Anxiety and depression are common non-motor symptoms of Parkinson's disease (PD) that significantly affect patients' quality of life. In recent years, our understanding of PD has advanced through multifaceted studies on the pathological mechanisms associated with anxiety and depression in PD. These classic psychiatric symptoms involve complex pathophysiology, with both distinct features and connections to the mechanisms underlying the aetiology of PD. Furthermore, the co-occurrence of anxiety and depression in PD blurs the boundaries between them. Therefore, a comprehensive summary of the pathogenic mechanisms associated with anxiety and depression will aid in better addressing the emergence of these classic psychiatric symptoms in PD. This article integrates neuroanatomical, neural projection, neurotransmitter, neuroinflammatory, brain-gut axis, neurotrophic, hypothalamic-pituitary-adrenal axis, and genetic perspectives to provide a comprehensive description of the core pathological alterations underlying anxiety and depression in PD, aiming to provide an up-to-date perspective and broader therapeutic prospects for PD patients suffering from anxiety or depression.

This multicenter, randomized, placebo-controlled, clinical trial was designed to investigate the efficacy and safety of esketamine (ESK) for smoking cessation. The study enrolled a sample of 236 patients diagnosed with lung cancer and major depression disorder (MDD). Treatment included intranasal delivery of ESK or placebo once a week for 8 sessions. The primary outcomes were self-reported and biologically verified continuous abstinence rates at the end of 6 months follow-up visit. The second outcomes were the severity changes of depression and anxiety. The cognitive function, the nicotine dependence, urge to smoke, respiratory symptoms and adverse events were also examined. We found that 8 sessions of ESK treatments significantly improved the self-reported (44.1 %) and biologically verified (28.8 %) continuous abstinence rates. Additionally, the severity of both depression and anxiety was also significantly relieved by ESK delivery. Furthermore, ESK was capable of improving cognitive function of the participants. Finally, the nicotine dependence, urge to smoke and smoking related respiratory symptoms of ESK group were also alleviated at the completion of follow-up. No serious adverse events were observed throughout the study. This clinical trial provides evidence that ESK treatment is efficacious and safe for quitting cigarette smoking among patients with lung cancer and MDD.

Nicotine stimulates ventral tegmental area (VTA) dopaminergic neurons, producing a rewarding effect that drives tobacco consumption. The interpeduncular nucleus (IPN) is thought to become engaged at high nicotine doses to limit drug intake, but its response dynamics are unknown. We developed a chemogenetic approach using a "suicide" antagonist that selectively attaches to designer β4 nicotinic acetylcholine receptors (nAChRs) in genetically modified mice, enabling sustained and pharmacologically specific antagonism. Local infusion in the IPN revealed that nicotine, even at low doses, simultaneously activates and inhibits two distinct populations of IPN neurons, with β4-containing nAChRs mediating only the activation response. Blocking nicotine-induced IPN activation enhanced VTA responses and increased the drug's rewarding effect in a conditioned place preference paradigm. Moreover, optogenetic inhibition of IPN projections to the laterodorsal tegmental nucleus (LDTg) replicated these behavioral effects. Our findings indicate that the IPN acts as a regulatory brake on the nicotine reward circuit via the LDTg.

Brain defensive mechanisms evolved to maintain low levels of state anxiety. However, risk factors such as stress exposure shifts activity within defensive circuits, resulting in increased anxiety. The amygdala is a crucial node for maintaining adaptive anxiety levels, and amygdala hyperactivity can lead to pathological anxiety through mechanisms that are not well understood.

We used chronic social defeat stress (CSD) in mice. We combined anatomical tracing methods, patch-clamp recordings and optogenetics to probe how synaptic inputs from the ventral tegmental area (VTA) to the basolateral amygdala (BLA) are affected by CSD. We performed in vivo fiber photometry recordings to track inputs onto basolateral amygdala. Array tomography and electron microscopy were used to unravel the structural composition of VTA-BLA synapses.

We identified the VTA as a source of glutamatergic inputs to the BLA potentiated by stress. In turn, inputs from mPFC were not potentiated. BLA-projecting VTA glutamatergic neurons are activated by social stress, increasing their excitability and synaptic strength. In vivo potentiation of VTA glutamatergic inputs in the BLA is sufficient to increase anxiety. We showed that stress-induced synaptic strengthening is mediated by insertion of GluA1-containing AMPA receptors. Impeding GluA1 subunit trafficking in BLA neurons with VTA upstream inputs prevents stress-induced increase in synaptic firing and anxiety.

