Molecular and Functional Studies of BDNF
Our laboratory focuses on ascertaining the cellular and molecular mechanisms utilized by brain-derived neurotrophic factor (BDNF) to regulate feeding and affective behavior. BDNF, a member of the neurotrophin family of signaling molecules, plays an integral role in the survival, differentiation and plasticity of neurons and signals through the tropomyosin related kinase B (TrkB) receptor. We use molecular, biochemical, electrophysiological, behavioral and mouse genetic tools to define the neural circuits and molecular pathways governed by BDNF to regulate behavior.
Role of BDNF in Appetite Control and Obesity Disorders
Our laboratory studies the role of BDNF in the regulation of energy balance and body weight. Energy balance is the tightly regulated equilibrium between caloric intake and expenditure. Factors informing the energy status of the animal act in complex neural circuits in the brain to mediate energy homeostasis and prevent excessive body weight gain or loss. We and others discovered that perturbing central BDNF signaling in mice results in increased food intake, dramatic obesity, hyperleptinemia, hyperinsulinemia, and hyperglycemia. In humans, BDNF haploinsufficiency was linked to elevated food intake and obesity. More recently, we found that caloric signals induce expression of BDNF and TrkB in the ventromedial hypothalamus (VMH), an energy balance-regulating center of the brain. Furthermore, when we selectively targeted Bdnf in the adult VMH of mice, they developed hyperphagic behavior and obesity, demonstrating that neural circuits involving the VMH require this neurotrophin to control appetite. Our efforts are currently focused on delineating molecular pathways under the control of BDNF in the VMH that mediate its homeostatic control of food intake. Furthermore, because feeding is also influenced by reward-related processes, we are currently investigating the role of BDNF in brain regions involved with hedonic feeding of palatable food, including the mesolimbic dopamine reward system.
Figure 1. Deleting Bdnf in the brains of mice triggers excessive eating and dramatic obesity. Mutant mouse (left) lacking BDNF in the brain exhibits dramatic increases in body weight compared to a wild type littermate (right).
BDNF and the Regulation of Affective Behavior
BDNF and its cognate receptor, TrkB, are expressed in the hippocampus, amygdala, hypothalamus and cerebral cortex. These brain regions comprise the limbic system and function, in part, to regulate emotion. Similar to disruptions in the limbic system, deficient BDNF signaling has been implicated in psychiatric disorders, such as depression, anxiety, bipolar disorder and schizophrenia. When we depleted BDNF in the brains of mice, we observed increases in aggressive, anxiety and depressive-like behaviors. We are currently investigating whether abnormal serotonergic neurotransmission in limbic regions of the brain might contribute to these behavioral alterations. We found that 5-HT2A receptor-mediated responses to serotonin in the prefrontal cortex and dorsal raphe nucleus are severely impaired in the absence of BDNF. More recent electrophysiological studies revealed additional serotonergic abnormalities in the BDNF mutant amygdala, a region pivotal for fear conditioning and associated with anxiety disorders. Current studies aim to ascertain the pathological molecular and cellular mechanisms underlying these alterations in 5-HT transmission and how they might be linked to the emergence of psychiatric disorders.