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Neuron Sep 2023The cardinal classes are a useful simplification of cortical interneuron diversity, but such broad subgroupings gloss over the molecular, morphological, and circuit...
The cardinal classes are a useful simplification of cortical interneuron diversity, but such broad subgroupings gloss over the molecular, morphological, and circuit specificity of interneuron subtypes, most notably among the somatostatin interneuron class. Although there is evidence that this diversity is functionally relevant, the circuit implications of this diversity are unknown. To address this knowledge gap, we designed a series of genetic strategies to target the breadth of somatostatin interneuron subtypes and found that each subtype possesses a unique laminar organization and stereotyped axonal projection pattern. Using these strategies, we examined the afferent and efferent connectivity of three subtypes (two Martinotti and one non-Martinotti) and demonstrated that they possess selective connectivity with intratelecephalic or pyramidal tract neurons. Even when two subtypes targeted the same pyramidal cell type, their synaptic targeting proved selective for particular dendritic compartments. We thus provide evidence that subtypes of somatostatin interneurons form cell-type-specific cortical circuits.
Topics: Interneurons; Neurons; Pyramidal Cells; Axons; Somatostatin; Parvalbumins
PubMed: 37390821
DOI: 10.1016/j.neuron.2023.05.032 -
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 -
Neuron Jul 2023Traditionally considered a homogeneous cell type, hippocampal pyramidal cells have been recently shown to be highly diverse. However, how this cellular diversity relates...
Traditionally considered a homogeneous cell type, hippocampal pyramidal cells have been recently shown to be highly diverse. However, how this cellular diversity relates to the different hippocampal network computations that support memory-guided behavior is not yet known. We show that the anatomical identity of pyramidal cells is a major organizing principle of CA1 assembly dynamics, the emergence of memory replay, and cortical projection patterns in rats. Segregated pyramidal cell subpopulations encoded trajectory and choice-specific information or tracked changes in reward configuration respectively, and their activity was selectively read out by different cortical targets. Furthermore, distinct hippocampo-cortical assemblies coordinated the reactivation of complementary memory representations. These findings reveal the existence of specialized hippocampo-cortical subcircuits and provide a cellular mechanism that supports the computational flexibility and memory capacities of these structures.
Topics: Rats; Animals; Hippocampus; Pyramidal Cells
PubMed: 37196658
DOI: 10.1016/j.neuron.2023.04.015 -
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 -
Brain Research Mar 2019In the brain, dendrites of pyramidal neurons contain intermingled excitatory and inhibitory synapses. Synaptic connections dynamically change during development and... (Review)
Review
In the brain, dendrites of pyramidal neurons contain intermingled excitatory and inhibitory synapses. Synaptic connections dynamically change during development and throughout our lifetime, yet the brain can properly maintain an optimal ratio of synaptic excitation to inhibition. Despite recent advances in our understanding of the formation and refinement of excitatory glutamatergic synapses, little is known about signals that regulate inhibitory GABAergic synapse development. In this review, we discuss previous and recent insights in the cellular and molecular mechanisms that underlie GABAergic synapse formation and plasticity, with a specific focus on the key roles of synaptic activity and postsynaptic membrane molecules.
Topics: Animals; Brain; GABAergic Neurons; Humans; Nerve Tissue Proteins; Neuronal Plasticity; Pyramidal Cells; Synapses; Synaptic Transmission
PubMed: 30439352
DOI: 10.1016/j.brainres.2018.11.014 -
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