Psychological stress susceptibility in juvenile female and male mice - Program Director/Principal Investigator (Iñiguez, Sergio, Diaz): ABSTRACT Epidemiologic reports indicate that mood-related illnesses, like major depressive disorder (MDD), are among the leading cause of morbidity and mortality in the juvenile population. To make matters worse, women are twice as likely to be diagnosed with MDD, a sex difference that becomes apparent during the adolescent stage of development. These disparities highlight the critical need for the development of novel preclinical models to uncover the neurobiological factors that underlie MDD as a function of age and sex – particularly, because most animal models mainly incorporate adult male rodents. To address this issue, our group developed the vicarious defeat stress (VDS) paradigm wherein a mouse witnesses the defeat bout of a male conspecific from the safety of an adjacent compartment, leading to a behavioral outcome that resembles some of the core symptoms of MDD (deficits in sociability, decreased preference for reward-related stimuli and body weight, along with increased helplessness behavior and corticosterone). A major strength of this innovative approach is that it allows for the experimental inclusion of females and juveniles – vulnerable populations that are commonly excluded in preclinical/clinical studies. As such, the experiments described in this proposal will evaluate whether exposing juvenile female and male mice to VDS results in behavioral outcomes that recapitulate a depression-related phenotype. This will be accomplished within the framework of the following specific aims: [1] assess the behavioral consequences of VDS on sensitivity to reward (cocaine, sucrose), affect, and memory-performance in adolescent female and male mice (postnatal day 35). Also, [2] to evaluate if traditional (fluoxetine) and novel (ketamine) antidepressant medications can reverse the VDS-induced behavioral deficits observed. Lastly, [3] to evaluate the integrity of mood-related biological markers [brain derived neurotropic factor (BDNF)-related signaling] within the hippocampus. It is expected that juvenile VDS will mediate behavioral alterations associated with enhanced drug abuse potential (i.e., cocaine), anhedonia (decreased sucrose preference), maladaptive responses to subsequent inescapable stress (despair), and memory-related impairment. Furthermore, that clinically relevant medications (fluoxetine and ketamine) will reverse the VDS-induced social dysfunction, mimicking what is observed at the clinic in juvenile populations. Additionally, it is expected that site-specific neurochemical adaptations (BDNF fluctuations within the hippocampus) will be observed after VDS exposure in an age and sex specific manner. Collectively, the outcome of these studies will provide behavioral, pharmacological, and molecular evidence of VDS-induced dysfunction that may underlie the convergent (both sexes experiencing MDD) and divergent (age- and sex- specific) neurobiological underpinnings of MDD. OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page Continuation Format Page
