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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 -
Cerebral Cortex (New York, N.Y. : 1991) May 2019Deficits in sensory processing in Fetal Alcohol Spectrum Disorders (FASD) implicate dysfunction in the somatosensory cortex. However, the effects of prenatal ethanol...
Deficits in sensory processing in Fetal Alcohol Spectrum Disorders (FASD) implicate dysfunction in the somatosensory cortex. However, the effects of prenatal ethanol exposure on the development of this region await elucidation. Here, we used an established mouse model of FASD with binge-type ethanol exposure from embryonic day 13.5-16.5 to investigate the effects of prenatal ethanol exposure on pyramidal neurons in the somatosensory cortex. Specifically, we focused on the radial migration of primordial pyramidal neurons during embryonic corticogenesis and their morphology and function during active synaptogenesis in early postnatal development. We found that prenatal ethanol exposure resulted in aberrant radial migration, particularly affecting the populations of postmitotic pyramidal neurons. In addition, there was an enduring effect of prenatal ethanol exposure on glutamate-mediated synaptic transmission in layer V/VI pyramidal neurons. This persisted beyond a transient decrease in pyramidal neuron dendritic complexity that was evident only during early postnatal development. Adolescent mice exposed prenatally to ethanol also displayed decreased tactile sensitivity, as revealed by a modified adhesive tape removal assay. Our findings demonstrate the persistent effects of binge-type in utero ethanol exposure on pyramidal neuron form and function and ultimately sensory processing, the latter being reminiscent of that seen in individuals with FASD.
Topics: Animals; Cell Movement; Disease Models, Animal; Ethanol; Female; Fetal Alcohol Spectrum Disorders; Male; Membrane Potentials; Mice, Inbred C57BL; Pyramidal Cells; Somatosensory Cortex
PubMed: 29688328
DOI: 10.1093/cercor/bhy094 -
The Journal of Experimental Biology Feb 2017With oxygen deprivation, the mammalian brain undergoes hyper-activity and neuronal death while this does not occur in the anoxia-tolerant goldfish (). Anoxic survival of...
With oxygen deprivation, the mammalian brain undergoes hyper-activity and neuronal death while this does not occur in the anoxia-tolerant goldfish (). Anoxic survival of the goldfish may rely on neuromodulatory mechanisms to suppress neuronal hyper-excitability. As γ-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain, we decided to investigate its potential role in suppressing the electrical activity of goldfish telencephalic neurons. Utilizing whole-cell patch-clamp recording, we recorded the electrical activities of both excitatory (pyramidal) and inhibitory (stellate) neurons. With anoxia, membrane potential () depolarized in both cell types from -72.2 mV to -57.7 mV and from -64.5 mV to -46.8 mV in pyramidal and stellate neurons, respectively. While pyramidal cells remained mostly quiescent, action potential frequency (AP) of the stellate neurons increased 68-fold. Furthermore, the GABA receptor reversal potential (-) was determined using the gramicidin perforated-patch-clamp method and found to be depolarizing in pyramidal (-53.8 mV) and stellate neurons (-42.1 mV). Although GABA was depolarizing, pyramidal neurons remained quiescent as was below the action potential threshold (-36 mV pyramidal and -38 mV stellate neurons). Inhibition of GABA receptors with gabazine reversed the anoxia-mediated response. While GABA receptor inhibition alone did not affect the anoxic response, co-antagonism of GABA and GABA receptors (gabazine and CGP-55848) led to the generation of seizure-like activities in both neuron types. We conclude that with anoxia, depolarizes towards which increases AP in stellate neurons and decreases AP in pyramidal neurons, and that GABA plays an important role in the anoxia tolerance of goldfish brain.
Topics: Action Potentials; Anaerobiosis; Animals; Fish Proteins; GABA-A Receptor Antagonists; GABA-B Receptor Antagonists; Goldfish; Humans; Hypoxia; Oxygen; Patch-Clamp Techniques; Pyramidal Cells; Receptors, GABA-A; Receptors, GABA-B; Telencephalon
PubMed: 27923876
DOI: 10.1242/jeb.146605 -
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 -
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 -
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 -
Journal of Visualized Experiments : JoVE Apr 2020It has been reported that the size and shape of dendritic spines is related to their structural plasticity. To identify the morphological structure of pyramidal neurons...
It has been reported that the size and shape of dendritic spines is related to their structural plasticity. To identify the morphological structure of pyramidal neurons and dendritic spines, a ballistic labeling technique can be utilized. In the present protocol, pyramidal neurons are labeled with DilC18(3) dye and analyzed using neuronal reconstruction software to assess neuronal morphology and dendritic spines. To investigate neuronal structure, dendritic branching analysis and Sholl analysis are performed, allowing researchers to draw inferences about dendritic branching complexity and neuronal arbor complexity, respectively. The evaluation of dendritic spines is conducted using an automatic assisted classification algorithm integral to the reconstruction software, which classifies spines into four categories (i.e., thin, mushroom, stubby, filopodia). Furthermore, an additional three parameters (i.e., length, head diameter, and volume) are also chosen to assess alterations in dendritic spine morphology. To validate the potential of wide application of the ballistic labeling technique, pyramidal neurons from in vitro cell culture were successfully labeled. Overall, the ballistic labeling method is unique and useful for visualizing neurons in different brain regions in rats, which in combination with sophisticated reconstruction software, allows researchers to elucidate the possible mechanisms underlying neurocognitive dysfunction.
Topics: Animals; Brain; Dendritic Spines; Primary Cell Culture; Pyramidal Cells; Rats; Staining and Labeling
PubMed: 32310238
DOI: 10.3791/60989