The Rate of Fall of Blood Glucose Determines the Necessity of Forebrain-Projecting Catecholaminergic Neurons for Male Rat Sympathoadrenal Responses

Abstract

Different onset rates of insulin-induced hypoglycemia use distinct glucosensors to activate sympathoadrenal counterregulatory responses (CRRs). Glucosensory elements in the portal-mesenteric veins are dispensable with faster rates when brain elements predominate, but are essential for responses to the slower-onset hypoglycemia that is common with insulin therapy. Whether a similar rate-associated divergence exists within more expansive brain networks is unknown. Hindbrain catecholamine neurons distribute glycemia-related information throughout the forebrain. We tested in male rats whether catecholaminergic neurons that project to the medial and ventromedial hypothalamus are required for sympathoadrenal CRRs to rapid- and slow-onset hypoglycemia and whether these neurons are differentially engaged as onset rates change. Using a catecholamine-specific neurotoxin and hyperinsulinemic-hypoglycemic clamps, we found that sympathoadrenal CRRs to slow- but not rapid-onset hypoglycemia require hypothalamus-projecting catecholaminergic neurons, the majority of which originate in the ventrolateral medulla. As determined with Fos, these neurons are differentially activated by the two onset rates. We conclude that 1) catecholaminergic projections to the hypothalamus provide essential information for activating sympathoadrenal CRRs to slow- but not rapid-onset hypoglycemia, 2) hypoglycemia onset rates have a major impact on the hypothalamic mechanisms that enable sympathoadrenal CRRs, and 3) hypoglycemia-related sensory information activates hindbrain catecholaminergic neurons in a rate-dependent manner.

Peripheral and Central Glucose Sensing In Hypoglycemic Detection

“…Concomitant with the suppression in the CRR is a failure for hindbrain neuronal activation, as denoted by Fos expression under these conditions (10). Interestingly, lesioning catecholaminergic afferents projecting from the hindbrain to the hypothalamus results in a similar impaired response to slow-onset hypoglycemia (48). Together, these data suggest an extended network of peripheral and hindbrain afferents critical for the detection of physiological decrements in blood glucose.…”

Revisiting How the Brain Senses Glucose—And Why

“…Activation of this PMV glucose sensing circuit (e.g., in response to hypoglycemia in the portal-splanchnic circulation) activates neurons in the NTS via spinal afferent nerves (predominantly sympathetic), rather than the vagus nerve (Chan and Sherwin, 2014; Jokiaho et al, 2014; Watts and Donovan, 2010). From the hindbrain, ascending catecholaminergic projections relay this afferent information to the hypothalamus, where it is specifically implicated in the response to hypoglycemia that is slow in onset (Chan and Sherwin, 2014; Jokiaho et al, 2014; Watts and Donovan, 2010). Neurons in the NTS also project extensively to the parabrachial nucleus, which contains neurons that project in turn to the VMN and are involved the response to glucopenia (Flak et al, 2014; Garfield et al, 2014).…”

“…With this background, it is not difficult to envision afferent input regarding glucose levels in the GI tract and hepatic portal vein being transmitted via spinal afferents to the hindbrain (Chan and Sherwin, 2014; Donovan, 2002; Jokiaho et al, 2014; Watts and Donovan, 2010), and from there to the VMN (Flak et al, 2014; Garfield et al, 2014). At the same time, information relevant to systemic (rather than PMV) glucose levels may be transmitted to the VMN by way of glucose-sensing neurons located outside the BBB, potentially including the ventromedial arcuate nucleus, median eminence, NTS, area postrema, or some combination thereof.…”

Activation of Medulla-Projecting Perifornical Neurons Modulates the Adrenal Sympathetic Response to Hypoglycemia: Involvement of Orexin Type 2 (OX2-R) Receptors

“…Local glucoprivation in the PeH possibly inhibited neurons that modulate the activity of orexin neurons, such as PeH-projecting neurons in the VMH (34). In fact, neurons in the forebrain and hindbrain press.endocrine.org/journal/endo 815 project to orexin neurons and contribute to changes in their excitability, for instance, catecholaminergic (4,35,36) and serotonergic (5) medullary neurons. Additionally, the VMH contains neurons that increase AMP-activated protein kinase in response to acute hypoglycemia (37).…”