Hypoxia activates a neuropeptidergic pathway from the paraventricular nucleus of the hypothalamus to the nucleus tractus solitarii

Abstract

The paraventricular nucleus of the hypothalamus (PVN) contributes to both autonomic and neuroendocrine function. PVN lesion or inhibition blunts cardiorespiratory responses to peripheral chemoreflex activation, suggesting that the PVN is required for full expression of these effects. However, the role of efferent projections to cardiorespiratory nuclei and the neurotransmitters/neuromodulators that are involved is unclear. The PVN sends dense projections to the nucleus tractus solitarii (nTS), a region that displays neuronal activation following hypoxia. We hypothesized that acute hypoxia activates nTS-projecting PVN neurons. Using a combination of retrograde tracing and immunohistochemistry, we determined whether hypoxia activates PVN neurons that project to the nTS and examined the phenotype of these neurons. Conscious rats underwent 2 hr normoxia (21% O, n=5) or hypoxia (10% O, n=6). Hypoxia significantly increased Fos immunoreactivity in nTS-projecting neurons, primarily in the caudal PVN. The majority of activated nTS-projecting neurons contained corticotropin releasing hormone (CRH). In the nTS, fibers expressing the CRH receptor CRFR2 were co-localized with oxytocin fibers and were closely associated with hypoxia-activated nTS neurons. A separate group of animals that received microinjection of AAV2-hSyn-GFP into the PVN exhibited GFP-expressing fibers in the nTS; a proportion of these fibers displayed OT immunoreactivity. Thus, nTS CRFR2s appear to be located on the fibers of PVN OT neurons that project to the nTS. Taken together, our findings suggest that PVN CRH projections to the nTS may modulate nTS neuronal activation, possibly via OTergic mechanisms, and thus contribute to chemoreflex cardiorespiratory responses.

Activation of alpha‐1 adrenergic receptors increases cytosolic calcium in neurones of the paraventricular nucleus of the hypothalamus

“…PVN over‐activity, including that caused by long‐term hypoxic exposure such as with obstructive sleep apnoea, correlates with negative health outcomes such as hypertension, heart failure and stroke . Within the PVN, hypoxia increases Fos expression in many PVN neurones, including CRH expressing neurones that are within the area that we isolated, and NE has been directly linked to increased plasma levels and the production of CRH, possibly as a result of α 1 ‐AR activation. The PVN also plays an important role in regulating feeding behaviour, as well as glucose and insulin levels in the blood .…”

“…Hypoxia activates PVN‐projecting adrenergic neurones, particularly those in the nTS, and NE increases PVN excitation . PVN over‐activity, including that caused by long‐term hypoxic exposure such as with obstructive sleep apnoea, correlates with negative health outcomes such as hypertension, heart failure and stroke .…”

“…Hypoxia activates PVN-projecting adrenergic neurones, particularly those in the nTS, 8,10 and NE increases PVN excitation. 1,2,4,[86][87][88] PVN over-activity, including that caused by long-term hypoxic exposure such as with obstructive sleep apnoea, 7 correlates with negative health outcomes such as hypertension, heart failure and stroke. 6,87 Within the PVN, hypoxia increases Fos expression in many PVN neurones, including CRH expressing neurones that are within the area that we isolated, 2,89 and NE has been directly linked to increased plasma levels and the production of CRH, 90 possibly as a result of α 1 -AR activation.…”

“…The hypothalamic paraventricular nucleus (PVN) is an integrative nucleus critical to producing the appropriate physiological response to a variety of stressors and stimuli, including during hypoxic exposure and chemoreflex activation. For example, hypoxia increases PVN Fos expression indicative of elevated neuronal activity, including in those neurones that express corticotrophin‐releasing hormone (CRH), vasopressin (AVP) and oxytocin, as well as those that project to the brainstem nucleus tractus solitarii (nTS) . These activated neurones are likely functionally important because inhibition or elimination of the PVN reduces the respiratory and pressor response to chemoreflex activation and hypoxia .…”

AMPK and the Need to Breathe and Feed: What’s the Matter with Oxygen?

“…The aforementioned findings are all the more intriguing, given recent work [136] that showed that expression of constitutively active AMPK in hypothalamic PVN neurons led to a preference for carbohydrate over fat in food choice of mice, through activation by AMPK of CPT1C, which promotes mitochondrial β-oxidation of fatty acids, within a subset of corticotrophin-releasing hormone-positive neurons in the rostral region of the PVN. It is possible that this affords a coordinating link between adaptive changes to feeding and food choice and ventilatory oxygen supply, given the evident reciprocal inputs between PVN and NTS ( Figure 4) that modify peripheral and central cardiorespiratory reflex responses during hypoxia [137][138][139][140].…”