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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 -
Neuron Dec 2014In medial entorhinal cortex, layer 2 principal cells divide into pyramidal neurons (mostly calbindin positive) and dentate gyrus-projecting stellate cells (mostly...
In medial entorhinal cortex, layer 2 principal cells divide into pyramidal neurons (mostly calbindin positive) and dentate gyrus-projecting stellate cells (mostly calbindin negative). We juxtacellularly labeled layer 2 neurons in freely moving animals, but small sample size prevented establishing unequivocal structure-function relationships. We show, however, that spike locking to theta oscillations allows assigning unidentified extracellular recordings to pyramidal and stellate cells with ∼83% and ∼89% specificity, respectively. In pooled anatomically identified and theta-locking-assigned recordings, nonspatial discharges dominated, and weakly hexagonal spatial discharges and head-direction selectivity were observed in both cell types. Clear grid discharges were rare and mostly classified as pyramids (19%, 19/99 putative pyramids versus 3%, 3/94 putative stellates). Most border cells were classified as stellate (11%, 10/94 putative stellates versus 1%, 1/99 putative pyramids). Our data suggest weakly theta-locked stellate border cells provide spatial input to dentate gyrus, whereas strongly theta-locked grid discharges occur mainly in hexagonally arranged pyramidal cell patches and do not feed into dentate gyrus.
Topics: Action Potentials; Animals; Entorhinal Cortex; Male; Neurons; Pyramidal Cells; Rats; Space Perception; Theta Rhythm
PubMed: 25482025
DOI: 10.1016/j.neuron.2014.11.009 -
Cell Feb 2020The mystery of general anesthesia is that it specifically suppresses consciousness by disrupting feedback signaling in the brain, even when feedforward signaling and...
The mystery of general anesthesia is that it specifically suppresses consciousness by disrupting feedback signaling in the brain, even when feedforward signaling and basic neuronal function are left relatively unchanged. The mechanism for such selectiveness is unknown. Here we show that three different anesthetics have the same disruptive influence on signaling along apical dendrites in cortical layer 5 pyramidal neurons in mice. We found that optogenetic depolarization of the distal apical dendrites caused robust spiking at the cell body under awake conditions that was blocked by anesthesia. Moreover, we found that blocking metabotropic glutamate and cholinergic receptors had the same effect on apical dendrite decoupling as anesthesia or inactivation of the higher-order thalamus. If feedback signaling occurs predominantly through apical dendrites, the cellular mechanism we found would explain not only how anesthesia selectively blocks this signaling but also why conscious perception depends on both cortico-cortical and thalamo-cortical connectivity.
Topics: Anesthetics, General; Animals; Cerebral Cortex; Cholinergic Antagonists; Consciousness; Dendrites; Excitatory Amino Acid Antagonists; Feedback, Physiological; Female; Male; Mice; Pyramidal Cells; Synaptic Transmission; Thalamus
PubMed: 32084339
DOI: 10.1016/j.cell.2020.01.024 -
Journal of Computational Neuroscience Aug 2022To elucidate how the flattening of sensory tuning due to a deficit in tonic inhibition slows motor responses, we simulated a neural network model in which a sensory...
To elucidate how the flattening of sensory tuning due to a deficit in tonic inhibition slows motor responses, we simulated a neural network model in which a sensory cortical network ([Formula: see text]) and a motor cortical network ([Formula: see text]) are reciprocally connected, and the [Formula: see text] projects to spinal motoneurons (Mns). The [Formula: see text] was presented with a feature stimulus and the reaction time of Mns was measured. The flattening of sensory tuning in [Formula: see text] caused by decreasing the concentration of gamma-aminobutyric acid (GABA) in extracellular space resulted in a decrease in the stimulus-sensitive [Formula: see text] pyramidal cell activity while increasing the stimulus-insensitive [Formula: see text] pyramidal cell activity, thereby prolonging the reaction time of Mns to the applied feature stimulus. We suggest that a reduction in extracellular GABA concentration in sensory cortex may interfere with selective activation in motor cortex, leading to slowing the activation of spinal motoneurons and therefore to slowing motor responses.
