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Cerebral Cortex (New York, N.Y. : 1991) Jan 2021The prefrontal cortex (PFC) plays a key role in higher order cognitive functions and psychiatric disorders such as autism, schizophrenia, and depression. In the PFC, the...
The prefrontal cortex (PFC) plays a key role in higher order cognitive functions and psychiatric disorders such as autism, schizophrenia, and depression. In the PFC, the two major classes of neurons are the glutamatergic pyramidal (Pyr) cells and the GABAergic interneurons such as fast-spiking (FS) cells. Despite extensive electrophysiological, morphological, and pharmacological studies of the PFC, the therapeutically utilized drug targets are restricted to dopaminergic, glutamatergic, and GABAergic receptors. To expand the pharmacological possibilities as well as to better understand the cellular and network effects of clinically used drugs, it is important to identify cell-type-selective, druggable cell surface proteins and to link developed drug candidates to Pyr or FS cell targets. To identify the mRNAs of such cell-specific/enriched proteins, we performed ultra-deep single-cell mRNA sequencing (19 685 transcripts in total) on electrophysiologically characterized intact PFC neurons harvested from acute brain slices of mice. Several selectively expressed transcripts were identified with some of the genes that have already been associated with cellular mechanisms of psychiatric diseases, which we can now assign to Pyr (e.g., Kcnn2, Gria3) or FS (e.g., Kcnk2, Kcnmb1) cells. The earlier classification of PFC neurons was also confirmed at mRNA level, and additional markers have been provided.
Topics: Animals; Electrophysiological Phenomena; Genetic Markers; Membrane Proteins; Mice; Mice, Inbred C57BL; Nerve Net; Neurons; Prefrontal Cortex; Pyramidal Cells; RNA, Messenger; Transcription, Genetic
PubMed: 32710103
DOI: 10.1093/cercor/bhaa195 -
The Journal of Neuroscience : the... Jan 2023Cortical computations emerge from the dynamics of neurons embedded in complex cortical circuits. Within these circuits, neuronal ensembles, which represent subnetworks...
Cortical computations emerge from the dynamics of neurons embedded in complex cortical circuits. Within these circuits, neuronal ensembles, which represent subnetworks with shared functional connectivity, emerge in an experience-dependent manner. Here we induced ensembles in cortical circuits from mice of either sex by differentially activating subpopulations through chronic optogenetic stimulation. We observed a decrease in voltage correlation, and importantly a synaptic decoupling between the stimulated and nonstimulated populations. We also observed a decrease in firing rate during Up-states in the stimulated population. These ensemble-specific changes were accompanied by decreases in intrinsic excitability in the stimulated population, and a decrease in connectivity between stimulated and nonstimulated pyramidal neurons. By incorporating the empirically observed changes in intrinsic excitability and connectivity into a spiking neural network model, we were able to demonstrate that changes in both intrinsic excitability and connectivity accounted for the decreased firing rate, but only changes in connectivity accounted for the observed decorrelation. Our findings help ascertain the mechanisms underlying the ability of chronic patterned stimulation to create ensembles within cortical circuits and, importantly, show that while Up-states are a global network-wide phenomenon, functionally distinct ensembles can preserve their identity during Up-states through differential firing rates and correlations. The connectivity and activity patterns of local cortical circuits are shaped by experience. This experience-dependent reorganization of cortical circuits is driven by complex interactions between different local learning rules, external input, and reciprocal feedback between many distinct brain areas. Here we used an approach to demonstrate how simple forms of chronic external stimulation can shape local cortical circuits in terms of their correlated activity and functional connectivity. The absence of feedback between different brain areas and full control of external input allowed for a tractable system to study the underlying mechanisms and development of a computational model. Results show that differential stimulation of subpopulations of neurons significantly reshapes cortical circuits and forms subnetworks referred to as neuronal ensembles.
Topics: Mice; Animals; Optogenetics; Neuronal Plasticity; Neurons; Pyramidal Cells; Homeostasis
PubMed: 36400529
DOI: 10.1523/JNEUROSCI.1104-22.2022 -
Physiological Reviews Jul 2021There are currently a number of theories of rodent hippocampal function. They fall into two major groups that differ in the role they impute to space in hippocampal... (Review)
Review
There are currently a number of theories of rodent hippocampal function. They fall into two major groups that differ in the role they impute to space in hippocampal information processing. On one hand, the cognitive map theory sees space as crucial and central, with other types of nonspatial information embedded in a primary spatial framework. On the other hand, most other theories see the function of the hippocampal formation as broader, treating all types of information as equivalent and concentrating on the processes carried out irrespective of the specific material being represented, stored, and manipulated. One crucial difference, therefore, is the extent to which theories see hippocampal pyramidal cells as representing nonspatial information independently of a spatial framework. Studies have reported the existence of single hippocampal unit responses to nonspatial stimuli, both to simple sensory inputs as well as to more complex stimuli such as objects, conspecifics, rewards, and time, and these findings been interpreted as evidence in favor of a broader hippocampal function. Alternatively, these nonspatial responses might actually be feature-in-place signals where the spatial nature of the response has been masked by the fact that the objects or features were only presented in one location or one spatial context. In this article, we argue that when tested in multiple locations, the hippocampal response to nonspatial stimuli is almost invariably dependent on the animal's location. Looked at collectively, the data provide strong support for the cognitive map theory.
