Allison Joy Brager, PhD - US grants

DESCRIPTION (provided by applicant): The circadian timing system is closely and reciprocally tied to reward systems mediating alcoholism. Using alcohol to mitigate work-related sleep/wake disturbances creates a vicious cycle of alcohol dependence and circadian disruption. This proposal will focus on delineating the compounding effects of nature (clock gene and neurotransmitter tonus) and nurture (environment) that disrupt circadian entrainment and promote alcohol dependence and alcoholism. A Per2-deficent mouse strain, a rotating schedule of simulated shift work, and constant dark/photic conditions will be utilized for: (1) The first assessment of the interactions of environmental disruptions and Per2 clock gene deletions on potentiated alcohol preference and relapse risk and altered circadian alcohol intake;(2) The first observation of the rescuing effects of the glutamate antagonist and alcohol relapse drug, acamprosate, on potentiated alcohol preference and relapse risk associated with environmental disruptions and/ or Per2 clock gene deletions;and (3) The first exploration of areas of the circadian timing and alcohol reward systems mediating acamprosate reduction of alcohol preference and relapse risk. The central hypothesis is that environmental disturbances, Per2 clock gene deletions, and related hyperglutamatergic states greatly potentiate alcohol preference and relapse risk, and that such potentiation can be rescued by systemic and intra-cranial acamprosate treatment. The proposed research addresses limitations from previous shift work and acamprosate studies, and optimally, will improve the quality of pharmacological and behavioral therapies available for the treatment of alcoholism. PUBLIC HEALTH RELEVANCE: This proposal will illustrate environmental (rotating shift work) and genetic (deletions) contributions to alcohol dependence and relapse risk. It will also localize areas of the central nervous system mediating alcohol dependence and relapse risk. This research shows the need for a combination of pharmacological and behavioral therapies for the treatment of alcoholism and prevention of relapse.

DESCRIPTION (provided by applicant): Insufficient sleep is a widespread public health problem that increases metabolic demands and subsequent related risks of morbidity and mortality. To better understand the mechanisms of recovery from insufficient sleep and the consequences of insufficient sleep, this training plan aims to examine central and peripheral molecular (BMAL1) regulation of sleep and metabolism at neurochemical, physiological, and cellular levels. BMAL1 is a central focus because it is a circadian transcription factor that is thought to influence daily sleep amount and recovery from sleep loss. The specific aims of this research proposal will be addressed by the use of transgenic mice that have amplification or rescue of BMAL1 expression specific to the brain or skeletal muscle. Use of the tetracycline transactivator system in these mice also permits for temporal knockdown or rescue of tissue-specific BMAL1 expression in order to delineate between developmental versus direct effects. The central hypothesis is that the extent of increases in central and peripheral metabolic demands during sleep loss, determined from levels of extracellular adenosine in the basal forebrain and glucose and oxygen utilization in skeletal muscle, and the extent of dissipations of these parameters during recovery sleep is dependent on tissue-specific BMAL1 expression. This information will advance our scientific understanding and resolve critical barriers of how and where BMAL1 influences sleep and metabolic processes during sleep loss. The execution of this central hypothesis requires a synthesis of past, present, and proposed research methods training and effective communication with my sponsors, who are experts in areas of sleep, circadian rhythms, and skeletal muscle physiology. The specific aims will also be supplemented with collaborative research projects, continued education, and teaching, which will provide additional training in metabolic, neurophysiological, and molecular research methods and professional development.