No abstract

The hippocampus of spontaneously hypertensive rats (SHR) and deoxycorticosterone (DOCA)-salt hypertensive rats shows decreased cell proliferation and astrogliosis as well as a reduced number of hilar cells. These defects are corrected after administration of 17β-oestradiol (E(2) ) for 2 weeks. The present work investigated whether E(2) treatment of SHR and of hypertensive DOCA-salt male rats modulated the expression of brain-derived neurotrophic factor (BDNF), a neurotrophin involved in hippocampal neurogenesis. The neurogenic response to E(2) was simultaneously determined by counting the number of doublecortin-immunopositive immature neurones in the subgranular zone of the dentate gyrus. Both hypertensive models showed decreased expression of BDNF mRNA in the granular zone of the dentate gyrus, without changes in CA1 or CA3 pyramidal cell layers, decreased BDNF protein levels in whole hippocampal tissue, low density of doublecortin (DCX)-positive immature neurones in the subgranule zone and decreased length of DCX+ neurites in the dentate gyrus. After s.c. implantation of a single E(2) pellet for 2 weeks, BDNF mRNA in the dentate gyrus, BDNF protein in whole hippocampus, DCX immunopositive cells and the length of DCX+ neurites were significantly raised in both SHR and DOCA-salt-treated rats. These results indicate that: (i) low BDNF expression and deficient neurogenesis distinguished the hippocampus of SHR and DOCA-salt hypertensive rats and (ii) E(2) was able to normalise these biologically important functions in the hippocampus of hypertensive animals.

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Mineralocorticoid effects in the brain include the control of cardiovascular functions, induction of salt appetite, interaction with the vasoactive neuropeptides arginine vasopressin (AVP) and angiotensin II and development or aggravation of hypertension. In this regard, mineralocorticoids may play a pathogenic role in rats with a genetic form of hypertension (spontaneously hypertensive rats, SHR). Our objective was to compare the response of the hypothalamic vasopressinergic system to mineralocorticoid administration in SHR and control Wistar-Kyoto (WKY) rats. Sixteen-week-old male SHR showing a systolic blood pressure of 190 ± 5 mm Hg and normotensive WKY rats (130 ± 5 mm Hg) were treated subcutaneously with oil vehicle or a single 10-mg dose of deoxycorticosterone acetate (DOCA). After 2 h, rats were sacrificed and brains prepared for immunocytochemistry of Fos and vasopressin V1a receptor (V1aR) and for non-isotopic in situ hybridization of AVP mRNA. In the basal state, SHR demonstrated a higher number of AVP mRNA- and V1aR-immunopositive cells in the magnocellular division of the paraventricular hypothalamic nucleus (PVN) than WKY rats. After DOCA injection, SHR responded with a significant increase in both parameters with respect to vehicle-injected SHR. In WKY rats, DOCA was without effect on AVP mRNA although it increased the number of V1aR-positive cells. Changes in the number of Fos-positive nuclei were measured in the PVN, median preoptic nucleus (MnPO) and organum vasculosum of the lamina terminalis (OVLT), a circumventricular region showing anatomical connections with the PVN. In vehicle-injected rats, the PVN of SHR showed a higher number of Fos-positive nuclei than in WKY rats, whereas after DOCA treatment, a significant increment occurred in the OVLT but not in the PVN or MnPO of the SHR group only. These data suggest that the enhanced response of the vasopressinergic system to mineralocorticoids may contribute to the abnormal blood pressure of SHR.

