Biology subjects

Antonoudiou, P.

Publications and source records attributed to Antonoudiou, P..

17 recordsLinked to original sources

bioRxiv2026

Basolateral amygdala neurons await oscillatory recruitment into valence-relevant ensembles

Impaired valence processing is a core feature of psychiatric illnesses. The ability to rapidly evaluate situations and stimuli and determine whether they have positive or negative implications, termed valence processing, is a highly adaptive brain function that is essential for survival. Despite its importance, we still lack a complete understanding of the neural computations involved. The basolateral amygdala (BLA) plays a critical role in valence processing and valence ensembles have been identified by their anatomical location within the BLA, their projection targets, their genetic identity, or some combination of these factors. In parallel, distinct BLA oscillatory states have been shown to drive divergent valence states. Despite abundant evidence separately supporting these processes, we have failed to reconcile these disparate contributions to valence processing. Here, we demonstrate that subpopulations of BLA principal neurons are recruited in response to specific frequencies of optogenetically-driven oscillations. We provide evidence showing ensemble recruitment is a product of individual neuronal sensitivities to input frequencies that can be driven by interneuron-driven oscillatory states. We also demonstrate that oscillations driven by interneuron stimulations can activate projection-specific populations and reactivate behaviorally-relevant ensembles. Together, these findings reveal a novel neural computational mechanism governing valence processing involving the ability of interneuron-driven oscillatory states to selectively recruit populations of frequency-, projection-, and valence-specific BLA neurons to evoke distinct behavioral outcomes.

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bioRxiv2025

Noradrenergic neuromodulation of cholecystokinin interneurons in the basolateral amygdala alters rhythmic activity and restrains fear memory

Norepinephrine (NE) release in the basolateral amygdala (BLA) during emotional arousal plays an essential role in the processing of fear. However, the cell type-specific NE neuromodulation of the fear circuit in the BLA has not been fully resolved. We reported previously a facilitation of fear memory by Gq-coupled receptor induction of repetitive bursting in parvalbumin-expressing interneurons and suppression of gamma oscillations in the BLA. Here, using patch clamp recordings, Cre-dependent DLX-driven intersectional targeting, and genetic manipulations, we demonstrate that NE also activates cholecystokinin (CCK)-expressing interneurons to generate synchronized trains of rhythmic CB1-sensitive IPSCs in BLA principal neurons via Gq-coupled 1A adrenoreceptor activation. The Gq-dependent mechanism in CCK interneurons is generalizable to chemogenetic Gq manipulation and Gq-coupled 5-HT2C serotoninergic receptor activation. We next tested the role of Gq neuromodulation of CCK interneurons in the regulation of BLA network activity associated with the behavioral expression of fear learning by rescued expression of 1A adrenoreceptors or chemogenetic Gq activation selectively in BLA CCK interneurons in a global 1A adrenoreceptor knockout mouse. Restoration of the rhythmic inhibitory synaptic activity via rescue of Gq-coupled receptor signaling in CCK interneurons enhanced LFP theta power in the BLA in vivo and decreased fear memory acquisition and recall. These data indicate an inhibitory role for CCK interneuron Gq signaling in fear learning via activation of patterned inhibitory synaptic input to principal neurons and enhanced theta oscillations in the BLA, and reveal a G protein-dependent, receptor-nonselective neuromodulatory mechanism in the BLA that regulates network and behavioral states.

