Publications by authors named "Pantelis Antonoudiou"

Stress is a common seizure trigger that has been implicated in worsening epilepsy outcomes, which encompasses psychiatric and cognitive comorbidities and sudden unexpected death in epilepsy (SUDEP) risk. 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 SUDEP in mice. Early life stress (ELS) reprograms the HPA axis into adulthood, impacting both the basal and stress-induced activity.

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Accumulating evidence supports a role for altered circuit function in impaired valence processing and altered affective states as a core feature of psychiatric illnesses. We review the circuit mechanisms underlying normal valence processing and highlight evidence supporting altered function of the basolateral amygdala, valence processing, and affective states across psychiatric illnesses. The mechanisms controlling network activity that governs valence processing are reviewed in the context of potential pathophysiological mechanisms mediating circuit dysfunction and impaired valence processing in psychiatric illnesses.

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Article Synopsis
  • Stress can make epilepsy worse and trigger seizures, especially in mice.
  • Early life stress (like being separated from mom) can change how the brain controls stress in adulthood.
  • This study found that early life stress affects seizures differently in male and female mice, with female mice showing more changes and less chance of sudden death from seizures.
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CTNNB1 syndrome is a rare monogenetic disorder caused by CTNNB1 de novo pathogenic heterozygous loss-of-function variants that result in cognitive and motor disabilities. Treatment is currently lacking; our study addresses this critical need. CTNNB1 encodes β-catenin which is essential for normal brain function via its dual roles in cadherin-based synaptic adhesion complexes and canonical Wnt signal transduction.

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It is well established that the basolateral amygdala (BLA) is an emotional processing hub that governs a diverse repertoire of behaviors. Selective engagement of a heterogeneous cell population in the BLA is thought to contribute to this flexibility in behavioral outcomes. However, whether this process is impacted by previous experiences that influence emotional processing remains unclear.

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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 epilepsy and depression.

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Despite the vast number of seizure detection publications there are no validated open-source tools for automating seizure detection based on electrographic recordings. Researchers instead rely on manual curation of seizure detection that is highly laborious, inefficient, error prone, and heavily biased. Here we developed an open-source software called SeizyML that uses sensitive machine learning models coupled with manual validation of detected events reducing bias and promoting efficient and accurate detection of electrographic seizures.

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Background: Adverse 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.

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The basolateral amygdala (BLA) mediates both fear and reward learning. Previous work has shown that parvalbumin (PV) interneurons in the BLA contribute to BLA oscillatory states integral to fear expression. However, despite it being critical to our understanding of reward behaviors, it is unknown whether BLA oscillatory states and PV interneurons similarly contribute to reward processing.

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Mutations in the AAA+ ATPase p97 cause multisystem proteinopathy 1, which includes amyotrophic lateral sclerosis; however, the pathogenic mechanisms that contribute to motor neuron loss remain obscure. Here, we use two induced pluripotent stem cell models differentiated into spinal motor neurons to investigate how p97 mutations perturb the motor neuron proteome. Using quantitative proteomics, we find that motor neurons harboring the p97 R155H mutation have deficits in the selective autophagy of lysosomes (lysophagy).

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Unlabelled: 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.

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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.

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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.

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Affective disorders such as depression and anxiety are among the most prevalent psychiatric illnesses and causes of disability worldwide. The recent FDA-approval of a novel antidepressant treatment, ZULRESSO® (Brexanolone), a synthetic neurosteroid has fueled interest into the role of neurosteroids in the pathophysiology of depression as well as the mechanisms mediating the antidepressant effects of these compounds. The majority of studies examining the impact of neurosteroids on affective states have relied on the administration of exogenous neurosteroids; however, neurosteroids can also be synthesized endogenously from cholesterol or steroid hormone precursors.

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Stress is a major risk factor for psychiatric illnesses and understanding the mechanisms through which stress disrupts behavioral states is imperative to understanding the underlying pathophysiology of mood disorders. Both chronic stress and early life stress alter valence processing, the process of assigning value to sensory inputs and experiences (positive or negative), which determines subsequent behavior and is essential for emotional processing and ultimately survival. Stress disrupts valence processing in both humans and preclinical models, favoring negative valence processing and impairing positive valence processing.

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Background: Chronic stress is a major risk factor for psychiatric illnesses, including depression. However, the pathophysiological mechanisms whereby stress leads to mood disorders remain unclear. Allopregnanolone acts as a positive allosteric modulator preferentially on δ subunit-containing GABA (gamma-aminobutyric acid A) receptors.

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Alcohol use, reported by 85% of adults in the United States, is highly comorbid with mood disorders, like generalized anxiety disorder and major depression. The basolateral amygdala (BLA) is an area of the brain that is heavily implicated in both mood disorders and alcohol use disorder. Importantly, the modulation of BLA network/oscillatory states via parvalbumin (PV)-positive GABAergic interneurons has been shown to control the behavioral expression of fear and anxiety.

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Patterned coordination of network activity in the basolateral amygdala (BLA) is important for fear expression. Neuromodulatory systems play an essential role in regulating changes between behavioral states, however the mechanisms underlying this neuromodulatory control of transitions between brain and behavioral states remain largely unknown. We show that chemogenetic Gq activation and α1 adrenoreceptor activation in mouse BLA parvalbumin (PV) interneurons induces a previously undescribed, stereotyped phasic bursting in PV neurons and time-locked synchronized bursts of inhibitory postsynaptic currents and phasic firing in BLA principal neurons.

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Article Synopsis
  • Brexanolone, a neurosteroid approved for postpartum depression, shows long-lasting antidepressant effects through its impact on GABA receptors, but its exact mechanisms are still unclear.
  • Research involved both animal and human studies using various advanced techniques, revealing how allopregnanolone and similar compounds affect brain oscillations and mood-related networks.
  • The study highlights the important role of specific GABA receptors and interneurons in the basolateral amygdala in enhancing brain oscillations and potentially improving behavioral responses to stress.
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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.

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γ-frequency oscillations (30-120 Hz) in cortical networks influence neuronal encoding and information transfer, and are disrupted in multiple brain disorders. While synaptic inhibition is important for synchronization across the γ-frequency range, the role of distinct interneuronal subtypes in slow (<60 Hz) and fast γ states remains unclear. Here, we used optogenetics to examine the involvement of parvalbumin-expressing (PV) and somatostatin-expressing (SST) interneurons in γ oscillations in the mouse hippocampal CA3 , using animals of either sex.

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Advances in membrane cell biology are hampered by the relatively high proportion of proteins with no known function. Such proteins are largely or entirely devoid of structurally significant domain annotations. Structural bioinformaticians have developed profile-profile tools such as HHsearch (online version called HHpred), which can detect remote homologies that are missed by tools used to annotate databases.

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