Myelination synchronizes cortical oscillations by consolidating parvalbumin-mediated phasic inhibition

Parvalbumin-positive (PV+) γ-aminobutyric acid (GABA) interneurons are critically involved in producing rapid network oscillations and cortical microcircuit computations but the significance of PV+ axon myelination to the temporal features of inhibition remains elusive. Here using toxic and genetic mouse models of demyelination and dysmyelination, respectively, we find that loss of compact myelin reduces PV+ interneuron presynaptic terminals, increases failures and the weak phasic inhibition of pyramidal neurons abolishes optogenetically driven gamma oscillations in vivo. Strikingly, during behaviors of quiet wakefulness selectively theta rhythms are amplified and accompanied by highly synchronized interictal epileptic discharges. In support of a causal role of impaired PV-mediated inhibition, optogenetic activation of myelin-deficient PV+ interneurons attenuated the power of slow theta rhythms and limited interictal spike occurrence. Thus, myelination of PV axons is required to consolidate fast inhibition of pyramidal neurons and enable behavioral state-dependent modulation of local circuit synchronization.

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Myelin speeds cortical oscillations by consolidating phasic parvalbumin-mediated inhibition

10.1101/2021.09.07.459122 ◽

2021 ◽

Author(s):

Mohit Dubey ◽

Maria Pascual-Garcia ◽

Koke Helmes ◽

Dennis Wever ◽

Mustafa S. Hamada ◽

...

Keyword(s):

Pyramidal Neurons ◽

Gamma Oscillations ◽

Interictal Spike ◽

Cortical Oscillations ◽

State Dependent ◽

Temporal Features ◽

Cortical Microcircuit ◽

Myelin Deficient

Parvalbumin-positive (PV+) γ-aminobutyric acid (GABA) interneurons are critically involved in producing rapid network oscillations and cortical microcircuit computations but the significance of PV+ axon myelination to the temporal features of inhibition remains elusive. Here using toxic and genetic models of demyelination and dysmyelination, respectively, we find that loss of compact myelin reduces PV+ interneuron presynaptic terminals, increases failures and the weak phasic inhibition of pyramidal neurons abolishes optogenetically driven gamma oscillations in vivo. Strikingly, during periods of quiet wakefulness selectively theta rhythms are amplified and accompanied by highly synchronized interictal epileptic discharges. In support of a causal role of impaired PV-mediated inhibition, optogenetic activation of myelin-deficient PV+ interneurons attenuated the power of slow theta rhythms and limited interictal spike occurrence. Thus, myelination of PV+ axons is required to consolidate fast inhibition of pyramidal neurons and enable behavioral state-dependent modulation of local circuit synchronization.

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Hippocampus Retains the Periodicity of Gamma Stimulation In Vivo

Journal of Neurophysiology ◽

10.1152/jn.00591.2002 ◽

2002 ◽

Vol 88 (5) ◽

pp. 2349-2354 ◽

Cited By ~ 4

Author(s):

J. E. Mikkonen ◽

T. Grönfors ◽

J. J. Chrobak ◽

M. Penttonen

Keyword(s):

Information Acquisition ◽

Pyramidal Cells ◽

Gamma Oscillations ◽

Short Term ◽

Ca1 Pyramidal Cells ◽

State Dependent ◽

Hippocampal Ca1 ◽

Oscillatory Rhythms ◽

The Brain

Several behavioral state dependent oscillatory rhythms have been identified in the brain. Of these neuronal rhythms, gamma (20–70 Hz) oscillations are prominent in the activated brain and are associated with various behavioral functions ranging from sensory binding to memory. Hippocampal gamma oscillations represent a widely studied band of frequencies co-occurring with information acquisition. However, induction of specific gamma frequencies within the hippocampal neuronal network has not been satisfactorily established. Using both in vivo intracellular and extracellular recordings from anesthetized rats, we show that hippocampal CA1 pyramidal cells can discharge at frequencies determined by the preceding gamma stimulation, provided that the gamma is introduced in theta cycles, as occurs in vivo. The dynamic short-term alterations in the oscillatory discharge described in this paper may serve as a coding mechanism in cortical neuronal networks.

