Ventrolateral ventromedial hypothalamic nucleus GABA neuron adaptation to recurring Hypoglycemia correlates with up-regulated 5′-AMP-activated protein kinase activity

Abdulrahman Alhamyani; Prabhat R Napit; Haider Ali; Mostafa MH Ibrahim; Karen P Briski; Abdulrahman Alhamyani; Prabhat R Napit; Haider Ali; Mostafa MH Ibrahim; Karen P Briski

doi:10.3934/Neuroscience.2021027

AIMS Neuroscience

2021, Volume 8, Issue 4: 510-525. doi: 10.3934/Neuroscience.2021027

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Ventrolateral ventromedial hypothalamic nucleus GABA neuron adaptation to recurring Hypoglycemia correlates with up-regulated 5′-AMP-activated protein kinase activity

School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, Monroe, LA 71201, USA

Received: 01 April 2021 Accepted: 05 August 2021 Published: 03 September 2021

Gamma-aminobutyric acid (GABA) acts on ventromedial hypothalamic targets to suppress counter-regulatory hormone release, thereby lowering blood glucose. Maladaptive up-regulation of GABA signaling is implicated in impaired counter-regulatory outflow during recurring insulin-induced hypoglycemia (RIIH). Ventromedial hypothalamic nucleus (VMN) GABAergic neurons express the sensitive energy gauge 5′-AMP-activated protein kinase (AMPK). Current research used high-neuroanatomical resolution single-cell microdissection tools to address the premise that GABAergic cells in the VMNvl, the primary location of ‘glucose-excited’ metabolic-sensory neurons in the VMN, exhibit attenuated sensor activation during RIIH. Data show that during acute hypoglycemia, VMNvl glutamate decarboxylase_65/67 (GAD)-immunoreactive neurons maintain energy stability, yet a regional subset of this population exhibited decreased GAD content. GABA neurons located along the rostrocaudal length of the VMNvl acclimated to RIIH through a shift to negative energy imbalance, e.g. increased phosphoAMPK expression, alongside amplification/gain of inhibition of GAD profiles. Acquisition of negative GAD sensitivity may involve altered cellular receptivity to noradrenergic input via α₂-AR and/or β₁-AR. Suppression of VMNvl GABA nerve cell signaling during RIIH may differentiate this neuroanatomical population from other, possibly non-metabolic-sensory GABA neurons in the MBH. Data here also provide novel evidence that VMNvl GABA neurons are direct targets of glucocorticoid control, and show that glucocorticoid receptors may inhibit RIIH-associated GAD expression in rostral VMNvl GABAergic cells through AMPK-independent mechanisms.
Citation: Abdulrahman Alhamyani, Prabhat R Napit, Haider Ali, Mostafa MH Ibrahim, Karen P Briski. Ventrolateral ventromedial hypothalamic nucleus GABA neuron adaptation to recurring Hypoglycemia correlates with up-regulated 5′-AMP-activated protein kinase activity[J]. AIMS Neuroscience, 2021, 8(4): 510-525. doi: 10.3934/Neuroscience.2021027

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Abstract

Gamma-aminobutyric acid (GABA) acts on ventromedial hypothalamic targets to suppress counter-regulatory hormone release, thereby lowering blood glucose. Maladaptive up-regulation of GABA signaling is implicated in impaired counter-regulatory outflow during recurring insulin-induced hypoglycemia (RIIH). Ventromedial hypothalamic nucleus (VMN) GABAergic neurons express the sensitive energy gauge 5′-AMP-activated protein kinase (AMPK). Current research used high-neuroanatomical resolution single-cell microdissection tools to address the premise that GABAergic cells in the VMNvl, the primary location of ‘glucose-excited’ metabolic-sensory neurons in the VMN, exhibit attenuated sensor activation during RIIH. Data show that during acute hypoglycemia, VMNvl glutamate decarboxylase_65/67 (GAD)-immunoreactive neurons maintain energy stability, yet a regional subset of this population exhibited decreased GAD content. GABA neurons located along the rostrocaudal length of the VMNvl acclimated to RIIH through a shift to negative energy imbalance, e.g. increased phosphoAMPK expression, alongside amplification/gain of inhibition of GAD profiles. Acquisition of negative GAD sensitivity may involve altered cellular receptivity to noradrenergic input via α₂-AR and/or β₁-AR. Suppression of VMNvl GABA nerve cell signaling during RIIH may differentiate this neuroanatomical population from other, possibly non-metabolic-sensory GABA neurons in the MBH. Data here also provide novel evidence that VMNvl GABA neurons are direct targets of glucocorticoid control, and show that glucocorticoid receptors may inhibit RIIH-associated GAD expression in rostral VMNvl GABAergic cells through AMPK-independent mechanisms.

Abbreviations

AMPK

5′-AMP-activated protein kinase

adrenergic receptor

α₁-AR

alpha₁-adrenergic receptor

α₂-AR

alpha₂-adrenergic receptor

β₁-AR

beta₁-adrenergic receptor

GABA

γ-aminobutyric acid

GAD

glutamate decarboxylase_65/67

glucocorticoid receptor

INS

insulin

IIH

insulin-induced hypoglycemia

MBH

mediobasal hypothalamus

pAMPK

phosphoAMPK

RIIH

recurrent insulin-induced hypoglycemia

VMN

ventromedial hypothalamic nucleus

VMNvl

ventrolateral ventromedial hypothalamic nucleus

Acknowledgments

NIH DK-109382.

Conflict of interest

The authors declare no conflict of interest.

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