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The Journal of Neuroscience : the... Jun 2019Neuronal circuits often display small-world network architecture characterized by neuronal cliques of dense local connectivity communicating with each other through a...
Neuronal circuits often display small-world network architecture characterized by neuronal cliques of dense local connectivity communicating with each other through a limited number of cells that participate in multiple cliques. The principles by which such cliques organize to encode information remain poorly understood. Similarly tuned pyramidal cells that preferentially target each other may form multicellular encoding units performing distinct computational tasks. The existence of such units can reflect upon both spontaneous and stimulus-driven population events.We applied two-photon calcium imaging to study spontaneous population bursts in layer 2/3 of area V1 in male C57BL/6 mice. To identify potential small-world cliques, we searched for pyramidal cells whose calcium events had a consistent temporal relationship with the events of local inhibitory interneurons. This was guided by the intuition that groups of neurons whose synchronous firing represents a temporally coherent computational unit should be inhibited together. Pyramidal members of these interneuron-centered clusters on average displayed stronger functional connectivity between each other than with nonmember pyramidal neurons. The structure of the clusters evolved during postnatal development: cluster size and overlap between clusters decreased with developmental maturation. Pyramidal neurons in a cluster showed higher than chance tuning function similarity between each other and with the linked interneuron. Thus, spontaneous population events in V1 are shaped by small-world subnetworks of pyramidal neurons that share functional properties and work as a coherent unit with a local interneuron. These interneuron-pyramidal cell partnerships may represent a fundamental neocortical unit of computation at the population level. Neuronal circuit in layer 2/3 of mouse area V1 possesses small-world network architecture, where cliques of densely interconnected neurons ("small worlds") communicate via restricted number of hub cells. We show that: (1) in mouse V1 individual small-world cliques preferably incorporate pyramidal neurons with similar visual feature tuning, and (2) ongoing population activity of such pyramidal neuron clique is temporally linked to the activity of the local interneuron sharing its feature tuning with the clique members. Functional grouping of similarly tuned interneurons and pyramidal cells into cliques may ensure that ensembles of functionally alike pyramidal cells recruited during perceptual tasks and spontaneous activity are also turned off together as a unit, with interneurons serving as organizers of linked pyramidal ensemble activity.
Topics: Action Potentials; Animals; Interneurons; Male; Mice; Nerve Net; Neurons; Optical Imaging; Photic Stimulation; Pyramidal Cells; Visual Cortex
PubMed: 30979814
DOI: 10.1523/JNEUROSCI.2275-18.2019 -
Journal of Neurophysiology Feb 2021Spontaneous neuronal and astrocytic activity in the neonate forebrain is believed to drive the maturation of individual cells and their integration into complex...
Spontaneous neuronal and astrocytic activity in the neonate forebrain is believed to drive the maturation of individual cells and their integration into complex brain-region-specific networks. The previously reported forms include bursts of electrical activity and oscillations in intracellular Ca concentration. Here, we use ratiometric Na imaging to demonstrate spontaneous fluctuations in the intracellular Na concentration of CA1 pyramidal neurons and astrocytes in tissue slices obtained from the hippocampus of mice at (P2-4). These occur at very low frequency (∼2/h), can last minutes with amplitudes up to several millimolar, and mostly disappear after the first postnatal week. To further investigate their mechanisms, we model a network consisting of pyramidal neurons and interneurons. Experimentally observed Na fluctuations are mimicked when GABAergic inhibition in the simulated network is made depolarizing. Both our experiments and computational model show that blocking voltage-gated Na channels or GABAergic signaling significantly diminish the neuronal Na fluctuations. On the other hand, blocking a variety of other ion channels, receptors, or transporters including glutamatergic pathways does not have significant effects. Our model also shows that the amplitude and duration of Na fluctuations decrease as we increase the strength of glial K uptake. Furthermore, neurons with smaller somatic volumes exhibit fluctuations with higher frequency and amplitude. As opposed to this, larger extracellular to intracellular volume ratio observed in neonatal brain exerts a dampening effect. Finally, our model predicts that these periods of spontaneous Na influx leave neonatal neuronal networks more vulnerable to seizure-like states when compared with mature brain. Spontaneous activity in the neonate forebrain plays a key role in cell maturation and brain development. We report spontaneous, ultraslow, asynchronous fluctuations in the intracellular Na concentration of neurons and astrocytes. We show that this activity is not correlated with the previously reported synchronous neuronal population bursting or Ca oscillations, both of which occur at much faster timescales. Furthermore, extracellular K concentration remains nearly constant. The spontaneous Na fluctuations disappear after the first postnatal week.