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bioRxiv2024

Early life stress influences epilepsy outcomes in mice

Stress is a common seizure trigger that has been implicated in worsening epilepsy outcomes. The neuroendocrine response to stress is mediated by the hypothalamic-pituitary-adrenal (HPA) axis and HPA axis dysfunction worsens epilepsy outcomes, increasing seizure burden, behavioral comorbidities, and risk for sudden unexpected death in epilepsy (SUDEP) in mice. Early life stress (ELS) reprograms the HPA axis into adulthood, impacting both the basal and stress-induced activity. Thus, we propose that ELS may influence epilepsy outcomes by influencing the function of the HPA axis. To test this hypothesis, we utilized the maternal separation paradigm and examined the impact on seizure susceptibility. We show that ELS exerts a sex dependent effect on seizure susceptibility in response to acute administration of the chemoconvulsant, kainic acid, which is associated with an altered relationship between seizure activity and HPA axis function. To further examine the impact of ELS on epilepsy outcomes, we utilized the intrahippocampal kainic acid model of chronic epilepsy in mice previously exposed to maternal separation. We find that the relationship between corticosterone levels and the extent of epileptiform activity is altered in mice subjected to ELS. We demonstrate that ELS impacts behavioral outcomes associated with chronic epilepsy in a sex-dependent manner, with females being more affected. We also observe reduced mortality (presumed SUDEP) in female mice subjected to ELS, consistent with previous findings suggesting a role for HPA axis dysfunction in SUDEP risk. These data demonstrate for the first time that ELS influences epilepsy outcomes and suggest that previous life experiences may impact the trajectory of epilepsy.

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bioRxiv2024

Sex-dependent effects of early life stress on network and behavioral states.

BackgroundAdverse childhood experiences (ACEs) are associated with numerous detriments in health, including increased vulnerability to psychiatric illnesses. Early life stress (ELS) in rodents has been shown to effectively model several of the behavioral and endocrine impacts of ACEs and has been utilized to investigate the underlying mechanisms contributing to disease. However, the precise neural mechanisms responsible for mediating the impact of ELS on vulnerability to psychiatric illnesses remain largely unknown. MethodsWe use behavior, immunoassay, in vivo LFP recording, histology, and patch clamp to describe the effects of ELS on stress behaviors, endocrinology, network states, protein expression, and cellular physiology in male and female mice. ResultsWe demonstrate that a murine maternal separation (MS) ELS model causes sex-dependent alterations in behavioral and hormonal responses following an acute stressor. Local field potential (LFP) recordings in the basolateral amygdala (BLA) and frontal cortex (FC) reveal similar sex-dependent alterations at baseline, in response to acute ethological stress, and during fear memory extinction, supporting a large body of literature demonstrating that these network states contribute to stress reactivity and vulnerability to psychiatric illnesses. Sex differences were accompanied by altered physiology of BLA principal neurons in males and BLA PV interneurons in females. ConclusionsCollectively, these results implicate novel, sex-dependent mechanisms through which ACEs may impact psychiatric health, involving altered cellular physiology and network states involved in emotional processing.

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bioRxiv2023

Loss of PV interneurons in the BLA contributes to altered network and behavioral states in chronically epileptic mice

Psychiatric disorders, including anxiety and depression, are highly comorbid in people with epilepsy. However, the mechanisms mediating the shared pathophysiology are currently unknown. There is considerable evidence implicating the basolateral amygdala (BLA) in the network communication of anxiety and fear, a process demonstrated to involve parvalbumin-positive (PV) interneurons. The loss of PV interneurons has been well described in the hippocampus of chronically epileptic mice and in postmortem human tissue of patients with temporal lobe epilepsy (TLE). We hypothesize that a loss of PV interneurons in the BLA may contribute to comorbid mood disorders in epilepsy. To test this hypothesis, we employed a ventral intrahippocampal kainic acid (vIHKA) model of chronic epilepsy in mice, which exhibits profound behavioral deficits associated with chronic epilepsy. We demonstrate a loss of PV interneurons and dysfunction of remaining PV interneurons in the BLA of chronically epileptic mice. Further, we demonstrate altered principal neuron function and impaired coordination of BLA network and behavioral states in chronically epileptic mice. To determine whether these altered network and behavioral states were due to the loss of PV interneurons, we ablated a similar percentage of PV interneurons observed in chronically epileptic mice by stereotaxically injecting AAV-Flex-DTA into the BLA of PV-Cre mice. Loss of PV interneurons in the BLA is sufficient to alter behavioral states, inducing deficits in fear learning and recall of fear memories. These data suggest that compromised inhibition in the BLA in chronically epileptic mice contributes to behavioral deficits, suggesting a novel mechanism contributing to comorbid anxiety and epilepsy. Significance StatementPsychiatric illnesses and epilepsy are highly comorbid and negatively impact the quality of life of people with epilepsy. The pathophysiological mechanisms mediating the bidirectional relationship between mood disorders and epilepsy remain unknown and, therefore, treatment options remain inadequate. Here we demonstrate a novel mechanism, involving the loss of PV interneurons in the BLA, leading to a corruption of network and behavioral states in mice. These findings pinpoint a critical node and demonstrate a novel cellular and circuit mechanism involved in the comorbidity of psychiatric illnesses and epilepsy.