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Phase Coupled Firing of Prefrontal Parvalbumin Interneuron With High Frequency Oscillations

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2020.610741 ◽

2020 ◽

Vol 14 ◽

Author(s):

Yanting Yao ◽

Mengmeng Wu ◽

Lina Wang ◽

Longnian Lin ◽

Jiamin Xu

Keyword(s):

High Frequency ◽

Pyramidal Neurons ◽

Temporal Dynamics ◽

Gamma Oscillations ◽

Cognitive Behaviors ◽

Firing Rates ◽

High Frequency Oscillations ◽

Electrophysiological Recordings ◽

Parvalbumin Interneuron

The prefrontal cortex (PFC) plays a central role in executive functions and inhibitory control over many cognitive behaviors. Dynamic changes in local field potentials (LFPs), such as gamma oscillation, have been hypothesized to be important for attentive behaviors and modulated by local interneurons such as parvalbumin (PV) cells. However, the precise relationships between the firing patterns of PV interneurons and temporal dynamics of PFC activities remains elusive. In this study, by combining in vivo electrophysiological recordings with optogenetics, we investigated the activities of prefrontal PV interneurons and categorized them into three subtypes based on their distinct firing rates under different behavioral states. Interestingly, all the three subtypes of interneurons showed strong phase-locked firing to cortical high frequency oscillations (HFOs), but not to theta or gamma oscillations, despite of behavior states. Moreover, we showed that sustained optogenetic stimulation (over a period of 10 s) of PV interneurons can consequently modulate the activities of local pyramidal neurons. Interestingly, such optogenetic manipulations only showed moderate effects on LFPs in the PFC. We conclude that prefrontal PV interneurons are consist of several subclasses of cells with distinct state-dependent modulation of firing rates, selectively coupled to HFOs.

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Altered GABAA,slow Inhibition and Network Oscillations in Mice Lacking the GABAA Receptor β3 Subunit

Journal of Neurophysiology ◽

10.1152/jn.00651.2009 ◽

2009 ◽

Vol 102 (6) ◽

pp. 3643-3655 ◽

Cited By ~ 23

Author(s):

Harald Hentschke ◽

Claudia Benkwitz ◽

Matthew I. Banks ◽

Mark G. Perkins ◽

Gregg E. Homanics ◽

...

Keyword(s):

Pyramidal Neurons ◽

Epileptiform Activity ◽

Gamma Oscillations ◽

Theta Oscillations ◽

Network Activity ◽

Inhibitory Synapses ◽

Gabaergic Inhibition ◽

Wild Type ◽

Hippocampal Network

Phasic GABAergic inhibition in hippocampus and neocortex falls into two kinetically distinct categories, GABAA,fast and GABAA,slow. In hippocampal area CA1, GABAA,fast is generally believed to underlie gamma oscillations, whereas the contribution of GABAA,slow to hippocampal rhythms has been speculative. Hypothesizing that GABAA receptors containing the β3 subunit contribute to GABAA,slow inhibition and that slow inhibitory synapses control excitability as well as contribute to network rhythms, we investigated the consequences of this subunit's absence on synaptic inhibition and network function. In pyramidal neurons of GABAA receptor β3 subunit-deficient (β3−/−) mice, spontaneous GABAA,slow inhibitory postsynaptic currents (IPSCs) were much less frequent, and evoked GABAA,slow currents were much smaller than in wild-type mice. Fittingly, long-lasting recurrent inhibition of population spikes was less powerful in the mutant, indicating that receptors containing β3 subunits contribute substantially to GABAA,slow currents in pyramidal neurons. By contrast, slow inhibitory control of GABAA,fast-producing interneurons was unaffected in β3−/− mice. In vivo hippocampal network activity was markedly different in the two genotypes. In β3−/− mice, epileptiform activity was observed, and theta oscillations were weaker, slower, less regular and less well coordinated across laminae compared with wild-type mice, whereas gamma oscillations were weaker and faster. The amplitude modulation of gamma oscillations at theta frequency (“nesting”) was preserved but was less well coordinated with theta oscillations. With the caveat that seizure-induced changes in inhibitory circuits might have contributed to the changes observed in the mutant animals, our results point to a strong contribution of β3 subunits to slow GABAergic inhibition onto pyramidal neurons but not onto GABAA,fast -producing interneurons and support different roles for these slow inhibitory synapses in the generation and coordination of hippocampal network rhythms.

