Chronic stress exposure impairs reward and motivation behaviors in mice

Millions of people experience at least one episode of major depressive disorder in their lifetime, and diagnostic rates are increasing. Depression is a heterogeneous and complex psychiatric disorder which has many antidepressant treatment options. However, most of these fail to treat the multitude of diverse symptoms that characterize depression. Understanding behavioral and neurobiological deficits caused by chronic stress, a substantial preceding factor in depression, will help to elucidate effective treatment strategies to provide targeted therapies to depressed individuals. A recent development from the National Institute of Mental Health (NIMH), the Research Domain Criteria (RDoC) aims to provide a new framework for translational research focusing on broad domains, which include negative and positive valence systems. Negative valence behavior has been studied more in translational research than positive valence, despite the importance of reward and motivation in depression, and the greater translational validity of these behaviors. Depression impairs reward processing, and the changes in neural circuitry mediating reward are not fully understood. Therefore, understanding how chronic stress causes impairments in positive valence behaviors will greatly inform mood disorders research. In this thesis, I first characterized the effects of chronic corticosterone (CORT) administration on positive valence behaviors in male mice. I found that chronic CORT administration reduces lever pressing in progressive ratio, reduces completed reversals in probabilistic reversal learning (PRL) and trended to reduce sensitivity to a devalued outcome. I then found that chronic CORT administration robustly shifts effortful behavior in a Y-maze barrier task. As females are understudied, I then used a chronic non-discriminatory social defeat stress (CNSDS) paradigm effective in female mice that I helped develop, to examine reward behavior in females. I found that CNSDS reduced sensitivity for a devalued outcome and reduced lever pressing for reward in progressive ratio, as well as total reinforcers earned, indicating reduced motivation in both sexes. Lastly, CNSDS-exposed mice shifted effort-based choice behavior in the Y-maze barrier task, and a sex difference emerged as the effort required increased. I next examined the role of BLA glutamatergic projections to the nucleus accumbens (NAc) in behavior. I inhibited or activated these BLA neurons using a chemogenetic approach (DREADDs). BLA-NAc inhibition reduced preference for sucrose but did not affect NSF or progressive ratio. In chronic CORT experiments, I found that feeding latency in the NSF was increased with chronic CORT but rescued with chemogenetic activation of BLA-NAc neurons. However, BLA-NAc activation had no effect on Progressive Ratio in mice subjected to chronic CORT. BLA-NAc activation robustly increased reward seeking in a nose-poke task in both Vehicle and CORT-administered mice without impacting free-feeding. Taken together, BLA-NAc neurons facilitated reward behavior, but in particular rescued reward deficits in mice subjected to chronic CORT administration.Ph.D.Includes bibliographical reference