Brain derived neurotrophic factor regulates affective behavior and the maturation of newborn neurons in the adult hippocampus

Brain-derived neurotrophic factor (BDNF) is a prominent support factor for neuronal function and plasticity in the adult brain. BDNF and its receptor TrkB are expressed in limbic regions of the brain involved in regulating affective behavior and decreased content of these proteins has been implicated in psychiatric disorders. However, the precise functions of this signaling pathway remain unclear. It was proposed that reduced BDNF signaling impairs central neural circuits that mediate adaptation to environmental stimuli, including stress, which is considered a risk factor for depression and anxiety disorders. In particular, BDNF activity in the adult hippocampal formation, a brain region important for spatial and fear learning, has been highlighted in this context. Patients of severe depression and animal models of stress show reduced volume of the hippocampal formation. Also thought to facilitate cognitive processes is the generation of new granule neurons that integrate into the adult hippocampal circuitry. Indeed, adult neurogenesis is necessary for the behavioral improvements observed after antidepressant drug administration in rodents. As BDNF mediates survival, growth and differentiation of neurons during early development, it emerges as candidate to mediate adult hippocampal neurogenesis and ultimately behavior.;The work described in this thesis encompasses studies designed to define behaviors modulated by BDNF action. Moreover, they address the role of BDNF in adult hippocampal neurogenesis. I used mice in which Bdnf was centrally depleted in the postnatal brain to examine its function in the adult. I show that BDNF mutants exhibited behaviors consistent with affective disorders, including depressive-like behavior, hyperactivity, and hyperaggression. Given that adult neurogenesis is implicated in antidepressant efficacy and spatial and fear learning, I examined this process in the BDNF mutants. I show that BDNF is required for the migration and terminal differentiation of newborn neurons in the adult hippocampal formation. These findings suggest that this neurotrophin might facilitate cognition and antidepressant efficacy by directing the full maturation of adult-generated granule neurons.