Mental Disease and Addiction
- Neurodegeneration and chronic drug-induced changes in brain signaling pathways.
- Stem cells, which are found in specific brain regions and form new neurons, could be involved in the regeneration of the brain during recovery from addiction. Binge drinking reduces proliferation of neural progenitor cells in brain.
- A third area of research involves the use of gene delivery to understand how alterations in genes alter brain function and behavior.
Mental disease, including addiction and neurodegeneration, are central themes of the laboratory's research. Addiction has many components, one of which is long term changes in gene expression and structure in brain. Binge drinking-induced changes in specific brain regions is hypothesized to contribute to the progression to addiction. This could overlap with brain structure/function changes in other mental diseases, particularly depression. The mechanisms of binge drinking-induced brain damage are not clearly understood but appear to involve oxidative changes in brain similar to aging and neurodegenerative disorders such as Alzheimer's disease. Alcoholics are known to have reduced brain mass which begins to grow back during recovery. Recent studies have suggested that neuroinflammation may contribute to degeneration and loss of neurogenesis during binge drinking. In contrast to the degeneration found during binge drinking there is a regeneration of brain cells during abstinence that could be related to recovery from addiction. Three key areas are investigated using rat models: the mechanisms, characteristics and functional consequences of binge drinking-induced brain damage. Histochemical, neurochemical and gene induction studies investigate the changes in brain and associated behaviors found with binge drinking induced brain damage. Current studies suggest that neuroinflammation contributes to degeneration and loss of neurogenesis, whereas regeneration during abstinence-recovery is related to increased neurogenesis. A second area of research interest involves stem cells, which are found in specific brain regions and form new neurons. These stem cells could be involved in the regeneration of the brain during recovery from addiction. Binge drinking reduces proliferation of neural progenitor cells in brain. A third area of research involves the use of gene delivery to understand how alterations in genes alter brain function and behavior.
As director of the UNC Bowles Center for Alcohol Studies, Dr. Crews has investigated how chronic ethanol induces structural and functional changes in the brain associated with binge drinking to determine if and how these changes contribute to behavioral changes that lead to addiction. His more recent studies follow changes in gene expression that contribute to a progressive degeneration with increasing impulsive-compulsive drug taking. He discovered that heavy alcohol use damages cortical brain regions involved in impulse control and planning capabilities. He was the first to discover that adult brain stem-progenetor cells are insulted by alcohol. Recently he discovered persistent brain neuroinflammatory gene induction secondary to systemic cytokines and identified reduced neurogenesis as factors in alcohol-related brain damage, difficulty with reversal learning tasks and inducing alcoholic depression-like behavior.
Dr. Crews is among the few neuroscientists investigating the adolescent brain as a unique neurodevelopmental period that has considerable risk for future alcoholism. He was instrumental in developing and working with colleagues across the country to submit and administrate a consortium for the initiative which coordinates a diverse group of basic neuroscientists in a multidisciplinary research project to clearly define the persistent effects of adolescent alcohol exposure on adults, and to begin to explore the neurobiological mechanisms. The overarching hypothesis is that models of human underage drinking will impact brain maturation resulting in persistent changes in adult brain function and structure.
Dr. Crews was instrumental in developing and working with colleagues across the country to submit and administrate a consortium for the initiative “Neurobiology of Adolescent Drinking in Adulthood”(NADIA). The NADIA coordinates a diverse group of basic neuroscientists in a multidisciplinary research project to clearly define the persistent effects of adolescent alcohol exposure on adults, and to begin to explore the neurobiological mechanisms. The overarching hypothesis of this consortium is that models of human underage drinking will impact brain maturation resulting in persistent changes in adult brain function and structure that relate to changes in behavior. This NADIA uses adolescent intermittent ethanol (AIE) rat models that mimic episodic human adolescent underage drinking. Multiple research components integrate molecular, cellular, physiological, endocrine, genetic neuroanatomical and behavioral studies utilizing cutting edge and novel approaches to investigate potential long term consequences of human underage drinking. An abundance of evidence suggests that during adolescence, cognition, affect, and reward driven behavioral repertoires are uniquely plastic and responsive to environmental influences. Maturation of brain circuitry that underlies motivation, affect and decision making are expected to be sensitive to ethanol disruption, resulting in increased adult psychopathology. This consortium integrates investigators that share common hypotheses and overlapping protocols. Each contribute to an improved understanding of the consequences of adolescent alcohol exposure on brain physiology, structure, chemistry, maturation and behavioral induces of affect, motivation, social functioning, decision-making cognitive assessments, impulsivity, circadian rhythms, and alcohol drinking behaviors using AIE. Components cover broad inter-related investigations of the neurocircuitry between frontal-cortical, striatal, hippocampal, extended amygdala and hypothalamic nuclei as well as hormonal maturation of hypothalamic-adrenal interactions across gender, providing a broad global investigation of the development of neural networks that underlie maturation of complex behaviors. The scientific core provides components with brain MRI-DTI (brain volume – structure), brain regional histology-immunohistochemistry and establishes a data repository for future brain network analysis. Understanding the impact of underage drinking on adult neurobiology is important to guide public health initiatives. Dr. Crews is PI for the administrative core of the consortium. He has successfully arranged and administered monthly WebEx seminars that continue conversation and convergence among the eight components. Dr. Crews is also lead PI for the scientific core that continues to analyze and report on MRI and histochemistry data among the eight cores. While managing the administrative and scientific core, Dr. Crews also has a component that looks at the adolescent behavior and brain mechanisms for the consortium.
Under Dr. Crews’ leadership, the Bowles Center has become a leading center in research on the molecular mechanisms of alcohol pathology