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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 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 -
Neuroscience Oct 2013Schizophrenia is a neurodevelopmental disorder whose clinical features include impairments in perception, cognition and motivation. These impairments reflect alterations... (Review)
Review
Schizophrenia is a neurodevelopmental disorder whose clinical features include impairments in perception, cognition and motivation. These impairments reflect alterations in neuronal circuitry within and across multiple brain regions that are due, at least in part, to deficits in dendritic spines, the site of most excitatory synaptic connections. Dendritic spine alterations have been identified in multiple brain regions in schizophrenia, but are best characterized in layer 3 of the neocortex, where pyramidal cell spine density is lower. These spine deficits appear to arise during development, and thus are likely the result of disturbances in the molecular mechanisms that underlie spine formation, pruning, and/or maintenance. Each of these mechanisms may provide insight into novel therapeutic targets for preventing or repairing the alterations in neural circuitry that mediate the debilitating symptoms of schizophrenia.
Topics: Dendritic Spines; Humans; Neocortex; Pyramidal Cells; Schizophrenia
PubMed: 22546337
DOI: 10.1016/j.neuroscience.2012.04.044 -
Nature Neuroscience Apr 2018Hippocampal network operations supporting spatial navigation and declarative memory are traditionally interpreted in a framework where each hippocampal area, such as the... (Review)
Review
Hippocampal network operations supporting spatial navigation and declarative memory are traditionally interpreted in a framework where each hippocampal area, such as the dentate gyrus, CA3, and CA1, consists of homogeneous populations of functionally equivalent principal neurons. However, heterogeneity within hippocampal principal cell populations, in particular within pyramidal cells at the main CA1 output node, is increasingly recognized and includes developmental, molecular, anatomical, and functional differences. Here we review recent progress in the delineation of hippocampal principal cell subpopulations by focusing on radially defined subpopulations of CA1 pyramidal cells, and we consider how functional segregation of information streams, in parallel channels with nonuniform properties, could represent a general organizational principle of the hippocampus supporting diverse behaviors.
Topics: Animals; Electronic Data Processing; Hippocampus; Humans; Neural Pathways; Pyramidal Cells
PubMed: 29593317
DOI: 10.1038/s41593-018-0118-0 -
Trends in Cognitive Sciences Jun 2020The first patch-clamp recordings from the dendrites of human neocortical neurons have recently been reported by Beaulieu-Laroche et al. and Gidon et al. These studies...
The first patch-clamp recordings from the dendrites of human neocortical neurons have recently been reported by Beaulieu-Laroche et al. and Gidon et al. These studies have shown that human dendrites are electrically excitable, exhibiting backpropagating action potentials and fast dendritic calcium spikes. This new frontier highlights the potential for interspecies differences in the biophysics of dendritic computation.
Topics: Action Potentials; Dendrites; Humans; Neurons; Patch-Clamp Techniques; Pyramidal Cells
PubMed: 32392467
DOI: 10.1016/j.tics.2020.03.002 -
Cerebral Cortex (New York, N.Y. : 1991) May 2022Neocortical layer 6 plays a crucial role in sensorimotor co-ordination and integration through functionally segregated circuits linking intracortical and subcortical...
Neocortical layer 6 plays a crucial role in sensorimotor co-ordination and integration through functionally segregated circuits linking intracortical and subcortical areas. We performed whole-cell recordings combined with morphological reconstructions to identify morpho-electric types of layer 6A pyramidal cells (PCs) in rat barrel cortex. Cortico-thalamic (CT), cortico-cortical (CC), and cortico-claustral (CCla) PCs were classified based on their distinct morphologies and have been shown to exhibit different electrophysiological properties. We demonstrate that these three types of layer 6A PCs innervate neighboring excitatory neurons with distinct synaptic properties: CT PCs establish weak facilitating synapses onto other L6A PCs; CC PCs form synapses of moderate efficacy, while synapses made by putative CCla PCs display the highest release probability and a marked short-term depression. For excitatory-inhibitory synaptic connections in layer 6, both the presynaptic PC type and the postsynaptic interneuron type govern the dynamic properties of the respective synaptic connections. We have identified a functional division of local layer 6A excitatory microcircuits which may be responsible for the differential temporal engagement of layer 6 feed-forward and feedback networks. Our results provide a basis for further investigations on the long-range CC, CT, and CCla pathways.
