Neuroscience
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Previous results from our laboratory showed that angiotensin II AT1 receptors (AT1-R) are involved in the neuroadaptative changes induced by amphetamine. The aim of the present work was to study functional and neurochemical responses to angiotensin II (ANG II) mediated by AT1-R activation in animals previously exposed to amphetamine. For this purpose male Wistar rats (250-320 g) were treated with amphetamine (2.5mg/kg/day intraperitoneal) or saline for 5 days and implanted with intracerebroventricular (i.c.v.) cannulae. Seven days after the last amphetamine administration the animals received ANG II (400 pmol) i.c.v. One group was tested in a free choice paradigm for sodium (2% NaCl) and water intake and sacrificed for Fos immunoreactivity (Fos-IR) determinations. In a second group of rats, urine and plasma samples were collected for electrolytes and plasma renin activity determination and then they were sacrificed for Fos-IR determination in Oxytocinergic neurons (Fos-OT-IR). ⋯ Repeated amphetamine exposure (a) prevented the increase in sodium intake and Fos-IR cells in caudate-putamen and accumbens nucleus induced by ANG II i.c.v. (b) potentiated urinary sodium excretion and Fos-OT-IR in hypothalamus and (c) increased the inhibitory response in plasma renin activity, in response to ANG II i.c.v. Our results indicate a possible functional desensitisation of AT1-R in response to ANG II, induced by repeated amphetamine exposure. This functional AT1-R desensitisation allows to unmask the effects of ANG II i.c.v. mediated by oxytocin. We conclude that the long lasting changes in brain AT1-R functionality should be considered among the psychostimulant-induced neuroadaptations.
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β-Site APP-cleaving enzyme 1 (BACE1) initiates the generation of amyloid-β (Aβ), thus representing a prime therapeutic target for Alzheimer's disease (AD). Previous work including ours has used BACE1 haploinsufficiency (BACE1(+/-); i.e., 50% reduction) as a therapeutic relevant model to evaluate the efficacy of partial β-secretase inhibition. However, it is unclear whether the extent of Aβ reductions in amyloid precursor protein (APP) transgenic mice with BACE1(+/-) gene ablation may vary with sex or disease progression. ⋯ Oligomeric Aβ and C99 levels were dramatically elevated in older 5XFAD mice. Although the β-metabolites of APP were significantly reduced by BACE1 haploinsufficiency in both age groups, high levels of these toxic amyloidogenic fragments remained in 12-14-month-old BACE1(+/-)·5XFAD mice. The present findings are consistent with our previous behavioral data showing that BACE1 haploinsufficiency rescues memory deficits in 5XFAD mice irrespective of sex but only in the younger age group.
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Interleukin-6 (IL-6) has been shown to promote post-stroke angiogenesis and long-term functional recovery; however, whether IL-6 could promote post-stroke neurogenesis remains unclear. This study aims to investigate the effects of IL-6 on neurogenesis after ischemic stroke. We also investigated whether pair housing (PH) could improve the experimental stroke outcome through IL-6. ⋯ We found that anti-IL-6 mAbs significantly reduced the proliferation and neuronal differentiation of NPCs in the ipsilateral SVZ, as well as functional recovery; whereas rIL-6 conferred the opposite effects. PH significantly promoted NPC proliferation and functional recovery compared with socially isolated cohorts; blockade of IL-6 with anti-IL-6 mAbs prevented this promoting effect. In conclusion, our results suggest that IL-6 is an important mediator of social interaction on neurogenesis and long-term functional recovery after ischemic stroke.
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Our study examined how different housing conditions modulated the acquisition of a spatial reference memory task and also, a reversal task in the 4-radial arm water maze (4-RAWM). The animals were randomly assigned to standard or enriched cages, and, as a type of complementary stimulation along with the environmental enrichment (EE), a group of rats also ran 15 min/day in a Rotarod. Elevated-zero maze results allowed us to discard that our exercise training increased anxiety-related behaviors. 4-RAWM results revealed that the non-enriched group had a worse performance during the acquisition and also, during the first trial of each session with respect to the enriched groups. ⋯ In the PL cortex, we did not find significant differences between the groups that performed the reversal task. Therefore, our short EE protocol improved the performance in a spatial memory and a reversal task, whereas the exercise training, combined with the EE, did not produce a greater benefit. This better performance seemed to be related with the specific pattern of c-Fos expression in brain regions involved in cognitive flexibility.
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The blockade of the central nucleus of the amygdala (CeA) with the GABAA receptor agonist muscimol significantly reduces hypertonic NaCl and water intake by sodium-depleted rats. In the present study we investigated the effects of previous injection of losartan, an angiotensin II type-1 (AT1) receptor antagonist, into the CeA on 0.3M NaCl and water intake reduced by muscimol bilaterally injected into the same areas in rats submitted to water deprivation-partial rehydration (WD-PR) and in rats treated with the diuretic furosemide (FURO). Male Sprague-Dawley rats with stainless steel cannulas bilaterally implanted into the CeA were used. ⋯ The negative effect of muscimol on sodium and water intake could also be blocked by pretreatment with losartan microinjected into the CeA in rats given FURO (n=8 rats/group). However, bilateral injections of losartan (50 μg/0.5 μl) alone into the CeA did not affect the NaCl or water intake. These results suggest that the deactivation of CeA facilitatory mechanisms by muscimol injection into the CeA is promoted by endogenous angiotensin II acting on AT1 receptors in the CeA, which prevents rats from ingesting large amounts of hypertonic NaCl and water.