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Scientific Data May 2023The apical dendrites of pyramidal neurons in sensory cortex receive primarily top-down signals from associative and motor regions, while cell bodies and nearby dendrites...
The apical dendrites of pyramidal neurons in sensory cortex receive primarily top-down signals from associative and motor regions, while cell bodies and nearby dendrites are heavily targeted by locally recurrent or bottom-up inputs from the sensory periphery. Based on these differences, a number of theories in computational neuroscience postulate a unique role for apical dendrites in learning. However, due to technical challenges in data collection, little data is available for comparing the responses of apical dendrites to cell bodies over multiple days. Here we present a dataset collected through the Allen Institute Mindscope's OpenScope program that addresses this need. This dataset comprises high-quality two-photon calcium imaging from the apical dendrites and the cell bodies of visual cortical pyramidal neurons, acquired over multiple days in awake, behaving mice that were presented with visual stimuli. Many of the cell bodies and dendrite segments were tracked over days, enabling analyses of how their responses change over time. This dataset allows neuroscientists to explore the differences between apical and somatic processing and plasticity.
Topics: Animals; Mice; Cell Body; Dendrites; Neurons; Pyramidal Cells; Visual Cortex
PubMed: 37198203
DOI: 10.1038/s41597-023-02214-y -
Molecular Psychiatry Sep 2021Both the NMDA receptor (NMDAR) positive allosteric modulator (PAM), and antagonist, can exert rapid antidepressant effects as shown in several animal and human studies....
Both the NMDA receptor (NMDAR) positive allosteric modulator (PAM), and antagonist, can exert rapid antidepressant effects as shown in several animal and human studies. However, how this bidirectional modulation of NMDARs causes similar antidepressant effects remains unknown. Notably, the initial cellular trigger, specific cell-type(s), and subunit(s) of NMDARs mediating the antidepressant-like effects of a PAM or an antagonist have not been identified. Here, we used electrophysiology, microdialysis, and NMR spectroscopy to evaluate the effect of a NMDAR PAM (rapastinel) or NMDAR antagonist, ketamine on NMDAR function and disinhibition-mediated glutamate release. Further, we used cell-type specific knockdown (KD), pharmacological, and behavioral approaches to dissect the cell-type specific role of GluN2B, GluN2A, and dopamine receptor subunits in the actions of NMDAR PAM vs. antagonists. We demonstrate that rapastinel directly enhances NMDAR activity on principal glutamatergic neurons in medial prefrontal cortex (mPFC) without any effect on glutamate efflux, while ketamine blocks NMDAR on GABA interneurons to cause glutamate efflux and indirect activation of excitatory synapses. Behavioral studies using cell-type-specific KD in mPFC demonstrate that NMDAR-GluN2B KD on Camk2a- but not Gad1-expressing neurons blocks the antidepressant effects of rapastinel. In contrast, GluN2B KD on Gad1- but not Camk2a-expressing neurons blocks the actions of ketamine. The results also demonstrate that Drd1-expressing pyramidal neurons in mPFC mediate the rapid antidepressant actions of ketamine and rapastinel. Together, these results demonstrate unique initial cellular triggers as well as converging effects on Drd1-pyramidal cell signaling that underlie the antidepressant actions of NMDAR-positive modulation vs. NMDAR blockade.
Topics: Animals; Antidepressive Agents; Humans; Interneurons; Ketamine; Prefrontal Cortex; Pyramidal Cells; Receptors, N-Methyl-D-Aspartate
PubMed: 32488125
DOI: 10.1038/s41380-020-0796-3 -
Proceedings of the National Academy of... Mar 2022SignificanceChandelier cells (ChCs) are a unique type of GABAergic interneuron that form axo-axonic synapses exclusively on the axon initial segment (AIS) of neocortical...
