Stephen J. Bonasera - US grants

DESCRIPTION (provided by applicant): Disinhibited behaviors (such as inattention, agitation, and poor socialization) are a significant problem that often accompanies mid- to late-stage dementia. These behaviors are likely caused in part by dysfunction of brain serotonin systems. This research plan addresses the role of serotonin 2C receptors (5-HT2CRs) in the control of behavioral inhibition. The research plan also provides a framework to guide the applicant's transition from senior fellow in geriatric medicine to an independent investigator who will make high quality contributions to the field of behavioral neuroscience. The studies proposed herein will test the primary hypothesis that 5-HT2C receptors regulate behavioral inhibition both by enhancing dopaminergic neurotransmission and diminishing GABA-ergic neurotransmission in the mesolimbic system. The specific aims of this project will test this hypothesis by demonstrating in wildtype and "knockout" mice lacking the 5-HT2C receptor that 1) 5-HT2CRs contribute to serotonergic influence on behavioral inhibition through regulation of mesolimbic dopamine activity, and 2) 5-HT2CRs contribute to serotonergic influence on behavioral inhibition through the regulation of GABA-ergic neurotransmission. Mice with targeted deletion of specific neurotransmitter receptors are ideal models to determine individual receptor contributions toward behavioral inhibition; furthermore, this data can be applied to the study of behavioral disturbances in aged subjects. Experimental design and methods to test these hypotheses are grounded in whole animal studies of behavior (including tests of exploration, sensorimotor gating, social interaction, locomotor coordination, locomotor activity, and anxiety-related behaviors). Neurochemical (microdialysis) and neuroanatomical studies (including in situ mRNA hybridization, and receptor immunocytochemistry) will be utilized to evaluate potential mechanisms underlying behaviors observed in wildtype and 5-HT2CR mutant mice. The applicant will take advantage of the many strengths unique to UCSF, including a highly reknowned faculty in both the basic sciences of Neuroscience and Genetics, and the clinical sciences of Medicine, Neurology, and Geriatrics. Data from this study will answer key questions regarding the mechanism of serotonin influences on control of behavioral inhibition, and will provide the groundwork to identify specific pharmacological interventions that may be successful in treating this refractory problem.

[unreadable] DESCRIPTION (provided by applicant): Normal aging is accompanied by alterations in both cognitive and emotional function. While these changes are of modest significance in otherwise healthy elders, they can have devastating impacts in persons with dementia or cognitive impairment. Unfortunately, current knowledge of the basic neuroscience underlying behavioral disturbances in the elderly remains very poorly understood. Aged mice are appropriate models to address this significant deficit. Neurophysiology of the aging mouse brain resembles that seen in man, and many behaviors observable in mice have close human parallels. For example, in both mouse and man there is an age-related decline in gross exploration of a new environment. Exploratory behavior is modulated in a specific manner by different neurotransmitter systems; thus, sophisticated analyses of exploratory behavior can provide important insights into age-related changes in CNS function. Currently, powerful tools to study exploratory behavior are lacking; we propose to develop these tools. We will develop a multiple behavioral state (MBS) representation of arena influences on mouse location, mouse locomotor activity (stop/pausing, turning, and progression), and other mouse ethological parameters (rearing, stretching, grooming, etc.). We will then extend this approach to study how acquisition of place memories alters variables within the MBS model. The entropy rate and predictive information will be calculated for these data and used to quantify the amount of randomness and complexity of the responses. Validation data will be collected in young (6 wk), mid-life (12 month) and aged (>24 month) C57BI6 mouse cohorts. Our preliminary results show that aged mice have less complex novel environment exploratory patterns compared to a younger cohort. The analytic tools developed in this study will be invaluable when evaluating the efficacy of future pharmacological or genetic-based therapies to enhance cognitive and emotional function in patients with dementia. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The coming decades will be marked by a "graying" of the United States population. The most rapidly growing demographic group in the country is that of elderly persons, and within this group, that of the "oldest old." These trends pose significant challenges to our current medical practice. For example, the underlying causes of age-related behavioral changes remain undetermined. This application will examine the relationship between aging and changes in functional behaviors (eating, drinking, activity) by testing the hypotheses that (1) Age-related changes in mouse functional behaviors correlate with changes in gene expression regulating inflammatory and immune mediators, and (2) exercise and environmental enrichment improve CNS functional reserve by delaying or diminishing differential expression of genes regulating immune and inflammatory processes. We propose a cross-sectional study of young, middle-aged, and aged mice. Behaviors will be monitored using a state-of-the-art system that finely classifies large behavioral data streams in a reliable and automated fashion. Measures of overall behavior, including those of circadian rhythm, time budget, and properties (duration, frequency, etc.) of movement, feeding, and drinking bouts will be analyzed. Preliminary data find alterations in these measures similar to those seen in aging human populations. Additionally, gene expression in the hypothalamus and frontal cortex will be assessed using microarray and QT-PCR methods. Differentially expressed gene products will be classified by gene purpose. This will allow us to test whether observed behaviors correlate with changes in genes regulating immune responses rather than genes regulating activity, movement, and ingestive behaviors. We will also use graph-theory approaches to identify specific metabolic pathways (e.g., Atf3-Mapk8-Tlr2) altered in the aging hypothalamus. We also propose a longitudinal study to test whether lifestyle modifications including exercise and environmental enrichment increase CNS functional reserve. We will use similar measures of mouse behavior and gene expression as outcomes in this study. Ultimately, we anticipate that these data will provide important insight regarding the nature of aging processes in the brain, and may suggest important genetic targets for therapeutic manipulation. PUBLIC HEALTH RELEVANCE: Ultimately, it is anticipated that these data will provide important insight regarding the nature of aging processes in the brain, and may suggest important genetic targets for therapeutic manipulation.

The coming decades will be marked by a graying of the United States population. The most rapidly growing demographic group in the country is that of elderly persons, and within this group, that of the oldest old. These trends pose significant challenges to our current medical practice. For example, the underlying causes of age-related behavioral changes remain undetermined. This application will examine the relationship between aging and changes in functional behaviors (eating, drinking, activity) by testing the hypotheses that (1) Age-related changes in mouse functional behaviors correlate with changes in gene expression regulating inflammatory & immune mediators, and (2) Exercise & environmental enrichment improve CNS functional reserve by delaying or diminishing differential expression of genes regulating immune & inflammatory processes. We propose a cross-sectional study of young, middle-aged, & aged mice. Behaviors will be monitored using a state-of-the-art system that finely classifies large behavioral data streams in a reliable and automated fashion. Measures of overall behavior, including those of circadian rhythm, time budget, & properties (duration, frequency, etc.) of movement, feeding, and drinking bouts will be analyzed. Preliminary data finds alterations in these measures similar to those seen in aging human populations. Additionally, gene expression in the hypothalamus and frontal cortex will be assessed using microarray and QT-PCR methods. Differentially expressed gene products will be classified by gene purpose. This will allow us to test whether observed behaviors correlate with changes in genes regulating immune responses rather than genes regulating activity, movement, & ingestive behaviors. We will also use graph-theory approaches to identify specific metabolic pathways (e.g., Atf3-Mapk8-Tlr2) altered in the aging hypothalamus. We also propose a longitudinal study to test whether lifestyle modifications including exercise & environmental enrichment increase CNS functional reserve. We will use similar measures of mouse behavior & gene expression as outcomes in this study. Ultimately, we anticipate that these data will provide important insight regarding the nature of aging processes in the brain, & may suggest important genetic targets for therapeutic manipulation.