The mechanisms of neuroplasticity during acclimatization to‐ and deacclimatization from chronic hypercapnia are fundamentally different

Abstract

A hallmark of respiratory-related diseases, such as chronic obstructive pulmonary disease (COPD), is chronic hypercapnia (CH). Common therapeutic intervention for patients experiencing CH is mechanical ventilation to restore blood-gas homeostasis. While many neurophysiological consequences of CH have been characterized, little is known about the effects reversing CH. The primary goal of the present study was to test the hypothesis that abrupt deacclimatization from CH would significantly alter markers of neuroplasticity and tryptophan metabolism, but not levels of excitatory neuromodulators. Utilizing our goat model of increased inspired CO2 (InCO2)-induced CH, adult female goats were exposed to an InCO2 of 6% for 30 days (d) followed by a return to room air for 24 hours (h). Following 24h of recovery, goats were euthanized, and brainstems were rapidly extracted. Tissue punches of key nuclei throughout the brainstem respiratory network (hypoglossal motor nucleus (XII), nucleus tractus solitarius (NTS)/dorsal motor nucleus of the vagus (DMV), ventral respiratory column (VRC), medullary raphe (MR), ventrolateral medulla (VLM), retrotrapezoid nucleus (RTN), and cuneate nucleus (CN)) were obtained and used for either western blot or HPLC analysis. Changes in glutamatergic signaling, neuroinflammation, tryptophan metabolism, and neuromodulators concentration, following recovery from CH, were assessed. Following 24h of recovery, there were no significant differences in AMPA or NMDA receptor expression or phosphorylation, compared to room air control goats, across all nuclei investigated. Similarly, there were no significant differences in the inflammatory cytokine IL1B following 24h recovery across all nuclei investigated, compared to room air control goats. However, there was significantly (P<0.05) lower expression of key enzymes of tryptophan metabolism (Indolamine 2,3-dioxygenase (IDO); Tryptophan Hydroxylase (TPH) and neuronal markers (NeuN) compared to control within the rostral VLM and MR. Within the solitary complex (NTS & DMV), there was significantly (P>0.05) greater concentrations in norepinephrine (+132%±49), serotonin (+348%±142), and dopamine (+86%±53) at 24h of recovery compared to 30d of CH. We conclude that although specific markers of neuroplasticity and neuroinflammation were unchanged from control during deacclimatization, there were brainstem-site dependent changes in excitatory neuromodulators during deacclimatization from CH. These data suggest that the mechanisms of neuroplasticity during acclimatization to- and deacclimatization from- CH are fundamentally different.