Hippocampal neuropathology is a recognised feature of the brain in spontaneously hypertensive rats (SHR), but similar studies are lacking in another model of hypertension, the mineralocorticoid-salt-treated rat. The present study aimed to compare changes in hippocampal parameters in 16-week-old male SHR (blood pressure approximately 190 mmHg) and their normotensive Wistar-Kyoto controls, with those of male Sprague-Dawley rats receiving (i) 10 mg deoxycorticosterone acetate (DOCA) every other day during 3 weeks and drinking 1% NaCl solution (blood pressure approximately 160 mmHg) and normotensive controls treated with (ii) DOCA and drinking water, (iii) drinking water only or (iv) 1% NaCl only. In these experimental groups, we determined: (i) cell proliferation in the dentate gyrus (DG) using the 5-bromo-2¢-deoxyuridine-labelling technique; (ii) the number of glial fibrillary acidic protein (GFAP) positive astrocytes under the CA1, CA3 and DG; (iii) the number of apolipoprotein E (ApoE) positive astrocytes as a marker of potential neuronal damage; and (iv) the number of neurones in the hilus of the DG, taken as representative of neuronal density in other hippocampal subfields. Changes were remarkably similar in both models, indicating a decreased cell proliferation in DG, an increased number of astrocytes immunopositive for GFAP and ApoE and a reduced number of hilar neurones. Although hypertension may be a leading factor for these abnormalities, endocrine mechanisms may be involved, because hypothalamic-pituitary function, mineralocorticoid receptors and sensitivity to mineralocorticoid treatment are stimulated in SHR, whereas high exogenous mineralocorticoid levels circulate in DOCA-treated rats. Thus, in addition to the deleterious effects of hypertension, endocrine factors may contribute to the abnormalities of hippocampus in SHR and DOCA-treated rats.

Salt appetite, a conditioning factor for hypertension and cardiovascular diseases, is produced when high doses of mineralocorticoids are given to experimental animals. A commonly used procedure to identify neuronal activation is to determine the number of Fos-immunoreactive cells. In rats with established salt appetite after 8 days of deoxycorticosterone acetate (DOCA) treatment, Fos-positive cells were studied in seven brain areas. Significant increases in Fos activity were recorded in the paraventricular (PVN) and supraoptic (SON) nuclei, median preoptic nucleus (MnPO), organum vasculosum of the lamina terminalis (OVLT), preoptic area (POA), bed nucleus of the stria terminalis (BNST) and amygdala (AMYG). In most of these areas, increased Fos expression was also observed early (2 h) after a single DOCA injection, well before salt appetite develops. Using a mineralocorticoid receptor (MR) antibody, we studied whether Fos-active regions also expressed MR. MR-positive cells were found in the OVLT, MnPO, AMYG and BNST, but not in the POA, PVN and SON. In the PVN and SON, nevertheless, prolonged or single DOCA treatment increased expression of mRNA for arginine vasopressin (AVP). The present demonstration of Fos activation, in conjunction with differential expression of MR and stimulation of AVP mRNA, suggests that a neuroanatomical pathway comprising the AMYG, osmosensitive brain regions and magnocellular nuclei becomes activated during DOCA effects on salt appetite. It is recognized, however, that DOCA effects may also depend on mechanisms and brain structures other than those considered in the present investigation. Since some Fos-positive regions were devoid of MR, a comprehensive view of DOCA-induced salt appetite should consider nongenomic pathways of steroid action, including the role of reduced DOC metabolites binding to GABAergic membrane receptors.

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The incorporation of newborn neurons with increased synaptic remodeling and activity-dependent plasticity in the dentate gyrus enhances hippocampal-dependent learning performances. Astrocytes and microglial cells are components of the neurogenic niche and regulate neurogenesis under normal and neurophatological conditions leading to functional consequences for learning and memory. Although cognitive impairments were reported in patients after spinal cord injury (SCI), only few studies have considered remote changes in brain structures which are not related with sensory and motor cortex. Thus, we examined neurogenesis and glial reactivity by stereological assessment in dentate gyrus sub-regions after three different intensities of thoracic spinal cord compression in rats. Sixty days after injury we observed a decrease in the Basso-Bresnahan-Beattie locomotor scale scores, rotarod performance and volume of spare tissue that correlated with the severity of the compression. Regarding the hippocampus, we observed that neurogenesis and hilar neurons were reduced after severe SCI, while only neurogenesis decreased in the moderately injured group. In addition, severe SCI induced reactive microglia and astrogliosis in all dentate gyrus sub-regions. Furthermore, the density of reactive microglia increased in the hilus whereas astrogliosis developed in the molecular layer after moderate SCI. No changes were observed in the mildly injured rats. These results suggest glial response and neurogenesis are associated with injury intensity. Interestingly, hippocampal neurogenesis is more sensitive to SCI than astrocytes or microglia reaction, as moderate injury impairs the generation of new neurons without changing glial response in the subgranular zone.