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Disrupted-in-Schizophrenia-1 is required for proper pyramidal cell-interneuron communication and network dynamics in the prefrontal cortex

10.1101/2021.12.10.472099 ◽

2021 ◽

Author(s):

Jonas-Frederic Sauer ◽

Marlene Bartos

Keyword(s):

Pyramidal Cell ◽

Gamma Oscillations ◽

Mutant Mice ◽

Potential Mechanism ◽

Excitatory Effect ◽

Fast Spiking ◽

Single Unit Recordings ◽

Circuit Function

AbstractWe interrogated prefrontal circuit function in mice lacking Disrupted-in-schizophrenia-1 (Disc1-mutant mice), a risk factor for psychiatric disorders. Single-unit recordings in awake mice revealed reduced average firing rates of fast-spiking interneurons (INTs), including optogenetically identified parvalbumin-positive cells, and a lower proportion of INTs phase-coupled to ongoing gamma oscillations. Moreover, we observed decreased spike transmission efficacy at local pyramidal cell (PYR)-INT connections in vivo, suggesting a reduced excitatory effect of local glutamatergic inputs as a potential mechanism of lower INT rates. On the network level, impaired INT function resulted in altered activation of PYR assemblies: While assembly activations were observed equally often, the expression strength of individual assembly patterns was significantly higher in Disc1-mutant mice. Our data thus reveal a role of Disc1 in shaping the properties of prefrontal assembly patterns by setting prefrontal INT responsiveness to glutamatergic drive.

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Hippocampal ghrelin signalling informs the decision to eat

10.1101/2021.11.05.467326 ◽

2021 ◽

Author(s):

Ryan WS Wee ◽

Karyna Mishchanchuk ◽

Rawan AlSubaie ◽

Andrew F MacAskill

Keyword(s):

Calcium Imaging ◽

Feeding Behaviour ◽

Pyramidal Neurons ◽

Internal State ◽

Ventral Hippocampus ◽

Direct Role ◽

Induced Changes ◽

In Vivo Calcium Imaging

Hunger is an internal state that not only invigorates behaviour towards feeding, but also acts as a contextual cue for the higher-order control of anticipatory feeding-related behaviour. The ventral hippocampus is a brain region important in encoding context, but how internal contexts such as hunger are represented in hippocampal circuits is not known. Pyramidal neurons in the ventral hippocampus, and in particular within the ventral CA1/subiculum border (vS) express the receptor for the peripheral hunger hormone ghrelin, and ghrelin is known to cross the blood brain barrier and directly influence hippocampal circuitry. However, what role vS neurons play during feeding related behaviour, and how ghrelin influences this role has not been directly investigated. In this study, we used a combination of whole-cell electrophysiology, optogenetics and molecular knockdown together with in vivo calcium imaging in mice to investigate the role of vS during feeding behaviour across different states of hunger. We found that activity of a unique subpopulation of vS neurons that project to the nucleus accumbens (vS-NAc) were active specifically when animals approached and investigated food, and that that this activity inhibited the transition to begin eating. Increases in peripheral ghrelin reduced vS-NAc activity during this anticipatory phase of feeding behaviour, by increasing the influence of synaptic inhibition. Furthermore, this effect required postsynaptic GHSR1a expression in vS-NAc neurons, suggesting a direct role of ghrelin signalling. Consistent with this role of hippocampal ghrelin signalling, removal of GHSR1a from vS-NAc neurons impaired ghrelin-induced changes in feeding-related behaviour. Together, these experiments define a ghrelin-sensitive hippocampal circuit that informs the decision to eat based on internal state.

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Early NMDA Receptor Ablation in Interneurons Causes an Activity-Dependent E/I Imbalance in vivo in Prefrontal Cortex Pyramidal Neurons of a Mouse Model Useful for the Study of Schizophrenia

Schizophrenia Bulletin ◽

10.1093/schbul/sbab030 ◽

2021 ◽

Author(s):

Diego E Pafundo ◽

Carlos A Pretell Annan ◽

Nicolas M Fulginiti ◽

Juan E Belforte

Keyword(s):

Prefrontal Cortex ◽

Mouse Model ◽

Pyramidal Neurons ◽

Gamma Oscillations ◽

Dependent Manner ◽

Early Postnatal Development ◽

Synaptic Inputs ◽

Selective Ablation ◽

Activity Dependent

Abstract Altered Excitatory/Inhibitory (E/I) balance of cortical synaptic inputs has been proposed as a central pathophysiological factor for psychiatric neurodevelopmental disorders, including schizophrenia (SZ). However, direct measurement of E/I synaptic balance have not been assessed in vivo for any validated SZ animal model. Using a mouse model useful for the study of SZ we show that a selective ablation of NMDA receptors (NMDAr) in cortical and hippocampal interneurons during early postnatal development results in an E/I imbalance in vivo, with synaptic inputs to pyramidal neurons shifted towards excitation in the adult mutant medial prefrontal cortex (mPFC). Remarkably, this imbalance depends on the cortical state, only emerging when theta and gamma oscillations are predominant in the network. Additional brain slice recordings and subsequent 3D morphological reconstruction showed that E/I imbalance emerges after adolescence concomitantly with significant dendritic retraction and dendritic spine re-localization in pyramidal neurons. Therefore, early postnatal ablation of NMDAr in cortical and hippocampal interneurons developmentally impacts on E/I imbalance in vivo in an activity-dependent manner.

