A cardinal feature of alcohol use disorder (AUD) is loss of control over drinking. The neural substrates that underlie transition from controlled social drinking to uncontrolled alcohol abuse are not fully understood but likely involve disruption of brain areas involved in assessing risk versus reward and in inhibiting maladaptive behaviors. During the current funding cycle, we focused on defining the actions of alcohol on neurons within the orbitofrontal cortex (OFC), a part of the prefrontal cortex that is critical for choice and decision making. Studies also examined how manipulating the activity OFC neurons affects drinking. Results show that acute alcohol inhibits OFC neuron activity via a glycine receptor and dopamine D1 receptor-dependent mechanism, while monoamine inhibition of OFC spiking requires D2, a2 and 5HT-1a receptors that are coupled to inhibitory GIRK channels. Following repeated cycles of chronic intermittent ethanol (CIE) exposure or voluntary drinking, OFC neurons were hyper- excitable and no longer sensitive to alcohol or monoamines. Blocking OFC output via excitotoxic lesions or inhibitory DREADDs had little effect on alcohol drinking in non-dependent animals but further enhanced elevated consumption in CIE-treated mice. In this renewal application, we propose three aims that complement and extend findings from the current project. These studies focus on defining how neurons in the OFC and basolateral amygdala (BLA) converge on and influence activity and functional output of medium spiny neurons (MSNs) in the dorsal striatum (DS). Studies will use our well-characterized mouse model of CIE exposure combined with operant alcohol self-administration and in vitro and in vivo measures of neural activity.
Aim 1 studies use ex vivo slice electrophysiology and retrograde labeling to examine the excitability and acute alcohol sensitivity of OFC and BLA neurons that project to the DS in non-dependent and alcohol-dependent male and female C57BL/6J mice. Dual color optogenetic constructs and transgenic reporter mice will be used to evoke OFC and BLA synaptic currents onto DS D1 and D2 MSNs in slices from Air and CIE treated mice.
Aim 2 studies use in vivo calcium fiber photometry to measure CIE-induced changes in the activity and alcohol sensitivity of DS projecting OFC and BLA neurons during operant self-administration of alcohol and alcohol with tastants that reduce (quinine) or enhance (sucrose) drinking in non-dependent mice. Complementary fiber photometry studies will monitor the activity of DS MSNs innervated by OFC and BLA inputs. Studies in Aim 3 will use in vivo optogenetics (e.g. Chronus, Chrimson, ArchT) to bi-directionally manipulate DS projecting OFC and BLA inputs to assess how these pathways regulate drinking and how this is altered by alcohol dependence. Overall, the results of these studies will advance our understanding of mechanisms that contribute to the escalation of drinking in alcohol- dependent subjects and provide key data needed to develop better treatments for individuals with AUD.
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