Topics: Action Potentials; Animals; Female; GABA Antagonists; GABAergic Neurons; Interneurons; Male; Mice; Mice, Inbred BALB C; Models, Neurological; Prosencephalon; Pyramidal Cells; Sodium; Sodium Channel Blockers; Sodium Channels
PubMed: 33236936
DOI: 10.1152/jn.00373.2020 -
Frontiers in Neural Circuits 2022Parvalbumin-positive neurons are the largest class of GABAergic, inhibitory neurons in the central nervous system. In the cortex, these fast-spiking cells provide... (Review)
Review
Parvalbumin-positive neurons are the largest class of GABAergic, inhibitory neurons in the central nervous system. In the cortex, these fast-spiking cells provide feedforward and feedback synaptic inhibition onto a diverse set of cell types, including pyramidal cells, other inhibitory interneurons, and themselves. Cortical inhibitory networks broadly, and cortical parvalbumin-expressing interneurons (cPVins) specifically, are crucial for regulating sensory plasticity during both development and adulthood. Here we review the functional properties of cPVins that enable plasticity in the cortex of adult mammals and the influence of cPVins on sensory activity at four spatiotemporal scales. First, cPVins regulate developmental critical periods and adult plasticity through molecular and structural interactions with the extracellular matrix. Second, they activate in precise sequence following feedforward excitation to enforce strict temporal limits in response to the presentation of sensory stimuli. Third, they implement gain control to normalize sensory inputs and compress the dynamic range of output. Fourth, they synchronize broad network activity patterns in response to behavioral events and state changes. Much of the evidence for the contribution of cPVins to plasticity comes from classic models that rely on sensory deprivation methods to probe experience-dependent changes in the brain. We support investigating naturally occurring, adaptive cortical plasticity to study cPVin circuits in an ethologically relevant framework, and discuss recent insights from our work on maternal experience-induced auditory cortical plasticity.
Topics: Animals; GABAergic Neurons; Interneurons; Mammals; Neuronal Plasticity; Parvalbumins; Pyramidal Cells
PubMed: 35601529
DOI: 10.3389/fncir.2022.886629 -
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 -
Journal of Neurophysiology Oct 2021The wide diversity of inhibitory cells across the brain makes them suitable to contribute to network dynamics in specialized fashions. However, the contributions of a...
The wide diversity of inhibitory cells across the brain makes them suitable to contribute to network dynamics in specialized fashions. However, the contributions of a particular inhibitory cell type in a behaving animal are challenging to untangle as one needs to both record cellular activities and identify the cell type being recorded. Thus, using computational modeling and theory to predict and hypothesize cell-specific contributions is desirable. Here, we examine potential contributions of interneuron-specific 3 (I-S3) cells-an inhibitory interneuron found in CA1 hippocampus that only targets other inhibitory interneurons-during simulated θ rhythms. We use previously developed multicompartment models of oriens lacunosum-moleculare (OLM) cells, the main target of I-S3 cells, and explore how I-S3 cell inputs during in vitro and in vivo scenarios contribute to θ. We find that I-S3 cells suppress OLM cell spiking, rather than engender its spiking via postinhibitory rebound mechanisms, and contribute to θ frequency spike resonance during simulated in vivo scenarios. To elicit recruitment similar to in vitro experiments, inclusion of disinhibited pyramidal cell inputs is necessary, implying that I-S3 cell firing broadens the window for pyramidal cell disinhibition. Using in vivo virtual networks, we show that I-S3 cells contribute to a sharpening of OLM cell recruitment at θ frequencies. Furthermore, shifting the timing of I-S3 cell spiking due to external modulation shifts the timing of the OLM cell firing and thus disinhibitory windows. We propose a specialized contribution of I-S3 cells to create temporally precise coordination of modulation pathways. How information is processed across different brain structures is an important question that relates to the different functions that the brain performs. Using modeling and theoretical analyses, we show that an inhibitory cell type that only inhibits other inhibitory cells can broaden the window for disinhibition of excitatory cells, manage input pathway switching, and modulate inhibitory cell spiking. This work contributes to the knowledge of how coordination between sensory and memory consolidation information can be attained.
Topics: Animals; CA1 Region, Hippocampal; Computer Simulation; Interneurons; Models, Biological; Nerve Net; Pyramidal Cells; Theta Rhythm
PubMed: 34379493
DOI: 10.1152/jn.00204.2021 -
ENeuro 2018The prefrontal cortex receives a dense serotonergic innervation that plays an important role in its regulation. However, how serotonin regulates different pyramidal and...