Potentiation of VTA inputs increases synaptic integration, enhancing amygdala activity and promoting maladaptive anxiety. Understanding the impact of amygdala hyperactivity could lead to targeted therapies, restoring circuit balance and offering new precision medicine approaches for anxiety disorders.

Nicotine is a significant alkaloid that is abundant in tobacco products. Given the addictive nature of tobacco products and the health risks associated with their consumption, accurate real-time monitoring of nicotine levels is necessary. Electrochemical sensors are low-cost and noninvasive devices for detecting various target molecules, even at trace levels, with advantages such as high sensitivity, portability, and fast response time. Nevertheless, reliable electrochemical detection of nicotine is particularly difficult because of the active interferents present in complex sample matrices. Recent advances in electrochemical sensing have focused on the development of chemically modified electrodes that mimic the oxidase activity of cytochrome P450, thereby improving the selectivity and sensitivity of nicotine detection. This paper discusses several innovative materials and strategies for the practical detection and quantification of nicotine in complex real-world samples. This study focuses on evaluating the factors influencing the sensing performance of the various electrode materials and electrochemical techniques used. The comprehensive information presented in this study will inform future research on the practical real-time monitoring of nicotine in tobacco products, emphasizing the simplicity, efficiency, and cost-effectiveness of the sensor design.

Depressive disorders, including major depressive disorder (MDD), represent one of the most prevalent set of disorders worldwide. MDD is characterized by a range of cognitive, behavioral, and neurobiological changes that contribute to the vast array of symptom profiles that make this disorder particularly difficult to treat. A multitude of established evidence suggests a role for the dopamine system, stemming in part from the ventral tegmental area (VTA), in mediating symptoms and behavioral changes that underlie depression. Developments in cutting-edge technologies in pre-clinical models of depressive phenotypes, such as retrograde tracing, electrophysiological recordings, immunohistochemistry, and molecular profiling, have allowed a deeper characterization of singular VTA neuron molecular, physiological, and projection properties. These developments have highlighted that the VTA is not a homogenous cell population but instead comprises vast cellular diversity that underscores its modular role across various functions related to reward processing, aversion, salience processing, learning and motivation. In this review, we begin by introducing the various cell types and brain regions that comprise the VTA circuitry. Then, we introduce the role of the VTA in reward processing as it compares to aversion processing. Next, we characterize distinct neural pathways within the VTA circuitry to understand the effects of chronic social and non-social stress and tie together how these neurobiological changes manifest into specific behavioral phenotypes. Finally, we relate these preclinical findings to clinical findings to parse the heterogeneity of depressive phenotypes and explain the efficacy of recent novel pharmacological interventions that may target the VTA in MDD.

Fenvalerate, a typical pyrethroid pesticide, is a neurological toxicant. This study aimed to evaluate the effect of paternal exposure to fenvalerate on depressive-like behaviours in adolescent offspring. Depression-like behavior was determined by Sucrose Preference Test (SPT), Tail Suspension Test (TST) and Forced Swimming Test (FST) in adolescent offspring. The level of dopamine was reduced in the midbrain of fenvalerate-exposed adolescent offspring. Tyrosine hydroxylase (Th), a rate limiting enzyme for dopamine synthesis, was significantly reduced in the midbrain of adolescent offspring exposed to fenvalerate. And Th was decreased in the midbrain and hindbrain of fetuses exposed to fenvalerate. Transcriptome analysis revealed growth factor receptor-bound protein 10 (Grb10) was decreased in the fetal hindbrain exposed to fenvalerate. Grb10 mRNA and protein were reduced in the fetal hindbrain exposed to fenvalerate. Interestingly, in vitro experiments, Th was reduced by si-Grb10. Conversely, Th was increased by oe-Grb10. Mechanistically, the 5mC content of Grb10 gene at one CpG fragment was reduced in the fetal hindbrain exposed to fenvalerate. And the 5mC content of Grb10 gene at eighteen CpG sites was decreased in paternal sperm exposed to fenvalerate. In summary, paternal fenvalerate exposure causes depressive-like behavior by altering DNA methylation of Grb10 gene in the sperm.

Physical exercise improves physical and mental health; however, the differences between voluntary and forced exercise protocols are unclear. In addition, knowledge regarding the consequences of differences in testing timing, such as light and dark phases, in response to exercise type is limited. We investigated the effects of chronic forced and voluntary wheel running on the changes in brain monoamine levels (5-HT: serotonin, DA: dopamine, NA: noradrenaline), anxiety-like behaviours, and physiological stress responses in the light and dark phases.

