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Research in the Charleston Alcohol Research Center

Center Organizational Structure

The Center is comprised of three cores (Administrative, Shared Resource, and Pilot Project) and four research components.

Administrative Core

The Administrative Core is led by the Center Director (Dr. Becker) and serves as the centralized coordinating nexus for the Charleston ARC, providing the organizational framework necessary for effective management of all administrative, research, training, and educational activities connected to the ARC.

The Administrative Core provides:
• scientific and administrative leadership for the ARC in promoting, facilitating, and integrating cohesive, multidisciplinary and translational-oriented research activities both within the Center and the general academic environment.
• organizational structure for unambiguous and efficient management of Center activities, priorities, and resource allocation, including oversight and quality control activities.
• administrative support for handling all fiscal services and management, as well as preparation of administrative reports.
• infrastructure for facilitating communication along with strategies for enhancing integration of ARC research and training activities.
• scientific enrichment activities, a vibrant and fertile training environment for the next generation of alcohol researchers and facilitates educational and outreach activities through dissemination of research discoveries to academic, treatment, and lay public audiences.

Shared Resource Core

Directed by the Center Director (Dr. Becker), the main objective of the ARC Shared Resource Core is to provide centralized resources and services that support and enhance research efforts in the ARC. The Shared Resource Core contains three components that address the resource and service needs of ARC investigators: these are the Animal Core component (Leader: Dr. Marcelo F. Lopez), Clinical Intake & Assessment Core component (Leader: Dr. Konstantin Voronin), and Biostatistics Core component (Leader: Dr. Michaela Hoffman).

• Animal Core component: This Core component provides basic research projects and pilot projects with animals uniformly treated in an established model of alcohol dependence that involves repeated cycles of chronic intermittent ethanol (CIE) exposure.
• Clinical Intake & Assessment (CIA) Core component: This Core component centralizes advertisement and recruitment efforts, performs initial screening of potential study participants, coordinates clinical lab tests, and utilizes assessment procedures to match and optimize allocation of subjects for enrollment in ARC clinical research projects/pilots. The core will also provide medical oversight for clinical studies in the Center (Dr. M. George).
• Biostatistics Core component: This Core component provides data management and statistical services to both preclinical and clinical research projects within the Center. This includes assisting in study design development, performing power analyses at the front end of the projects, construction of appropriate databases, conducting analyses utilizing various contemporary statistical approaches, and assisting in preparation of manuscripts and presentations for dissemination of study results.

Pilot Project Core

Drs. Patrick Mulholland and Lisa McTeague co-direct the Pilot Core - a most valuable component of the Charleston ARC. The primary objective of the Pilot Core is to attract new investigators with diverse research backgrounds and expertise to broaden, complement, and further bolster research efforts that are congruent with the ARC’s overall objectives and goal to advance treatment efforts for alcohol use disorder (AUD). The ARC strives to support a balanced portfolio of preclinical and clinical pilot research projects. Emphasis is placed on recruiting early-stage investigators and investigators that are new to the alcohol field to contribute to the research mission of the ARC. Active collaboration and mentorship by senior alcohol researchers is a key factor in the success of the pilot core, with many pilot projects generating data that supports successful extramural grant applications.

Pilot Core activities that are key to its success include:
• Providing infrastructure to recruit and mentor basic science and clinical investigators into the alcohol research field and promote their ability to generate data for publications and independent grant funding.
• Identifying critical areas where basic science and clinical practice overlap and facilitate approaches and strategies to address translational gaps in the alcohol research field.
• Incorporating emerging technologies to advance our knowledge and understanding of mechanisms responsible for excessive alcohol drinking and development of AUD.

Research Components

The major tenet and underlying premise of research conducted in the Center is that progression of alcohol addiction is characterized by adaptations in cortical circuits and processes that contribute to enhanced alcohol reward valence and salience, increased focus on alcohol-related behaviors (alcohol-biased choice), as well as impaired executive function that favors persistent (inflexible) and excessive patterns of drinking. Chronic alcohol-induced adaptations in specific cortical-striatal-limbic circuits and networks are hypothesized to fuel transition from moderate and regulated alcohol consumption to excessive, uncontrolled, and compulsive-like drinking.

