Neuroscience
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Preclinical as well as limited clinical studies indicate that ketamine, a non-competitive glutamate N-methyl-D-aspartate (NMDA) receptor antagonist, may exert a quick and prolonged antidepressant effect. It has been postulated that ketamine action is due to inhibition of NMDA and stimulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors. Here, we sought to determine whether ketamine would exert antidepressant effects in Wistar-Kyoto (WKY) rats, a putative animal model of depression and whether this effect would be associated with changes in AMPA/NMDA receptor densities in the hippocampus. ⋯ These results indicate a rapid and lasting antidepressant-like effect of a low ketamine dose in WKY rat model of depression. Moreover, the increase in AMPA/NMDA receptor density in the hippocampus could be a contributory factor to behavioral effects of ketamine. These findings suggest potential therapeutic benefit in simultaneous reduction of central NMDA and elevation of AMPA receptor function in treatment of depression.
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Autophagy, the bulk intracellular degradation of cytoplasmic constituents, can be a pro-survival or a pro-death mechanism depending on the context. A recent study showed that autophagy was activated in the phase of early brain injury following subarachnoid hemorrhage (SAH). However, whether autophagy activation after SAH is protective or harmful is still elusive. ⋯ The results showed that RAP administration decreased Bax translocation to the mitochondria and downstream cytochrome c release from the mitochondria to the cytosol. Taken together, our study indicates that activation of autophagic pathways reduces early brain injury after SAH. This neuroprotective effect is likely exerted by anti-apoptotic mechanisms.
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Noninvasive neural imaging has become an important tool in both applied and theoretical applications. The hemodynamic properties that are measured in functional magnetic resonance imaging (fMRI), for example, are generally used to infer neuronal characteristics. In an attempt to provide empirical data to connect the hemodynamic measurements with neural function, we have conducted previous studies in which neural activity and tissue oxygen metabolic functions are determined together in co-localized regions of the central visual pathway. ⋯ In this investigation we have used several specific spatial stimulus patterns presented to either the CRF or the surrounding region or to both areas together in order to determine spatial response patterns. Within the CRF, we find that neural and metabolic responses sum in a nonlinear fashion but changes in these two measurements are closely coupled. For stimuli that extend beyond the CRF, neural activity is generally reduced while oxygen response exhibits uncoupled changes.
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X-linked adrenoleukodystrophy (X-ALD) and pseudo neonatal adrenoleukodystrophy (P-NALD) are neurodegenerative demyelinating diseases resulting from the functional loss of the peroxisomal ATP-binding cassette transporter D (ABCD1) and from single peroxisomal enzyme deficiency (Acyl-CoA oxidase1: ACOX1), respectively. As these proteins are involved in the catabolism of very long chain fatty acids (VLCFA: C24:0, C26:0), X-ALD and P-NALD patients are characterized by the accumulation of VLCFA in plasma and tissues. Since peroxisomes are involved in the metabolism of reactive oxygen species (ROS) and nitrogen species (RNS), we examined the impact of VLCFA on the oxidative status of 158N murine oligodendrocytes expressing or not Abcd1 or Acox1. ⋯ SiRNA knockdown of Abcd1 or Acox1 increased ROS and RNS production even in the absence of VLCFA, and especially potentialized VLCFA-induced ROS overproduction. Moreover, mainly in cells with reduced Acox1 level, the levels of VLCFA and neutral lipids were strongly enhanced both in untreated and VLCFA - treated cells. Our data obtained on 158N murine oligodendrocytes highlight that VLCFA induce an oxidative stress, and demonstrate that Abcd1 or Acox1 knockdown contributes to disrupt RedOx equilibrium supporting a link between oxidative stress and the deficiency of Abcd1 or Acox1 peroxisomal proteins.
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The neuromodulator adenosine maintains brain homeostasis and regulates complex behaviour via activation of inhibitory and excitatory adenosine receptors (ARs) in a brain region-specific manner. AR antagonists such as caffeine have been shown to ameliorate cognitive impairments in animal disease models but their effects on learning and memory in normal animals are equivocal. An alternative approach to reduce AR activation is to lower the extracellular tone of adenosine, which can be achieved by up-regulating adenosine kinase (ADK), the key enzyme of metabolic adenosine clearance. ⋯ To this end, we investigated mutant 'fb-Adk-def' mice in which ADK expression was specifically reduced in the telencephalon leading to a selective increase in cortical/hippocampal adenosine, while the rest of the brain remained as adenosine-deficient as in Adk-tg mice. The fb-Adk-def mice showed an even greater impairment in spatial working memory and a more pronounced motor response to NMDAR blockade than Adk-tg mice. These outcomes suggest that maintenance of cortical/hippocampal adenosine homeostasis is essential for effective spatial memory and deviation in either direction is detrimental with increased expression seemingly more disruptive than decreased expression.