Repeated chemogenetic activation of ventrolateral medulla catecholamine neurons significantly attenuated subsequent hyperglycemic responses, mimicking hypoglycemia associated autonomic failure.
Does repeated chemogenetic activation of VLM CA neurons reduce subsequent glucoprivic responses and mimic HAAF in female TH-Cre transgenic rats?
Repeated stimulation of VLM CA neurons mimics hypoglycemia-associated autonomic failure (HAAF) and may be a cause of impaired counterregulatory responses.
Abstract In diabetic patients, hypoglycemia associated autonomic failure (HAAF) is a potentially lethal condition that results in attenuation of critical protective responses to low blood glucose, following repeated prior hypoglycemic episodes. The underlying mechanism(s) of HAAF is not fully understood. We previously demonstrated that activation of catecholamine (CA) neurons in the ventrolateral medulla (VLM) is both required and sufficient to elicit key protective responses to glucose deficit. Here we test the hypothesis that repeated selective activation of VLM CA neurons is sufficient to induce HAAF, even in the absence of glucose deficit. Using stereotaxic injections of an adeno-associated virus in female TH-Cre transgenic rats, we transfected rostral C1 CA neurons to express hM3D(Gq). In these rats, we found that a single clozapine-N-oxide (CNO) injection evoked robust hyperglycemia, with a magnitude and time course similar to those evoked by the glucoprivic agent, 2-deoxy-D-glucose (2DG). However, following repeated CNO injections in these same rats, the hyperglycemic response evoked by either CNO or 2DG were significantly attenuated. Moreover, plasma epinephrine levels, and Fos expression in VLM CA neurons and in the adrenal medulla, also were attenuated following repeated CNO injections. This constellation of effects is similar to those that define HAAF. Taken together our results suggest that repeated stimulation of VLM CA neurons mimics and could be a cause of the impairment of counterregulatory responses associated with pathogenesis of HAAF.
Li et al. (Thu,) conducted a other in Hypoglycemia associated autonomic failure (HAAF). Repeated chemogenetic activation of VLM CA neurons (CNO injections) vs. Single CNO injection / 2DG was evaluated on Hyperglycemic response, plasma epinephrine levels, and Fos expression. Repeated chemogenetic activation of ventrolateral medulla catecholamine neurons significantly attenuated subsequent hyperglycemic responses, mimicking hypoglycemia associated autonomic failure.