Sungkun Chun

Resilience requires neural systems that mobilise active coping during stress while limiting its persistence to preserve homeostasis under sustained challenge ^1–4 . Here we identify a self-limiting orexin–habenula circuit in which lateral hypothalamic orexin neurons engage aromatic L-amino acid decarboxylase-expressing D-neurons (encoded by Ddc ) in the lateral habenula via orexin receptor type 2 (OX2R) ^5–7 . Activation of this pathway increased nucleus accumbens dopamine and promoted active coping and positive valence. Optotagging revealed rapid stress-evoked recruitment followed by post-stress suppression. In lateral habenula neurons, orexin peptides exerted dissociable effects: orexin-A engaged an OX2R-dependent inhibitory programme superimposed on a parallel inward current, whereas orexin-B did not reproduce this inhibitory profile and instead exerted a distinct membrane effect. Chronic stress disrupted this buffering system through coordinated inflammatory activation, promoter methylation and erosion of D-neuron identity and orexin responsiveness. Restoring orexin-A reversed behavioural and molecular deficits through OX2R-dependent suppression of nuclear factor kappa B signalling, preservation of Tet2 expression, and demethylation-linked maintenance of the Ddc programme. Together, these findings define a self-limiting orexin–habenula resilience circuit that enables adaptive coping while constraining stress-induced vulnerability.

Bioactive WG@DOX microparticles integrate NIR-triggered drug delivery and photothermal therapy with osteoinductive properties for synergistic osteosarcoma treatment and bone regeneration.

Thi-Hung Le, Ling Li, Fatima Zahra Rami, Jung-Mi Oh, Sungkun Chun, Young-Chul Chung. Clin Psychopharmacol Neurosci 2025;23:110-9. https://doi.org/10.9758/cpn.24.1212

The concurrent use of hyperthermia and chemotherapy has attracted considerable interest in the in situ treatment of cancer after surgical resection. In this study, poly(ε-caprolactone) (PCL) is embedded with iron oxide nanoparticles (IONPs) and ammonium bicarbonate pH-responsive moieties that conjugate with the DOX anticancer drug incorporated into the core of nanofibers. The synthesized composite nanofibers were characterized using FESEM, EDS, FTIR, and XRD analyses. The composite nanofibers display a temperature increase in a concentration dependant manner with IONPs using an FLIR camera under AMF excitation. The main advantage of our scaffold is that it can be directly implanted in the tumor site, thus ensuring high IONP loading and higher magnetic response. When exposed to the characteristic acidic pH of tumor tissues, the ammonium bicarbonate pH-responsive moieties dissociate, releasing the DOX, and intelligently convert the pH-triggered drug release into a tumor-triggered drug release. Simultaneously, the hyperthermal capability of the IONPs in the nanofibers, generated by applying an alternating magnetic field (AMF), results in localized heating of the tumor tissues and hence synergistic tumoricidal activities. In vitro cytotoxicity experiments further confirmed that PIAD composite nanofiber mats showed an enhanced inhibitory effect against MCF7 cells by the combination of hyperthermia and chemotherapy. Therefore, the magnetic polymeric nanofibers produced by electrospinning provide a promising controlled drug delivery nanosystem for postsurgical breast cancer treatment.

Obesity, as a major cause of many chronic diseases such as diabetes, cardiovascular disease, and cancer, is among the most serious health problems. Increased monoamine oxidase (MAO) activity has been observed in the adipose tissue of obese humans and animals. Although previous studies have already demonstrated the potential of MAO-B inhibitors as a treatment for this condition, the mechanism of their effect has been insufficiently elucidated. In this study, we investigated the anti-obesity effect of selegiline, a selective MAO-B inhibitor, using in vivo animal models. The effect was evaluated through an assessment of body energy homeostasis, glucose tolerance tests, and biochemical analysis. Pharmacological inhibition of MAO-B by selegiline was observed to reduce body weight and fat accumulation, and improved glucose metabolism without a corresponding change in food intake, in HFD-fed obese mice. We also observed that both the expression of adipogenenic markers, including C/EBPα and FABP4, and lipogenic markers such as pACC were significantly reduced in epididymal white adipose tissues (eWATs). Conversely, increased expression of lipolytic markers such as ATGL and pHSL and AMPK phosphorylation were noted. Treating obese mice with selegiline significantly increased expression levels of UCP1 and promoted eWAT browning, indicating increased energy expenditure. These results suggest that selegiline, by inhibiting MAO-B activity, is a potential anti-obesity treatment.

Thi-Hung Le, Jung-Mi Oh, Fatima Zahra Rami, Ling Li, Sung-Kun Chun, Young-Chul Chung. Clin Psychopharmacol Neurosci -0001;0:. https://doi.org/10.9758/cpn.23.1077

Stress management is necessary for vertebrate survival. Chronic stress drives depression by excitation of the lateral habenula (LHb), which silences dopaminergic neurons in the ventral tegmental area (VTA) via GABAergic neuronal projection from the rostromedial tegmental nucleus (RMTg). However, the effect of acute stress on this LHb-RMTg-VTA pathway is not clearly understood. Here, we used fluorescent in situ hybridisation and in vivo electrophysiology in mice to show that LHb aromatic l-amino acid decarboxylase-expressing neurons (D-neurons) are activated by acute stressors and suppress RMTg GABAergic neurons via trace aminergic signalling, thus activating VTA dopaminergic neurons. We show that the LHb regulates RMTg GABAergic neurons biphasically under acute stress. This study, carried out on male mice, has elucidated a molecular mechanism in the efferent LHb-RMTg-VTA pathway whereby trace aminergic signalling enables the brain to manage acute stress by preventing the hypoactivity of VTA dopaminergic neurons.