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bioRxiv2023

Semi-automated seizure detection using interpretable machine learning models

Numerous methods have been proposed for seizure detection automation, yet the tools to harness these methods and apply them in practice are limited. Here we compare four interpretable and widely-used machine learning models (decision tree, gaussian naive bayes, passive aggressive classifier, stochastic gradient descent classifier) on an extensive electrographic seizure dataset collected from chronically epileptic mice. We find that the gaussian naive bayes model achieved the highest precision and f1 score, while also detecting all seizures in our dataset and only requires a small amount of data to train the model and achieve good performance. We use this model to create an open-source python application SeizyML that couples model performance with manual curation allowing for efficient and accurate detection of electrographic seizures. Author SummarySeizure detection based on electrographic recordings is critical for epilepsy diagnosis and research. However, the current gold standard for seizure detection is manual curation, which is biased, costly, incredibly laborious, and requires extensive training and expertise, prohibiting advances in epilepsy diagnosis and research. Here we demonstrate that fast, simple, and interpretable machine learning (ML) models are sufficient to detect all seizures in an extensive dataset collected from a well-established mouse model of epilepsy. Importantly, we created an open-source python application, SeizyML, that integrates the most precise model tested here with human curation of the detected events. This semi-automated approach greatly enhances efficiency and precision of seizure detection while also being transparent. We believe that the adoption of semi-automated and transparent technologies is indispensable for understanding ML model predictions, improving their reliability, and fostering trust between ML models and neurodiagnostic professionals.

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bioRxiv2023

Early life stress impairs VTA coordination of BLA network and behavioral states

Motivated behaviors, such as social interactions, are governed by the interplay between mesocorticolimbic structures, such as the ventral tegmental area (VTA), basolateral amygdala (BLA), and medial prefrontal cortex (mPFC). Adverse childhood experiences and early life stress (ELS) can impact these networks and behaviors, which is associated with increased risk for psychiatric illnesses. While it is known that the VTA projects to both the BLA and mPFC, the influence of these inputs on local network activity which govern behavioral states - and whether ELS impacts VTA-mediated network communication - remains unknown. Our study demonstrates that VTA inputs influence BLA oscillations and mPFC activity, and that ELS weakens the ability of the VTA to coordinate BLA network states, likely due to ELS-induced impairments in dopamine signaling between the VTA and BLA. Consequently, ELS mice exhibit increased social avoidance, which can be recapitulated in control mice by inhibiting VTA-BLA communication. These data suggest that ELS impacts social reward via the VTA-BLA dopamine network.

