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.