Activation of microglial cells is presumed to play a key role in the pathogenesis of Parkinson's disease (PD). The activity of microglia is regulated by the histamine-4 receptor (H4R), thus providing a novel target to prevent the progression of PD. However, this putative mechanism has so far not been validated. In our previous post-mortem study, we found that mRNA expression of H4R was upregulated in the basal ganglia of PD patients. In the present study, we found indeed an upregulation of microglia associated inflammation markers from microarray data of the substantia nigra pars compacta (SNpc) of PD patients. We validated the mechanism underlying our human PD results using the rotenone-induced PD rat model, in which the expression of H4R and microglial markers mRNA were significantly increased in the SNpc. Inhibition of H4R in rotenone-induced rats by infusion of the specific H4R antagonist JNJ7777120 into the left lateral ventricle blocked microglial activation, reduced apomorphine-induced rotational behaviour, and prevented dopaminergic neuron degeneration and associated decreases in striatal dopamine levels. These changes were accompanied by a reduction of Lewy body-like neuropathology. Our results provide first proof of the efficacy of an H4R antagonist in a commonly used 3 PD rat model, and provides a lead for a promising therapeutic strategy aimed at modifying H4R activation to clinically tackle microglial activation and thereby the progression of PD.

studies from other species 12,13 , we have freely released all data and the generated code.

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Task-free functional connectivity in animal models provides an experimental framework to examine connectivity phenomena under controlled conditions and allows comparison with invasive or terminal procedures. To date, animal acquisitions are performed with varying protocols and analyses that hamper result comparison and integration. We introduce StandardRat, a consensus rat functional MRI acquisition protocol tested across 20 centers. To develop this protocol with optimized acquisition and processing parameters, we initially aggregated 65 functional imaging datasets acquired in rats from 46 centers. We developed a reproducible pipeline for the analysis of rat data acquired with diverse protocols and determined experimental and processing parameters associated with a more robust functional connectivity detection. We show that the standardized protocol enhances biologically plausible functional connectivity patterns, relative to pre-existing acquisitions. The protocol and processing pipeline described here are openly shared with the neuroimaging community to promote interoperability and cooperation towards tackling the most important challenges in neuroscience.

Epidemiological researches have demonstrated the relationship between PM 2.5 exposure and increased morbidity and mortality of cardiovascular injury. However, no effective therapeutic method was established. The purpose of this study is to investigate the effect of acute PM 2.5 exposure on the mice heart tissue and explore the therapeutic effects of compound essential oils (CEOs) in this model. In this study, after mice were exposed to PM 2.5 intratracheally, some obvious histopathological changes as well as some great alterations of proinflammatory cytokines were observed in the heart tissue. The imbalance of oxidative stress, the altered Ca 2+ channel related proteins and the increased intracellular free Ca 2+ were all involved in the heart impairment and would also be investigated in this model. The CEOs alleviated the heart impairment via its antioxidant effect rather than its anti-inflammatory function because our results revealed that oxidative stress related indicators were restored after CEOs administration. At the same time, increased concentration of intracellular free Ca 2+ and ROS induced by PM 2.5 were reduced after NAC (N-Acetyl-L-cysteine) administration. These data suggested that the acute PM 2.5 exposure would damage heart tissue by inducing the inflammatory response, oxidative stress and intracellular free Ca 2+ overload. PM 2.5 -induced oxidative stress probably increase intracellular free Ca 2+ via RYR2 and SERCA2a. CEOs have the potential to be a novel effective and convenient therapeutic method to prevent and treat the acute heart impairment induced by PM 2.5 via its antioxidant function.