Topics: Animals; Hippocampus; Memory; Place Cells; Pyramidal Cells
PubMed: 33591856
DOI: 10.1152/physrev.00014.2020 -
Scientific Reports May 2022The axon initial segment (AIS) is a region of the neuron that is critical for action potential generation as well as for the regulation of neural activity. This...
The axon initial segment (AIS) is a region of the neuron that is critical for action potential generation as well as for the regulation of neural activity. This specialized structure-characterized by the expression of different types of ion channels as well as adhesion, scaffolding and cytoskeleton proteins-is subjected to morpho-functional plastic changes in length and position upon variations in neural activity or in pathological conditions. In the present study, using immunocytochemistry with the AT8 antibody (phospho-tau S202/T205) and 3D confocal microscopy reconstruction techniques in brain tissue from Alzheimer's disease patients, we found that around half of the cortical pyramidal neurons with hyperphosphorylated tau showed changes in AIS length and position in comparison with AT8-negative neurons from the same cortical layers. We observed a wide variety of AIS alterations in neurons with hyperphosphorylated tau, although the most common changes were a proximal shift or a lengthening of the AISs. Similar results were found in neocortical tissue from non-demented cases with neurons containing hyperphosphorylated tau. These findings support the notion that the accumulation of phospho-tau is associated with structural alterations of the AIS that are likely to have an impact on normal neuronal activity, which might contribute to neuronal dysfunction in AD.
Topics: Alzheimer Disease; Axon Initial Segment; Humans; Neurons; Pyramidal Cells; tau Proteins
PubMed: 35610289
DOI: 10.1038/s41598-022-12700-9 -
Current Opinion in Neurobiology Aug 2018A rich literature describes inhibitory innervation of pyramidal neurons in terms of the distinct inhibitory cell types that target the soma, axon initial segment, or... (Review)
Review
A rich literature describes inhibitory innervation of pyramidal neurons in terms of the distinct inhibitory cell types that target the soma, axon initial segment, or dendritic arbor. Less attention has been devoted to how localization of inhibition to specific parts of the pyramidal dendritic arbor influences dendritic signal detection and integration. The effect of inhibitory inputs can vary based on their placement on dendritic spines versus shaft, their distance from the soma, and the branch order of the dendrite they inhabit. Inhibitory synapses are also structurally dynamic, and the implications of these dynamics depend on their dendritic location. Here we consider the heterogeneous roles of inhibitory synapses as defined by their strategic placement on the pyramidal cell dendritic arbor.
Topics: Animals; Dendrites; Neural Inhibition; Pyramidal Cells; Synapses
PubMed: 29454834
DOI: 10.1016/j.conb.2018.01.013 -
Cell Reports Aug 2022Hippocampal place cells receive a disparate collection of excitatory and inhibitory currents that endow them with spatially selective discharges and rhythmic activity....
Hippocampal place cells receive a disparate collection of excitatory and inhibitory currents that endow them with spatially selective discharges and rhythmic activity. Using a combination of in vivo intracellular and extracellular recordings with opto/chemogenetic manipulations and computational modeling, we investigate the influence of inhibitory and excitatory inputs on CA1 pyramidal cell responses. At the cell bodies, inhibition leads and is stronger than excitation across the entire theta cycle. Pyramidal neurons fire on the ascending phase of theta when released from inhibition. Computational models equipped with the observed conductances reproduce these dynamics. In these models, place field properties are favored when the increased excitation is coupled with a reduction of inhibition within the field. As predicted by our simulations, firing rate within place fields and phase locking to theta are impaired by DREADDs activation of interneurons. Our results indicate that decreased inhibitory conductance is critical for place field expression.
Topics: Action Potentials; Hippocampus; Interneurons; Models, Neurological; Pyramidal Cells; Synaptic Transmission; Theta Rhythm
PubMed: 36001959
DOI: 10.1016/j.celrep.2022.111232 -
Neuron Dec 2021The axon initial segment of hippocampal pyramidal cells is a key subcellular compartment for action potential generation, under GABAergic control by the "chandelier" or...
The axon initial segment of hippocampal pyramidal cells is a key subcellular compartment for action potential generation, under GABAergic control by the "chandelier" or axo-axonic cells (AACs). Although AACs are the only cellular source of GABA targeting the initial segment, their in vivo activity patterns and influence over pyramidal cell dynamics are not well understood. We achieved cell-type-specific genetic access to AACs in mice and show that AACs in the hippocampal area CA1 are synchronously activated by episodes of locomotion or whisking during rest. Bidirectional intervention experiments in head-restrained mice performing a random foraging task revealed that AACs inhibit CA1 pyramidal cells, indicating that the effect of GABA on the initial segments in the hippocampus is inhibitory in vivo. Finally, optogenetic inhibition of AACs at specific track locations induced remapping of pyramidal cell place fields. These results demonstrate brain-state-specific dynamics of a critical inhibitory controller of cortical circuits.
