Glucoprivic sensitivity of hindbrain catecholamine neurons is astrocyte‐dependent

Abstract

Hypoglycemia poses a threat to survival. Endocrine, metabolic, and behavioral counter‐regulatory responses (CRRs) act to correct blood glucose deficit. These responses require sensor, integrator, and effector elements to restore glucose homeostasis. Groups of hindbrain catecholamine (CA) neurons are essential for implementation of different CRRs which include activation of descending sympathetic pathways controlling epinephrine and glucagon release and ascending pathways controlling feeding behavior and glucocorticoids (3, 4). Hindbrain astrocytes respond to low glucose (1, 2, 5). Therefore, we postulated that CA neurons are activated by astrocytes during glucose deficit. To directly test the proposition that CA neuron responses to glucoprivic challenges are astrocyte dependent, we utilized male and female transgenic mice in which the calcium reporter construct (GCaMP5) was expressed selectively in tyrosine hydroxylase neurons (TH‐GCaMP5; TH+). We conducted live‐cell calcium imaging studies on tissue slices containing the nucleus of the solitary tract (NST) and the ventrolateral medulla (VLM); loci of glucoregulatory circuitry (4). Results show that hindbrain TH+ neurons are robustly activated by a glucoprivic challenge and that this response is dependent on functional astrocytes. Pretreatment of hindbrain slices with fluorocitrate (an astrocytic metabolic suppressor) abolished TH+ neuronal responses to glucoprivation, but not to glutamate stimulation. Pharmacologic results suggest that the astrocytic connection with TH+ neurons is purinergic via P2 receptors. Parallel imaging studies on hindbrain slices of NST from wild type C57BL/6J mice (astrocytes and neurons were prelabeled with a calcium reporter dye and an astrocytic vital dye) show that both cell types are activated by glucoprivation but astrocytes responded nearly a minute sooner than neurons. Pretreatment of these hindbrain slices with fluorocitrate eliminated both astrocytic and neuronal responses to glucoprivation; pretreatment with P2 antagonists only abolished neuronal responses to glucoprivation without interruption of astrocyte responses. These results support earlier work suggesting that the primary detection of glucoprivic signals by the hindbrain is mediated by astrocytes which utilize purinergic gliotransmission to activate critical effector neurons.Support or Funding InformationNIH NIDDK 108765, U54 GM 104940, ADA‐1‐15‐JF‐37,This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.