The mammalian target of rapamycin in complex 1 (mTORC1) is a kinase that plays a key role in protein translation at dendrites, synaptic plasticity, and learning and memory. We discovered that mTORC1 plays a major role in behaviors associated with alcohol abuse disorders (AUD) including excessive alcohol seeking and intake, as well as memories associated with alcohol reward. We further found that mTORC1 contributes to synaptic and structural plasticity in the nucleus accumbens via the translation of synaptic proteins. More recently we found that repeated cycles of alcohol binge drinking and withdrawal activate mTORC1 signaling in the Orbitofrontal Cortex (OFC), a brain region important for associative learning and reward value. We further showed that inhibition of mTORC1 in the OFC of rats attenuates alcohol seeking and habitual alcohol responding. Finally, we generated data suggesting that NMDA receptors (NMDAR) in the OFC participate in mTORC1 activation and alcohol seeking and habit. The OFC receives glutamatergic inputs from the basolateral amygdala (BLA) and mediodorsal thalamic nucleus (MDmc), and projects to the dorsal striatum (DS), and the BLA. We hypothesize that recruitment of glutamatergic BLA and/or MDmc neurons in response to alcohol activates mTORC1 signaling in the OFC to drive habitual alcohol seeking (Aim 1). We further hypothesize that mTORC1 is activated by alcohol in specific OFC projecting neurons to initiate alcohol seeking and habitual responding (Aim 2).
In Aim 3, we will determine the molecular mechanisms underlying the aforementioned behavioral outcomes. Specifically, we will study the contribution of the mTORC1 downstream target, collapsin response mediator protein II (CRMP-2), to alcohol seeking and habit. We will also conduct an RNA sequencing analysis to identify novel downstream targets of mTORC1 in the OFC whose translation is increased by alcohol. To address these hypotheses, and test the contribution of the mTORC1 signaling in the context of OFC circuitries, we plan to use novel molecular tools in combination with behavioral paradigms in rats. Together, this research proposal will allow us for the first time, to elucidate the role of an important molecular target of alcohol in the context of key neural circuits. Furthermore, the contribution of the OFC to AUD has been understudied, and our research effort will greatly expand the knowledge on this topic. Finally, our studies on mTORC1 and its downstream targets will contribute to drug development efforts for the treatment of AUD.

Public Health Relevance

This proposal is aimed to study how the kinase mTORC1 in brain circuitries that centers around the brain region, OFC, contributes to two clinically relevant phenotypes, alcohol seeking and habit. To do so, we will use state of the art molecular approaches in combination with behavioral paradigms in rats. Our study will not only expand our knowledge on the neuroadaptations that underlie alcohol actions in the brain but will also enable the identification of new targets for future drug development to treat AUD.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Special Emphasis Panel (ZAA1)
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Cui, Changhai
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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