Douglas C. Smith - US grants

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It is generally accepted that some memories, such as those associated with important events, are retained better than others. One factor that appears to be important in the modulation of memory storage processes is the degree of arousal associated with the experience. Memories of events that are associated with moderate degrees of behavioral arousal tend to be retained better than memories associated with either very low or very high levels of arousal. Research over the past two decades has demonstrated that memory modulation is mediated by the presence of hormones from the pituitary and the adrenals that are associated with arousal. For example, injection of epinephrine, norepinephrine, ACTH, vasopressin, enkephalins, or the endorphins all modulate retention performance. However, none of these substances freely crosses the blood brain barrier to influence activity in the brain that mediates memory storage. In an attempt to resolve this apparent problem, recent research suggests that the vagus nerve may be a pathway by which peripheral arousal enhances memory. These studies demonstrated in laboratory rats that subdiaphragmic vagotomy attenuates the memory modulatory effects of some of these agents and that electrical stimulation of the vagus nerve, at a moderate intensity, can enhance memory of an avoidance task. Further, low-, but not high-intensity vagus nerve stimulation can enhance verbal learning in human subjects. Therefore, it appears that arousal results in the release of adrenal and pituitary hormones that activate peripheral receptors. These receptors then initiate neural messages, which travel to the brain via the vagus to modulate mnemonic processes. The goal of the current research project is to gain a better understanding of the neural events produced by activity in the vagus nerve that alters the strength of memory storage. A series of pharmacological, electrophysiological, and behavioral studies will be conducted. The behavioral studies are linked to electrophysiological studies that focus on characterizing changes in hippocampal responses produced by vagus nerve stimulation and a search for their underlying causes. The goal of the first set of studies is to characterize changes in electrical activity in the hippocampus, a brain structure known to be importantly involved in memory, produced by vagus nerve stimulation. Other studies will determine whether pharmacological agents that enhance memory produce effects similar to those seen following vagus nerve stimulation and whether blockade of vagus nerve activity alters these responses. The results obtained from these studies should yield a better understanding of the brain mechanisms that underlie the modulation of memory storage processes.

[unreadable] DESCRIPTION (provided by applicant): The Center for Disease Control estimates that over two million Americans suffer traumatic brain injury each year and, of them, around 70,000 suffer permanent disability. The proposed research will evaluate the effectiveness of vagus nerve stimulation (VNS) as a treatment for brain injury. Stimulation of the vagus is known to have anti-seizure properties and it also facilitates neural plasticity as seen in its capacity to enhance memory storage. The proposed research will use the fluid percussion model of traumatic brain injury in rats to evaluate the capacity of VNS to facilitate recovery of function. This technique produces reliable and reproducible brain damage and the time course of recovery of animals that receive chronic vagus nerve stimulation and control animals will be evaluated on neurological tests such as spontaneous forelimb placing, beam walk, a skilled forelimb reaching task and a spatial localization task. Pilot data is presented which demonstrates that VNS produces enhanced behavioral recovery in some tasks; however, additional information, such as the frequency and intensity of VNS that is most effective, as well as the temporal window of therapeutic effectiveness, neuroanatomical sequelae and the mechanism(s) of the effectiveness of VNS in promoting recovery remain unknown and are specifically addressed in this proposal. Fluid percussion injury is known to cause a progressive loss of cortical and subcortical neurons, as well as a loss of GABA motor neurons in the cortex adjacent to the site of injury and in the hilar region of the hippocampus. Experiments will be performed to determine whether VNS following head injury attenuates cell loss in these regions. These studies will use quantitative morphometry as well as immunocytochemistry for glutamic acid decarboxylase and GABA. Finally, in an effort to understand the mechanism(s) that mediate the effects of VNS on recovery, severing the vagus afferents or efferents, in vivo microdialysis of regional levels of norepinephrine following fluid percussion injury and VNS, neurotoxic lesions of the locus coeruleus, and specific noradrenergic receptor antagonists will be used in order to determine how they influence the ability of VNS to enhance recovery. The combination of all of these aims will result in determining whether vagus nerve stimulation might be a useful treatment in promoting recovery following traumatic brain injury, as well as provide specific information about the neural mechanism(s) involved.

DESCRIPTION (provided by applicant): Although emerging adults (EA, aged 18-25) account for approximately one-fifth of all publicly funded treatment episodes, we know very little about whether existing alcohol treatments are developmentally appropriate. Most of our knowledge about alcohol interventions for this age group is from studies in college settings, but according to the National Survey on Drug Use and Health, only 53% of emerging adults with Alcohol Use Disorders (AUD) are in college. Treatments that alter social networks may be especially promising for emerging adults, because alcohol and drug-free social opportunities may be particularly scarce during this developmental period. To address these problems, Dr. Smith will develop and pilot test a Peer-Enhanced Community Reinforcement Approach (PE-CRA) intervention, in which close friends of emerging adults receiving publicly funded AUD treatments will attend therapy sessions. This application requests funds to provide the mentoring needed for Dr. Smith, an experienced clinician, to develop and investigate the efficacy of the proposed PE-CRA intervention. Dr. Smith will receive mentoring from two senior health services researchers, Drs Michael Dennis (primary) and Mark Godley (co-mentor), that focuses on knowledge gains in advanced data analytic skills for health services research (i.e., propensity score matching, methods for dealing missing data, analysis of moderators and mediators), clinical research designs and study implementation, knowledge about the EA period of development. Support from the K23 mechanism will relieve Dr. Smith from teaching duties and allow him to dedicate 75% effort toward developing this line of research. His other 25% effort will be dedicated to teaching addictions coursework to social workers. It is anticipated that Dr. Smith will secure independent research funding for further studies that improve our understanding of what characteristics of EA mediate treatment effectiveness. PUBLIC HEALTH RELEVANCE: As the prevalence of alcohol use disorders (AUD) peaks in emerging adulthood, developmentally appropriate treatments tailored to the specific needs of this population could have high public health relevance. This proposal studies treatments for emerging adults presenting for treatment in publicly funded settings, which is a large and understudied population.