Acrobatic training prevents learning impairments and astrocyte remodeling in the hippocampus of rats undergoing chronic cerebral hypoperfusion: sex-specific benefits.

Background: Chronic cerebral hypoperfusion (CCH) leads to memory and learning impairments associated with degeneration and gliosis in the hippocampus. Treatment with physical exercise carries different therapeutic benefits for each sex. We investigated the effects of acrobatic training on astrocyte remodeling in the CA1 and CA3 subfields of the hippocampus and spatial memory impairment in male and female rats at different stages of the two-vessel occlusion (2VO) model. Methods: Wistar rats were randomly allocated into four groups of males and females: 2VO acrobatic, 2VO sedentary, sham acrobatic, and sham sedentary. The acrobatic training was performed for 4 weeks prior to the 2VO procedure. Brain samples were collected for morphological and biochemical analysis at 3 and 7 days after 2VO. The dorsal hippocampi were removed and prepared for Western blot quantification of Akt, p-Akt, COX IV, cleaved caspase-3, PARP, and GFAP. GFAP immunofluorescence was performed on slices of the hippocampus to count astrocytes and apply the Sholl's circle technique. The Morris water maze was run after 45 days of 2VO. Results: Acutely, the trained female rats showed increased PARP expression, and the 2VO-trained rats of both sexes presented increased GFAP levels in Western blot. Training, mainly in males, induced an increase in the number of astrocytes in the CA1 subfield. The 2VO rats presented branched astrocytes, while acrobatic training prevented branching. However, the 2VO-induced spatial memory impairment was partially prevented by the acrobatic training. Conclusion: Acrobatic training restricted the astrocytic remodeling caused by 2VO in the CA1 and CA3 subfields of the hippocampus. The improvement in spatial memory was associated with more organized glial scarring in the trained rats and better cell viability observed in females.

Bumetanide Attenuates Cognitive Deficits and Brain Damage in Rats Subjected to Hypoxia-Ischemia at Two Time Points of the Early Postnatal Period.

Neonatal hypoxia-ischemia (HI) is one of the main causes of tissue damage, cell death, and imbalance between neuronal excitation and inhibition and synaptic loss in newborns. GABA, the major inhibitory neurotransmitter of the central nervous system (CNS) in adults, is excitatory at the onset of neurodevelopment and its action depends on the chloride (Cl-) cotransporters NKCC1 (imports Cl-) and KCC2 (exports Cl-) expression. Under basal conditions, the NKCC1/KCC2 ratio decreases over neurodevelopment. Thus, changes in this ratio caused by HI may be related to neurological disorders. The present study evaluated the effects of bumetanide (NKCC cotransporters inhibitor) on HI impairments in two neurodevelopmental periods. Male Wistar rat pups, 3 (PND3) and 11 (PND11) days old, were submitted to the Rice-Vannucci model. Animals were divided into 3 groups: SHAM, HI-SAL, and HI-BUM, considering each age. Bumetanide was administered intraperitoneally at 1, 24, 48, and 72 h after HI. NKCC1, KCC2, PSD-95, and synaptophysin proteins were analyzed after the last injection by western blot. Negative geotaxis, righting reflex, open field, object recognition test, and Morris water maze task were performed to assess neurological reflexes, locomotion, and memory function. Tissue atrophy and cell death were evaluated by histology. Bumetanide prevented neurodevelopmental delay, hyperactivity, and declarative and spatial memory deficits. Furthermore, bumetanide reversed HI-induced brain tissue damage, reduced neuronal death and controlled GABAergic tone, maintained the NKCC1/KCC2 ratio, and synaptogenesis close to normality. Thereby, bumetanide appears to play an important therapeutic role in the CNS, protecting the animals against HI damage and improving functional performance.

Long-term environmental modifications affect BDNF concentrations in rat hippocampus, but not in serum.

The role of mBDNF on the beneficial effects of cognitive stimulation on the brain remains controversial, as well as the potential of peripheral mBDNF as a biomarker of environmental effects on its central status. We investigated the effect of different environmental conditions on recognition memory, proBDNF, mBDNF and synaptophysin levels in the hippocampus, and on mBDNF levels in blood. Male Wistar rats (6 and 17 months-old) were assigned to cognitively enriched (EE), standard (SE) and impoverished (IE) environmental conditions for twelve weeks. Novel object recognition was performed at week 10. When the animals were 9 and 20-months old, hippocampus was collected for mBDNF, proBDNF and synaptophysin analysis; serum was analyzed for mBDNF levels. The cognitively EE improved recognition memory, resulted in a trend to increased hippocampal mBDNF and augmented synaptophysin levels. Accordingly, hippocampal mBDNF, proBDNF and synaptophysin were significantly higher in EE than IE animals. Hippocampal mBDNF was positively correlated to proBDNF, cellular and behavioral plasticity markers. No effect of age was seen on the studied variables. Moreover, no significant effects of EE or IE on serum mBDNF were observed. Serum mBDNF also failed to correlate with hippocampal mBDNF, proBDNF and with the cellular and behavioral plasticity markers. These findings indicate that mBDNF is involved in neuronal and behavioral plasticity mechanisms induced by cognitively enriched environments, and that peripheral mBDNF may not always be a reliable biomarker of the effects of environmental settings on central mBDNF and plasticity, which is of special interest from a translational research perspective.