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Abstract WP329: The Role of miR-34b/c in Global Ischemic Stroke

Stroke ◽

10.1161/str.51.suppl_1.wp329 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Hyae-Ran Byun ◽

Morgan Porch ◽

Fabrizio Pontarelli ◽

Brenda L Court Vazquez ◽

R.Suzanne Zukin ◽

...

Keyword(s):

Ischemic Stroke ◽

Cognitive Deficits ◽

Neuronal Death ◽

Target Genes ◽

Pyramidal Neurons ◽

Unmet Need ◽

Global Ischemia ◽

Hippocampal Ca1

Transient global ischemia arising as a consequence of cardiac arrest in humans causes selective, delayed death of hippocampal CA1 pyramidal neurons and cognitive impairment. Effective treatments to ameliorate the neurodegeneration and cognitive dysfunction associated with global ischemia are an unmet need. Emerging evidence points to a widespread role for microRNAs (miRNAs) as key modulators of target gene expression in neurons. Accordingly, dysregulation of miRNAs are implicated in the pathophysiology of neurodegenerative disease and neurological disorders. Our findings, derived via miRNA-seq, indicate that expression of a subset of microRNAs are altered in postischemic CA1 including miR-34b/c, miR-21, miR-331, miR-181 and miR-29. Ingenuity pathway analysis reveals that miR-34b/c is the leading miR candidate implicated in cell death and survival. A role for miR-34 in the pathogenesis of global ischemia is, as yet, unclear. Here we show ischemia induces p53-dependent activation of miR-34b/c and downregulation of its target genes Bcl-2 and Sirt1, which together promote neuronal death in selectively vulnerable hippocampal CA1 in vivo . Consistent with this, inhibition of miR-34b/c affords neuroprotection, rescues impaired synaptic plasticity and reduces memory deficits in global ischemia. These findings document a causal role for p53-dependent activation of miR-34b/c in neuronal death and identify a novel therapeutic target for amelioration of the neurodegeneration and cognitive deficits associated with ischemic stroke.

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Neuromodulation-induced burst firing in parvalbumin interneurons of the basolateral amygdala mediates transition between fear-associated network and behavioral states

10.1101/2021.04.19.440525 ◽

2021 ◽

Author(s):

Xin Fu ◽

Eric Teboul ◽

Jamie Maguire ◽

Jeffrey G Tasker

Keyword(s):

Basolateral Amygdala ◽

Critical Role ◽

Field Potential ◽

Gamma Oscillations ◽

Receptor Activation ◽

Neuron Activity ◽

Behavioral States ◽

Fear Expression

Network orchestration of behavioral states involves coordinated oscillations within and between brain regions. The network communication between the basolateral amygdala (BLA) and the medial prefrontal cortex (PFC) plays a critical role in fear expression. Neuromodulatory systems play an essential role in regulating changes between behavioral states, however, a mechanistic understanding of how amygdalar circuits mediate transitions between brain and behavioral states remains largely unknown. Here, we examine the role of Gq-mediated neuromodulation of parvalbumin (PV)-expressing interneurons in the BLA in coordinating network and behavioral states using combined chemogenetics, patch clamp and field potential recordings. We demonstrate that Gq-signaling via hM3D designer receptor and α1 adrenoreceptor activation shifts the pattern of activity of the PV interneurons from tonic to phasic by stimulating a previously unknown, highly stereotyped bursting pattern of activity. This, in turn, generates bursts of inhibitory postsynaptic currents (IPSCs) and phasic firing in BLA principal neurons. The Gq-induced transition from tonic to phasic firing in BLA PV interneurons suppressed amygdalo-frontal gamma oscillations in vivo, consistent with the critical role of tonic PV neuron activity in gamma generation. The suppression of gamma oscillations by hM3D and α1 receptor activation in BLA PV interneurons also facilitated fear memory recall, in line with the inhibitory effect of gamma on fear expression. Thus, our data reveal a BLA parvalbumin neuron-specific neuromodulatory mechanism that mediates the transition to a fear-associated brain network state via regulation of amygdalo-frontal gamma oscillations.

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