There is also a detailed similarity between the lamprey and mammals with regard to other forebrain structures like the basal ganglia in which the general organisation, connectivity, transmitters and their receptors, neuropeptides, and expression of ion channels are virtually identical. These initially unexpected results allow for the possibility that many aspects of the basic design of the vertebrate forebrain had evolved before the lamprey diverged from the evolutionary line leading to mammals. Based on a detailed comparison between the mammalian forebrain and that of the lamprey and with due consideration of data from other vertebrate groups, we propose a compelling account of a pan-vertebrate schema for basic forebrain structures, suggesting a common ancestry of over half a billion years of vertebrate evolution.
Topics: Animals; Biological Evolution; Lampreys; Mammals; Prosencephalon; Vertebrates
PubMed: 34192700
DOI: 10.1159/000517492 -
Nature Neuroscience Jan 2024The striatal and pallidal complexes are basal ganglia structures that orchestrate learning and execution of flexible behavior. Models of how the basal ganglia subserve... (Review)
Review
The striatal and pallidal complexes are basal ganglia structures that orchestrate learning and execution of flexible behavior. Models of how the basal ganglia subserve these functions have evolved considerably, and the advent of optogenetic and molecular tools has shed light on the heterogeneity of subcircuits within these pathways. However, a synthesis of how molecularly diverse neurons integrate into existing models of basal ganglia function is lacking. Here, we provide an overview of the neurochemical and molecular diversity of striatal and pallidal neurons and synthesize recent circuit connectivity studies in rodents that takes this diversity into account. We also highlight anatomical organizational principles that distinguish the dorsal and ventral basal ganglia pathways in rodents. Future work integrating the molecular and anatomical properties of striatal and pallidal subpopulations may resolve controversies regarding basal ganglia network function.
Topics: Corpus Striatum; Globus Pallidus; Basal Ganglia; Neurons; Neostriatum; Neural Pathways
PubMed: 38057614
DOI: 10.1038/s41593-023-01518-x -
Trends in Cognitive Sciences Dec 2022Early hypotheses of claustrum function were fueled by neuroanatomical data and yielded suggestions that the claustrum is involved in processes ranging from salience... (Review)
Review
Early hypotheses of claustrum function were fueled by neuroanatomical data and yielded suggestions that the claustrum is involved in processes ranging from salience detection to multisensory integration for perceptual binding. While these hypotheses spurred useful investigations, incompatibilities inherent in these views must be reconciled to further conceptualize claustrum function amid a wealth of new data. Here, we review the varied models of claustrum function and synthesize them with developments in the field to produce a novel functional model: network instantiation in cognitive control (NICC). This model proposes that frontal cortices direct the claustrum to flexibly instantiate cortical networks to subserve cognitive control. We present literature support for this model and provide testable predictions arising from this conceptual framework.
Topics: Humans; Claustrum; Basal Ganglia; Neural Pathways; Frontal Lobe; Cognition
PubMed: 36192309
DOI: 10.1016/j.tics.2022.09.006 -
Annual Review of Neuroscience Jul 2020The claustrum is one of the most widely connected regions of the forebrain, yet its function has remained obscure, largely due to the experimentally challenging nature... (Review)
Review
The claustrum is one of the most widely connected regions of the forebrain, yet its function has remained obscure, largely due to the experimentally challenging nature of targeting this small, thin, and elongated brain area. However, recent advances in molecular techniques have enabled the anatomy and physiology of the claustrum to be studied with the spatiotemporal and cell type-specific precision required to eventually converge on what this area does. Here we review early anatomical and electrophysiological results from cats and primates, as well as recent work in the rodent, identifying the connectivity, cell types, and physiological circuit mechanisms underlying the communication between the claustrum and the cortex. The emerging picture is one in which the rodent claustrum is closely tied to frontal/limbic regions and plays a role in processes, such as attention, that are associated with these areas.
Topics: Animals; Basal Ganglia; Cerebral Cortex; Claustrum; Frontal Lobe; Neural Pathways; Prefrontal Cortex
PubMed: 32084328
DOI: 10.1146/annurev-neuro-092519-101637 -
Current Opinion in Neurobiology Oct 2020The hippocampus performs two complementary processes, pattern separation and pattern completion, to minimize interference and maximize the storage capacity of memories.... (Review)
Review
The hippocampus performs two complementary processes, pattern separation and pattern completion, to minimize interference and maximize the storage capacity of memories. Classic computational models have suggested that the dentate gyrus (DG) supports pattern separation and the putative attractor circuitry in CA3 supports pattern completion. However, recent evidence of functional heterogeneity along the CA3 transverse axis of the hippocampus suggests that the DG and proximal CA3 work as a functional unit for pattern separation, while distal CA3 forms an autoassociative network for pattern completion. We propose that the outputs of these functional circuits, combined with direct projections from entorhinal cortex to CA1, form interconnected, parallel processing circuits to support accurate memory storage and retrieval.
Topics: Dentate Gyrus; Entorhinal Cortex; Hippocampus; Memory
PubMed: 32502734
DOI: 10.1016/j.conb.2020.03.004 -
International Journal of Molecular... May 2021A prolonged developmental timeline for GABA (γ-aminobutyric acid)-expressing inhibitory neurons (GABAergic interneurons) is an amplified trait in larger, gyrencephalic... (Review)
Review
A prolonged developmental timeline for GABA (γ-aminobutyric acid)-expressing inhibitory neurons (GABAergic interneurons) is an amplified trait in larger, gyrencephalic animals. In several species, the generation, migration, and maturation of interneurons take place over several months, in some cases persisting after birth. The late integration of GABAergic interneurons occurs in a region-specific pattern, especially during the early postnatal period. These changes can contribute to the formation of functional connectivity and plasticity, especially in the cortical regions responsible for higher cognitive tasks. In this review, we discuss GABAergic interneuron development in the late gestational and postnatal forebrain. We propose the protracted development of interneurons at each stage (neurogenesis, neuronal migration, and network integration), as a mechanism for increased complexity and cognitive flexibility in larger, gyrencephalic brains. This developmental feature of interneurons also provides an avenue for environmental influences to shape neural circuit formation.
Topics: Animals; Animals, Newborn; Female; Gestational Age; Interneurons; Pregnancy; Prosencephalon; gamma-Aminobutyric Acid
PubMed: 34066025
DOI: 10.3390/ijms22105113