Adult male Wistar rats were equally and randomly assigned to four groups: sedentary control, voluntary exercise (free running on a wheel, V-EX), voluntary limited exercise (wheel available only 1 h/day, VL-EX), and forced exercise (running on a motorised wheel, F-EX). Each group was further divided into dark- or light-experimental condition groups. After 4 weeks, the rats underwent an open-field test. The monoamines and their metabolite levels were measured in the major neural cell bodies and the projection areas related to behaviour, cognition, anxiety, and stress in the brain.

Adrenal hypertrophy and elevated body temperature, except during the exercise period, were observed in the F-EX rats that exhibited anxiety-like behaviour. The levels of monoamines and their metabolites, particularly the 5-HTergic and DAergic systems, in specific areas, were significantly altered in the rats in the V-EX group compared to those in the VL-EX and other groups. These differences were observed only in the dark phase.

The results suggest that V-EX mainly stimulates the 5-HTergic and DAergic systems, while F-EX induces physiological stress and increases anxiety-like behaviour during the dark phase. This study highlights the importance of accounting for exercise types and light/dark phases in behavioural neuroscience experiments.

Research on nicotine's neurobiological effects has rarely focused on aerosols, despite their primary role in tobacco product consumption. Here, we utilized in vivo electrophysiology to examine brain activity in mice exposed to nicotine aerosols, both alone and with flavor additives (citric acid and menthol). Local field potential (LFP) recordings from the nucleus accumbens (NAc), basolateral amygdala (BLA), ventral tegmental area (VTA), and ventral posteromedial nucleus (VPM) were analyzed under saline, nicotine, nicotine with citric acid(CA + NIC), and nicotine with menthol(MENT + NIC) conditions. Nicotine exposure significantly reduced power spectral density (PSD) in the NAc-Alpha, NAc-Beta, and BLA-Beta bands, unaffected by flavor additives. Coherence between key brain regions (e.g., VPM-VTA in Beta, VPM-BLA in Alpha) also decreased with nicotine but was restored with citric acid or menthol, suggesting their role in mitigating nicotine's disruptive effects on neural synchronization. Our findings show that LFPs can effectively capture nicotine's neural effects and highlight the modulatory role of flavor additives, offering new insights into nicotine exposure management and tobacco product design.

Anxiety disorders, prevalent mental health conditions, receive significant attention globally due to their intricate etiology and the suboptimal effectiveness of existing therapies. Research is increasingly recognizing that the genesis of anxiety involves not only neurochemical brain alterations but also changes in gut microbiota. The microbiota-gut-brain axis (MGBA), serving as a bidirectional communication pathway between the gut microbiota and the central nervous system (CNS), is at the forefront of novel approaches to deciphering the complex pathophysiology of anxiety disorders. This review scrutinizes the role and recent advancements in the MGBA concerning anxiety disorders through a review of the literature, emphasizing mechanisms via neural signals, endocrine pathways, and immune responses. The evidence robustly supports the critical influence of MGBA in both the development and progression of these disorders. Furthermore, this discussion explores potential therapeutic avenues stemming from these insights, alongside the challenges and issues present in this realm. Collectively, our findings aim to enhance understanding of the pathological mechanisms and foster improved preventative and therapeutic strategies for anxiety disorders.

Although alcohol and nicotine are two of the most commonly co-used drugs with upwards of 90% of adults with an alcohol use disorder (AUD) in the US also smoking, we don't tend to study alcohol and nicotine use this way. The current studies sought to develop and assess a novel alcohol + nicotine co-access self-administration (SA) model in adult male and female Long-Evans rats. Further, both drugs are implicated in neuroimmune function, albeit in largely opposing ways. Chronic alcohol use increases neuroinflammation via toll-like receptors (TLRs) which in turn increases alcohol intake. By contrast, nicotine produces anti-inflammatory effects, in part, through the monomeric alpha7 receptor (ChRNa7). Following long-term co-access (6 months), rats reliably administered both drugs during daily sessions, however males generally responded for more alcohol and females for nicotine. This was reflected in plasma analysis with translationally relevant intake levels of both alcohol and nicotine, making it invaluable in studying the effects of co-use on behavior and CNS function. Moreover, male rats show sensitivity to alterations in alcohol concentration whereas females show sensitivity to alterations in nicotine concentration. Rats trained on this procedure also developed an anxiogenic phenotype. Finally, we assessed alterations in neuroimmune-related gene expression in the medial prefrontal cortex - prelimbic, (mPFC-PL), nucleus accumbens core (AcbC), and ventral tegmental area (VTA). In the AcbC, where α7 expression was increased and β2 was decreased, markers of pro-inflammatory activity were decreased, despite increases in TLR gene expression suggesting that co-use with nicotine modulates inflammatory state downstream from the receptor level. By contrast, in mPFC-PL where α7 was not increased, both TLRs and downstream proinflammatory markers were increased. Taken together, these findings support that there are brain regional and sex differences with co-use of alcohol + nicotine SA and suggest that targeting nicotinic α7 may represent a novel strategy for treating alcohol + nicotine co-dependence.