Our research, reflecting multidisciplinary, integrative, and translational approaches, utilizes state-of-the-art experimental techniques in addressing a common research focus and overall theme of the ARC. Basic science projects are investigating neurocircuitry adaptations and their behavioral sequelae that reflect characteristics of excessive drinking in alcohol dependent animals while the clinical research project examines a novel treatment approach that targets specific cortical systems and mechanisms that might mitigate disruptive adaptations in these circuits, leading to reduced, better controlled drinking.

Research Components

Effects of Chronic Alcohol Exposure on Valence-Selective Neurons in the OFC-BLA-Striatal Circuitry and Their Role in Excessive Alcohol Drinking.

PI: John J. Woodward, Ph.D.; Co-I: Meghan Flanigan, Ph.D.

This research project focuses on elucidating chronic alcohol-induced alterations in hedonic valence encoding within cortical-limbic-striatal circuitry that may underlie excessive, inflexible alcohol drinking associated with dependence. Specifically, studies will use CIE-treated male and female mice generated by the Animal Core to identify reward- and aversion-sensitive neurons via an innovative Fos-dependent “trapping” approach. The project will test the overarching hypothesis that chronic alcohol alters the encoding of alcohol-related stimuli by valence-selective neurons in the orbitofrontal cortex (OFC) and basolateral amygdala (BLA), with particular focus on those projecting to the dorsomedial striatum (DMS). The project will employ ex vivo slice electrophysiology, chemogenetic, and in vivo neural activity (calcium fiber photometry) approaches to examine how adaptations in these valence-selective neuronal subpopulations contribute to emergence of aversion-resistant and alcohol-biased drinking behaviors.

Specific Aims of the project include:

  • Test the hypothesis that alcohol-responsive neurons in the OFC and BLA map onto discrete populations of reward (sucrose) and aversion (quinine) responsive neurons and that this pattern is altered by CIE exposure.
  • Test the hypothesis that CIE exposure.induces differential effects on the excitability of valence-selective neurons in the OFC and BLA.
  • Test the hypothesis that manipulating valence-selective neurons in the OFC and BLA alters alcohol consumption and the expression of alcohol-biased choice in CIE-exposed mice.



Role of mPFC Infralimbic Neuronal-Astroglial Ensembles in the Transition from Controlled to Excessive Alcohol Drinking.

PI: Jennifer A. Rinker, Ph.D.; Co-I: Michael Scofield, Ph.D.; Co-I: Judson Chandler, Ph.D.

The scientific premise of this project is that chronic alcohol exposure produces unique adaptations in neuronal and astroglial ensembles within the infralimbic (IfL) subregion of medial prefrontal cortex (mPFC). These changes in neuron-astrocyte networks within cortical-striatal-limbic circuitry are hypothesized to contribute to dependence-related behavioral inflexibility and excessive, uncontrolled alcohol self-administration. Studies will use CIE-exposed male and female mice generated by the ARC Animal Core in an established head-fixed model of alcohol self-administration in conjunction with 2-photon imaging and molecular tools to examine dependence-related changes in functional activity of neuronal and astroglial ensembles that are engaged in the IfL during alcohol seeking and consumption behaviors. Studies will then interrogate the effects of manipulating IfL astrocytes on functional activity of dopamine receptor-1 (D1) IfL neurons projecting to the BLA or nucleus accumbens (NAcShell). This innovative and novel approach enables powerful capability to longitudinally track functional changes in neuronal-astrocytic network dynamics within cortical-striatal-limbic circuits that predict and/or accompany alcohol dependence related enhanced alcohol self-administration that reflects behavioral inflexibility.


Specific Aims of the project include:

  • Test the hypothesis that unique neuronal ensembles in the IfL cortex decode alcohol-seeking behavior.

  • Test the hypothesis that unique astrocytic ensembles in the IfL cortex decode alcohol-seeking behavior.

  • Test the hypothesis that disruption of coordinated astrocyte activity patterns during alcohol self-administration will alter neuronal ensemble formation and alcohol seeking.

Chronic Alcohol Disruption of Cortical Processes in Decision-Making and Excessive Drinking. 

PI: Patrick J. Mulholland, Ph.D.; Co-I: Rachel Penrod-Martin, Ph.D.

