Chronic alcohol-induced alterations in CB1 receptor modulation of corticostriatal circuits governing the shift between goal-directed and habitual actions. Alcoholism involves initial controlled alcohol use that, with time, develops habitual components and decreased sensitivity to associated negative consequences. However, the mechanisms through which alcohol use alters control of these decision-making processes remain largely unknown. While the development of habitual behaviors observed in addiction may in part be due to alcohol's primary reinforcing effects, alcohol exposure may also directly affect neural circuits involved in decision-making and control of the shift between goal-directed and habitual actions. Understanding how previous chronic alcohol exposure itself disrupts mechanisms controlling function and plasticity of neural circuits underlying decision-making processes will provide needed information on disease processes underlying alcohol use disorders. The objective of the current proposal is to understand how chronic intermittent alcohol exposure vapor exposure and repeated withdrawal (CIE) affects the plasticity of corticostriatal circuits controlling the shift between goal-directed and habitual actions. The central hypothesis of this proposal is that CIE results in altered CB1 receptor modulation of orbitofrontal- striatal synapses, disrupting the shift between goal-directed and habitual actions.
In aim 1, CIE effects on action strategy will be investigated in mice shifting between goal- directed and habitual actions.
In aim 2, following CIE, corticostriatal neural activity will be examined via simultaneous in-vivo recordings and in-vivo manipulations in orbital frontal cortex (OFC), dorsal medial and dorsal lateral striatum during the learning and execution of goal-directed and habitual actions in mice lacking CB1 receptors on OFC projection neurons.
In aim 3, changes in CB1 receptor modulation of long-term plasticity at mouse orbitostriatal synapses following CIE will be examined. This proposal is significant because it takes an innovative approach that will yield unprecedented findings on how previous alcohol exposure can alter implicated molecular mechanisms governing plasticity in specific corticostriatal circuits controlling the shift between goal- directed and habitual actions. The work described in this proposal represents a necessary advancement towards my career goals by using a combination of techniques that I have already perfected during my Ph.D. and early postdoctoral training, as well as techniques that I will learn during the (K99) training period. My long-term goal is to oversee my own research program as an independent investigator at an academic research institution investigating alcohol-induced alterations in learning circuits controlling alcohol-use disorders. My intermediate goal is to understand how alcohol affects corticostriatal circuits controlling action selection. My short-term goals are: (1) to obtain expertise in ex- vivo physiology to probe endocannabinoid-mediated mechanisms controlling plasticity of orbital frontal-dorsal striatal synapses governing the shift between goal-directed and habitual responding, (2) to obtain an independent tenure-track position as an assistant professor and transition to R00 funding at the end of the two year training period, (3) to obtain R01 funding within the timeframe of this proposal. With the opportunities provided by the K99 portion of the Pathway to Independence Award, I will be well equipped to pursue the objectives outlined in the R00 component of this proposal.
Alcohol abuse and dependence represent a major health issue in the United States, afflicting 1 in every 12 adults. Alcohol-use disorders are thought to involve initial controlled alcohol use that, with time, develops habitual components and decreased sensitivity to associated negative consequences due to dysfunction in associated brain circuits. Using mice, this project seeks to understand how previous chronic alcohol exposure alters specific mechanisms within these brain circuits resulting in a bias towards habitual behaviors.