Topics: Models, Neurological; Neural Networks, Computer; Neurons; Pyramidal Cells; gamma-Aminobutyric Acid
PubMed: 35695984
DOI: 10.1007/s10827-022-00821-z -
CNS Drugs Jul 2021Psychosis occurs across a wide variety of dementias with differing etiologies, including Alzheimer's dementia, Parkinson's dementia, Lewy body dementia, frontotemporal... (Review)
Review
Psychosis occurs across a wide variety of dementias with differing etiologies, including Alzheimer's dementia, Parkinson's dementia, Lewy body dementia, frontotemporal dementia, and vascular dementia. Pimavanserin, a selective serotonin 5-HT receptor (5-HTR) inverse agonist, has shown promising results in clinical trials by reducing the frequency and/or severity of hallucinations and delusions and the risk of relapse of these symptoms in patients with dementia-related psychosis. A literature review was conducted to identify mechanisms that explain the role of 5-HTRs in both the etiology and treatment of dementia-related psychosis. This review revealed that most pathological changes commonly associated with neurodegenerative diseases cause one or more of the following events to occur: reduced synaptic contact of gamma aminobutyric acid (GABA)-ergic interneurons with glutamatergic pyramidal cells, reduced cortical innervation from subcortical structures, and altered 5-HTR expression levels. Each of these events promotes increased pyramidal cell hyperexcitability and disruption of excitatory/inhibitory balance, facilitating emergence of psychotic behaviors. The brain regions affected by these pathological changes largely coincide with areas expressing high levels of 5-HTRs. At the cellular level, 5-HTRs are most highly expressed on cortical glutamatergic pyramidal cells, where they regulate pyramidal cell excitability. The common effects of different neurodegenerative diseases on pyramidal cell excitability together with the close anatomical and functional connection of 5-HTRs to pyramidal cell excitability may explain why suppressing 5-HTR activity could be an effective strategy to treat dementia-related psychosis.
Topics: Antipsychotic Agents; Cortical Excitability; Dementia; Psychotic Disorders; Pyramidal Cells; Receptor, Serotonin, 5-HT2A; Serotonin 5-HT2 Receptor Antagonists
PubMed: 34224112
DOI: 10.1007/s40263-021-00836-7 -
Experimental Brain Research Mar 2018Schizophrenia is a disabling psychiatric disease characterized by symptoms including hallucinations, delusions, social withdrawal, loss of pleasure, and inappropriate...
Schizophrenia is a disabling psychiatric disease characterized by symptoms including hallucinations, delusions, social withdrawal, loss of pleasure, and inappropriate affect. Although schizophrenia is marked by dysfunction in dopaminergic and glutamatergic signaling, it is not presently clear how these dysfunctions give rise to symptoms. The aberrant salience hypothesis of schizophrenia argues that abnormal attribution of motivational salience to stimuli is one of the main contributors to both positive and negative symptoms of schizophrenia. The proposed mechanisms for this hypothesis are overactive striatal dopaminergic and hypoactive glutamatergic signaling. The current study assessed salience attribution in mice (n = 72) using an oddball paradigm in which an infrequent stimulus either co-occurred with shock (conditioned group) or was presented alone (non-conditioned group). Behavioral response (freezing) and electroencephalogram (whole brain and amygdala) were used to assess salience attribution. Mice with pyramidal cell-selective knockout of ionotropic glutamate receptors (GluN1) were used to reproduce a prominent physiological change involved in schizophrenia. Non-conditioned knockout mice froze significantly more in response to the unpaired stimulus than non-conditioned wild-type mice, suggesting that this irrelevant cue acquired motivational salience for the knockouts. In accordance with this finding, low-frequency event-related spectral perturbation was significantly increased in non-conditioned knockout mice relative to both conditioned knockout and non-conditioned wild-type mice. These results suggest that pyramidal cell-selective GluN1 knockout leads to inappropriate attribution of salience for irrelevant stimuli as characterized by abnormalities in both behavior and brain circuitry functions.
Topics: Amygdala; Animals; Behavior, Animal; Brain; Conditioning, Classical; Disease Models, Animal; Electroencephalography; Fear; Freezing Reaction, Cataleptic; Mice; Mice, Knockout; Motivation; Nerve Tissue Proteins; Pyramidal Cells; Receptors, N-Methyl-D-Aspartate; Schizophrenia
PubMed: 29350251
DOI: 10.1007/s00221-017-5152-8 -
Hippocampus Dec 2019Numerous synaptic and intrinsic membrane mechanisms have been proposed for generating oscillatory activity in the hippocampus. Few studies, however, have directly...
Numerous synaptic and intrinsic membrane mechanisms have been proposed for generating oscillatory activity in the hippocampus. Few studies, however, have directly measured synaptic conductances and membrane properties during oscillations. The time course and relative contribution of excitatory and inhibitory synaptic conductances, as well as the role of intrinsic membrane properties in amplifying synaptic inputs, remains unclear. To address this issue, we used an isolated whole hippocampal preparation that generates autonomous low-frequency oscillations near the theta range. Using 2-photon microscopy and expression of genetically encoded fluorophores, we obtained on-cell and whole-cell patch recordings of pyramidal cells and fast-firing interneurons in the distal subiculum. Pyramidal cell and interneuron spiking shared similar phase-locking to local field potential oscillations. In pyramidal cells, spiking resulted from a concomitant and balanced increase in excitatory and inhibitory synaptic currents. In contrast, interneuron spiking was driven almost exclusively by excitatory synaptic current. Thus, similar to tightly balanced networks underlying hippocampal gamma oscillations and ripples, balanced synaptic inputs in the whole hippocampal preparation drive highly phase-locked spiking at the peak of slower network oscillations.
