Perineuronal Nets in the VMH Regulating Energy and Glucose Balance - Brain-derived neurotrophic factor (BDNF) and its receptor TrkB play essential roles in the central regulation of energy and glucose homeostasis. Accordingly, mice with BDNF depletion throughout the brain (BDNF2L/2LCk-cre) are hyperphagic and severely obese and exhibit metabolic disturbances, including insulin resistance and hyperglycemia. These findings have significant clinical implications as the BdnfVal66Met variant, which interferes with BDNF signaling, is highly prevalent among the human population. Energy and glucose balance control results from coordinated appetitive and physiological responses to nutrient and hormonal signals informing the caloric status of the animal. Complex neural networks, including those involving the ventromedial hypothalamus (VMH), are critical in orchestrating these responses. It is now recognized that feeding circuits are not hardwired but highly plastic and remodel in response to caloric status signals to meet the energy demands of the animal. Our recent studies indicate that this plasticity takes place in the adult VMH, resulting in increased excitatory tone onto and activity of anorexigenic VMH neurons in the fed state. Notably, this plasticity is absent in BDNF2L/2LCk-cre mice, which always exhibit a fasted-like pattern of diminished excitatory drive in the VMH independently of feeding status. This exploratory project seeks to test the hypothesis that BDNF facilitates synaptic plasticity in metabolic circuits in the VMH via regulation of perineuronal nets (PNNs). PNNs consist of extracellular matrix (ECM) glycoproteins surrounding the cell bodies, dendrites and axon initial segments of selected neuronal subpopulations in the brain. Although their understanding is limited, they are thought to limit synaptic plasticity by stabilizing synapses and impeding access of new afferents to post synaptic sites. Our pilot data suggest that density of PNNs-like structures in the VMH is increased in mice with depletion of central BDNF. Furthermore, transcriptional profiling in VMH of BDNF2L/2LCk-cre mice indicates altered expression of several genes known to regulate the structure and degradation of PNNs. To follow up on these findings, we will test the idea that BDNF negatively regulates PNNs to facilitate synaptic plasticity, rewiring of excitatory inputs onto VMH neurons, and energy and glucose balance control.