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bioRxiv2023

Basolateral amygdala parvalbumin interneurons coordinate oscillations to drive reward behaviors

The basolateral amygdala (BLA) has been implicated in mediating both fear and reward learning. Parvalbumin interneurons (PVs) in the BLA have previously been shown to contribute to BLA oscillatory states integral to fear expression, but whether BLA oscillatory states and PV interneurons also contribute to reward learning is unknown and critical to our understanding of reward processing. Local field potentials in the BLA were collected as animals consumed a sucrose reward, where prominent changes in the beta band (15-30 Hz) emerged with reward experience. Rhythmic optogenetic stimulation of PV interneurons to entrain the BLA network to 20Hz during consumption of one bottle during a two-bottle choice test produced a robust bottle preference. Finally, to demonstrate that PV activity is necessary for reward value use, PVs were chemogenetically targeted and inhibited following outcome devaluation, rendering those animals incapable of using updated reward value information to guide their behavior. Taken together, these experiments provide novel information regarding the physiological signatures of reward learning while highlighting the importance of PV interneurons in reward learning. This work builds upon the fields established knowledge of PV involvement in fear expression and provides evidence that PV orchestration of unique BLA network states is involved in both learning types.

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bioRxiv2023

Experience-dependent information routing through the basolateral amygdala

The basolateral amygdala (BLA) is an emotional processing hub and is well-established to influence both positive and negative valence processing. Selective engagement of a heterogeneous cell population in the BLA is thought to contribute to this flexibility in valence processing. However, how this process is impacted by previous experiences which influence valence processing is unknown. Here we demonstrate that previous positive (EE) or negative (chronic unpredictable stress) experiences differentially influence the activity of specific populations of BLA principal neurons projecting to either the nucleus accumbens core or bed nucleus of the stria terminalis. Using chemogenetic manipulation of these projection-specific neurons we can mimic or occlude the effects of chronic unpredictable stress or enriched environment on valence processing to bidirectionally control avoidance behaviors and stress-induced helplessness. These data demonstrate that previous experiences influence the responsiveness of projection-specific BLA principal neurons, biasing information routing through the BLA, to govern valence processing.

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bioRxiv2023

ALS-related p97 R155H mutation disrupts lysophagy in iPSC-derived motor neurons

Mutations in the AAA+ ATPase p97 (also known as valosin containing protein, VCP) cause multisystem proteinopathy 1 (MSP-1) which includes amyotrophic-lateral sclerosis (ALS); however, the pathogenic mechanisms that contribute to motor neuron loss in familial ALS caused by p97 mutations remain obscure. Here, we use two distinct induced pluripotent stem cell models differentiated into spinal motor neurons to investigate how p97 mutations perturb the motor neuron proteome. Using multiplexed quantitative proteomics in these cells, we find that motor neurons harboring the p97 R155H mutation have deficits in lysosome quality control and the selective autophagy of lysosomes (lysophagy). p97 R155H motor neurons are unable to efficiently clear damaged lysosomes and have reduced viability. Additionally, lysosomes in mutant motor neurons have increased pH compared to their wildtype counterparts. The endo-lysosomal damage repair (ELDR) complex is required for clearance of damaged lysosomes and involves UBXD1-p97 interaction which is disrupted in mutant motor neurons. Finally, we report that inhibition of the ATPase activity of p97 R155H using the ATP competitive inhibitor CB-5083 rescues lysophagy defects in mutant motor neurons. These results add to the increasing evidence that endo-lysosomal dysfunction is a key aspect of disease pathogenesis in p97-related disorders.

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bioRxiv2023

Network States in the Basolateral Amygdala Predicts Voluntary Alcohol Consumption