SignificanceChandelier cells (ChCs) are a unique type of GABAergic interneuron that form axo-axonic synapses exclusively on the axon initial segment (AIS) of neocortical pyramidal neurons (PyNs), allowing them to exert powerful yet precise control over PyN firing and population output. The importance of proper ChC function is further underscored by the association of ChC connectivity defects with various neurological conditions. Despite this, the cellular mechanisms governing ChC axo-axonic synapse formation remain poorly understood. Here, we identify microglia as key regulators of ChC axonal morphogenesis and AIS synaptogenesis, and show that disease-induced aberrant microglial activation perturbs proper ChC synaptic development/connectivity in the neocortex. In doing so, such findings highlight the therapeutic potential of manipulating microglia to ensure proper brain wiring.
Topics: Animals; Axon Initial Segment; GABAergic Neurons; Mice; Microglia; Pyramidal Cells; Synapses
PubMed: 35263225
DOI: 10.1073/pnas.2114476119 -
ENeuro 2022Parvalbumin (PV)-producing neurons are the largest subpopulation of cortical GABAergic interneurons, which mediate lateral, feedforward, and feedback inhibition in local...
Parvalbumin (PV)-producing neurons are the largest subpopulation of cortical GABAergic interneurons, which mediate lateral, feedforward, and feedback inhibition in local circuits and modulate the activity of pyramidal neurons. Clarifying the specific connectivity between pyramidal and PV neurons is essential for understanding the role of PV neurons in local circuits. In the present study, we visualized somas and dendrites of PV neurons using transgenic mice in which PV neurons specifically express membrane-targeted GFP, and intracellularly labeled local axons of 26 pyramidal neurons in layers 2-6 in acute slices of the motor-associated cortex from transgenic mice. We mapped morphologically distribution of inputs from a pyramidal neuron to PV neurons based on contact sites (appositions) between the axons from an intracellularly filled pyramidal neuron and the dendrites of PV neurons. Layer 6 corticothalamic (CT)-like pyramidal neurons formed appositions to PV neurons at a significantly higher rate than other pyramidal neurons. The percentage of apposed varicosities to all the labeled varicosities of layer 6 CT-like neurons was 28%, and that of the other pyramidal neurons was 12-19%. Layer 6 CT-like neurons preferentially formed appositions with PV neurons in layers 5b-6, while other pyramidal neurons uniformly formed appositions with PV neurons in all layers. Furthermore, both layer 6 CT-like and corticocortical-like neurons more frequently formed compound appositions, where two or more appositions were located on a dendritic branch, than other pyramidal neurons. Layer 6 CT neurons may contribute to intracortical information processing through preferential connections with PV neurons in layers 5b-6.
Topics: Animals; Dendrites; Interneurons; Mice; Mice, Transgenic; Parvalbumins; Pyramidal Cells
PubMed: 34965927
DOI: 10.1523/ENEURO.0567-20.2021 -
Science (New York, N.Y.) Sep 2022Information processing in neuronal networks involves the recruitment of selected neurons into coordinated spatiotemporal activity patterns. This sparse activation...
Information processing in neuronal networks involves the recruitment of selected neurons into coordinated spatiotemporal activity patterns. This sparse activation results from widespread synaptic inhibition in conjunction with neuron-specific synaptic excitation. We report the selective recruitment of hippocampal pyramidal cells into patterned network activity. During ripple oscillations in awake mice, spiking is much more likely in cells in which the axon originates from a basal dendrite rather than from the soma. High-resolution recordings in vitro and computer modeling indicate that these spikes are elicited by synaptic input to the axon-carrying dendrite and thus escape perisomatic inhibition. Pyramidal cells with somatic axon origin can be activated during ripple oscillations by blocking their somatic inhibition. The recruitment of neurons into active ensembles is thus determined by axonal morphological features.
