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Regional distribution of hypothalamic paraventricular nucleus neurons activated by acute intermittent hypoxia

Upon returning to normoxic ventilation following exposure to acute intermittent hypoxia (AIH), sympathetic nerve activity (SNA) is observed to progressively increase – a response termed sympathetic long term facilitation (sLTF). We recently reported that inhibition of the hypothalamic paraventricular nucleus (PVN) prior to AIH attenuated post‐AIH sLTF in anesthetized rats. Although this study implicated PVN neuronal activity in post‐AIH sLTF, the specific PVN cell groups involved and their neurochemical phenotypes were not determined. Here we hypothesized that AIH activates parvocellular subregions of the PVN enriched with sympathetic regulatory neurons, and tested this using c‐Fos IHC to identify neurons activated by 10 cycles of AIH in awake rats. Separate groups were exposed to AIH in which FIO2 was reduced every 6 minutes to nadirs of 10%, 8%, or 6%, with each nadir lasting ~75 s. Compared to control rats exposed to sham AIH (n=6), the number of Fos+ nuclei in the medial parvocellular (MP) region of the PVN was progressively greater in rats exposed to AIH to 10% (367%, P<0.01, n=4), 8% (566%, P<0.01, n=5) and 6% (1054%, P<0.01, n=4) FIO2. Fos+ counts increased in the dorsal parvocellular and central magnocellular regions of the PVN as well, but only in response to AIH to 6% FIO2 (P<0.05, n=4–5). No level of AIH increased Fos+ nuclei in the caudally located lateral parvocellular area (P>0.05, n=4–5). Neurochemical phenotypes of neurons activated by AIH to 8% FIO2 were examined by co‐immunostaining for corticotropin‐releasing hormone (CRH) or arginine vasopressin (AVP), which are stress‐responsive neurons enriched in the MP region. AIH to 8% FIO2 was selected for this analysis because it induced robust Fos expression without eliciting escape behavior as was observed in rats exposed to AIH to 6% FIO2. Whereas CRH+ neurons (~772) outnumbered AVP+ neurons (~50), the population size of each was similar between sham treated and AIH exposed rats. A significantly greater fraction of CRH+ neurons (~14%, P<0.05) and AVP+ neurons (~13%, P<0.05) was Fos+ in AIH exposed rats (n=4) compared to sham treated controls (CRH+, ~3%; AVP+, ~0%; n=4). Further analysis revealed that ~30% of AIH‐activated PVN neurons were CRH+ (110/371) while only ~2% (7/371) were AVP+. Thus a sizable fraction of AIH‐activated PVN neurons were CRH‐containing, while the neurochemical phenotype(s) of the majority of activated neurons (~68%) remains to be identified. These data suggest that responses to AIH are unlikely to be mediated by PVN‐AVP neurons, and raise the possibility that CRH neurons could contribute to endocrine and/or autonomic responses to AIH, including post‐AIH sLTF. Studies are needed to test the latter possibility and to define the role of AIH‐activated PVN neurons whose chemical phenotypes remain unknown. Determining intrinsic and synaptic mechanisms leading to AIH activation of PVN neurons could provide insight into mechanisms of persistent sympathetic activation in cardiovascular and metabolic diseases.