Topics: Animals; Excitatory Postsynaptic Potentials; Female; Gamma Rhythm; Hippocampus; Interneurons; Male; Mice; Mice, Transgenic; Organ Culture Techniques; Pyramidal Cells; Synapses; Synaptic Transmission
PubMed: 31301195
DOI: 10.1002/hipo.23131 -
Cerebral Cortex (New York, N.Y. : 1991) Mar 2023Perisomatic GABAergic innervation in the cerebral cortex is carried out mostly by basket and chandelier cells, which differentially participate in the control of...
Perisomatic GABAergic innervation in the cerebral cortex is carried out mostly by basket and chandelier cells, which differentially participate in the control of pyramidal cell action potential output and synchronization. These cells establish multiple synapses with the cell body (and proximal dendrites) and the axon initial segment (AIS) of pyramidal neurons, respectively. Using multiple immunofluorescence, confocal microscopy and 3D quantification techniques, we have estimated the number and density of GABAergic boutons on the cell body and AIS of pyramidal neurons located through cortical layers of the human and mouse neocortex. The results revealed, in both species, that there is clear variability across layers regarding the density and number of perisomatic GABAergic boutons. We found a positive linear correlation between the surface area of the soma, or the AIS, and the number of GABAergic terminals in apposition to these 2 neuronal domains. Furthermore, the density of perisomatic GABAergic boutons was higher in the human cortex than in the mouse. These results suggest a selectivity for the GABAergic innervation of the cell body and AIS that might be related to the different functional attributes of the microcircuits in which neurons from different layers are involved in both human and mouse.
Topics: Humans; Mice; Animals; Axon Initial Segment; Neocortex; Cell Body; Neurons; Pyramidal Cells; Axons; Synapses
PubMed: 36058205
DOI: 10.1093/cercor/bhac314 -
Reviews in the Neurosciences Dec 2019Spikelets are small spike-like depolarizations that are found in somatic recordings of many neuron types. Spikelets have been assigned important functions, ranging from... (Review)
Review
Spikelets are small spike-like depolarizations that are found in somatic recordings of many neuron types. Spikelets have been assigned important functions, ranging from neuronal synchronization to the regulation of synaptic plasticity, which are specific to the particular mechanism of spikelet generation. As spikelets reflect spiking activity in neuronal compartments that are electrotonically distinct from the soma, four modes of spikelet generation can be envisaged: (1) dendritic spikes or (2) axonal action potentials occurring in a single cell as well as action potentials transmitted via (3) gap junctions or (4) ephaptic coupling in pairs of neurons. In one of the best studied neuron type, cortical pyramidal neurons, the origins and functions of spikelets are still unresolved; all four potential mechanisms have been proposed, but the experimental evidence remains ambiguous. Here we attempt to reconcile the scattered experimental findings in a coherent theoretical framework. We review in detail the various mechanisms that can give rise to spikelets. For each mechanism, we present the biophysical underpinnings as well as the resulting properties of spikelets and compare these predictions to experimental data from pyramidal neurons. We also discuss the functional implications of each mechanism. On the example of pyramidal neurons, we illustrate that several independent spikelet-generating mechanisms fulfilling vastly different functions might be operating in a single cell.
Topics: Action Potentials; Animals; Brain; Cortical Excitability; Humans; Pyramidal Cells; Synaptic Potentials
PubMed: 31437125
DOI: 10.1515/revneuro-2019-0044 -
Neuroscience Nov 2023The blockade of 5-HT receptors represents an experimental approach that might ameliorate the memory deficits associated with brain disorders, including Alzheimer's...
The blockade of 5-HT receptors represents an experimental approach that might ameliorate the memory deficits associated with brain disorders, including Alzheimer's disease and schizophrenia. However, the synaptic mechanism by which 5-HT receptors control the GABAergic and glutamatergic synaptic transmission is barely understood. In this study, we demonstrate that pharmacological manipulation of 5-HT receptors with the specific agonist EMD 386088 (7.4 nM) or the antagonist SB-399885 (300 nM) modulates the field inhibitory postsynaptic potentials of the dorsal hippocampus and controls the strength of the population spike of pyramidal cells. Likewise, pharmacological modulation of 5-HT controls the magnitude of paired-pulse inhibition, a phenomenon mediated by GABAergic interneurons acting via GABA receptors of pyramidal cells. The effects of pharmacological manipulation of the 5-HT receptor were limited to GABAergic transmission and did not affect the strength of field excitatory postsynaptic potentials mediated by the Schaffer collaterals axons. Lastly, in a modified version of the Pavlovian autoshaping task that requires the activation of the hippocampal formation, we demonstrated that the anti-amnesic effect induced by the blockade of the 5-HT receptor is prevented when the GAT1 transporter is blocked, suggesting that modulation of GABAergic transmission is required for the anti-amnesic properties of 5-HT receptor antagonists.
Topics: Rats; Animals; Rats, Wistar; Hippocampus; Receptors, Serotonin; Pyramidal Cells; Synaptic Transmission; Receptors, GABA-A
PubMed: 37776946
DOI: 10.1016/j.neuroscience.2023.09.013