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Neuron Mar 2021Interneurons expressing cholecystokinin (CCK) and parvalbumin (PV) constitute two key GABAergic controllers of hippocampal pyramidal cell output. Although the temporally...
Interneurons expressing cholecystokinin (CCK) and parvalbumin (PV) constitute two key GABAergic controllers of hippocampal pyramidal cell output. Although the temporally precise and millisecond-scale inhibitory regulation of neuronal ensembles delivered by PV interneurons is well established, the in vivo recruitment patterns of CCK-expressing basket cell (BC) populations has remained unknown. We show in the CA1 of the mouse hippocampus that the activity of CCK BCs inversely scales with both PV and pyramidal cell activity at the behaviorally relevant timescales of seconds. Intervention experiments indicated that the inverse coupling of CCK and PV GABAergic systems arises through a mechanism involving powerful inhibitory control of CCK BCs by PV cells. The tightly coupled complementarity of two key microcircuit regulatory modules demonstrates a novel form of brain-state-specific segregation of inhibition during spontaneous behavior.
Topics: Animals; CA1 Region, Hippocampal; Cholecystokinin; Female; Interneurons; Male; Mice, Inbred C57BL; Mice, Transgenic; Parvalbumins; Pyramidal Cells; Synaptic Transmission; Mice
PubMed: 33529646
DOI: 10.1016/j.neuron.2021.01.003 -
Nature Oct 2021Diverse types of glutamatergic pyramidal neurons mediate the myriad processing streams and output channels of the cerebral cortex, yet all derive from neural progenitors...
Diverse types of glutamatergic pyramidal neurons mediate the myriad processing streams and output channels of the cerebral cortex, yet all derive from neural progenitors of the embryonic dorsal telencephalon. Here we establish genetic strategies and tools for dissecting and fate-mapping subpopulations of pyramidal neurons on the basis of their developmental and molecular programs. We leverage key transcription factors and effector genes to systematically target temporal patterning programs in progenitors and differentiation programs in postmitotic neurons. We generated over a dozen temporally inducible mouse Cre and Flp knock-in driver lines to enable the combinatorial targeting of major progenitor types and projection classes. Combinatorial strategies confer viral access to subsets of pyramidal neurons defined by developmental origin, marker expression, anatomical location and projection targets. These strategies establish an experimental framework for understanding the hierarchical organization and developmental trajectory of subpopulations of pyramidal neurons that assemble cortical processing networks and output channels.
Topics: Animals; Cell Lineage; Cerebral Cortex; Gene Expression Regulation; Glutamic Acid; Male; Mice; Pyramidal Cells; Transcription Factors
PubMed: 34616069
DOI: 10.1038/s41586-021-03955-9 -
Nature Aug 2022Microglia are specialized macrophages in the brain parenchyma that exist in multiple transcriptional states and reside within a wide range of neuronal environments....
Microglia are specialized macrophages in the brain parenchyma that exist in multiple transcriptional states and reside within a wide range of neuronal environments. However, how and where these states are generated remains poorly understood. Here, using the mouse somatosensory cortex, we demonstrate that microglia density and molecular state acquisition are determined by the local composition of pyramidal neuron classes. Using single-cell and spatial transcriptomic profiling, we unveil the molecular signatures and spatial distributions of diverse microglia populations and show that certain states are enriched in specific cortical layers, whereas others are broadly distributed throughout the cortex. Notably, conversion of deep-layer pyramidal neurons to an alternate class identity reconfigures the distribution of local, layer-enriched homeostatic microglia to match the new neuronal niche. Leveraging the transcriptional diversity of pyramidal neurons in the neocortex, we construct a ligand-receptor atlas describing interactions between individual pyramidal neuron subtypes and microglia states, revealing rules of neuron-microglia communication. Our findings uncover a fundamental role for neuronal diversity in instructing the acquisition of microglia states as a potential mechanism for fine-tuning neuroimmune interactions within the cortical local circuitry.
Topics: Animals; Cell Count; Mice; Microglia; Neocortex; Pyramidal Cells; Single-Cell Analysis; Somatosensory Cortex; Transcriptome
PubMed: 35948630
DOI: 10.1038/s41586-022-05056-7 -
Cell Apr 2023Cortical circuits are composed predominantly of pyramidal-to-pyramidal neuron connections, yet their assembly during embryonic development is not well understood. We...
