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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 Feb 2021Behavioural experiences activate the FOS transcription factor in sparse populations of neurons that are critical for encoding and recalling specific events. However,...
Behavioural experiences activate the FOS transcription factor in sparse populations of neurons that are critical for encoding and recalling specific events. However, there is limited understanding of the mechanisms by which experience drives circuit reorganization to establish a network of Fos-activated cells. It is also not known whether FOS is required in this process beyond serving as a marker of recent neural activity and, if so, which of its many gene targets underlie circuit reorganization. Here we demonstrate that when mice engage in spatial exploration of novel environments, perisomatic inhibition of Fos-activated hippocampal CA1 pyramidal neurons by parvalbumin-expressing interneurons is enhanced, whereas perisomatic inhibition by cholecystokinin-expressing interneurons is weakened. This bidirectional modulation of inhibition is abolished when the function of the FOS transcription factor complex is disrupted. Single-cell RNA-sequencing, ribosome-associated mRNA profiling and chromatin analyses, combined with electrophysiology, reveal that FOS activates the transcription of Scg2, a gene that encodes multiple distinct neuropeptides, to coordinate these changes in inhibition. As parvalbumin- and cholecystokinin-expressing interneurons mediate distinct features of pyramidal cell activity, the SCG2-dependent reorganization of inhibitory synaptic input might be predicted to affect network function in vivo. Consistent with this prediction, hippocampal gamma rhythms and pyramidal cell coupling to theta phase are significantly altered in the absence of Scg2. These findings reveal an instructive role for FOS and SCG2 in establishing a network of Fos-activated neurons via the rewiring of local inhibition to form a selectively modulated state. The opposing plasticity mechanisms acting on distinct inhibitory pathways may support the consolidation of memories over time.
Topics: Animals; CA1 Region, Hippocampal; Cholecystokinin; Exploratory Behavior; Female; Gamma Rhythm; Interneurons; Male; Memory Consolidation; Mice; Nerve Net; Neural Inhibition; Neuronal Plasticity; Parvalbumins; Proto-Oncogene Proteins c-fos; Pyramidal Cells; Secretogranin II; Spatial Navigation; Theta Rhythm
PubMed: 33299180
DOI: 10.1038/s41586-020-3031-0 -
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 -
Brain : a Journal of Neurology Feb 2021Extracellular vesicles are highly transmissible and play critical roles in the propagation of tau pathology, although the underlying mechanism remains elusive. Here, for...
Extracellular vesicles are highly transmissible and play critical roles in the propagation of tau pathology, although the underlying mechanism remains elusive. Here, for the first time, we comprehensively characterized the physicochemical structure and pathogenic function of human brain-derived extracellular vesicles isolated from Alzheimer's disease, prodromal Alzheimer's disease, and non-demented control cases. Alzheimer's disease extracellular vesicles were significantly enriched in epitope-specific tau oligomers in comparison to prodromal Alzheimer's disease or control extracellular vesicles as determined by dot blot and atomic force microscopy. Alzheimer's disease extracellular vesicles were more efficiently internalized by murine cortical neurons, as well as more efficient in transferring and misfolding tau, than prodromal Alzheimer's disease and control extracellular vesicles in vitro. Strikingly, the inoculation of Alzheimer's disease or prodromal Alzheimer's disease extracellular vesicles containing only 300 pg of tau into the outer molecular layer of the dentate gyrus of 18-month-old C57BL/6 mice resulted in the accumulation of abnormally phosphorylated tau throughout the hippocampus by 4.5 months, whereas inoculation of an equal amount of tau from control extracellular vesicles, isolated tau oligomers, or fibrils from the same Alzheimer's disease donor showed little tau pathology. Furthermore, Alzheimer's disease extracellular vesicles induced misfolding of endogenous tau in both oligomeric and sarkosyl-insoluble forms in the hippocampal region. Unexpectedly, phosphorylated tau was primarily accumulated in glutamic acid decarboxylase 67 (GAD67) GABAergic interneurons and, to a lesser extent, glutamate receptor 2/3-positive excitatory mossy cells, showing preferential extracellular vesicle-mediated GABAergic interneuronal tau propagation. Whole-cell patch clamp recordings of CA1 pyramidal cells showed significant reduction in the amplitude of spontaneous inhibitory post-synaptic currents. This was accompanied by reductions in c-fos+ GAD67+ neurons and GAD67+ neuronal puncta surrounding pyramidal neurons in the CA1 region, confirming reduced GABAergic transmission in this region. Our study posits a novel mechanism for the spread of tau in hippocampal GABAergic interneurons via brain-derived extracellular vesicles and their subsequent neuronal dysfunction.
Topics: Alzheimer Disease; Animals; Brain; Extracellular Vesicles; Female; GABAergic Neurons; Hippocampus; Humans; Interneurons; Male; Mice, Inbred C57BL; Pyramidal Cells; tau Proteins; Mice
PubMed: 33246331
DOI: 10.1093/brain/awaa376 -
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 -
ELife Jun 2022Pyramidal neurons with axons that exit from dendrites rather than the cell body itself are relatively common in non-primates, but rare in monkeys and humans.
Pyramidal neurons with axons that exit from dendrites rather than the cell body itself are relatively common in non-primates, but rare in monkeys and humans.
Topics: Axons; Cell Body; Neurons; Pyramidal Cells
PubMed: 35647816
DOI: 10.7554/eLife.79839 -
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 -
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 -
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