This project focuses on examining projection-specific adaptations in cortical (anterior cingulate; ACC) neurons that contribute to aberrant decision-making and cognitive inflexibility associated with dependence-related excessive alcohol drinking. Specifically, studies will use CIE-exposed male and female mice generated by the ARC Animal Core to interrogate structural and functional plasticity changes in ACC neuronal projections to the NAcCore (and BLA) in relation to maladaptive cognitive and motivational behaviors, including enhanced alcohol-biased drinking. In a comprehensive series of studies, ex vivo slice electrophysiology, chemogenetic, and fiber photometry approaches will be employed to examine how chronic alcohol-induced adaptations in this cortical-striatal-limbic circuit promote excessive levels of alcohol drinking along with alterations in decision-making behavioral tasks that measure risk-reward, behavioral flexibility, and alcohol-bias choice. The project will also use proteomics to identify cross-species adaptations in the ACC from the mouse dependence model and postmortem human ACC samples from age/gender-matched control and AUD cases.

Specific Aims of the project include:

  • Test the hypothesis that adaptations in ACC projection neurons drive impairments in decision-making in alcohol dependent male and female C57BL/6J mice.
  • Test the hypothesis that CIE exposure produces functional adaptations in ACC projection neurons in mice.
  • Test the hypothesis that CIE exposure disrupts activity of ACC projection neurons during choice behaviors.


Targeting Incentive Salience and Cognitive Flexibility Circuitry: Evaluating the Effects of Accelerated rTMS in Alcohol Use Disorder. 

PI: Lisa McTeage, Ph.D.; Co-PI: James Prisciandaro, Ph.D.; Co-I: William Mellick, Ph.D.; Co-I: Christopher Sege, Ph.D.

This project evaluates the therapeutic potential of transcranial magnetic stimulation (TMS) to counter aberrant alcohol cue-induced brain activation and connectivity (fMRI), perturbations in neurochemical measures of cortical excitatory-inhibitory balance (MR Spectroscopy), and excessive craving and alcohol-choice drinking in individuals with AUD. Specifically, the project, evaluates effects of repetitive TMS (rTMS) that targets specific circuit nodes associated with excess craving and drinking and poor decision-making on alcohol drinking and metrics of cognitive flexibility. Non-treatment seeking individuals with AUD recruited via the ARC CIA Core will receive an accelerated regimen of continuous theta burst (inhibitory) rTMS to ventromedial PFC (vmPFC; hub for incentive salience/reward circuit: vmPFCventral striatum) or pre-supplementary motor area (preSMA; hub for cognitive flexibility circuit: SMAdorsal striatum). The project will evaluate pre-to-post rTMS effects (relative to sham) on: (1) alcohol craving and drinking in a ”bar-lab” setting and natural environment; (2) alcohol cue-induced brain activation and functional connectivity changes (fMRI); (3) excitatory and inhibitory neurometabolite levels via proton MR spectroscopy (MRS); and (4) neurophysiological (EEG/ERP) assessment of affective cue reactivity and cognitive probes of executive functioning. An exploratory aim will examine whether efficacy of rTMS on the various outcomes is influenced by whether individuals with AUD are classified as those who attribute incentive salience more to reward-predicting cues (sign trackers) vs. rewards themselves (goal trackers). This comprehensive clinical research project strives to provide valuable insights regarding the promise of individualized neurocircuit-based brain stimulation treatment to target heterogeneous impairments in AUD.

Specific Aims of the project include:

  • Test the hypothesis that non-treatment seeking individuals with AUD receiving rTMS to vmPFC or to pre-SMA will drink less than the sham group.
  • Test the hypothesis that rTMS to vmPFC but not preSMA or sham will reduce vmPFC-ventral striatal (i.e., reward circuitry) functional connectivity for alcohol cues while rTMS to preSMA but not vmPFC will reduce mid-cingulate-dorsal striatum functional connectivity for alcohol cues.
  • Test the hypothesis that avmPFC and preSMA rTMS relative to sham will each decrease striatal glutamine, glycine, and glutamate levels.
  • Test the hypothesis that rTMS to vmPFC will reduce P3/late positive potentials to alcohol cues (i.e., promoting adaptive incentive salience processing) while rTMS to preSMA will improve electrocortical discrimination/ performance in stop-signal and reversal learning tasks - indicating improved cognitive flexibility.
  • Test the exploratory hypothesis that those individuals who attribute incentive salience to cues will respond more to vmPFC rTMS while those who do not will respond more to preSMA rTMS

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.

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