Lateral habenula IL-10 controls GABAA receptor trafficking and modulates depression susceptibility after maternal separation.

Maternal separation (MS), a form of early life adversity, increases the risk of psychiatric disorders in adulthood by intricately linking cytokines and mood-regulating brain circuits. The Lateral Habenula (LHb) encodes aversive experiences, contributes to negative moods, and is pivotal in depression development. However, the precise impact of MS on LHb cytokine signaling and synaptic plasticity remains unclear. We reported that adolescent MS offspring mice displayed susceptibility to depression behavioral phylotypes, with neuronal hyperactivity and an imbalance in pro-inflammatory and anti-inflammatory cytokines in the LHb. Moreover, the decreased IL-10 level negatively correlated with depressive-like behaviors in susceptible mice. Functionally, LHb IL-10 overexpression restored decreased levels of PI3K, phosphorylated AKT (pAKT), gephyrin, and membrane GABAA receptor proteins while reducing abnormally elevated GSK3ß and Fos expression, rescuing the MS-induced depression. Conversely, LHb neuronal IL-10 receptor knockdown in naive mice increased Fos expression and elicited depression-like symptoms, potentially through impaired membrane GABAA receptor trafficking by suppressing the PI3K/pAKT/gephyrin cascades. Hence, this work establishes a mechanism by which MS promotes susceptibility to adolescent depression by impeding the critical role of IL-10 signaling on neuronal GABAA receptor function.

Association between RMTg Neuropeptide Genes and Negative Effect during Alcohol Withdrawal in Mice.

Alcohol use disorders (AUDs) frequently co-occur with negative mood disorders, such as anxiety and depression, exacerbating relapse through dopaminergic dysfunction. Stress-related neuropeptides play a crucial role in AUD pathophysiology by modulating dopamine (DA) function. The rostromedial tegmental nucleus (RMTg), which inhibits midbrain dopamine neurons and signals aversion, has been shown to increase ethanol consumption and negative emotional states during abstinence. Despite some stress-related neuropeptides acting through the RMTg to affect addiction behaviors, their specific roles in alcohol-induced contexts remain underexplored. This study utilized an intermittent voluntary drinking model in mice to induce negative effect behavior 24 h into ethanol (EtOH) abstinence (post-EtOH). It examined changes in pro-stress (Pnoc, Oxt, Npy) and anti-stress (Crf, Pomc, Avp, Orx, Pdyn) neuropeptide-coding genes and analyzed their correlations with aversive behaviors. We observed that adult male C57BL/6J mice displayed evident anxiety, anhedonia, and depression-like symptoms at 24 h post-EtOH. The laser-capture microdissection technique, coupled with or without retrograde tracing, was used to harvest total ventral tegmental area (VTA)-projecting neurons or the intact RMTg area. The findings revealed that post-EtOH consistently reduced Pnoc and Orx levels while elevating Crf levels in these neuronal populations. Notably, RMTg Pnoc and Npy levels counteracted ethanol consumption and depression severity, while Crf levels were indicative of the mice's anxiety levels. Together, these results underscore the potential role of stress-related neuropeptides in the RMTg in regulating the negative emotions related to AUDs, offering novel insights for future research.

Brachial Plexus Root Avulsion Injury-Induced Endothelin-Converting Enzyme-Like 1 Overexpression Is Associated with Injured Motor Neurons Survival.

Brachial plexus root avulsion (BPRA) injury arises from challenging delivery during childbirth, sports-related incidents, or car accidents, leading to extensive loss of motor neurons (MNs) and subsequent paralysis, including both motor and sensory impairment. Surgical nerve re-implantation cannot effectively restore motor function, and the survival of injured MNs is vital for axon regeneration and re-innervating the target muscles. Therefore, identifying novel molecular targets to improve injured MNs survival is of great significance in the treatment of BPRA injuries. Endothelin-converting enzyme-like 1 (ECEL1), a membrane-bound metallopeptidase, was initially identified as a molecule associated with nerve injuries. Damaged neurons exhibit a significant increase in the expression of ECEL1 following various types of nerve injuries, such as optic nerve injury and sciatic nerve injury. This study aimed to investigate the relationship between ECEL1 overexpression and the survival of injured MNs following BPRA injury. Our results observed a significant elevation in ECEL1 expression in injured MNs and positively correlated with MNs survival following BPRA injury. The transcription of ECEL1 is regulated by the transcription factors c-Jun and ATF3 in the context of BPRA injury, which is consistent with previous other nerve injuries study. In addition, the expression of TrkA gradually decreases in ECEL1-positive MNs and ECEL1 possibly preserves the activity of downstream AKT-GSK3ß pathway of TrkA in injured MNs. In conclusion, our results introduce a promising therapeutic molecular target to assist re-implantation surgery for the treatment of BPRA injury.

