Alcoholism, also known as alcohol use disorder, is a chronic debilitating disorder characterized by excessive ingestion of alcohol and impairment in social and occupational functioning. While most investigations of brain mechanisms mediating this disorder have studied the hypothalamus or mesolimbic regions, recent evidence focuses attention on a relatively understudied area, the paraventricular nucleus of the thalamus (PVT), which provides an important relay point between the homeostasis-regulating hypothalamus and emotion-regulating limbic nuclei. Utilizing the intermittent access model that leads to voluntary consumption of ethanol at pharmacologically-relevant levels, I plan to test th overall hypothesis that ethanol drinking stimulates the hypothalamic neuropeptide orexin (OX) to act in the PVT, primarily at the orexin 2 rather than orexin 1 receptor (and rather than melanin-concentrating hormone at its receptor) and specifically in the anterior rather than posterior subregion, and that this action, in turn, increases local levels of the opioid enkephali (ENK) to promote further ethanol intake. With this sequence of events possibly being critically important in promoting disordered alcohol use, I propose, in Aim 1, to investigate the neurochemical events that occur following ethanol drinking, from OX transcription in the hypothalamus to ENK release in the anterior PVT.
In Aim 2, I will examine the behavioral results of these neurochemical changes, testing the effects of OX and ENK injection in the PVT on ethanol drinking and emotional behaviors and the possibility that these behaviors are naturally increased by elevated endogenous peptide levels.
In Aim 3, I will then look at molecular mechanisms of this OX-to-ENK connection and examine the possibility that this is necessary for promoting ethanol drinking. Collectively, by using techniques as varied as primary neuronal culture, in situ hybridization, and behavioral assessment tests, these studies should provide significant new information on a relatively understudied nucleus, the PVT, and its potentially major involvement in ethanol intake. In addition to the publications that should come out of this work, which will allow me to integrate molecular, cellular, and behavioral findins, the funding of this grant proposal will give me the necessary training in both researh and career development to attain independence as a scientist. I will additionally take part in advanced coursework and attend seminars and workshops at The Rockefeller University and through the Tri-Institutional Collaboration Network, while participating in national society meetings. I will receive expert mentorship from my sponsor, Dr. Sarah Leibowitz, as well as my advisory committee which, together with the abundant resources at The Rockefeller University, will allow me to learn new experimental methods and gain new perspectives on my research questions. Thus, in the process of conducting innovative new research, I will gain the skills necessary to successfully transition into a position as an independent research scientist and to make a significant contribution to the field of alcohol research.
The goal of the current grant application is to examine an understudied region of the brain, the thalamic paraventricular nucleus, for its potentialy major role in the overconsumption of ethanol. The overall hypothesis is that ethanol intake stimulates the hypothalamic neuropeptide orexin specifically to act at the orexin 2 receptor within the anterior region of the thalamic paraventricular nucleus, a structure associated with motivated arousal, and that this effect, through activation of the opioid enkephalin, promotes further ethanol intake and ultimately addiction. The results of these studies will provide a new direction for research on alcoholism, pointing to a specific brain area and neurochemical circuit that may contribute to excessive ethanol drinking.
