ORCID
https://orcid.org/0000-0001-5944-1167
Date of Award
9-11-2023
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
Mental health in the elderly is an escalating social problem as the world population ages rapidly. Older adults are more susceptible to stressors like social isolation, which is a common risk factor for many mental disorders and health issues. However, how aging affects specific mental functions like motivational drive and stress responses, as well as the underlying neurobiological mechanisms, remains largely unstudied. We comprehensively examined behavioral phenotypes in both young and aged mice under the normal grouped-housing condition versus chronic social isolation treatment. The results suggested that natural aging and social isolation both impaired motivational behaviors and induce depressive- and anxiety-like behaviors, but in distinct manners. Using the operant progressive-ratio test (PR), we found that old mice showed substantially reduced motivation levels to work for palatable sugar reward when food deprived, particularly during the dark time. We then identified an age-associated general decrease of brain-derived neurotrophic factor (Bdnf) expression in the ventral tegmental area (VTA) of the brain by qRT-PCR and FISH. Moreover, knocking down Bdnf specifically in the VTA of young mice reduced the fasting-induced motivational behaviors driven by palatable food, partially recapitulating the loss of motivation in aged mice. To investigate how aging affects stress responses, we independently compared the effects of social isolation in young and old mice. For depressive-like and motivated behaviors, while isolated old mice appeared to manifest more deficits in voluntary wheel-running recording and tail suspension test, isolated young mice showed larger responses in the PR and sucrose preference test. Interestingly, only young mice showed altered exploratory behaviors and decreased social preference after social isolation, whereas socially isolated mice of both age groups showed elevated activities in the “safe area” of an exploratory arena. The behavioral phenotypes in young and old mice are likely mediated by both shared and distinct molecular mechanisms, which are potentially related to dopamine and serotonin metabolism and synaptic plasticity in the brain, stress hormone regulation, and metabolic changes, as implied by the gene expression analyses and physiological measurements. Overall, social isolation seemed to affect young mice more than old mice. The current study identified BDNF in the VTA as an essential player to regulate reward and motivation. Moreover, the depletion of VTA Bdnf expression over aging may contribute to the reduction of food-seeking motivation in aged mice. Furthermore, we presented a behavioral and molecular profile for the effects of social isolation stress in young and aged mice, revealing altered, and mostly attenuated, responses to social deprivation by aging. Collectively, we demonstrated that aging blunts the appropriate responses to the lack of food and social resources. Our findings provide a better understanding of the age-related mental impairments as well as new insights into the molecular basis of brain aging.
Language
English (en)
Chair and Committee
Shin-ichiro Imai
Recommended Citation
Lei, Hanyue, "Drives Blunted by Time: The Effects of Aging on Motivational Behaviors and Responses to Social Isolation in Mice" (2023). Arts & Sciences Electronic Theses and Dissertations. 3167.
https://openscholarship.wustl.edu/art_sci_etds/3167