Lateral septum adenosine A2A receptors control stress-induced depressive-like behaviors via signaling to the hypothalamus and habenula.

Major depressive disorder ranks as a major burden of disease worldwide, yet the current antidepressant medications are limited by frequent non-responsiveness and significant side effects. The lateral septum (LS) is thought to control of depression, however, the cellular and circuit substrates are largely unknown. Here, we identified a subpopulation of LS GABAergic adenosine A2A receptors (A2AR)-positive neurons mediating depressive symptoms via direct projects to the lateral habenula (LHb) and the dorsomedial hypothalamus (DMH). Activation of A2AR in the LS augmented the spiking frequency of A2AR-positive neurons leading to a decreased activation of surrounding neurons and the bi-directional manipulation of LS-A2AR activity demonstrated that LS-A2ARs are necessary and sufficient to trigger depressive phenotypes. Thus, the optogenetic modulation (stimulation or inhibition) of LS-A2AR-positive neuronal activity or LS-A2AR-positive neurons projection terminals to the LHb or DMH, phenocopied depressive behaviors. Moreover, A2AR are upregulated in the LS in two male mouse models of repeated stress-induced depression. This identification that aberrantly increased A2AR signaling in the LS is a critical upstream regulator of repeated stress-induced depressive-like behaviors provides a neurophysiological and circuit-based justification of the antidepressant potential of A2AR antagonists, prompting their clinical translation.

Tanshinone IIA reduces the risk of Alzheimer's disease by inhibiting iNOS, MMP­2 and NF­κBp65 transcription and translation in the temporal lobes of rat models of Alzheimer's disease.

Tanshinone IIA (Tan IIA), one of the major active constituents of the medicinal herb Salvia miltiorrhiza, has been reported to possess neuroprotective effects against the pathological features of Alzheimer's disease (AD), but the molecular mechanism underlying this effect remains unclear. To examine the effect of Tan IIA on AD, as well as the underlying molecular mechanisms, in vivo animal experiments and in vitro molecular biology investigations were employed in the present study. Firstly, a rat model of AD was successfully established by direct injection of the amyloid beta protein (Aß) and then these rats were administered an interventional treatment of Tan IIA. The learning and memory ability of rats was evaluated in four groups (Control, Sham, AD and Tan IIA) utilizing a Morris water maze test. Quantitative (q)PCR was employed to detect the mRNA expression of inducible nitric oxide synthase (iNOS), matrix metalloproteinase­2 (MMP­2) and nuclear transcription factor kappa (NF­κBp65) in temporal lobe tissues and protein expression was determined with western blot analysis. In addition, association analyses between iNOS, MMP­2 and NF­κBp65 at a transcriptional and translational level were performed utilizing Spearman's correlation analysis. In the present study, the results revealed that rats in the AD group demonstrated significant disruptions in learning and memory ability, and the symptoms were evidently reduced by Tan IIA. Furthermore, the upregulation of iNOS, MMP­2 and NF­κBp65 at a transcriptional and translational level in AD rats was distinctly inhibited by Tan IIA. Therefore, it was concluded that iNOS, MMP­2 and NF­κBp65 are involved in AD development, and Tan IIA may reduce AD risk by inhibiting transcription and translation of these genes. Furthermore, the positive correlation of iNOS and MMP­2 with NF­κBp65, respectively, provides evidence supporting the hypothesis that Tan IIA reduces AD risk by inhibiting iNOS and MMP­2 at a transcriptional and translational level through the NF­κB pathway. In summary, Tan IIA is an effective neuroprotective agent for AD therapy, and iNOS, MMP­2 and NF­κBp65 may be the potential molecular targets for manipulating this effect therapeutically.

P2X receptors are expressed on neurons containing luteinizing hormone-releasing hormone in the mouse hypothalamus.

Expression of P2X(1), P2X(2), P2X(3), P2X(4), P2X(5) and P2X(6) receptors, members of a family of ATP-gated cation channels, on neurons containing luteinizing hormone-releasing hormone (LHRH) in the mouse hypothalamus was studied with double-labeling fluorescence immunohistochemistry. This study demonstrated that different combinations of P2X receptor subunits were expressed on the perikarya and axon terminals of LHRH-producing neurons. It was shown for the first time that P2X(2), P2X(4), P2X(5) and P2X(6) receptor subunits were expressed on the perikarya of LHRH-producing neurons and P2X(2) and P2X(6) on their axon terminals. These results suggest that activation of P2X receptors by ATP via different homomeric or heteromeric P2X receptors at both presynaptic and postsynaptic sites could be involved in the regulation of LHRH secretion at the forebrain level.

P2X5 receptors are expressed on neurons containing arginine vasopressin and nitric oxide synthase in the rat hypothalamus.

In this study, the P2X(5) receptor was found to be distributed widely in the rat hypothalamus using single and double labeling immunofluorescence and reverse transcriptase-polymerase chain reaction (RT-PCR) methods. The regions of the hypothalamus with the highest expression of P2X(5) receptors in neurons are the paraventricular and supraoptic nuclei. The intensity of P2X(5) immunofluorescence in neurons of the ventromedial nucleus was low. 70-90% of the neurons in the paraventricular nucleus and 46-58% of neurons in the supraoptic and accessory neurosecretory nuclei show colocalization of P2X(5) receptors and arginine vasopressin (AVP). None of the neurons expressing P2X(5) receptors shows colocalization with AVP in the suprachiasmatic and ventromedial nuclei. 87-90% of the neurons in the lateral and ventral paraventricular nucleus and 42-56% of the neurons in the accessory neurosecretory, supraoptic and ventromedial nuclei show colocalization of P2X(5) receptors with neuronal nitric oxide synthase (nNOS). None of the neurons expressing P2X(5) receptors in the suprachiasmatic nucleus shows colocalization with nNOS. These findings provide a morphological basis for possible functional interactions between the purinergic and nitrergic or vasopressinergic neurotransmitter systems.