Cortical circuits are composed predominantly of pyramidal-to-pyramidal neuron connections, yet their assembly during embryonic development is not well understood. We show that mouse embryonic Rbp4-Cre cortical neurons, transcriptomically closest to layer 5 pyramidal neurons, display two phases of circuit assembly in vivo. At E14.5, they form a multi-layered circuit motif, composed of only embryonic near-projecting-type neurons. By E17.5, this transitions to a second motif involving all three embryonic types, analogous to the three adult layer 5 types. In vivo patch clamp recordings and two-photon calcium imaging of embryonic Rbp4-Cre neurons reveal active somas and neurites, tetrodotoxin-sensitive voltage-gated conductances, and functional glutamatergic synapses, from E14.5 onwards. Embryonic Rbp4-Cre neurons strongly express autism-associated genes and perturbing these genes interferes with the switch between the two motifs. Hence, pyramidal neurons form active, transient, multi-layered pyramidal-to-pyramidal circuits at the inception of neocortex, and studying these circuits could yield insights into the etiology of autism.
Topics: Animals; Female; Mice; Pregnancy; Autistic Disorder; Mutation; Neocortex; Neurons; Pyramidal Cells
PubMed: 37071993
DOI: 10.1016/j.cell.2023.03.025 -
General anesthesia globally synchronizes activity selectively in layer 5 cortical pyramidal neurons.Neuron Jun 2022General anesthetics induce loss of consciousness, a global change in behavior. However, a corresponding global change in activity in the context of defined cortical cell...
General anesthetics induce loss of consciousness, a global change in behavior. However, a corresponding global change in activity in the context of defined cortical cell types has not been identified. Here, we show that spontaneous activity of mouse layer 5 pyramidal neurons, but of no other cortical cell type, becomes consistently synchronized in vivo by different general anesthetics. This heightened neuronal synchrony is aperiodic, present across large distances, and absent in cortical neurons presynaptic to layer 5 pyramidal neurons. During the transition to and from anesthesia, changes in synchrony in layer 5 coincide with the loss and recovery of consciousness. Activity within both apical and basal dendrites is synchronous, but only basal dendrites' activity is temporally locked to somatic activity. Given that layer 5 is a major cortical output, our results suggest that brain-wide synchrony in layer 5 pyramidal neurons may contribute to the loss of consciousness during general anesthesia.
Topics: Anesthesia, General; Anesthetics, General; Animals; Dendrites; Mice; Pyramidal Cells; Unconsciousness
PubMed: 35452606
DOI: 10.1016/j.neuron.2022.03.032 -
Neuron Jul 2017Synaptic plasticity (e.g., long-term potentiation [LTP]) is considered the cellular correlate of learning. Recent optogenetic studies on memory engram formation assign a... (Review)
Review
Synaptic plasticity (e.g., long-term potentiation [LTP]) is considered the cellular correlate of learning. Recent optogenetic studies on memory engram formation assign a critical role in learning to suprathreshold activation of neurons and their integration into active engrams ("engram cells"). Here we review evidence that ensemble integration may result from LTP but also from cell-autonomous changes in membrane excitability. We propose that synaptic plasticity determines synaptic connectivity maps, whereas intrinsic plasticity-possibly separated in time-amplifies neuronal responsiveness and acutely drives engram integration. Our proposal marks a move away from an exclusively synaptocentric toward a non-exclusive, neurocentric view of learning.
Topics: Animals; Brain; Cerebellum; Cerebral Cortex; Hippocampus; Learning; Long-Term Potentiation; Membrane Potentials; Neuronal Plasticity; Neurons; Pyramidal Cells; Synaptic Transmission
PubMed: 28683265
DOI: 10.1016/j.neuron.2017.05.021 -
Cell Mar 2022We assembled a semi-automated reconstruction of L2/3 mouse primary visual cortex from ∼250 × 140 × 90 μm of electron microscopic images, including pyramidal and...
We assembled a semi-automated reconstruction of L2/3 mouse primary visual cortex from ∼250 × 140 × 90 μm of electron microscopic images, including pyramidal and non-pyramidal neurons, astrocytes, microglia, oligodendrocytes and precursors, pericytes, vasculature, nuclei, mitochondria, and synapses. Visual responses of a subset of pyramidal cells are included. The data are publicly available, along with tools for programmatic and three-dimensional interactive access. Brief vignettes illustrate the breadth of potential applications relating structure to function in cortical circuits and neuronal cell biology. Mitochondria and synapse organization are characterized as a function of path length from the soma. Pyramidal connectivity motif frequencies are predicted accurately using a configuration model of random graphs. Pyramidal cells receiving more connections from nearby cells exhibit stronger and more reliable visual responses. Sample code shows data access and analysis.
