Effect of Type 2 Diabetes on the Expression and Composition of Perineuronal Nets in Hypothalamus

Perineuronal nets (PNNs) are lattice-like extracellular matrix (ECM) specializations that enmesh, and regulate network interactions of key glucoregulatory neurons in defined circuits within the arcuate nucleus (Arc) of the mediobasal hypothalamus (MBH). The first aim of this award proposes to determine whether aberrant changes in PNN assembly and/or MBH chondroitin sulfate (CS)-glycosaminoglycan (GAG) ECM composition is 1) observed in multiple rat models T2D, 2) induced by PNN matrix manipulation in normoglycemic rats, and 3) whether loss of Arc PNNs results in hypothalamic hormonal and nutrient signaling dysregulation. The second aim of this proposal is to translate these PNN changes in humans by examining both PNN structure and MBH CS-GAG composition throughout 3 regions of human hypothalamic tissue from patients with both chronic and acute hyperglycemia compared to normoglycemic controls. Determining whether changes in hypothalamic PNNs associate with diabetes disease pathology in humans would provide a compelling rationale for future studies to target ECM/PNN remodeling as a long-term therapy for diabetes.