Perineuronal net formation during the critical period for neuronal maturation in the hypothalamic arcuate nucleus

Abstract

Summary In leptin-deficient ob/ob mice, obesity and diabetes are associated with abnormal development of neurocircuits in the hypothalamic arcuate nucleus (ARC) 1 , a critical brain area for energy and glucose homeostasis 2 , 3 . As this developmental defect can be remedied by systemic leptin administration, but only if given before postnatal day 28, a critical period (CP) for leptin-dependent development of ARC neurocircuits has been proposed 4 . In other brain areas, CP closure coincides with the appearance of perineuronal nets (PNNs), extracellular matrix specializations that restrict the plasticity of neurons that they enmesh 5 . Here we report that in humans as well as rodents, subsets of neurons in the mediobasal aspect of the ARC are enmeshed by PNN-like structures. In mice, these neurons are densely-packed into a continuous ring that encircles the junction of the ARC and median eminence, which facilitates exposure of ARC neurons to the circulation. Most of the enmeshed neurons are both GABAergic and leptin receptor-positive, including a majority of Agrp neurons. Postnatal formation of the PNN-like structures coincides precisely with closure of the CP for Agrp neuron maturation and is dependent on input from circulating leptin, as postnatal ob/ob mice have reduced ARC PNN-like material that is restored by leptin administration during the CP. We conclude that neurons crucial to metabolic homeostasis are enmeshed by PNN-like structures and organized into a densely packed cluster situated circumferentially at the ARC-ME junction, where metabolically-relevant humoral signals are sensed.

Role of hypothalamic MAPK/ERK signaling in diabetes remission induced by the central action of fibroblast growth factor 1

“…Also reminiscent of the current findings is our recent report that hypothalamic perineuronal nets (PNNs, defined as extracellular matrix specializations combined of proteoglycans and hyaluronan), which were recently shown to enmesh neurons in the ARC-ME 28 , are also targets for the glucose-lowering action of FGF1. Indeed, PNN formation increases rapidly in the ARC-ME following icv FGF1 injection and, in a rat model of T2D, disruption of this PNN response blocks the sustained antidiabetic action induced by icv FGF1 injection, while having no impact on the acute, transient effects of FGF1 on food intake, body weight, and glycemia 8 .…”

Shifting Developmental Trajectories During Critical Periods of Brain Formation

“…Control of critical period plasticity through PNN regulation in other brain regions influences brain function beyond sensory-motor and complex behaviors. In animal models of obesity and diabetes, critical period for leptin-dependent development of the hypothalamic acuate nucleus—involved in metabolic homeostasis—is accompanied by a reorganization of PNNs around leptin-receptor positive GABAergic neurons (Mirzadeh et al, 2019 ). Thus, PNNs remain central molecular hallmarks in the study of critical periods associated to the pathophysiology and the treatment of a range of neuropsychiatric disorders and related metabolic comorbidities (Bradshaw et al, 2018 ; for review Wen et al, 2018 ).…”

Hypothalamic perineuronal net assembly is required for sustained diabetes remission induced by fibroblast growth factor 1 in rats

“…We recently showed that perineuronal nets (PNNs) enmesh glucoregulatory neurons in the arcuate nucleus (Arc) of the mediobasal hypothalamus (MBH) 1 , but whether these PNNs play a role in either the pathogenesis of type 2 diabetes (T2D) or its treatment remains unclear. Here we show that compared to normoglycemic rats, PNN abundance within the Arc is markedly reduced in the Zucker Diabetic Fatty (ZDF) rat model of T2D, correlating with altered PNN-associated chondroitin sulfate (CS) glycosaminoglycan (GAG) sulfation patterns in the MBH.…”