ARC Research Components

Effect of Chronic Alcohol Exposure on OFC-BLA-Striatal Circuitry and Excessive Alcohol Drinking

Principal Investigator: John J. Woodward, Ph.D.

This research project focuses on the role of chronic alcohol-induced adaptations in orbitofrontal cortex (OFC) in mediating dependence-related excessive alcohol drinking. The project extends analysis to adaptations in cortico-limbic-striatal circuitry that may underlie heavy, compulsive-like alcohol drinking associated with dependence. Specifically, studies will use chronic alcohol (CIE)-treated mice generated by the ARC Animal Core along with electrophysiology, optogenetic, and fiber photometry (calcium imaging) approaches to test the overarching hypothesis that chronic alcohol produces adaptations in convergent glutamatergic inputs to the dorsal striatum arising from the lateral OFC and basolateral amygdala (BLA), and whether these adaptations contribute to excessive, compulsive-like alcohol drinking associated with dependence.

Specific Aims of the project include:

• Test the hypothesis that the excitability and alcohol sensitivity of OFC and BLA neurons projecting to the dorsal striatum are altered by repeated cycles of CIE exposure.
• Test the hypothesis that the in vivo activity of OFC and BLA neurons projecting to the dorsal striatum during alcohol drinking is altered by repeated cycles of CIE exposure.
• Test the hypothesis that real-time manipulation of OFC and BLA neurons projecting to dorsal striatum alters drinking in Air (control) and CIE-exposed mice.

Effects of a Novel mGluR5 Negative Allosteric Modulator on Alcohol Drinking, Neurochemistry, and Brain Reactivity to Alcohol Cues in Alcohol Use Disorder

Principal Investigator: James Prisciandaro, Ph.D.
Co-Investigator: William Mellick, Ph.D.
Collaborator/Consultant: Robert Malcolm, M.D.

This research component focuses on evaluating the therapeutic potential of a novel medication (GET73) in treating individuals with AUD. Preclinical and clinical evidence suggests that GET73, a metabotropic glutamate subtype 5 receptor (mGluR5) negative allosteric modulator may reduce alcohol consumption. This project will enroll non-treatment-seeking individuals with AUD (referred by the ARC Clinical Intake & Assessment Core) to test whether GET73, compared to placebo, reduces drinking in a bar-lab paradigm and in the natural environment. Further, neuroimaging indicators will probe purported mechanisms of GET73 action. Specifically, MR Spectroscopy and fMRI will be used to examine whether GET73 mitigates AUD-related neurochemical adaptations (cortical glutamate/GABA balance) and alcohol cue-induced brain activation in cortical and striatal areas, respectively.

Specific Aims of the project include:

• Test the hypothesis that GET73, relative to placebo, will reduce both bar-lab and naturalistic alcohol drinking.

• Test the hypothesis that GET73, relative to placebo and to baseline, will increase fronto-cortical glutamate and GABA levels (1H-MRS), and these effects will mediate GET73 effects on drinking.

• Test the hypothesis that GET73, relative to placebo and to baseline, will reduce vmPFC, OFC, ACC, and VS activation to alcohol cues (fMRI), and these effects will mediate GET73 effects on drinking.

Adaptations in Corticostriatal Networks in Alcohol Dependence Related Goal-Directed and Habitual Drinking

Principal Investigator: L. Judson Chandler, Ph.D.
Co-Investigator: Rachel Penrod-Martin, Ph.D.

The overarching hypothesis being tested in this project is that chronic alcohol exposure facilitates the expression of habitual responding for alcohol, and adaptations in specific subpopulations of neurons within the medial prefrontal cortex (mPFC) play a critical role in this process. Specifically, studies will examine chronic alcohol-induced adaptations in dopamine (DA) D1-like and D2-like expressing neurons in a sub-region of the mPFC - the infralimbic (IfL) cortex (ventromedial PFC) as part of corticostriatal networks that contribute to the shift in bias from goal-directed to habit-based motivated behavior (inflexible, excessive alcohol self-administration associated with dependence). Studies will use chronic alcohol (CIE)-treated mice generated by the ARC Animal Core and employ in vivo multielectrode recordings, fiber photometry of calcium transients, targeted (cell-specific) chemogenetic manipulations, and patch-clamp electrophysiology to address the overall study hypotheses in a comprehensive manner.