Although most adults in the United States will drink alcohol in their life, only about 6% will go on to develop an alcohol use disorder (AUD). While a great deal of work has furthered our understanding of the cycle of addiction, it remains unclear why certain people transition to disordered drinking. Altered activity in regions implicated in AUDs, like the basolateral amygdala (BLA), has been suggested to play a role in the pathophysiology of AUDs, but how these networks contribute to alcohol misuse remains unclear. Our recent work demonstrated that alcohol can modulate BLA network states and that GABAergic parvalbumin (PV) interneurons are crucial modulators of network activity in the BLA. Further, our lab has demonstrated that {delta} subunit-containing GABAA receptors, which are modulated by alcohol, are highly expressed on PV interneurons in the BLA. These receptors on PV interneurons have also been shown to influence alcohol intake in a voluntary binge drinking paradigm and anxiety-like behavior in withdrawal. Therefore, we hypothesized that alcohol may impact BLA network states via {delta} subunit-containing GABAA receptors on PV interneurons to impact the extent of alcohol use. To test this hypothesis, we measured the impact of acute alcohol exposure on oscillatory states in the basolateral amygdala and then assessed the relationship to the extent of voluntary ethanol consumption in the Intermittent Access, Drinking-in-the-Dark-Multiple Scheduled Access, and Chronic Intermittent Ethanol exposure paradigms. Remarkably, we demonstrate that the average alcohol intake negatively correlates with {delta} subunit-containing GABAA receptor expression on PV interneurons and gamma power in the BLA after the first exposure to alcohol. These data implicate {delta} subunit-containing GABAA receptor expression on PV interneurons in the BLA in voluntary alcohol intake and suggest that BLA network states may serve as a useful biomarker for those at risk for alcohol misuse. Significance StatementOscillatory states in the BLA have been demonstrated to drive behavioral states involved in emotional processing, including negative valence processing. Given that negative emotional states/hyperkatifeia contribute to the cycle of AUDs, our previous work demonstrating the ability of alcohol to modulate BLA network states and thereby behavioral states suggests that this mechanism may influence alcohol intake. Here we demonstrate a relationship between the ability of alcohol to modulate oscillations in the BLA and future alcohol intake such that the extent to which alcohol influences BLA network states predict the extent of future voluntary alcohol intake. These findings suggest that individual variability in the sensitivity of the BLA network to alcohol influences voluntary alcohol consumption.

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bioRxiv2022

Hypothalamic-pituitary-adrenal axis dysfunction worsens epilepsy outcomes and increases SUDEP risk

Epilepsy is often comorbid with psychiatric illnesses, including anxiety and depression. Despite the high incidence of psychiatric comorbidities in people with epilepsy, few studies address the underlying mechanisms. Stress can trigger both epilepsy and depression and significant accumulating evidence, from both human and animal studies, support that hypothalamic-pituitary-adrenal (HPA) axis dysfunction may contribute to the comorbidity of these two disorders1. Here we directly investigate the contribution of HPA axis dysfunction to epilepsy outcomes and psychiatric comorbidities. We generated a novel mouse model (KCC2/Crh mice) that lacks the K+/Cl- co-transporter, KCC2, in corticotropin-releasing hormone (CRH) neurons, which exhibit stress- and seizure-induced hyperactivation of the HPA axis.2,3 Here we demonstrate that HPA axis dysfunction in KCC2/Crh mice is associated with increased vulnerability to behavioral deficits in chronically epileptic mice and more severe neuropathological features associated with chronic epilepsy (e.g. increased mossy fiber sprouting). Despite equivalent seizure burden, HPA axis dysfunction in these chronically epileptic mice increased the incidence of sudden unexpected death in epilepsy (SUDEP). Suppressing HPA axis hyperexcitability in this model using a pharmacological or chemogenetic approach decreased SUDEP incidence, supporting HPA axis dysfunction in SUDEP vulnerability. We also observed changes in neuroendocrine markers in individuals that died of SUDEP compared to people with epilepsy or individuals without a history of epilepsy. Together, these findings describe a novel, nongenetic mouse model of SUDEP which will benefit preclinical SUDEP research to gain a better understanding of the underlying pathological mechanisms contributing to SUDEP. HPA axis dysfunction increases vulnerability to psychiatric comorbidities in epilepsy and may be a risk factor for SUDEP.

