Perineuronal Net Formation during the Critical Period for Neuronal Maturation in the Hypothalamic Arcuate Nucleus

Authors

Zaman Mirzadeh, Department of Neurosurgery, Barrow Neurological Institute, Phoenix, AZ, USA.
Kimberly M. Alonge, Diabetes Institute, School of Medicine, University of Washington, Seattle, WA, USA.
Elaine Cabrales, Department of Neurosurgery, Barrow Neurological Institute, Phoenix, AZ, USA.
Vicente Herranz-Pérez, Laboratory of Comparative Neurobiology, Instituto Cavanilles, CIBERNED, Universidad de Valencia, 46980 Valencia, Spain.
Jarrad M. Scarlett, Diabetes Institute, School of Medicine, University of Washington, Seattle, WA, USA.
Jenny M. Brown, Diabetes Institute, School of Medicine, University of Washington, Seattle, WA, USA.
Rim Hassouna, Naomi Berrie Diabetes Center, Columbia University, New York, NY, USA.
Miles E. Matsen, Diabetes Institute, School of Medicine, University of Washington, Seattle, WA, USA.
Hong T. Nguyen, Diabetes Institute, School of Medicine, University of Washington, Seattle, WA, USA.
Jose Manuel Garcia-Verdugo, Laboratory of Comparative Neurobiology, Instituto Cavanilles, CIBERNED, Universidad de Valencia, 46980 Valencia, Spain.
Lori M. Zeltser, Naomi Berrie Diabetes Center, Columbia University, New York, NY, USA.
Michael W. Schwartz, Diabetes Institute, School of Medicine, University of Washington, Seattle, WA, USA.

Document Type

Article

Abstract

In leptin-deficient mice, obesity and diabetes are associated with abnormal development of neurocircuits in the hypothalamic arcuate nucleus (ARC), a critical brain area for energy and glucose homeostasis. 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. 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. 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 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.

Medical Subject Headings

Animals; Arcuate Nucleus of Hypothalamus (cytology, metabolism); Leptin (metabolism); Mice; Mice, Inbred C57BL; Nerve Net; Neurons (cytology, metabolism); Obesity (genetics, metabolism)

Publication Date

2-1-2019

Publication Title

Nature metabolism

E-ISSN

2522-5812

Volume

1

Issue

2

First Page

212

Last Page

221

PubMed ID

31245789

Digital Object Identifier (DOI)

10.1038/s42255-018-0029-0

Recommended Citation

Mirzadeh, Zaman; Alonge, Kimberly M.; Cabrales, Elaine; Herranz-Pérez, Vicente; Scarlett, Jarrad M.; Brown, Jenny M.; Hassouna, Rim; Matsen, Miles E.; Nguyen, Hong T.; Garcia-Verdugo, Jose Manuel; Zeltser, Lori M.; and Schwartz, Michael W., "Perineuronal Net Formation during the Critical Period for Neuronal Maturation in the Hypothalamic Arcuate Nucleus" (2019). Translational Neuroscience. 1243.
https://scholar.barrowneuro.org/neurobiology/1243