Topics: Action Potentials; Animals; Axons; Computer Simulation; Dendrites; Inhibitory Postsynaptic Potentials; Mice; Pyramidal Cells
PubMed: 36137045
DOI: 10.1126/science.abj1861 -
Hippocampus Jun 2023The hippocampus is a center for spatial and episodic memory formation in rodents. Understanding the composition of subregions and circuitry maps of the hippocampus is... (Review)
Review
The hippocampus is a center for spatial and episodic memory formation in rodents. Understanding the composition of subregions and circuitry maps of the hippocampus is essential for elucidating the mechanism of memory formation and recall. For decades, the trisynaptic circuit (entorhinal cortex layer II-dentate gyrus - CA3-CA1) has been considered the neural network substrate responsible for learning and memory. Recently, CA2 has emerged as an important area in the hippocampal circuitry, with distinct functions from those of CA3. In this article, we review the historical definition of the hippocampal area CA2 and the differential projection patterns between CA2 and CA3 pyramidal neurons. We provide a concise and comprehensive map of CA2 outputs by comparing (1) ipsi versus contra projections, (2) septal versus temporal projections, and (3) lamellar structures of CA2 and CA3 pyramidal neurons.
Topics: Animals; Rodentia; Hippocampus; Pyramidal Cells; Entorhinal Cortex
PubMed: 36855258
DOI: 10.1002/hipo.23519 -
Cerebral Cortex (New York, N.Y. : 1991) Jul 2021Pyramidal neurons are the most abundant and characteristic neuronal type in the cerebral cortex and their dendritic spines are the main postsynaptic elements of cortical...
Pyramidal neurons are the most abundant and characteristic neuronal type in the cerebral cortex and their dendritic spines are the main postsynaptic elements of cortical excitatory synapses. Previous studies have shown that pyramidal cell structure differs across layers, cortical areas, and species. However, within the human cortex, the pyramidal dendritic morphology has been quantified in detail in relatively few cortical areas. In the present work, we performed intracellular injections of Lucifer Yellow at several distances from the temporal pole. We found regional differences in pyramidal cell morphology, which showed large inter-individual variability in most of the morphological variables measured. However, some values remained similar in all cases. The smallest and least complex cells in the most posterior temporal region showed the greatest dendritic spine density. Neurons in the temporal pole showed the greatest sizes with the highest number of spines. Layer V cells were larger, more complex, and had a greater number of dendritic spines than those in layer III. The present results suggest that, while some aspects of pyramidal structure are conserved, there are specific variations across cortical regions, and species.
Topics: Adult; Dendrites; Dendritic Spines; Epilepsy; Female; Humans; Image Processing, Computer-Assisted; Imaging, Three-Dimensional; Individuality; Male; Middle Aged; Neuroimaging; Neurons; Pyramidal Cells; Temporal Lobe
PubMed: 33723567
DOI: 10.1093/cercor/bhab034 -
Molecular Psychiatry Oct 2022In psychiatric disorders, mismatches between disease states and therapeutic strategies are highly pronounced, largely because of unanswered questions regarding specific...
In psychiatric disorders, mismatches between disease states and therapeutic strategies are highly pronounced, largely because of unanswered questions regarding specific vulnerabilities of different cell types and therapeutic responses. Which cellular events (housekeeping or salient) are most affected? Which cell types succumb first to challenges, and which exhibit the strongest response to drugs? Are these events coordinated between cell types? How does disease and drug effect this coordination? To address these questions, we analyzed single-nucleus-RNAseq (sn-RNAseq) data from the human anterior cingulate cortex-a region involved in many psychiatric disorders. Density index, a metric for quantifying similarities and dissimilarities across functional profiles, was employed to identify common or salient functional themes across cell types. Cell-specific signatures were integrated with existing disease and drug-specific signatures to determine cell-type-specific vulnerabilities, druggabilities, and responsiveness. Clustering of functional profiles revealed cell types jointly participating in these events. SST and VIP interneurons were found to be most vulnerable, whereas pyramidal neurons were least. Overall, the disease state is superficial layer-centric, influences cell-specific salient themes, strongly impacts disinhibitory neurons, and influences astrocyte interaction with a subset of deep-layer pyramidal neurons. In absence of disease, drugs profiles largely recapitulate disease profiles, offering a possible explanation for drug side effects. However, in presence of disease, drug activities, are deep layer-centric and involve activating a distinct subset of deep-layer pyramidal neurons to circumvent the disease state's disinhibitory circuit malfunction. These findings demonstrate a novel application of sn-RNAseq data to explain drug and disease action at a systems level.
