SUMMARY/ABSTRACT
The overarching goal of this proposal is to identify and characterize mechanistic pathways in astrocytes
responsible for changes in drug-evoked structural and synaptic plasticity that underlie the maladaptive behavior
in opioid drug abuse. Astrocytes are a logical focus for these studies, as they are intimately involved in diverse
neuronal function, including modulation of synaptic function and plasticity, regulating concentrations of the
excitatory neurotransmitter glutamate, and yet secrete and response to neuroinflammatory cytokines,
chemokines, and growth factors. These processes are themselves regulated by autophagy: the process by which
cells both engage in orderly degradation and recycling of cellular components as well as balancing energy
metabolism. Although astrocyte-mediated excitation and inflammation have been implicated in neuroadaptations
and drug-seeking behavior, the role of astrocytes autophagy in the mechanism underlying the intersection
between the glutamate system and neuroimmune signaling, is not well understood. Findings from our lab showed
that a key autophagy protein, Beclin1, is strongly associated with the secretion of cytokines, chemokines, and
growth factors released from glia and neurons. We also showed that activation of autophagy increases glutamate
uptake along with glutamate transporters expressed in astrocytes, collectively establishing a strong premise for
the current proposed investigations. Extending our initial studies, here we hypothesize that autophagy-
mediated neuroimmune signaling and glutamate metabolism in astrocytes ± HIV alters neuronal circuitry
to promote opioid use disorder (OUD) and abuse. Since opioid and HIV-infection are common comorbidities,
and opioids are commonly prescribed to HIV-infected individuals experiencing pain, studies will include
assessment of HIV-infection through use of EcoHIV in a series of mouse models, facilitating the needed
behavioral, neuroanatomical, and mechanistic studies to address the current knowledge gap. In Specific Aim
(SA) 1 we will use Becn1+/- and Becn1+/+ mice to define the role of astrocyte autophagy with or without HIV and/or
chronic opioid exposure on the progression and magnitude of opioid addiction, withdrawal, long-term abstinence,
and relapse in validated behavioral models. In SA 2 we will use brain tissue harvested from mice tested in Aim
1 to decipher the interlink between excitation and inflammation-evoked changes in neurochemical and
neuroanatomical plasticity and maladaptive behavior in opioid drug abuse (with or without HIV), through the lens
of astrocytes autophagy. In SA 3 we will use brain cells to further investigate the mechanisms by which Beclin1
interacts with the μ-opioid receptor and/or associated proteins and analyze how Beclin1 activity modulates
endolysosomal trafficking and degradation of MOR intracellular trafficking in brain cells in response to opioid
(with and without HIV). Findings are expected to produce mechanistic insights into how autophagy regulates the
underlying crosstalk between astrocytes and neuronal circuitry mediating OUD and abuse behaviors, yielding
both novel therapeutic targets for development and strategies for preventing OUD in at risk HIV populations.