The prefrontal cortex receives a dense serotonergic innervation that plays an important role in its regulation. However, how serotonin regulates different pyramidal and interneuron cell classes in this area is incompletely understood. Previous work in rats has shown that serotonin differentially regulates two classes of pyramidal cells in layer 5. It excites one class by activating 5-HT receptors, whereas it more subtly modulates the integrative properties of the other by co-activating 5-HT and 5-HT receptors. Here we have used electrophysiological recordings, combined with retrograde labeling and morphological reconstruction, to show that the first cell class corresponds to long range corticofugal neurons and the second corresponds to intratelencephalic neurons. These results suggest that, in rats, serotonin facilitates subcortical output while more subtly modulating cortico-cortical and cortico-striatal output. Interestingly, these results obtained in rats differ from those previously reported for mouse prefrontal cortex. Therefore we reinvestigated the effects of serotonin in mice and confirmed that serotonin predominantly activates inhibitory 5-HT receptors on long-range corticofugal cells. Thus serotonin exerts opposite effects on these cells in rats and mice. Finally, we determined whether cortical serotonin responsiveness in mice is regulated during development. Serotonin elicited predominantly depolarizing inward current responses during the early postnatal period, whereas inhibitory 5-HT receptor-mediated responses did not become evident until the end of the second postnatal week. These results reveal commonalities as well as unexpected differences in the serotonergic regulation of long-range corticofugal and intratelencephalic neurons of layer 5 in rat and mouse.
Topics: Animals; Female; Male; Membrane Potentials; Mice; Prefrontal Cortex; Pyramidal Cells; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT1A; Receptor, Serotonin, 5-HT2A; Serotonin; Tissue Culture Techniques
PubMed: 29445767
DOI: 10.1523/ENEURO.0305-17.2018 -
The Journal of Neuroscience : the... Feb 2022Nonlinear synaptic integration in dendrites is a fundamental aspect of neural computation. One such key mechanism is the Ca spike at the apical tuft of pyramidal...
Nonlinear synaptic integration in dendrites is a fundamental aspect of neural computation. One such key mechanism is the Ca spike at the apical tuft of pyramidal neurons. Characterized by a plateau potential sustained for tens of milliseconds, the Ca spike amplifies excitatory input, facilitates somatic action potentials (APs), and promotes synaptic plasticity. Despite its essential role, the mechanisms regulating it are largely unknown. Using a compartmental model of a layer 5 pyramidal cell (L5PC), we explored the plateau and termination phases of the Ca spike under input current perturbations, long-step current-injections, and variations in the dendritic high-voltage-activated Ca conductance (that occur during cholinergic modulation). We found that, surprisingly, timed excitatory input can shorten the Ca spike duration while inhibitory input can either elongate or terminate it. A significant elongation also occurs when the high-voltage-activated Ca channels (Ca) conductance is increased. To mechanistically understand these phenomena, we analyzed the currents involved in the spike. The plateau and termination phases are almost exclusively controlled by the Ca inward current and the I outward K current. We reduced the full model to a single-compartment model that faithfully preserved the responses of the Ca spike to interventions and consisted of two dynamic variables: the membrane potential and the K-channel activation level. A phase-plane analysis of the reduced model provides testable predictions for modulating the Ca spike and reveals various dynamical regimes that explain the robust nature of the spike. Regulating the duration of the Ca spike significantly impacts the cell synaptic-plasticity window and, as we show, its input-output relationship. Pyramidal neurons are the cortex's principal projection neurons. In their apical tuft, dendritic Ca spikes significantly impact information processing, synaptic plasticity, and the cell's input-output relationship. Therefore, it is essential to understand the mechanisms regulating them. Using a compartmental model of a layer 5 pyramidal cell (L5PC), we explored the Ca spike responses to synaptic perturbations and cholinergic modulation. We showed a counterintuitive phenomenon: early excitatory input shortens the spike, whereas weak inhibition elongates it. Also, we demonstrated that acetylcholine (ACh) extends the spike. Through a reduced model containing only the membrane potential and the K-channel activation level, we explained these phenomena using a phase-plane analysis. Our work provides new information about the robustness of the Ca spike and its controlling mechanisms.
Topics: Acetylcholine; Action Potentials; Animals; Calcium; Dendrites; Humans; Models, Neurological; Neuronal Plasticity; Pyramidal Cells; Synapses
PubMed: 34893549
DOI: 10.1523/JNEUROSCI.1470-21.2021 -
Cell Reports Feb 2022Elucidating how neurons encode network activity is essential to understanding how the brain processes information. Neocortical pyramidal cells receive excitatory input...
Elucidating how neurons encode network activity is essential to understanding how the brain processes information. Neocortical pyramidal cells receive excitatory input onto spines distributed along dendritic branches. Local dendritic branch nonlinearities can boost the response to spatially clustered and synchronous input, but how this translates into the integration of patterns of ongoing activity remains unclear. To examine dendritic integration under naturalistic stimulus regimes, we use two-photon glutamate uncaging to repeatedly activate multiple dendritic spines at random intervals. In the proximal dendrites of two populations of layer 5 pyramidal neurons in the mouse motor cortex, spatially restricted synchrony is not a prerequisite for dendritic boosting. Branches encode afferent inputs with distinct rate sensitivities depending upon cell and branch type. Thus, inputs distributed along a dendritic branch can recruit supralinear boosting and the window of this nonlinearity may provide a mechanism by which dendrites can preferentially amplify slow-frequency network oscillations.