Topics: Humans; Gyrus Cinguli; Interneurons; Neurons; Pyramidal Cells
PubMed: 35754044
DOI: 10.1038/s41380-022-01657-w -
Molecules (Basel, Switzerland) May 2023Biocytin, a chemical compound that is an amide formed from the vitamin biotin and the amino acid L-lysine, has been used as a histological dye to stain nerve cells....
Biocytin, a chemical compound that is an amide formed from the vitamin biotin and the amino acid L-lysine, has been used as a histological dye to stain nerve cells. Electrophysiological activity and morphology are two key characteristics of neurons, but revealing both the electrophysiological and morphological properties of the same neuron is challenging. This article introduces a detailed and easy-to-operate procedure for single-cell labeling in combination with whole-cell patch-clamp recording. Using a recording electrode filled with a biocytin-containing internal solution, we demonstrate the electrophysiological and morphological characteristics of pyramidal (PNs), medial spiny (MSNs) and parvalbumin neurons (PVs) in brain slices, where the electrophysiological and morphological properties of the same individual cell are elucidated. We first introduce a protocol for whole-cell patch-clamp recording in various neurons, coupled with the intracellular diffusion of biocytin delivered by the glass capillary of the recording electrode, followed by a post hoc procedure to reveal the architecture and morphology of biocytin-labeled neurons. An analysis of action potentials (APs) and neuronal morphology, including the dendritic length, number of intersections, and spine density of biocytin-labeled neurons, were performed using ClampFit and Fiji Image (ImageJ), respectively. Next, to take advantage of the techniques introduced above, we uncovered defects in the APs and the dendritic spines of PNs in the primary motor cortex (M1) of deubiquitinase cylindromatosis (CYLD) knock-out () mice. In summary, this article provides a detailed methodology for revealing the morphology as well as the electrophysiological activity of a single neuron that will have many applications in neurobiology.
Topics: Animals; Mice; Lysine; Patch-Clamp Techniques; Neurons; Pyramidal Cells; Deubiquitinating Enzyme CYLD
PubMed: 37241833
DOI: 10.3390/molecules28104092 -
ELife Nov 2021Cellular diversity supports the computational capacity and flexibility of cortical circuits. Accordingly, principal neurons at the CA1 output node of the murine...
Cellular diversity supports the computational capacity and flexibility of cortical circuits. Accordingly, principal neurons at the CA1 output node of the murine hippocampus are increasingly recognized as a heterogeneous population. Their genes, molecular content, intrinsic morpho-physiology, connectivity, and function seem to segregate along the main anatomical axes of the hippocampus. Since these axes reflect the temporal order of principal cell neurogenesis, we directly examined the relationship between birthdate and CA1 pyramidal neuron diversity, focusing on the ventral hippocampus. We used a genetic fate-mapping approach that allowed tagging three groups of age-matched principal neurons: pioneer, early-, and late-born. Using a combination of neuroanatomy, slice physiology, connectivity tracing, and cFos staining in mice, we show that birthdate is a strong predictor of CA1 principal cell diversity. We unravel a subpopulation of pioneer neurons recruited in familiar environments with remarkable positioning, morpho-physiological features, and connectivity. Therefore, despite the expected plasticity of hippocampal circuits, given their role in learning and memory, the diversity of their main components is also partly determined at the earliest steps of development.
Topics: Animals; CA1 Region, Hippocampal; Female; Male; Mice; Neurogenesis; Pyramidal Cells
PubMed: 34723790
DOI: 10.7554/eLife.69270