Wednesday, May 1, 2024
5/1/2024
ABSTRACT Adolescent binge drinking promotes enduring cognitive deficits and higher incidence of alcohol use disorder in adulthood. Studies using a rat model of adolescent binge drinking (EtOH) demonstrate long-term deficits in hippocampal neuronal structure, function, and behavior; however, the underlying mechanisms are not well understood. Coincident with changes in CA1 hippocampal neuronal circuit function, adolescent EtOH exposure results in astrocyte reactivity and chronic dysregulation of astrocyte-secreted signaling factors known to be involved in synaptic remodeling. Astrocytes tightly regulate synaptic activity and ion homeostasis through their perisynaptic astrocyte processes (PAPs), allowing for bi-directional communication through various contact- mediated and secreted signaling factors that modulate synaptic transmission. In addition, the behavioral relevance of astrocyte/synaptic communication is beginning to emerge through exciting new advances showing astrocytes to be involved in behavioral resiliency, fear learning, and remote memory, and contribute to working memory deficits following drug exposure. Current data demonstrates that EtOH-induced persistence of immature dendritic spines (i.e. sites of excitatory synaptic input) is spatiotemporally linked with PAP-synaptic decoupling. Based on preliminary data the researchers predict that disruption of PAP proximity to synapses compromises neuron-to-astrocyte signaling and the ability of astrocytes to regulate synaptic homeostasis. Therefore, the overall objective of this application is to elucidate how EtOH-induced disruption of PAP-synaptic coupling and neuron-astrocyte crosstalk contributes to long-term changes in synaptic function. Achieving this objective will allow the researchers to reach their long-term goal, which is to identify the cellular and molecular mechanisms that may inform novel treatments for the prevention and reversal of synaptic dysfunction and the emergence of AUD after repeated adolescent EtOH exposure. The central hypothesis is that repeated adolescent EtOH exposure triggers PAP-synaptic decoupling and lasting changes in astrocyte-neuronal crosstalk. The rationale behind the project is that understanding the novel mediators that drive EtOH-induced maladaptive astrocyte-neuronal crosstalk will contribute key insight into the mechanisms underlying synaptic dysfunction following adolescent EtOH exposure. The proposed research is significant since successful completion will result in the identification of non-neuronal processes critical for the prevention and reversal of neuronal circuit dysfunction following adolescent ethanol exposure. An interdisciplinary team of investigators and consultants with expertise in the field of adolescent alcohol, astrocytes, and electrophysiology will conduct this innovative project.
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