Objective 1: Explore the Neurobiological Mechanisms of Alcohol Misuse and Alcohol Use Disorder

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The addiction cycle is a validated heuristic framework for understanding the development, progression, and heterogeneity of AUD. The framework is based on dysregulation in three functional and neurocircuitry domains: incentive salience (reward drinking), negative emotional states (relief drinking), and executive function (loss of control). Drinking to cope with stress has received renewed attention as a major driver of alcohol misuse and AUD, and has emphasized the role of negative emotionality (also known as hyperkatifeia) as a target for treatment.

The COVID-19 pandemic further exacerbated the role of stress in alcohol misuse. NIAAA-supported research on the relationships between alcohol misuse and stress has yielded new insights into the neurotransmitter and neurocircuit dynamics that underlie excessive alcohol use and relapse, as well as the negative emotional states and executive function deficits associated with the addiction cycle. These studies have also shed light on the role of neuroinflammation and sex differences in mediating AUD and stress-related behaviors, as well as the bidirectional relationship between alcohol misuse and other co-occurring behavioral health disorders.

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Life stage is a key factor that influences how alcohol impacts brain function. For example, research has demonstrated that alcohol misuse can impact the delicate balance of brain development that occurs during adolescence and continues into a person’s mid-20s. Additionally, with the rapid increase of the older adult population, the impact of alcohol misuse on the aging brain has come into the spotlight. Not only is the prevalence of alcohol misuse and AUD increasing among older adults, but alcohol misuse has been associated with a faster cognitive decline and other aging-related effects. Research to better understand the neurobiological links between alcohol and age-related effects on brain health could reveal novel targets for prevention and treatment.

NIAAA encourages innovative research and integrated approaches to build on existing knowledge of the biological mechanisms that mediate alcohol misuse across the life span and at all levels of the addiction cycle. Some specific examples of high-priority research gaps include:

• Identifying molecular, cellular, and functional brain connectivity that underlies the development of, maintenance of, return to, and recovery from alcohol misuse and AUD, using animal models, human imaging studies, and multilevel translational approaches—such multilevel analyses may include modern neurobiological techniques from single-cell physiology to computational neuroscience and artificial intelligence (AI) approaches across species
• Characterizing the dynamic interactions of extraneuronal contributors to alcohol misuse and AUD, including the extracellular matrix, neuroimmune cells, perineuronal cells, and peripheral neuromodulatory targets
• Identifying the roles of interoceptive cues, including autonomic, neuroimmune, and gut microbiome cues, in alcohol misuse and AUD
• Understanding how social determinants of health (e.g., childhood trauma, psychiatric comorbidity, social isolation, socioeconomic challenges, and health care availability) interact with neurobiological mechanisms to mediate alcohol misuse and AUD
• Elucidating the neurobiological mechanisms that mediate the interactions between alcohol misuse and cognitive decline, including cognitive decline related to Alzheimer’s disease and other dementias, in the context of aging
• Examining the mechanisms by which sex differences influence individual differences in the brain’s response to alcohol as individuals progress from alcohol use to misuse to AUD
• Exploring neuroadaptations as well as other biological measures and/or -omic signatures in combination with data science approaches to develop diagnostic biomarkers for the prevention, diagnosis, and treatment of alcohol misuse and AUD

Objective 2: Elucidate the Underlying Mechanisms of Alcohol-Induced Tissue and Organ Damage

Alcohol misuse has devastating effects on organs, systemic health, and life expectancy. Alcohol affects many organs and tissues in the body. Alcohol misuse is associated with increased liver disease, pancreatitis, cardiomyopathy, lung pathologies, skeletal muscle myopathy, diminished bone strength and impaired recovery from trauma, infectious diseases, and several types of cancers (including head and neck, esophageal, liver, breast, and colorectal cancers). Alcohol consumption also disrupts body-wide systems, specifically the immune system, the endocrine system, and the lymphatic system.

Research suggests alcohol damage occurs through both shared and tissue- and organ-specific mechanisms. For example, alcohol-related dysfunction of the immune system and associated inflammation contributes to some, but not all, mechanisms of alcohol-associated organ damage. Understanding features of alcohol damage that are unique to specific tissues or organs will inform focused prevention and treatment approaches. Identifying specific risk and protective factors could also reveal individual differences in targets for prevention and treatment.

NIAAA encourages research to further characterize the biological factors that contribute to alcohol-associated damage to the body’s tissues, organs, and organ systems, with an emphasis on research that will identify targets for development of effective therapies to prevent and treat these devastating conditions. Currently, there are no U.S. Food and Drug Administration (FDA)-approved medications for the treatment of alcohol-associated damage to any organ. Examples of NIAAA research priorities in this area include:

• Investigating mechanisms mediating the susceptibility and development of the following clinically significant alcohol-associated conditions with the goal of better prevention and treatment of alcohol-associated conditions: liver disease, pancreatitis, cardiomyopathy, lung disease, skeletal muscle myopathy, disrupted bone homeostasis, infectious diseases, and cancers
• Exploring tissue-specific molecular, cellular, and systemic responses to alcohol misuse and AUD on metabolism, inflammation, tissue repair, regeneration, and homeostasis and their contribution to alcohol-related tissue and organ damage across ages and biological sex
• Characterizing the effects of alcohol’s disruption of components of the immune system on the body’s defense against infection and related comorbidities
• Exploring alcohol’s effects on organ-organ interactions, such as interactions among gut-liver-brain, gut-brain axis, gut-lung, and other organ interactions that are still unexplored but clinically relevant

Objective 3: Enhance Translation of Basic Research Findings to Clinical Practice

A mechanistic understanding of the conditions that give rise to alcohol misuse and AUD requires work in model systems where invasive techniques can be used. Major goals are to translate physiological findings derived from preclinical studies into clinical applications for AUD as well as to back translate human findings to validate preclinical models for further research.

Barriers to translation and back translation include different data collection methods, different temporal scales, species-specific approaches to behavioral regulation, and lack of biological homology across species. Predictions derived from computational modeling approaches can be examined through conventional laboratory approaches and provide the basis for developing and testing novel treatment strategies. Identifying similar computations employed across species provides a basis for predictive models that capture pathologies that underlie alcohol misuse and AUD.

NIAAA also supports the development and application of complementary methods, models, and technologies, along with the integration and translation of data across multiple species and levels of analyses, to understand the causes and improve the treatment of AUD and other alcohol-related health conditions. The effects of alcohol on tissue can be investigated with defined cellular systems of stem cells, induced pluripotent cells, and organoids.

Examples of research that NIAAA encourages to advance translation include:

• Developing high-throughput screening models to identify compounds having potential to treat alcohol misuse, AUD, and alcohol-related organ damage
• Expanding the validation of candidate biomarkers in the discovery phase to improve prevention, diagnosis, and treatment of alcohol-associated conditions
• Identifying phenotype-specific multi-omic profiles of AUD in the context of alcohol-associated organ damage that include genomics, proteomics, transcriptomics, metabolomics, and epigenomics to inform cross-organ analyses in understanding alcohol misuse and AUD
• Conducting back translation studies on mechanisms using molecular genetic approaches, such as gene editing and stem cell studies, to understand mechanisms for alcohol misuse or organ injury based on human data for alcohol research
• Expanding computational modeling approaches to provide a basis for predictive models that capture pathologies that underlie alcohol misuse and AUD