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bioRxiv2022

Sex differences in the alcohol-mediated modulation of BLA network states

About 85% of adults in the United States report drinking alcohol in their lifetime. Mood disorders, like generalized anxiety disorder and major depression, are highly comorbid with alcohol use. The basolateral amygdala (BLA) is an area of the brain that is heavily implicated in both mood disorders and alcohol use disorder. Importantly, modulation of BLA network/oscillatory states via parvalbumin-positive (PV) GABAergic interneurons has been shown to control the behavioral expression of fear and anxiety. Further, PV interneurons express a high density of {delta}-subunit-containing GABAA receptors (GABAARs), which are sensitive to low concentrations of alcohol. Our lab previously demonstrated that {delta}-subunit-containing GABAARs on PV interneurons in the BLA influence voluntary ethanol intake and anxiety-like behavior in withdrawal. Therefore, we hypothesized that the effects of alcohol may modulate BLA network states that have been associated with fear and anxiety behaviors via {delta}-GABAARs on PV interneurons in the BLA. Given the impact of ovarian hormones on the expression of {delta}-GABAARs, we examined the ability of alcohol to modulate local field potentials (LFPs) in the BLA from male and female C57BL/6J and Gabrd-/- mice after acute and repeated exposure to alcohol. Here, we demonstrate that acute and repeated alcohol can differentially modulate oscillatory states in male and female C57BL/6J mice, a process which involves {delta}-GABAARs. This is the first study to demonstrate that alcohol is capable of altering network states implicated in both anxiety and alcohol use disorders. Significance StatementAlcohol use disorder and mood disorders are highly comorbid. The basolateral amygdala (BLA) is implicated in both of these disorders, but the mechanisms contributing to their shared pathophysiology remain uncertain. Here we demonstrate that acute and repeated alcohol exposure can alter network oscillations in the BLA which control the behavioral expression of fear and anxiety. These data suggest that alcohol may directly influence network states associated with mood. Further, we demonstrate sex differences in alcohols ability to modulate BLA network states, an effect involving {delta}-GABAA receptors, which may contribute to sex differences in alcohol intake and comorbid mood disorders. These data potentially point to a novel mechanism mediating the effects of alcohol on affective states. O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

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bioRxiv2022

Impaired endogenous neurosteroid signaling contributes to behavioral deficits associated with chronic stress

Chronic stress is a major risk factor for psychiatric illnesses, including depression; however, the pathophysiological mechanisms whereby stress leads to mood disorders remain unclear. The recent FDA approval of antidepressants with novel mechanisms of action, like Zulresso(R), a synthetic neuroactive steroid analog with molecular pharmacology similar to allopregnanolone, has spurred interest in new therapeutic targets and, potentially, novel pathophysiological mechanisms for depression. Allopregnanolone acts as a positive allosteric modulator of GABAA receptors (GABAARS), acting preferentially at {delta} subunit-containing receptors ({delta}-GABAARS). Accumulating clinical and preclinical evidence supports the antidepressant effects of exogenous administration of allopregnanolone and allopregnanolone analogs; however, the role of endogenous neurosteroids in the pathophysiology of depression remains unknown. Here, we examine whether altered neurosteroid signaling may contribute to behavioral deficits following chronic unpredictable stress (CUS) in mice. We first identified reductions in expression of {delta}-GABAARs, the predominant site of action of 5a-reduced neuroactive steroids, following CUS. Additionally, utilizing LC-MS/MS we discovered a decrease in levels of allopregnanolone in the BLA, but not plasma of mice following CUS, an indication of impaired neurosteroid synthesis. CRISPR knockdown the rate-limiting enzymes involved in allopregnanolone synthesis, 5-reductase type 1 and 2, in the BLA mimicked the behavioral deficits associated with CUS in mice. Furthermore, overexpression expression of 5-reductase type 1 and 2 in the BLA improved behavioral outcomes. Collectively, this suggests chronic stress impairs endogenous neurosteroid signaling in the BLA which is sufficient to induce behavioral deficits similar to those observed following CUS. Further, these studies suggest that the therapeutic efficacy of allopregnanolone-based treatments may be due to their ability to directly target the underlying pathophysiology of mood disorders. Therefore, targeting endogenous neurosteroidogenesis may offer a novel therapeutic strategy for the treatment of mood disorders.

