UC San Diego

Major depressive disorder (MDD) and other depressive disorders are highly prevalent in the world today. A pervasive and debilitating symptom of MDD, that is also seen in other depressive disorders, is anhedonia – the lack of interest or pleasure, a consequence of dysfunction of reward circuits. Chronic stress induces anhedonia in susceptible, but not resilient individuals, a phenomenon observed in humans as well as animal models. The molecular mechanisms underlying this are not well understood. The study described in this dissertation was based on the hypothesis that plasticity of the serotonergic system, which is implicated in stress, reward and antidepressant therapy, plays a role in determining susceptibility and resilience. Stress-induced anhedonia was assessed in adult male rats using social defeat and intracranial self-stimulation (ICSS), while changes in serotonergic phenotype were investigated using immunohistochemistry and in situ hybridization. Susceptible, but not resilient, rats displayed an increased number of neurons expressing the enzyme for serotonin, tryptophan-hydroxylase-2 (TPH2), in the ventral subnucleus of the dorsal raphe nucleus (DRv). Further, a decrease in the number of DRv neurons expressing the glutamatergic marker, vesicular-glutamate-transporter-3 (VGLUT3), was observed in all stressed rats. Neuronal activity was decreased in the DRv, specifically in non-serotonergic neurons, in all stressed rats. These changes occurred without a change in total neuron number in the DRv, suggestive of a neurotransmitter plasticity mechanism. This was dependent on DR activity, as was revealed by chemogenetic manipulation of the central amygdala, a stress-sensitive nucleus that forms a major input to the DR. Activation of amygdalar corticotropin releasing hormone (CRH)+ neurons abolished the increase in DRv TPH2+ neurons and ameliorated stress-induced anhedonia in susceptible rats. Therefore, activation of amygdalar CRH+ neurons induces resilience, and suppresses the characteristic phenotype of susceptible rats. The molecular signature of vulnerability to stress-induced anhedonia and the active nature of resilience could be a target of new treatments for stress-related disorders like depression. This dissertation also discusses further research questions that can be pursued in the light of this study and the experimental approaches to address them.