Stress related network activity in the intact adrenal medulla

Abstract The adrenal medulla has long been recognized as playing a critical role in mammalian homeostasis and the stress response. The adrenal medulla is populated by clustered chromaffin cells that secrete epinephrine or norepinephrine along with other peptides into the general bloodstream affecting multiple distant target organs. Although the sympatho-adrenal pathway has been heavily studied, detailed knowledge on the central control and in-situ spatiotemporal responsiveness remains poorly understood. For this work we implemented electrophysiological techniques originally developed to elucidate CNS circuitry to characterize the functional micro-architecture of the adrenal medulla. To achieve this, we continuously monitored the electrical activity inside the adrenal medulla in the living anesthetized rat under basal conditions and under physiological stress. Under basal conditions, chromaffin cells fired action potentials with frequencies between ∼0.2 and 4 Hz. Activity was exclusively driven by sympathetic inputs coming through the splanchnic nerve. Furthermore, chromaffin cells were organized into arrays of independent local networks in which cells fire in a specific order, with latencies from hundreds of microseconds to few milliseconds. Electrical stimulation of the splanchnic nerve evoked the exact same spatiotemporal firing patterns that occurred spontaneously. Induction of hypoglycemic stress by administration of insulin resulted in an increase in the activity of a subset of the chromaffin cell networks. In contrast, respiratory arrest induced by anesthesia overdose resulted in an increase in the activity of the entire adrenal medulla before cessation of all activity when the animal died. The results suggest the differential activation of specific networks inside the adrenal gland depending on the stressor. These results revealed a surprisingly complex electrical organization and circuitry of the adrenal medulla that likely reflects the dynamic nature of its neuroendocrine output during basal conditions and during different types of physiological stress. To our knowledge, these experiments are the first to use multi-electrode arrays in vivo to examine the electrical and functional architecture of any endocrine gland. Significance Statement Stress from extrinsic (environmental, psychological) and intrinsic (biological) challenges plays a critical role in disturbing the homeostatic balance. While the body’s responses to stress are designed to ameliorate these imbalances, prolonged and dysregulated stress often drives adverse health consequences in many chronic illnesses. The better understanding of the sympatho-adrenal stress response, will potentially impact and improve the treatment of several stress related illnesses. This work focusses on the study of the functional architecture of the adrenal medulla, a key component in neuronal stress response.