Neuroscience
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Ketamine is a widely used clinical drug that has several functional and clinical applications, including its use as an anaesthetic, analgesic, anti-depressive, anti-suicidal agent, among others. Among its diverse behavioral effects, it influences short-term memory and induces psychedelic effects. At the neural level across different brain areas, it modulates neural firing rates, neural tuning, brain oscillations, and modularity, while promoting hypersynchrony and random connectivity between neurons. ⋯ This model has potential implications for focused modulation of cortical networks in clinical settings. Finally, we identify current gaps in research and suggest directions for future studies, particularly emphasizing the need for more animal experiments to establish a platform for effective translation and synergistic therapies combining ketamine with other protocols such as training and adaptation. In summary, investigating ketamine's broader systemic effects, not only provides deeper insight into cognitive functions and consciousness but also paves the way to advance therapies for neuropsychiatric disorders.
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N-methyl-D-aspartate receptors (NMDARs) play a crucial role in mediating Amyloid-β (Aβ) synaptotoxicity. Our previous studies have demonstrated an opposite (neuroprotection and neurotoxicity) effect of activating astrocytic and neuronal NMDARs with higher dose (10 μM) of NMDA, an agonist of NMDARs. By contrast, activating neuronal or astrocyitc NMDARs with lower dose (1 μM) of NMDA both exerts neuroprotective effect in Aβ-induced neurotoxicity. ⋯ Furthermore, blockade of astrocytic GluN2A with TCN201 abrogated the ability of 1 μM NMDA to counteract the effects of Aβ decreasing BDNF, and increasing GFAP, C3 and activation of NF-κB. These findings suggest that activation of astrocytic NMDARs protect against Aβ-induced synaptotoxicity probably through elevating BDNF and suppressing GFAP and C3. Our present research provides valuable insights for elucidating the underlying mechanism of astrocytic NMDARs activation resisting the toxic effects of Aβ.
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Disruption of circadian rhythms contributes to deficits in cognitive functions during aging. Up to date, the biochemical, molecular and chronobiological bases of such deterioration have not been completely elucidated. Here, we aim: 1) to investigate the endogenous nature of 24 h-rhythms of antioxidant defenses, oxidative stress, clocḱ's, and neurotrophic factors expression, in the rat temporal cortex (TC), and 2) to study the consequences of aging on the circadian organization of those factors. ⋯ Noteworthy, such circadian organization disappears in the TC of aged rats. Aging also reduces glutathione peroxidase activity and expression, and it increases lipid peroxidation, throughout a 24 h-period. An increased oxidative stress makes the cellular redox environment change into an oxidative status which alters the endogenous clock activity and disrupts the circadian organization of, at least part, of the molecular basis of the synaptic plasticity in the TC.
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Cisplatin-based chemotherapy is a common treatment for paediatric cancer. Unfortunately, cisplatin treatment causes neuropathic pain, a highly prevalent adverse health related complication in adult childhood cancer survivors. Due to minimal understanding of this condition, there are currently no condition tailored analgesics available. ⋯ Nerve growth factor (NGF) induced TrkA activation led to sensory neuritogenesis and nociceptor sensitisation, which could be prevented through pharmacological TrkA inhibition (GW441756 either s.c. 100 nM or i.p. 2 mg/kg). Administration of TrkA antagonist suppressed cisplatin induced TRPV1 mediated nociceptor sensitisation and prevented cisplatin induced neuropathic pain. These studies provide greater understanding of the underlying mechanisms that cause cisplatin induced childhood cancer survivorship pain and allowing identification of potential therapeutic targets.
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Long-term potentiation (LTP) impairment has been reported in many studies of autistic models. The aim of the present study was to investigate the effects of interval training (IT) and continuous training (CT) exercises on LTP in the hippocampal dentate gyrus (DG) neurons of valproic acid (VPA) rat model of autism. To induce an autism-like model, pregnant rats were injected 500 mg/kg NaVPA (intraperitoneal) on the embryonic day 12.5. ⋯ CT exercise training (but not IT) increased LTP in VPA-exposed male offspring. Both IT and CT exercise trainings had no effect on intact LTP in VPA-exposed female offspring. Our work suggests that there may be differences in the benefits of exercise interventions based on sex, and CT exercise training could be more beneficial for LTP improvements.