Specific Aims of the project include:

• Test the hypothesis that dependence-induced facilitation of habitual responding for alcohol is associated with changes in population activity and network organization in the intralimbic (IfL) cortex.
• Test the hypothesis that DA D1 and D2 receptor-expressing neurons in the IfL cortex modulate dependence-induced facilitation of the expression of habitual responding for alcohol.
• Test the hypothesis that dependence-induced facilitation of habitual responding for alcohol is associated with alterations in the biophysical properties of DA D1 and D2 receptor-expressing neurons in the IfL cortex.

mPFC Theta Burst Stimulation as a Treatment Tool for Alcohol Use Disorder: Effects on Drinking and Incentive Salience

Principal Investigator: Lisa McTeague, Ph.D.
Co-Investigator: Hesheng Liu, Ph.D.
Co-Investigator: Sarah W. Book, M.D.

This research component builds on previous work in the ARC that involved examining the capacity of transcranial magnetic stimulation (TMS) to blunt alcohol cue-induced brain activation (fMRI) and measures of craving in individuals with AUD. This project extends this work to evaluate the therapeutic potential of this novel intervention in a clinical outpatient treatment setting. Treatment-seeking individuals with AUD recruited via the ARC Clinical Intake & Assessment Core will receive a 4-week treatment regimen of theta burst stimulation (TBS) targeting the mPFC. Alcohol drinking (self-report and biomarker indices) will be assessed at monthly follow-ups, and neuroimaging indices (pre- vs. post-treatment) will be used to assess alcohol reward-blunting and negative affect components of AUD. Hypotheses to be tested are that mPFC-targeted TBS, compared to sham control, will: (a) improve AUD treatment (drinking) outcomes; (b) reduce alcohol cue reactivity and reward circuit (cortico-limbic-striatal) functional connectivity; and (c) normalize enhanced reward circuit reactivity to alcohol vs. naturalistic reward cues and enhanced reactivity to aversive (threat) cues. The overall goal is to evaluate the efficacy of mPFC-targeted TBS in improving AUD treatment outcomes and determine whether neurocircuit-based reductions in incentive salience bias to alcohol cues mediate the clinical outcomes.

Specific Aims of the project include:

• Test the hypothesis that active TBS to vmPFC, relative to sham, will result in fewer heavy drinking days and more abstinence days, as indicated by both self-report and objective (biomarker) measures.
• Test the hypothesis that at baseline participants will demonstrate increased activation foremost in vmPFC and striatal regions (i.e., reward circuitry) during exposure to alcohol cues, and that active relative to sham stimulation will result in reduced alcohol (cue) reward circuit activation (ventral striatum, vmPFC), an effect that will mediate TMS effects on drinking outcomes.
• Test the hypothesis that active compared to sham TBS, will “normalize” motivational neurocircuit responses, as evidenced by reduced responses to alcohol cues to a level similar to naturalistic reward cue reactivity, along with reduced reactivity to naturalistic threat cues.

Alcohol Dependence and Loss of Reward-Based Flexible Behavior: Role of Mediodorsal Thalamus to PFC Circuit

Principal Investigator: Patrick J. Mulholland, Ph.D.
Co-Investigator: Jennifer A. Rinker, Ph.D.

This research project examines chronic alcohol-induced functional changes in the mediodorsal thalamus (MDT) that contribute to inflexible, excessive alcohol drinking associated with dependence. The MDT serves as a hub for integration of cortical (OFC, PFC) and subcortical (striatal, limbic) information involved in executive cognitive function. Studies will use unique transgenic (FosTRAP2) mice to first identify populations of neurons in the MDT that are activated by alcohol drinking and then examine how chronic alcohol exposure alters functional activity in these neural ensembles in the MDT that project to the mPFC (IfL cortex). Studies also will probe how functional adaptations in these cortical-projecting MDT neurons contribute to dependence-related inflexible alcohol drinking. Animals will receive chronic alcohol (CIE) treatment in the ARC Animal Core, followed by slice electrophysiology, fiber photometry, and chemogenetic manipulations to test the overarching hypothesis that chronic alcohol-induced alterations in cortical-projecting MDT neurons drive excessive, compulsive-like drinking and alcohol-biased choice behaviors that reflect loss of reward-based flexible behaviors.

Specific Aims of the project include:

• Identify neural ensembles and characterize functional adaptations (slice electrophysiology) of cortically projecting neurons in the mediodorsal thalamus (MDT) that are activated by alcohol drinking and dependence.
• Test the hypothesis that functional activity of MDT→IfL neurons (fiber photometry) will be modulated by alcohol drinking (licking behavior) and this pattern of activity will be altered in alcohol-dependent mice.
• Test the hypothesis that cortical projecting MDT neurons drive excessive drinking and alcohol-biased choice behaviors in dependent male and female C57BL/6J mice.