Project Summary: The striatum is implicated in learning, reward and addiction, including alcoholism. Within
the striatum, ablation of cholinergic interneurons (CINs) results in behavioral and cognitive deficits similar to
those observed in alcoholics. Interestingly, there is evidence indicating a decrease in CINs following chronic
ethanol exposure. In agreement, I have found that striatal cholinergic function is impaired in monkeys following
long-term ethanol consumption. Therefore, the overarching hypothesis of this proposal is that chronic
ethanol exposure decreases striatal CIN numbers or function and that these ethanol-induced cholinergic
impairments underlie the behavioral and cognitive deficits associated with alcoholism. To test this
hypothesis, I propose three specific aims: Specific Aim 1 – I will determine the effect of acute ethanol on striatal
CIN subtypes using transgenic mice, immunohistochemical, RNAscope, and electrophysiological techniques.
The characterization of CIN subtype sensitivity to ethanol will be of broad interest to alcohol and basal ganglia
researchers alike. Specific Aim 2 – I will determine if chronic ethanol-induced deficits in striatal CINs are due
to a loss of CINs, an impairment of CIN function, or both. There is agreement in the literature that the striatal
cholinergic circuit is hypo-functional following chronic ethanol exposure but the source of this dysfunction is not
clear. Therefore, I will determine if CINs are lost and/or if CIN function is compromised (with electrophysiology)
following chronic ethanol exposure. These results will be the first to examine the effects of chronic ethanol on
striatal CIN function. Specific Aim 3 – I will then determine if in vivo chemogenetic manipulation of CIN activity
after chronic ethanol are sufficient to ameliorate the behavioral and cognitive deficits that accompany chronic
ethanol exposure including ethanol consumption and performance on an operant reversal learning task.
Throughout my career, I have been interested in the mechanisms underlying normal and aberrant behaviors. I
have been fortunate to have mentors that taught me the skills required to engage in meaningful research. At
every stage of my career, I have advanced in my technical ability and scientific sophistication and as I continue
to train, my mentors, Kim Blackwell and David Lovinger, will challenge me to constantly improve as a scientist
and to ask impactful questions, to design compelling experiments to address those questions, and to present my
findings clearly and effectively in manuscripts and presentations. Furthermore, we have a plan to ensure that I
receive training to conduct exciting experiments, run a successful lab, and mentor trainees. In addition, Drs.
Adron Harris and Marisa Roberto, two successful researchers, have agreed to serve on my advisory committee
to ensure that I am successful in my transition to an independent investigator. Thus, I am confident that with the
mentorship of my mentors, my extramural advisory committee, my technical consultants, and the institutional
support of NIAAA and George Mason University, I will be able to execute the proposed experiments, attain a
faculty position, and thrive as a successful independent neuroscientist.