Topics: Action Potentials; Animals; Dendrites; Dendritic Spines; Female; Male; Mice, Transgenic; Neocortex; Pyramidal Cells
PubMed: 35172157
DOI: 10.1016/j.celrep.2022.110382 -
The Journal of Neuroscience : the... May 2020Emerging evidence suggests that there is a reduction in overall cortical excitatory to inhibitory balance in major depressive disorder (MDD), which afflicts ∼14%-20%...
Emerging evidence suggests that there is a reduction in overall cortical excitatory to inhibitory balance in major depressive disorder (MDD), which afflicts ∼14%-20% of individuals. Reduced pyramidal cell arborization occurs with stress and MDD, and may diminish excitatory neurotransmission. Enhanced deposition of perineuronal net (PNN) components also occurs with stress. Since parvalbumin-expressing interneurons are the predominant cell population that is enveloped by PNNs, which enhance their ability to release GABA, excess PNN deposition likely increases pyramidal cell inhibition. In the present study, we investigate the potential for matrix metalloprotease-9 (MMP-9), an endopeptidase secreted in response to neuronal activity, to contribute to the antidepressant efficacy of the serotonin/norepinephrine reuptake inhibitor venlafaxine in male mice. Chronic venlafaxine increases MMP-9 levels in murine cortex, and increases both pyramidal cell arborization and PSD-95 expression in the cortex of WT but not MMP-9-null mice. We have previously shown that venlafaxine reduces PNN deposition and increases the power of γ oscillations in conventionally housed mice. γ power is increased with pyramidal cell disinhibition and with remission from MDD. Herein we observe that PNN expression is increased in a corticosterone-induced stress model of disease and reduced by venlafaxine. Compared with mice that receive concurrent venlafaxine, corticosterone-treated mice also display reduced γ power and impaired working memory. Autopsy-derived PFC samples show elevated MMP-9 levels in antidepressant-treated MDD patients compared with controls. These preclinical and postmortem findings highlight a link between extracellular matrix regulation and MDD. Reduced excitatory neurotransmission occurs with major depressive disorder, and may be normalized by antidepressant treatment. Underlying molecular mechanisms are, however, not well understood. Herein we investigate a potential role for an extracellular protease, released from neurons and known to play a role in learning and memory, in antidepressant-associated increases in excitatory transmission. Our data suggest that this protease, matrix metalloprotease-9, increases branching of excitatory neurons and concomitantly attenuates the perineuronal net to potentially reduce inhibitory input to these neurons. Matrix metalloprotease-9 may thus enhance overall excitatory/inhibitory balance and neuronal population dynamics, which are important to mood and memory.
Topics: Adult; Aged; Animals; Cells, Cultured; Cerebral Cortex; Depressive Disorder, Major; Female; Gamma Rhythm; Humans; Male; Matrix Metalloproteinase 9; Memory, Short-Term; Mice; Mice, Inbred C57BL; Middle Aged; Neural Inhibition; Pyramidal Cells; Serotonin and Noradrenaline Reuptake Inhibitors; Stress, Psychological; Venlafaxine Hydrochloride
PubMed: 32269106
DOI: 10.1523/JNEUROSCI.2387-19.2020 -
Scientific Reports Jun 2021New neurons continuously arise from neural progenitor cells in the dentate gyrus of the adult hippocampus to support ongoing learning and memory formation. To generate...
New neurons continuously arise from neural progenitor cells in the dentate gyrus of the adult hippocampus to support ongoing learning and memory formation. To generate functional adult-born neurons, neural progenitor cells proliferate to expand the precursor cell pool and differentiate into neurons. Newly generated cells then undergo postmitotic maturation to migrate to their final destination and develop elaborate dendritic branching, which allows them to receive input signals. Little is known about factors that regulate neuronal differentiation, migration, and dendrite maturation during adult hippocampal neurogenesis. Here, we show that the transcriptional repressor protein capicua (CIC) exhibits dynamic expression in the adult dentate gyrus. Conditional deletion of Cic from the mouse dentate gyrus compromises the adult neural progenitor cell pool without altering their proliferative potential. We further demonstrate that the loss of Cic impedes neuronal lineage development and disrupts dendritic arborization and migration of adult-born neurons. Our study uncovers a previously unrecognized role of CIC in neurogenesis of the adult dentate gyrus.
Topics: Animals; Cell Differentiation; Dentate Gyrus; Hippocampus; Mice; Mice, Knockout; Neural Stem Cells; Neurogenesis; Pyramidal Cells; Repressor Proteins
PubMed: 34083623
DOI: 10.1038/s41598-021-91168-5