Title: Characterization, treatment, and prevention of stress-induced psychopathology
Description: Mood disorders are chronic and debilitating psychiatric diseases that affect 450 million people worldwide. Despite their overwhelming prevalence, the etiology and pathophysiology of these disorders are poorly understood. As a result, mood disorders are diagnosed by symptom presentation, not disease processes. Furthermore, our incomplete understanding of the biological underpinnings of these disorders is a major impediment to the development of effective treatments. Animal models offer a tractable means of examining the molecular and cellular processes that contribute to the pathogenesis of psychiatric disorders. Chronic social defeat (SD) stress is a novel ethologically-relevant mouse model of affective psychopathology. Like all animal models, face, construct, and predictive validity must first be established for SD before findings in this model can be extrapolated to the clinic. Though the depressive-like and anxious phenotypes induced by SD are well-established, cognitive symptoms have yet to be validated.

As cognitive impairment is a significant but understudied core symptom of affective disorders, we sought to determine if SD would recapitulate this dimension of psychopathology. First we confirmed that SD induced depressive-like and anxious behavior (ethological validity), as well as decreased adult neurogenesis in the dentate gyrus of the hippocampus--an established correlate of depressive behavior (biomarker validity), in our experimental mouse strain. We then tested mice in two learning paradigms: 1-shock contextual fear conditioning (CFC) and novel object recognition (NOR). SD mice were significantly impaired in CFC fear memory recall, as well as in NOR. Having identified a robust cognitive impairment in 1-shock CFC, we sought to locate a neural correlate of this deficit. As both 1-shock CFC and NOR are hippocampus-dependent tasks, and knowing that SD alters hippocampal architecture by decreasing adult hippocampal neurogenesis, we chose to examine cellular activity patterns in the dentate gyrus and its downstream target, CA3.

We found that impaired fear expression during context re-exposure correlated with decreased reactivation in CA3. Having confirmed SD as a viable model for the study of affective disorders, we then used this model to explore the antidepressant potential of ketamine. Classical antidepressants have a delayed onset of therapeutic efficacy of approximately four to six weeks. Ketamine, an NMDA receptor antagonist, has recently been identified as a rapid-acting antidepressant in humans. In order to explore ketamine's antidepressant mechanism of action, mouse models of ketamine administration need to be established and optimized. Though several groups have begun to investigate the antidepressant effect of ketamine in mice, dose, strain, and behavioral paradigms have yet to be systematically titrated. We found only a modest antidepressant effect of ketamine following SD. In conjunction with other murine ketamine studies, this modest effect argues for a more rigorous optimization of ketamine administration paradigms in mice.

We next sought to determine if ketamine could protect against the induction of psychopathology. Psychiatric disorders are not traditionally approached from a preventive perspective. This is in part because the etiology of these disorders remains largely unknown. It is known, however, that stress can precipitate affective disorders such as major depressive disorder and post-traumatic stress disorder, as well as trigger symptomatic episodes in patients with prior psychiatric diagnoses. However, stress does not ubiquitously induce psychopathology in all exposed individuals. Stress resilience, the capability to withstand stress without developing an affective disorder, varies across individuals. Using the SD model of chronic stress, we sought to determine if ketamine could enhance stress resilience, thereby protecting mice from the depressive-like sequelae of chronic stress exposure. We found that a single subanesthetic dose of ketamine was protective against stress-induced depressive-like behavior for at least three weeks following administration.

The drug was given a week prior to SD and, as ketamine has a half-life of only a few hours, was fully washed out by the commencement of the stress paradigm. This finding demonstrates that ketamine induces an actively self-maintaining form of resilience. Though we observed a protective effect of ketamine out to three weeks, it is possible that this effect persists even longer in duration. If this prophylactic effect translates to humans, ketamine could potentially be used in at-risk populations, such as active-duty soldiers, to inoculate against stress-induced psychopathology. In summary, this thesis establishes chronic social defeat stress as a valid model of the cognitive behavioral symptoms of affective disorders, as well as identifies decreased reactivation in CA3 as a cellular correlate of stress-induced cognitive impairment. Furthermore, we find that ketamine has a modest antidepressant effect when administered following two weeks of defeat stress. Most importantly, however, we show that a single subanesthetic dose of ketamine can induce robust, long-lasting, self-maintaining stress resilience.

The work in this thesis establishes prophylactic ketamine as a novel model of stress resilience and identifies ketamine as the first clinic-ready pharmaceutical with the potential to prevent psychiatric disorders.