Neuroscience
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The Ventral Tegmental Area (VTA) contains a considerable population of rhythmically firing dopaminergic neurons, which are influenced by auto-inhibition due to extra-synaptic dopamine release resulting in volume transmission. Using a Multi-Electrode-Array we simultaneously recorded in vitro from multiple VTA dopamine neurons in the rat and studied their mutual interactions. We observed that the dopamine sensitivity (EC50) of the neurons (i.e. the relation between dopamine concentration and firing rate) was quite variable within the recorded population. ⋯ Highly sensitive neurons became followers (of the population rhythm), whereas less sensitive dopamine neurons played a more leading role. This was confirmed by the application of sulpiride which reduces the dopamine sensitivity of all neurons through competition and abolishes the structure in the interactions. These findings imply that therapeutics, which have an easy to understand effect on firing rate, could have a more complicated effect on the functional organization of the local VTA population, through volume transmission principles.
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Repeated use of opioids can lead to the development of analgesic tolerance and dependence. Additionally, chronic opioid exposure can cause a paradoxical emergence of heightened pain sensitivity to noxious stimuli, termed hyperalgesia, which may drive continued or escalated use of opioids to manage worsening pain symptoms. Opioid-induced hyperalgesia has traditionally been measured in rodents via reflex-based assays, including the von Frey method. ⋯ We next investigated individual relationships between pain avoidance-like behavior and alterations in protein phosphorylation in central motivation-related brain areas. We discovered that pain avoidance-like behavior was significantly correlated with alterations in phosphorylation status of protein kinases (ERK, CaMKII), transcription factors (CREB), presynaptic markers of neurotransmitter release (Synapsin), and the rate-limiting enzyme for dopamine synthesis (TH) across specific brain regions. Our findings suggest that alterations in phosphorylation events in specific brain centers may support cognitive/motivational responses to avoid pain.
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Although inflammation-induced peripheral sensitization oftentimes resolves as an injury heals, this sensitization can be pathologically maintained and contribute to chronic inflammatory pain. Numerous inflammatory mediators increase the production of reactive oxygen (ROS) and nitrogen species (RNS) during inflammation and in animal models of chronic neuropathic pain. Our previous studies demonstrate that ROS/RNS and subsequent DNA damage mediate changes in neuronal sensitivity induced by anticancer drugs and by ionizing radiation in sensory neurons, thus we investigated whether inflammation and inflammatory mediators also could cause DNA damage in sensory neurons and whether that DNA damage alters neuronal sensitivity. ⋯ Genetically enhancing the expression of the DNA repair enzyme, apurinic/apyrimidinic endonuclease (APE1) or treatment with a small-molecule modulator of APE1 DNA repair activity, both which enhance DNA repair, attenuated DNA damage and the changes in neuronal sensitivity elicited by LPS or MCP-1. In conclusion, our studies demonstrate that inflammation or exposure to inflammatory mediators elicits DNA damage in sensory neurons. By enhancing DNA repair, we demonstrate that this DNA damage mediates the alteration of neuronal function induced by inflammatory mediators in peptidergic sensory neurons.
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Sirtuin 6 (SIRT6), a member of the sirtuin family of NAD(+)-dependent deacetylases, has been shown to produce beneficial effects in myocardial ischemia/reperfusion (I/R). However, the role of SIRT6 in cerebral I/R is largely unclear. In this study, we investigated the effects of SIRT6 overexpression in regulating I/R injury in a mouse cerebral I/R model in vivo and in oxygen-glucose-deprivation/reoxygenation (OGD/R)-stimulated neuro-2a neuroblastoma cells in vitro. ⋯ Moreover, in OGD/R-stimulated neuro-2A cells, SIRT6 overexpression produced similar protective effects to those induced by the antioxidant NAC, but no added benefits were detected when SIRT6 overexpression was used in combination with NAC (P > 0.05). These findings provide evidence that SIRT6 can protect the brain from cerebral I/R injury by suppressing oxidative stress via NRF2 activation. Thus, SIRT6 may serve as a potential therapeutic target for ischemic stroke.
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The regions of the olfactory epithelium affected by hydrogen sulfide (H2S) toxicity in the rat present a striking similarity with the developmental olfactory zone 1 described in the mouse. This zone which is the only region containing neurons expressing NAD(P)H quinone dehydrogenase 1 (NQO1) is involved in complex behavioral responses in rodents, and other mammals, triggered by specific olfactory stimuli. We therefore sought to determine whether (1) olfactory neurons expressing NQO1 are located in the same regions in the rats and in the mice and (2) there is an overlap between olfactory neurons expressing this protein and those affected by the toxicity of H2S. ⋯ The degree of agreement or overlap between these two populations of neurons (necrosis vs. NQO1 expression) reached 80.2%. Although the underlying mechanisms accounted for the high sensitivity for NQO1 neurons -or the relative protection of non NQO1 neurons- to sulfide toxicity remain to be established, this observation is offering an intriguing approach that could be used to acutely suppress the pool of neural cells in olfactory zone I and to understand the mechanisms of toxicity and protection of other populations of neurons exposed to sulfide.