Topics: Animals; Axons; Hippocampus; Interneurons; Mice; Pyramidal Cells; Synapses; gamma-Aminobutyric Acid
PubMed: 34648750
DOI: 10.1016/j.neuron.2021.09.033 -
Cell Reports Dec 2022Maintaining an appropriate balance between excitation and inhibition is critical for neuronal information processing. Cortical neurons can cell-autonomously adjust the...
Maintaining an appropriate balance between excitation and inhibition is critical for neuronal information processing. Cortical neurons can cell-autonomously adjust the inhibition they receive to individual levels of excitatory input, but the underlying mechanisms are unclear. We describe that Ste20-like kinase (SLK) mediates cell-autonomous regulation of excitation-inhibition balance in the thalamocortical feedforward circuit, but not in the feedback circuit. This effect is due to regulation of inhibition originating from parvalbumin-expressing interneurons, while inhibition via somatostatin-expressing interneurons is unaffected. Computational modeling shows that this mechanism promotes stable excitatory-inhibitory ratios across pyramidal cells and ensures robust and sparse coding. Patch-clamp RNA sequencing yields genes differentially regulated by SLK knockdown, as well as genes associated with excitation-inhibition balance participating in transsynaptic communication and cytoskeletal dynamics. These data identify a mechanism for cell-autonomous regulation of a specific inhibitory circuit that is critical to ensure that a majority of cortical pyramidal cells participate in information coding.
Topics: Pyramidal Cells
PubMed: 36476865
DOI: 10.1016/j.celrep.2022.111757 -
Neuron Jan 2024Neurotransmission in the brain is unreliable, suggesting that high-frequency spike bursts rather than individual spikes carry the neural code. For instance, cortical...
Neurotransmission in the brain is unreliable, suggesting that high-frequency spike bursts rather than individual spikes carry the neural code. For instance, cortical pyramidal neurons rely on bursts in memory formation. Protein synthesis is another key factor in long-term synaptic plasticity and learning but is widely considered unnecessary for synaptic transmission. Here, however, we show that burst neurotransmission at synapses between neocortical layer 5 pyramidal cells depends on axonal protein synthesis linked to presynaptic NMDA receptors and mTOR. We localized protein synthesis to axons with laser axotomy and puromycylation live imaging. We whole-cell recorded connected neurons to reveal how translation sustained readily releasable vesicle pool size and replenishment rate. We live imaged axons and found sparsely docked RNA granules, suggesting synapse-specific regulation. In agreement, translation boosted neurotransmission onto excitatory but not inhibitory basket or Martinotti cells. Local axonal mRNA translation is thus a hitherto unappreciated principle for sustaining burst coding at specific synapse types.
Topics: Synapses; Axons; Neurons; Pyramidal Cells; Synaptic Transmission; Neuronal Plasticity
PubMed: 37944518
DOI: 10.1016/j.neuron.2023.10.011 -
Scientific Reports Dec 2019Brain rhythms recorded in vivo, such as gamma oscillations, are notoriously variable both in amplitude and frequency. They are characterized by transient epochs of...
Brain rhythms recorded in vivo, such as gamma oscillations, are notoriously variable both in amplitude and frequency. They are characterized by transient epochs of higher amplitude known as bursts. It has been suggested that, despite their short-life and random occurrence, bursts in gamma and other rhythms can efficiently contribute to working memory or communication tasks. Abnormalities in bursts have also been associated with e.g. motor and psychiatric disorders. It is thus crucial to understand how single cell and connectivity parameters influence burst statistics and the corresponding brain states. To address this problem, we consider a generic stochastic recurrent network of Pyramidal Interneuron Network Gamma (PING) type. Using the stochastic averaging method, we derive dynamics for the phase and envelope of the amplitude process, and find that they depend on only two meta-parameters that combine all the model parameters. This allows us to identify an optimal parameter regime of healthy variability with similar statistics to those seen in vivo; in this regime, oscillations and bursts are supported by synaptic noise. The probability density for the rhythm's envelope as well as the mean burst duration are then derived using first passage time analysis. Our analysis enables us to link burst attributes, such as duration and frequency content, to system parameters. Our general approach can be extended to different frequency bands, network topologies and extra populations. It provides the much needed insight into the biophysical determinants of rhythm burst statistics, and into what needs to be changed to correct rhythms with pathological statistics.
Topics: Action Potentials; Animals; Brain; Electroencephalography; Gamma Rhythm; Humans; Interneurons; Memory, Short-Term; Models, Neurological; Models, Theoretical; Pyramidal Cells; Respiratory Burst
PubMed: 31797877
DOI: 10.1038/s41598-019-54444-z