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 energy and glucose balance and affective behavior. BDNF is a highly conserved member of the neurotrophin family of signaling molecules. It plays an integral role in the survival, differentiation and plasticity of neurons and signals through the tropomyosin related kinase B (TrkB) receptor.
Role of BDNF in Appetite and Glycemic Control and Obesity Disorders
The Rios lab studies cellular and molecular mechanisms acting in the brain to regulate energy balance and glycemic control. Energy balance is the tightly regulated equilibrium between caloric intake and expenditure and its dysregulation leads to obesity and associated metabolic disorders, including diabetes. Investigations in the Rios lab focus on dissecting the role of BDNF in hypothalamic feeding circuits and defining downstream molecular effectors of this neurotrophin. They emanate from the finding that perturbing central BDNF signaling in mice results in over eating, dramatic obesity, hyperleptinemia, hyperinsulinemia, and hyperglycemia. In humans, blunted BDNF signaling was linked to elevated food intake and obesity. Current projects in the lab investigate recently identified molecular pathways acting downstream of BDNF to facilitate synaptic plasticity and critically regulate activity of hypothalamic neurons involved in appetite suppression and glucose metabolism. The role of hypothalamic astrocytes shaping neurotransmission in feeding circuits and facilitating energy and glucose homeostasis is also a current area of interest. The Rios lab tackles these questions using multidisciplinary approaches including mouse genetics, electrophysiology, biochemistry, behavioral and advanced imaging and molecular techniques.
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.