Switching control of sympathetic activity from forebrain to hindbrain in chronic dehydration

Abstract

Non-technical summary Dehydration, a life-threatening condition, occurs when the body does not replace adequate water lost through urination, sweating or when ill with diarrhoea. This presents the body with a major challenge of maintaining blood pressure -essential for consciousness that is dependent on the degree of body hydration, which dictates blood volume. We know that a major control mechanism involves a brain region called the hypothalamus that automatically maintains blood pressure. Our study has described the gene networks in key brain regions involved in the response to dehydration. We reveal a new structure in the brain that regulates blood pressure in dehydration and a unique genetic mechanism that exists within it. Moreover, our study unearths a remarkable form of flexibility within the brain during dehydration that involves switching control of blood pressure between two spatially distinct structures. We have provided new mechanistic insight to explain how the brain maintains body stability in face of the significant challenge of low water content.Abstract We investigated the mechanisms responsible for increased blood pressure and sympathetic nerve activity (SNA) caused by 2-3 days dehydration (DH) both in vivo and in situ preparations. In euhydrated (EH) rats, systemic application of the AT 1 receptor antagonist Losartan and subsequent pre-collicular transection (to remove the hypothalamus) significantly reduced thoracic (t)SNA. In contrast, in DH rats, Losartan, followed by pre-collicular and pontine transections, failed to reduce tSNA, whereas transection at the medulla-spinal cord junction massively reduced tSNA. In DH but not EH rats, selective inhibition of the commissural nucleus tractus solitarii (cNTS) significantly reduced tSNA. Comparable data were obtained in both in situ and in vivo (anaesthetized/conscious) rats and suggest that following chronic dehydration, the control of tSNA transfers from supra-brainstem structures (e.g. hypothalamus) to the medulla oblongata, particularly the cNTS. As microarray analysis revealed up-regulation of AP1 transcription factor JunD in the dehydrated cNTS, we tested the hypothesis that AP1 transcription factor activity is responsible for dehydration-induced functional plasticity. When AP1 activity was blocked in the cNTS using a viral vector expressing a dominant negative FosB, cNTS inactivation was ineffective. However, tSNA was decreased after pre-collicular transection, a response similar to that seen in EH rats. Thus, the dehydration-induced switch in control of tSNA from hypothalamus to cNTS seems to be mediated via activation of AP1 transcription factors in the cNTS. If AP1 activity is blocked in the cNTS during dehydration, sympathetic activity control reverts back to forebrain regions. This unique reciprocating neural structure-switching plasticity between brain centres emphasizes the multiple mechanisms available for the adaptive response to dehydration.

Inhibitory mechanism of the nucleus of the solitary tract involved in the control of cardiovascular, dipsogenic, hormonal, and renal responses to hyperosmolality

“…Hyperosmolality increases sympathetic nerve activity (2,12,13,52). Even considering that commNTS lesions affect sympathoexcitatory responses (14,34,44,45,55), it is not possible to exclude the participation of sympathetic mechanisms in the residual pressor response in commNTS-lesioned rats treated with intragastric 2 M NaCl.…”

“…Peripheral osmoreceptors make their first synapse in the NTS (commissural and intermediate) and area postrema (AP) and, according to previous studies (19,28), it was expected a reduction in water intake in commNTS-lesioned rats. Similar to the peripheral osmoreceptor-induced facilitation of water intake, it was recently demonstrated that the commNTS has also an excitatory role in the control of sympathetic nerve activity and arterial pressure during the chronic increase in plasma osmolality produced by 3 days of water deprivation (12). Therefore, other signals and not those from peripheral osmoreceptors might be those that activate the inhibitory mechanisms in the commNTS.…”

ΔFosB in the supraoptic nucleus contributes to hyponatremia in rats with cirrhosis

“…Overexpression of ⌬JunD has been shown to block ⌬FosB-dependent behavioral adaptations associated with cocaine administration in the orbitofrontal cortex (52) and an animal model of posttraumatic stress disease in the nucleus accumbens (51). Dominant negative inhibition of ⌬FosB in the NTS prevents changes in the network control of sympathetic nerve activity that occur during dehydration (16). Therefore, we used the same approach to test the hypothesis that ⌬FosB may have a similar role in activity-dependent changes of magnocellular neurosecretory cells of the SON following BDL.…”

“…⌬FosB has a much longer half-life than Fos, resulting in its accumulation with chronic or intermittent stimulation of the CNS (17,25,42) and has been linked to changes in neuronal morphology, receptor expression, and cell signaling related to depression, drug addiction, and other motivated behaviors (24,38,42,45,54). AP-1 transcriptional activity has also been shown to play a critical role in the adaptive control of sympathetic outflow during dehydration (16) indicating that ⌬FosB and other AP-1 proteins may play similar roles in neural networks that regulate vegetative function.…”

Purinergic and glutamatergic interactions in the hypothalamic paraventricular nucleus modulate sympathetic outflow

“…This preparation is advantageous as it eliminates the need for anesthetic use, which has been shown to have significant depressive effects on the neural control of autonomic function [44]. We have validated and used this preparation extensively in the past to study the central control of SNA [42,45]. Another advantage of the preparation is the removal of all circulating blood-borne substances such as angiotensin II and other hormones, which can affect sympathetic nerve discharge and obfuscate the data.…”