LPA1 receptors in the lateral habenula regulate negative affective states associated with alcohol withdrawal.

The role of lysophosphatidic acid (LPA) signaling in psychiatric disorders and drug abuse is significant. LPA receptors are widely expressed in the central nervous system, including the lateral habenula (LHb). Recent studies suggest that LHb is involved in a negative emotional state during alcohol withdrawal, which can lead to relapse. The current study examines the role of LHb LPA signaling in the negative affective state associated with alcohol withdrawal. Adult male Long-Evans rats were trained to consume either alcohol or water for eight weeks. At 48 h of withdrawal, alcohol-drinking rats showed anxiety- and depression-like symptoms, along with a significant increase in LPA signaling and related neuronal activation molecules, including autotaxin (ATX, Enpp2), LPA receptor 1/3 (LPA1/3), ßCaMKII, and c-Fos. However, there was a decrease in lipid phosphate phosphatase-related protein type 4 (LPPR4) in the LHb. Intra-LHb infusion of the LPA1/3 receptor antagonist ki-16425 or PKC-γ inhibitor Go-6983 reduced the abnormal behaviors and elevated relapse-like ethanol drinking. It also normalized high LPA1/3 receptors and enhanced AMPA GluA1 phosphorylation in Ser831 and GluA1/GluA2 ratio. Conversely, selective activation of LPA1/3 receptors by intra-LHb infusion of 18:1 LPA induced negative affective states and upregulated ßCaMKII-AMPA receptor phosphorylation in Naive rats, which were reversed by pretreatment with intra-LHb Go-6983. Our findings suggest that disturbances in LPA signaling contribute to adverse affective disorders during alcohol withdrawal, likely through PKC-γ/ßCaMKII-linked glutamate signaling. Targeting LPA may therefore be beneficial for individuals suffering from alcohol use disorders.

Rostromedial tegmental nucleus nociceptin/orphanin FQ (N/OFQ) signaling regulates anxiety- and depression-like behaviors in alcohol withdrawn rats.

Recent studies indicate that stimulation of the rostromedial tegmental nucleus (RMTg) can drive a negative affective state and that nociceptin/orphanin FQ (N/OFQ) may play a role in affective disorders and drug addiction. The N/OFQ precursor prepronociceptin encoding genes Pnoc are situated in RMTg neurons. To determine whether N/OFQ signaling contributes to the changes in both behavior phenotypes and RMTg activity of alcohol withdrawn (Post-EtOH) rats, we trained adult male Long-Evans rats, randomly assigned into the ethanol and Naïve groups to consume either 20% ethanol or water-only under an intermittent-access procedure. Using the fluorescence in situ hybridization technique combined with retrograde tracing, we show that the ventral tegmental area projecting RMTg neurons express Pnoc and nociceptin opioid peptide (NOP) receptors encoding gene Oprl1. Also, using the laser capture microdissection technique combined with RT-qPCR, we detected a substantial decrease in Pnoc but an increase in Oprl1 mRNA levels in the RMTg of Post-EtOH rats. Moreover, RMTg cFos expression is increased in Post-EtOH rats, which display anxiety- and depression-like behaviors. Intra-RMTg infusion of the endogenous NOP agonist nociceptin attenuates the aversive behaviors in Post-EtOH rats without causing any notable change in Naïve rats. Conversely, intra-RMTg infusion of the NOP selective antagonist [Nphe1]nociceptin(1-13)NH2 elicits anxiety- and depression-like behaviors in Naïve but not Post-EtOH rats. Furthermore, intra-RMTg infusion of nociceptin significantly reduces alcohol consumption. Thus, our results show that the deficiency of RMTg NOP signaling during alcohol withdrawal mediates anxiety- and depression-like behaviors. The intervention of NOP may help those individuals suffering from alcohol use disorders.