Neuroscience
-
Mitochondrial oxidative stress is one of the characteristics of secondary brain injury (SBI) after intracerebral hemorrhage (ICH), contributing largely to the apoptosis of neurons. Celastrol, a quinone methide triterpene that possesses antioxidant and mitochondrial protective properties, has emerged as a neuroprotective agent. However, the activity of celastrol has not been tested in ICH-induced SBI. ⋯ In view of this, by culturing OPA1-deficient primary neurons and constructing neuron-specific OPA1 conditional knockout mice, we found that the protective effects of celastrol on mitochondrial morphology and function after ICH were counteracted in the absence of OPA1. Further experiments also showed that OPA1 is indispensable for the protective effects of celastrol on ICH-induced secondary brain injury. In summary, we have demonstrated that celastrol is a potential drug for the treatment of ICH and have revealed a novel mechanism by which celastrol exerts its antioxidant effects by promoting OPA1-mediated mitochondrial fusion.
-
Hypoxia-induced anapyrexia is thought to be a regulated decrease in body core temperature (Tcore), but the underlying mechanism remains unclear. Recent evidence suggests that lactate, a glycolysis product, could modulate neuronal excitability through the G protein-coupled receptor 81 (GPR81). The present study aims to elucidate the role of central lactate and GPR81 in a rat model of hypoxia-induced anapyrexia. ⋯ The number of c-Fos+ cells in the PO/AH increased after exposure to 11.1% O2 for 2 h, but administration of DCA to the 3 V blunted this response. Injection of CHBA to the 3 V also increased the number of c-Fos+ cells in the PO/AH under normoxia. In light of these, our research has uncovered the pivotal role of central lactate-GPR81 signaling in anapyrexia, thereby providing novel insights into the mechanism of hypoxia-induced anapyrexia.
-
The primary motor cortex (M1) receives dopaminergic (DAergic) projections from the midbrain which play a key role in modulating motor and cognitive processes, such as motor skill learning. However, little is known at the level of individual neurons about how dopamine (DA) and its receptors modulate the intrinsic properties of the different neuronal subpopulations in M1 and if this modulation depends on age. ⋯ Then, combining whole-cell patch-clamp recordings and pharmacology, we explored ex vivo in young and adult mice the impact of activation or blockade of D1 receptors on D1+ PN intrinsic properties. While the bath application of the D1 receptor agonist induced an increase in the excitability of layer V PNs both in young and adult, we identified a distinct modulation of intrinsic electrical properties of layer V D1+ PNs by D1 receptor antagonist depending on the age of the animal.
-
The first synapses of the afferents of peripheral chemoreceptors are located in the Nucleus Tractus Solitarius (NTS) and there is evidence that short-term sustained hypoxia (SH - 24 h, FiO2 0.1) facilitates glutamatergic transmission in NTS neurons of rats. Adenosine is an important neuromodulator of synaptic transmission and hypoxia contributes to increase its extracellular concentration. The A2A receptors mediate the excitatory actions of adenosine and are active players in the modulation of neuronal networks in the NTS. ⋯ SH increased the amplitude of evoked glutamatergic currents of NTS neurons from WT mice by a non-presynaptic mechanism, but this enhancement was not observed in NTS neurons of A2AKO mice. Under normoxia, the amplitude of evoked glutamatergic currents was similar between WT and A2AKO mice. The data indicate that A2A receptors (a) modulate spontaneous glutamatergic currents, (b) do not modulate the evoked glutamatergic transmission in the NTS neurons under control conditions, and (c) are required for the enhancement of glutamatergic transmission observed in the NTS neurons of mice submitted to SH.