Tobacco smoking is the leading cause of preventable death and disease. Although there are some FAD-approved medicines for controlling smoking, the relapse rate remains very high. Among the factors that could induce nicotine relapse, stress might be the most important one. In the last decades, preclinical studies have generated many new findings that lead to a better understanding of stress-induced relapse of nicotine-seeking. Several molecules such as α3β4 nicotinic acetylcholine receptor, α2-adrenergic receptors, cannabinoid receptor 1, trace amine-associated receptor 1, and neuropeptide systems (corticotropin-releasing factor and its receptors, dynorphine and kappa opioid receptor) have been linked to stress-induced nicotine relapse. In this review, we discuss recent advances in the neurobiology, treatment targets, and potential therapeutics of stress-induced nicotine relapse. We also discuss some factors that may influence stress-induced nicotine relapse and that should be considered in future studies. In the final section, a perspective on some research directions is provided. Further investigation on the neurobiology of stress-induced nicotine relapse will shed light on the development of new medicines for controlling smoking and will help us understand the interactions between the stress and reward systems in the brain.

Circular RNAs (circRNAs) are a unique class of endogenous, single-stranded non-coding RNAs characterized by a covalently closed circular structure. They exhibit tissue-specific expression patterns and have been implicated in the pathogenesis of a wide range of diseases. In the brain, circRNAs are abundantly expressed and evolutionarily conserved, where they play critical roles in neurodevelopment, neuronal differentiation, and synaptic plasticity. Recent studies have revealed that circRNAs are broadly expressed across eukaryotic species and display distinct expression profiles associated with various pathological conditions, particularly neuropsychiatric disorders. However, despite the identification of thousands of circRNAs through high-throughput sequencing technologies, only a small subset has been functionally characterized. In this review, we underscore the emerging significance of circRNAs in neurological and psychiatric disorders. Their exceptional stability and diverse modes of action suggest that circRNAs could serve as key nodes within future precision medicine frameworks. Nevertheless, progress toward clinical translation is currently limited by incomplete mechanistic understanding, small study cohorts, and persistent challenges in therapeutic development. To overcome these barriers, more systematic, large-scale, and mechanism-driven investigations, coupled with innovative strategies and technologies, will be required to fully realize the clinical potential of circRNAs.

Background: The claustrum (CLA), a subcortical area between the insular cortex and striatum, innervates almost all cortical regions of the mammalian brain. There is growing evidence that CLA participates in many brain functions, including memory, cognition, and stress response. It is proposed that dysfunction or malfunction of the CLA might be the pathology of some brain diseases, including stress-induced depression and anxiety. However, the role of the CLA in fear memory and anxiety disorders remains largely understudied.Methods: We evaluated the influences of neurotoxic lesions of the CLA using auditory-cued fear memory and anxiety-like behaviors in rats.Results: We found that lesions of anterior CLA (aCLA) but not posterior CLA (pCLA) before fear conditioning attenuated fear retrieval, facilitated extinction, and reduced freezing levels during the extinction retention test. Post-learning lesions of aCLA but not pCLA facilitated fear extinction and attenuated freezing behavior during the extinction retention test. Lesions of aCLA or pCLA did not affect anxiety-like behaviors evaluated by the open field test and elevated plus-maze test.Conclusion: These data suggested that aCLA but not pCLA was involved in fear memory and extinction. Future studies are needed to further investigate the anatomical and functional connections of aCLA subareas that are involved in fear conditioning, which will deepen our understanding of CLA functions.

Substance use disorder (SUD) represents a substantial challenge in neuropsychiatric medicine, with the molecular mechanisms underlying its etiology remaining elusive. The molecular underpinnings of SUD suggest a pivotal role for circular RNAs (circRNAs) in its pathophysiology. Herein, we present a study on circHomer1, a circRNA enriched in neurons, which is abnormal expression upon cocaine exposure. Employing models of repeated cocaine exposure and conditioning place preference (CPP), alongside virus-mediated gene regulation techniques, we revealed the contribution of circHomer1 in cocaine-induced rewarding effects and synaptic adaptations. We found a notably downregulation of circHomer1 expression in the prelimbic cortex consequent to repeated cocaine exposure in both rat model and patients with cocaine use disorder. Elevation of circHomer1 levels resulted in a pronounced attenuation of cocaine-induced CPP, whereas suppression of circHomer1 expression enhanced the rewarding effects. These outcomes were specifically observed in excitatory neurons, implicating a cell type-specific function of circHomer1. Furthermore, the restoration of circHomer1 rescued the reduction of mushroom-type dendritic spines and rectified deficits in the frequency of spontaneous excitatory postsynaptic currents associated with prolonged cocaine exposure. Mechanistically, circHomer1 appears to modulate cocaine-induced behavioral responses through dopamine D1 receptor signaling pathways. Notably, circHomer1’s behavioral effects showed specificity for psychostimulants (cocaine and methamphetamine), without affecting food- or opioid-associated rewards. Our findings highlight the significant role of circHomer1 in regulating cocaine reward and identify a novel molecular regulator of the actions of cocaine on the brain’s reward circuitry, providing a new strategy for treating drug addiction.

Temporomandibular disorders (TMD) pain is the most common orofacial pain with limited effective treatments. Here, we observed elevated lysophosphatidic acid (LPA), a bioactive lipid, in blood, trigeminal ganglion (TG), and peri-temporomandibular joint (TMJ) tissues in mouse models of TMD-like pain induced by TMJ inflammation or masseter muscle injury. Notably, LPA levels were also elevated in TMD patients’ blood and positively correlated with their pain intensity. LPA receptors (LPAR) 1 and 3 were expressed in mouse and human TG neurons and upregulated in TMD-like pain models. Inhibition or knockout of LPAR1 or LPAR3 attenuated TMD-like pain, while LPA injection into the TMJ or masseter muscle evoked pain. Furthermore, we demonstrated that LPA/LPAR signaling upregulates and sensitizes PIEZO2, a mechanosensitive ion channel, in TG neurons via extracellular signal-regulated kinase (ERK). Specific deletion or inhibition of PIEZO2 and suppression of ERK activation in TG neurons mitigated TMD-like pain. These findings suggest that LPA/LPAR signaling drives TMD-like pain via PIEZO2, offering potential therapeutic targets.