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bioRxiv2021

Allopregnanolone mediates affective switching through modulation of oscillatory states in the basolateral amygdala

Brexanolone (allopregnanolone), was recently approved by the FDA for the treatment of post-partum depression, demonstrating long-lasting antidepressant effects. Despite our understanding of the mechanism of action of neurosteroids as positive allosteric modulators (PAMs) of GABAO_SCPLOWAC_SCPLOW receptors, we still do not fully understand how allopregnanolone exerts these persistent antidepressant effects. Here, we demonstrate that allopregnanolone and similar synthetic neuroactive steroid analogs, SGE-516 (tool-compound) and zuranolone (SAGE-217, investigational-compound), are capable of modulating oscillatory states across species, which we propose may contribute to long-lasting changes in behavioral states. We identified a critical role for interneurons in generating oscillations in the basolateral amygdala (BLA) and a role for delta-containing GABAO_SCPLOWAC_SCPLOWRs in mediating the ability of neurosteroids to modulate network and behavioral states. Actions of allopregnanolone in the BLA is sufficient to alter behavioral states and enhance BLA high-theta oscillations (6-12Hz) through delta-containing GABAO_SCPLOWAC_SCPLOW receptors, a mechanism distinct from other GABAO_SCPLOWAC_SCPLOW PAMs, such as benzodiazepines. Moreover, treatment with the allopregnanolone analog SGE-516 induces long-lasting protection from chronic stress-induced disruption of network states, which correlates with improved behavioral outcomes. Our findings demonstrate a novel molecular and cellular mechanism mediating the well-established anxiolytic and antidepressant effects of neuroactive steroids.

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bioRxiv2020

Miro1-dependent Mitochondrial Dynamics in Parvalbumin Interneurons

The spatiotemporal distribution of mitochondria is crucial for precise ATP provision and calcium buffering required to support neuronal signaling. Fast-spiking GABAergic interneurons expressing parvalbumin (PV) have a high mitochondrial content reflecting their large energy utilization. The importance for correct trafficking and precise mitochondrial positioning remains poorly elucidated in inhibitory neurons. Miro1 is a Ca2+-sensing adaptor protein that links mitochondria to the trafficking apparatus, for their microtubule-dependent transport along axons and dendrites, in order to meet the metabolic and Ca2+-buffering requirements of the cell. Here, we explore the role of Miro1 in parvalbumin interneurons and how changes in mitochondrial trafficking could alter brain network activity. By employing live and fixed imaging, we found that the impairments in Miro1-directed trafficking in PV+ interneurons altered their mitochondrial distribution and axonal arborization. These changes were accompanied by an increase in the ex vivo hippocampal {gamma}-oscillation (30 - 80 Hz) frequency and promoted anxiolysis. Our findings show that precise regulation of mitochondrial dynamics in PV+ interneurons is crucial for proper neuronal signaling and network synchronization.

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bioRxiv2019

Complementary roles for parvalbumin and somatostatin interneurons in the generation of hippocampal gamma oscillations

Gamma-frequency oscillations (30-120 Hz) can be separated into fast (>60 Hz) and slow oscillations, with different roles in neuronal encoding and information transfer. While synaptic inhibition is important for synchronization across the gamma-frequency range, the role of distinct interneuronal subtypes in fast and slow gamma states remains unclear. Here, we used optogenetics to examine the involvement of parvalbumin (PV+) and somatostatin (SST+) expressing interneurons in gamma oscillations in the mouse hippocampal CA3 ex vivo. Disrupting either PV+ or STT+ interneuron activity, via either photo-inhibition or photo-excitation, led to a decrease in the power of cholinergically-induced slow gamma oscillations. Furthermore, photo-excitation of SST+ interneurons induced fast gamma oscillations, which depended on both synaptic excitation and inhibition. Our findings support a critical role for both PV+ and SST+ interneurons in slow hippocampal gamma oscillations, and further suggest that STT+ interneurons are capable of switching the network between slow and fast gamma states.

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