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Principal Investigator: Hoonkyo Suh
Organization: CLEVELAND CLINIC LERNER COM-CWRU
Fiscal Year: 2024
Award: $494,202
Funding agency: National Institute on Alcohol Abuse and Alcoholism
Abstract
Alcohol withdrawal (AW) after chronic alcohol exposure produces a series of symptoms. Among
them, generalized tonic-clonic seizures and impairments in cognition and emotion are the most
severe and dangerous symptoms. Despite alcohol’s aversive effects, alcohol’s positive-
reinforcing effects of euphoria, anxiolysis, and reduction in pain and seizures dramatically
increase the vulnerability to relapse and alcohol abuse. The severity and susceptibility to relapse
and perpetuation of alcohol abuse underscore the urgent need to understand mechanisms
underlying alcohol dependence and withdrawal in order to develop new therapeutic strategies to
intervene and treat AW-associated syndromes. In this application, we will test the novel
hypothesis that structural and functional changes in hippocampal newborn dentate granule cells
(DGCs) underlie the development and maintenance of AW-associated physiological and
psychological dysfunctions. DGCs are continuously produced and integrate into hippocampal
neural circuits, and this process has been implicated in seizures, as well as cognitive and
emotional function. The central goal of this proposal is to use novel, genetic methods for mapping
and understanding hippocampal neural circuits that are responsible for maladaptation during
alcohol exposure and withdrawal. In Aim 1, we will determine whether AW alters synaptic,
neuronal, and functional connectivity of DGCs by using structural, electrophysiological, and rabies
virus-mediated mapping methods. In Aim 2, to test the essential role of newborn DGCs in AW-
induced seizure expression, we will use a DREADD (Designer Receptors Exclusively Activated
by Designer Drugs) method and produce models with gain-of-function and loss-of-function in
newborn DGCs. Using this method, we will assess whether specific activation and inhibition of
newborn DGCs will enhance and decrease AW seizures, respectively. In Aim 3, we will determine
whether altered activity of newborn DGCs is responsible for deficits in cognition and emotion
during abstinence. Our studies will unveil the essential function of hippocampal newborn DGCs
in AW syndromes at the level of neural circuits and provide a critical foundation for understanding
and treating AW-induced physiological and psychological dysfunctions.
Terms: <0-4 weeks old><3-D><3-Dimensional><3D><Abstinence><Adeno-Associated Viruses><Alcohol Chemical Class><Alcohol Withdrawal Seizures><Alcohol Withdrawal-Induced Seizure><Alcohol abuse><Alcohol dependence><Alcohol withdrawal syndrome><Alcoholic Seizures><Alcohols><American><Ammon Horn><Anxiety><Axon><Behavior><Behavioral><Brain><Brain Nervous System><Chronic><Cognition><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Cornu Ammonis><DREADDs><Dangerousness><Data><Dendritic Spines><Dependoparvovirus><Dependovirus><Development><Disturbance in cognition><Dysfunction><Electron Microscopy><Electrophysiology><Electrophysiology (science)><Emotions><Encephalon><Epilepsy><Epileptic Seizures><Epileptics><EtOH abuse><Euphoria><Foundations><Functional disorder><Genetic><Genetic study><Goals><Hippocampus><Hour><Human><Impaired cognition><Impairment><Label><Maintenance><Maps><Mediating><Memory Deficit><Memory impairment><Methods><Modeling><Modern Man><Nature><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Neurophysiology / Electrophysiology><Newborn Infant><Newborns><Outcome><Pain><Painful><Pathogenesis><Physical Function><Physiologic><Physiological><Physiopathology><Predisposition><Process><Psyche structure><Rabies lyssavirus><Rabies mapping><Rabies trans synaptic tracing><Rabies virus><Rabies virus mediated mapping><Relapse><Retroviridae><Retroviruses><Role><Seizure Disorder><Seizures><Series><Severities><Spinal Column><Spine><Structure><Susceptibility><Symptoms><Synapses><Synaptic><Syndrome><Testing><Tonic - clonic seizures><Vertebral column><Virus-Retrovirus><abstaining from alcohol><abstaining from ethanol><abstinence from alcohol><abstinence from ethanol><adeno associated virus group><alcohol abstinence><alcohol addiction><alcohol co-abuse><alcohol dependency><alcohol dependent><alcohol effect><alcohol exposed><alcohol exposure><alcohol problem><alcohol relapse><alcohol withdrawal><associated symptom><backbone><co-morbid symptom><co-occuring symptom><cognitive dysfunction><cognitive function><cognitive loss><comorbid symptom><concurrent symptom><cooccuring symptom><dendrite spine><density><designer receptors exclusively activated by designer drugs><developmental><electrophysiological><emotional functioning><epilepsia><epileptogenic><ethanol abstinence><ethanol abuse><ethanol effect><ethanol exposed><ethanol exposure><ethanol relapse><ethanol withdrawal><excitatory neuron><experience><experiment><experimental research><experimental study><experiments><exposed to alcohol><exposed to ethanol><exposure to alcohol><exposure to ethanol><gain of function><grand mal seizure><granule cell><hazardous alcohol use><hippocampal><inhibitory neuron><loss of function><memory dysfunction><mental><mental function><mouse model><murine model><neural adaptation><neural circuit><neural circuitry><neural network><neuroadaptation><neurocircuitry><neurogenesis><neuronal><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><newborn child><newborn children><newborn neuron><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><pathophysiology><pharmacologic><pre-synaptic nerve><pre-synaptic neurons><presynaptic><presynaptic nerve><presynaptic neurons><problem alcohol use><problem drinking><problematic alcohol consumption><problematic alcohol use><psychologic><psychological><rabies based mapping><rabies based retrograde mapping><rabies circuit tracing><rabies mediated retrograde monosynaptic tracing><rabies retrograde tracing><rabies tracer><rabies tracing><rabies viral tracing><rabies virus mediated circuit mapping><rabies virus monosynaptic circuit tracing><rabies virus monosynaptic tracing><rabies virus retrograde tracing><rabies virus tracing><social role><symptom association><symptom comorbidity><synapse><synaptic circuit><synaptic circuitry><three dimensional><tracing with rabies><withdrawal from alcohol>