The role of microglia in the sympathetic control of blood pressure in normotension and hypertension

Microglia are an essential component of the central nervous system (CNS), and are known to play a key role in the maintenance of neuronal/synaptic activity levels within their working physiological range. Microglia are present throughout the CNS and constantly survey their immediate environment for signs of over-, or under-, activity, or damage. Caudal and rostral ventrolateral medullary (CVLM and RVLM, respectively) regions of the brainstem are crucial in the cardiovascular arm of the sympathetic nervous system (SNS). Recently, dysfunction of normal microglial physiology in cardiovascular brain sites, involved in the sympathetic control of blood pressure (BP), is suggested to play a role in the pathology of neurogenic hypertension. The overall aim of this thesis was to determine if microglia in the ventrolateral medullary nuclei of the brainstem are involved in regulation of the cardiovascular system. Data from Chapter 3 show that the microglial number, in a given catecholaminergic nucleus of the brainstem (such as A1, A2, C1, C3, A5 or A6), is closely related to the number of tyrosine hydroxylase immunoreactive (TH-ir) neurons in all 3 strains of rats examined (Sprague-Dawley (SD), Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR)). The pattern of variation observed in the microglial number was similar to the pattern of variation observed in the TH-ir neuronal number, in catecholaminergic nuclei of the brainstem. This suggests that microglial distribution is strongly related to its local environment. Data from Chapter 4 show that microglia in the CVLM and the RVLM of SD rats are capable of sensing, and responding to, changes introduced in their local environment in response to altered baseline levels of BP. In this study, we demonstrate that alterations in BP do not induce any significant changes in microglial morphology, or require microglia to polarize to extreme activated phenotypes (M1/M2), in the CVLM and the RVLM. Instead, microglia, in the CVLM and the RVLM, alter their level of synaptic sampling (increased by ≈30% following 6 h of phenylephrine induced hypertension and decreased by >20% following 6 h of hydralazine induced hypotension) accompanied by a subtle rearrangement of microglial spatial distribution. Data from Chapter 5 show that the microglial response to changes in BP is exaggerated in the RVLM of SHR (a model of neurogenic hypertension), when compared to that of the control strain (WKY). Following 2 h of phenylephrine induced hypertension, the % of colocalisation between microglia (Iba1) and synapses (synapsin) increased by ≈133% in the RVLM of SHR, as compared to a decrease of ≈55% seen in the RVLM of WKY. Similarly, following 2 h of hydralazine induced hypotension, the % of colocalisation between microglia (Iba1) and synapses (synapsin) increased by ≈72% in the RVLM of SHR, but no changes were observed in the RVLM of WKY. Collectively, data presented in this thesis highlight microglia as key elements of the CNS involved in the sympathetic control of BP homeostasis. We provide the first, and substantial, evidence that microglia in the ventrolateral medulla of the brainstem respond to changes in their local environment introduced by altered BP levels, and that this microglial response to altered BP in a strain with existing neurogenic hypertension (SHR) is impaired in the RVLM compared to its normotensive control.