Topics: Animals; Excitatory Postsynaptic Potentials; Interneurons; Neural Pathways; Pyramidal Cells; Rats; Synapses
PubMed: 34628499
DOI: 10.1093/cercor/bhab340 -
PLoS Computational Biology Sep 2022Improving biological plausibility and functional capacity are two important goals for brain models that connect low-level neural details to high-level behavioral...
Improving biological plausibility and functional capacity are two important goals for brain models that connect low-level neural details to high-level behavioral phenomena. We develop a method called "oracle-supervised Neural Engineering Framework" (osNEF) to train biologically-detailed spiking neural networks that realize a variety of cognitively-relevant dynamical systems. Specifically, we train networks to perform computations that are commonly found in cognitive systems (communication, multiplication, harmonic oscillation, and gated working memory) using four distinct neuron models (leaky-integrate-and-fire neurons, Izhikevich neurons, 4-dimensional nonlinear point neurons, and 4-compartment, 6-ion-channel layer-V pyramidal cell reconstructions) connected with various synaptic models (current-based synapses, conductance-based synapses, and voltage-gated synapses). We show that osNEF networks exhibit the target dynamics by accounting for nonlinearities present within the neuron models: performance is comparable across all four systems and all four neuron models, with variance proportional to task and neuron model complexity. We also apply osNEF to build a model of working memory that performs a delayed response task using a combination of pyramidal cells and inhibitory interneurons connected with NMDA and GABA synapses. The baseline performance and forgetting rate of the model are consistent with animal data from delayed match-to-sample tasks (DMTST): we observe a baseline performance of 95% and exponential forgetting with time constant τ = 8.5s, while a recent meta-analysis of DMTST performance across species observed baseline performances of 58 - 99% and exponential forgetting with time constants of τ = 2.4 - 71s. These results demonstrate that osNEF can train functional brain models using biologically-detailed components and open new avenues for investigating the relationship between biophysical mechanisms and functional capabilities.
Topics: Action Potentials; Animals; Models, Neurological; Neurons; Pyramidal Cells; Synapses
PubMed: 36074765
DOI: 10.1371/journal.pcbi.1010461 -
Neuron Oct 2017Excitatory control of inhibitory neurons is poorly understood due to the difficulty of studying synaptic connectivity in vivo. We inferred such connectivity through...
Excitatory control of inhibitory neurons is poorly understood due to the difficulty of studying synaptic connectivity in vivo. We inferred such connectivity through analysis of spike timing and validated this inference using juxtacellular and optogenetic control of presynaptic spikes in behaving mice. We observed that neighboring CA1 neurons had stronger connections and that superficial pyramidal cells projected more to deep interneurons. Connection probability and strength were skewed, with a minority of highly connected hubs. Divergent presynaptic connections led to synchrony between interneurons. Synchrony of convergent presynaptic inputs boosted postsynaptic drive. Presynaptic firing frequency was read out by postsynaptic neurons through short-term depression and facilitation, with individual pyramidal cells and interneurons displaying a diversity of spike transmission filters. Additionally, spike transmission was strongly modulated by prior spike timing of the postsynaptic cell. These results bridge anatomical structure with physiological function.
Topics: Action Potentials; Animals; CA1 Region, Hippocampal; Female; Interneurons; Male; Mice; Mice, Transgenic; Nerve Net; Optogenetics; Pyramidal Cells; Random Allocation
PubMed: 29024669
DOI: 10.1016/j.neuron.2017.09.033