Topics: Animals; Mice; Microscopy, Electron; Neocortex; Organelles; Pyramidal Cells; Synapses
PubMed: 35216674
DOI: 10.1016/j.cell.2022.01.023 -
Nature Neuroscience Mar 2023Understanding how cortical circuits generate complex behavior requires investigating the cell types that comprise them. Functional differences across pyramidal neuron...
Understanding how cortical circuits generate complex behavior requires investigating the cell types that comprise them. Functional differences across pyramidal neuron (PyN) types have been observed within cortical areas, but it is not known whether these local differences extend throughout the cortex, nor whether additional differences emerge when larger-scale dynamics are considered. We used genetic and retrograde labeling to target pyramidal tract, intratelencephalic and corticostriatal projection neurons and measured their cortex-wide activity. Each PyN type drove unique neural dynamics, both at the local and cortex-wide scales. Cortical activity and optogenetic inactivation during an auditory decision task revealed distinct functional roles. All PyNs in parietal cortex were recruited during perception of the auditory stimulus, but, surprisingly, pyramidal tract neurons had the largest causal role. In frontal cortex, all PyNs were required for accurate choices but showed distinct choice tuning. Our results reveal that rich, cell-type-specific cortical dynamics shape perceptual decisions.
Topics: Pyramidal Cells; Neurons; Frontal Lobe; Interneurons; Optogenetics
PubMed: 36690900
DOI: 10.1038/s41593-022-01245-9 -
Cell Reports Sep 2023Fear-related disorders arise from inefficient fear extinction and have immeasurable social and economic costs. Here, we characterize mouse phenotypes that spontaneously...
Fear-related disorders arise from inefficient fear extinction and have immeasurable social and economic costs. Here, we characterize mouse phenotypes that spontaneously show fear-independent behavioral traits predicting adaptive or maladaptive fear extinction. We find that, already before fear conditioning, specific morphological, electrophysiological, and transcriptomic patterns of cortical and amygdala pyramidal neurons predispose to fear-related disorders. Finally, by using an optogenetic approach, we show the possibility to rescue inefficient fear extinction by activating infralimbic pyramidal neurons and to impair fear extinction by activating prelimbic pyramidal neurons.
Topics: Mice; Animals; Prefrontal Cortex; Fear; Transcriptome; Extinction, Psychological; Amygdala; Pyramidal Cells
PubMed: 37656620
DOI: 10.1016/j.celrep.2023.113066 -
Biological Psychiatry Sep 2022Individuals with schizophrenia (SZ) exhibit cognitive performance below expected levels based on familial cognitive aptitude. One such cognitive process, working memory... (Review)
Review
Individuals with schizophrenia (SZ) exhibit cognitive performance below expected levels based on familial cognitive aptitude. One such cognitive process, working memory (WM), is robustly impaired in SZ. These WM impairments, which emerge over development during the premorbid and prodromal stages of SZ, appear to reflect alterations in the neural circuitry of the dorsolateral prefrontal cortex. Within the dorsolateral prefrontal cortex, a microcircuit formed by reciprocal connections between excitatory layer 3 pyramidal neurons and inhibitory parvalbumin basket cells (PVBCs) appears to be a key neural substrate for WM. Postmortem human studies indicate that both layer 3 pyramidal neurons and PVBCs are altered in SZ, suggesting that levels of excitation and inhibition are lower in the microcircuit. Studies in monkeys indicate that features of both cell types exhibit distinctive postnatal developmental trajectories. Together, the results of these studies suggest a model in which 1) genetic and/or early environmental insults to excitatory signaling in layer 3 pyramidal neurons give rise to cognitive impairments during the prodromal phase of SZ and evoke compensatory changes in inhibition that alter the developmental trajectories of PVBCs, and 2) synaptic pruning during adolescence further lowers excitatory activity to a level that exceeds the compensatory capacity of PVBC inhibition, leading to a failure of the normal maturational improvements in WM during the prodromal and early clinical stages of SZ. Findings that support as well as challenge this model are discussed.
Topics: Cognitive Dysfunction; Humans; Parvalbumins; Prefrontal Cortex; Pyramidal Cells; Schizophrenia
PubMed: 35568522
DOI: 10.1016/j.biopsych.2022.03.002