Hypothalamic neuropeptide orexin has been implicated in the pathophysiology of psychiatric disorders and accumulating clinical evidence indicates a potential link between orexin and depression. However, the exact role of orexin in depression, particularly the underlying neural substrates and mechanisms, remains unknown. In this study, we reveal a direct projection from the hypothalamic orexinergic neurons to the ventral pallidum (VP), a structure that receives an increasing attention for its critical position in rewarding processing, stress responses, and depression. We find that orexin directly excites GABAergic VP neurons and prevents depressive-like behaviors in rats. Two orexin receptors, OX1R and OX2R, and their downstream Na-Ca exchanger and L-type Ca channel co-mediate the effect of orexin. Furthermore, pharmacological blockade or genetic knockdown of orexin receptors in VP increases depressive-like behaviors in forced swim test and sucrose preference test. Intriguingly, blockage of orexinergic inputs in VP has no impact on social proximity in social interaction test between novel partners, but remarkably strengthens social avoidance under an acute psychosocial stress triggered by social rank. Notably, a significantly increased orexin level in VP is accompanied by an increase in serum corticosterone in animals exposed to acute stresses, including forced swimming, food/water deprivation and social rank stress, rather than non-stress situations. These results suggest that endogenous orexinergic modulation on VP is especially critical for protecting against depressive reactions to stressful events. The findings define an indispensable role for the central orexinergic system in preventing depression by promoting stress resilience.

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Background:Emerging data have demonstrated that peroxisome proliferator-activated receptor δ (PPARδ) activation confers a potentially neuroprotective role in some neurodegenerative diseases. However, whether PPARδ is involved in depression is unknown.Methods:In this study, PPARδ was firstly investigated in the chronic mild stress (CMS) and learned helplessness (LH) models of depression. The changes in depressive behaviors and hippocampal neurogenesis were investigated after PPARδ overexpression by microinfusion of the lentiviral vector, containing the coding sequence of mouse PPARδ (LV-PPARδ), into the bilateral dentate gyri of the hippocampus or PPARδ activation by repeated systemic administration of PPARδ agonist GW0742 (5 or 10mg/kg.d, i.p., for 21 d).Results:We found that both CMS and LH resulted in a significant decrease in the PPARδ expression in the hippocampi of mice, and this change was reversed by treatment with the antidepressant fluoxetine. PPARδ overexpression and PPARδ activation each suppressed the CMS- and LH-induced depressive-like behavior and produced an antidepressive effect. In vivo or in vitro studies also showed that both overexpression and activation of PPARδ enhanced proliferation or differentiation of neural stem cells in the hippocampi of mice.Conclusions:These results suggest that hippocampal PPARδ upregulation represses stress-induced depressive behaviors, accompanied by enhancement of neurogenesis.

It has been acknowledged that circulating tumor cells (CTCs) are promising biomarkers in liquid biopsy for cancer diagnosis and prognosis. However, the relationship between the CTC number and gastric cancer has scarcely been quantitatively investigated. Moreover, the single criterion of epithelial cell adhesion molecule (EpCAM) antibody/aptamer to specifically recognize epithelial CTCs cannot be universally applied for clinical applications, as it fails to recognize EpCAM-negative CTCs. Herein, we propose simple, low-cost, dual-aptamer (EpCAM and PTK7)modified immunomagnetic Fe 3 O 4 particles (IMNs) for efficient capture of heterogeneous CTCs and downstream analysis in gastric cancer patients. High PTK7 expression and a significant negative correlation between PTK7 and EpCAM expression were observed in primary gastric cancer tissues. Taking MGC-803 and BGC-823 cells as CTC models, the obtained dual-targeting IMNs could distinguishably recognize these cells with both high or low EpCAM and PTK7 expressions, which enhanced the accuracy of CTC recognition in gastric cancer. More than 95% of these two kinds of cells could be captured within 20 min of incubation, which was significantly more efficient than that of single EpCAM-or PTK7-modified IMNs. With this strategy, as low as five CTCs could be captured from phosphate-buffered saline (PBS), a cell mixture containing THP-1 cells, and lysed blood mediums. Moreover, the obtained CTCs can be used for subsequent gene analysis. Finally, the fabricated IMNs were successfully applied for CTC capture in 1.0 mL of peripheral blood samples from patients with gastric cancer. The detected CTC numbers in 72 participants were found to have close relationships with chemotherapy sensitivity, diagnosis, stage, and distant metastasis of patients. This work provides important references for further investigations on CTC-related diagnosis and individualized treatment.

The ventral pallidum (VP) is a crucial component of the limbic loop of the basal ganglia and participates in the regulation of reward, motivation, and emotion. Although the VP receives afferent inputs from the central histaminergic system, little is known about the effect of histamine on the VP and the underlying receptor mechanism. Here, we showed that histamine, a hypothalamic-derived neuromodulator, directly depolarized and excited the GABAergic VP neurons which comprise a major cell type in the VP and are responsible for encoding cues of incentive salience and reward hedonics. Both postsynaptic histamine H1 and H2 receptors were found to be expressed in the GABAergic VP neurons and co-mediate the excitatory effect of histamine. These results suggested that the central histaminergic system may actively participate in VP-mediated motivational and emotional behaviors via direct modulation of the GABAergic VP neurons. Our findings also have implications for the role of histamine and the central histaminergic system in psychiatric disorders.