Effects of tACS on alcohol-induced cognitive and neurochemical deficits

ABSTRACT: Alcohol is one of the most widely used drugs by adolescents and is often consumed in a binge drinking pattern. Binge drinking alcohol during this critical developmental period can lead to lasting cognitive impairments for which there are few effective treatments. One domain that is disrupted following adolescent

binge alcohol use is behavioral flexibility, defined as the ability to adapt behavior to a changing environment. The neurocircuitry underlying behavioral flexibility is complex but includes the medial prefrontal cortex (mPFC), the orbitofrontal cortex (OFC), and the anterior insula cortex (aIC), all regions that are among those perturbed by

adolescent alcohol use. To better understand the neural mechanisms underlying adolescent alcohol induced cognitive impairments and to test novel treatment paradigms, our lab utilizes a rat model of adolescent binge alcohol exposure (adolescent intermittent exposure, or AIE). We have identified deficits in behavioral flexibility

as measured by an attentional set shifting task in AIE-exposed rats compared to controls. Furthermore, we have recently identified AIE-induced changes in perineuronal nets (PNNs), a component of the extracellular matrix that preferentially forms around parvalbumin (PV) interneurons and modulates their activity. AIE was shown to

increase PNN density in the mPFC and OFC, and a higher proportion of PV+ interneurons were surrounded by PNNs. Additionally, we have collected preliminary data suggesting that AIE leads to a higher proportion of PV+ interneurons surrounded by PNNs in the aIC. As these altered neurochemical markers are found in the mPFC,

OFC, and aIC, they may underpin the observed deficits in behavioral flexibility following AIE. One potential strategy to improve deficits in behavioral flexibility is by using transcranial alternating current stimulation (tACS), a noninvasive neuromodulatory technique used in humans. tACS has been reverse translated and has been

shown to restore flexible behavior in rats that have drug-induced impairments. Further, tACS is known to alter gamma oscillations, which are regulated by PV interneurons. However, it is not known whether tACS treatment will restore adolescent alcohol-induced deficits in behavioral flexibility. Additionally, it is currently unknown

whether tACS can alter neurochemical markers. This F32 proposal will: 1) determine if tACS treatment normalizes PNN density in adult AIE-exposed rats; and 2) determine if tACS treatment restores alcohol-induced

deficits in behavioral flexibility. Clinically, these studies will be impactful because they test the ability of tACS to ameliorate alcohol-induced deficits in behavioral flexibility, something known to be disrupted in humans following adolescent binge-alcohol consumption. The results generated from these Aims will lay the necessary

groundwork for future investigations and grant proposals, such as a K99/R00 application. Completion of the proposed study will allow me to be trained in a highly clinically relevant technique (tACS), as well as expand my expertise in immunohistochemistry and behavior, and by doing so, prepare me to address important questions

in the field of alcohol research as I progress towards my goal of becoming an independent investigator.