Ischemic stroke remains a leading cause of global mortality and disability, with neuroinflammation playing a critical role in determining patient outcomes. Microglia, the brain's resident immune cells, can both exacerbate neuroinflammation and neuronal damage by releasing neurotoxic mediators and engaging in excessive phagocytosis, while also aiding recovery through the production of anti-inflammatory cytokines and debris clearance. However, the molecular mechanisms governing microglial activation and polarization after ischemic stroke are not well elucidated. In this study, we combined integrative transcriptomic analyses with experimental validation in a murine model of middle cerebral artery occlusion/reperfusion (MCAO/R) to explore microglial heterogeneity and identify key regulatory factors in ischemic stroke. Bioinformatics analysis identified Cd72 as a novel pro-inflammatory modulator within ischemia-associated microglial phenotypes. We observed significant upregulation of Cd72 in microglia following MCAO/R, and selective knockdown of Cd72 using CX3CR1Cre/ERT2 mice and Cre recombinase-dependent adeno-associated virus reduced MCAO/R-induced infarct volume, neuronal apoptosis, and neurological deficits. Furthermore, Cd72 expression in microglia was positively correlated with pro-inflammatory pathways and cytokines, including TNF-α, IL-1β, and IL-6. Knockdown of Cd72 significantly reduced these pro-inflammatory factors, highlighting its potential as a therapeutic target for mitigating inflammation in ischemic stroke. In conclusion, this study identifies Cd72 as a critical pro-inflammatory regulator in microglia following ischemic stroke, with its knockdown effectively reducing neuroinflammation and associated brain injury, highlighting Cd72 as a promising therapeutic target.

Fear extinction leads to a decrease of originally acquired fear responses after the threat is no longer present. Fear extinction is adaptive and critical for organism's survival, but deficits in extinction may lead to exaggerated fear in animals or post-traumatic stress disorder (PTSD) in humans. Dopamine has recently emerged as essential for fear extinction and PTSD, however the neural circuits serving this dopamine function are only beginning to be investigated, and the dopamine intracellular signaling pathways are unknown. We generated gastrin-releasing peptide gene knockout (Grp-/-) mice and found that they exhibit enhanced fear memory in a stress-enhanced fear learning (SEFL) paradigm, which combines stress exposure and fear extinction, two features critical for developing PTSD. Using in vivo fiber photometry to record dopamine signals, we found that the susceptibility of Grp-/- mice to SEFL is paralleled by an increase in basolateral amygdala (BLA) dopaminergic binding during fear conditioning and early extinction. Combined optogenetics and ex vivo electrophysiology showed an increase in presynaptic ventral tegmental area (VTA)-BLA connectivity in Grp-/- mice, demonstrating a role of dysregulated input from the VTA on BLA function in the absence of the GRP. When examining gene transcription using RNA-seq and qPCR, we discovered concerted down-regulation in dopamine-related genes in the BLA of Grp-/- mice following long-term SEFL memory recall that was not observed in naïve conditions. These experiments demonstrate that the GRP regulates dopamine function in stress-enhanced fear processing and identify the Grp as the first gene known to regulate dopaminergic control of fear extinction.

Anxiety disorders are one of the most prevalent mental health conditions worldwide, imposing a significant burden on individuals affected by them and society in general. Current research endeavors aim to enhance the effectiveness of existing anxiolytic drugs and reduce their side effects through optimization or the development of new treatments. Several anxiolytic novel drugs have been produced as a result of discovery-focused research. However, many drug candidates that show promise in preclinical rodent model studies fail to offer any substantive clinical benefits to patients. This review provides an overview of the diagnosis and classification of anxiety disorders together with a systematic review of anxiolytic drugs with a focus on their targets, therapeutic applications, and side effects. It also provides a concise overview of the constraints and disadvantages associated with frequently administered anxiolytic drugs. Additionally, the study comprehensively reviews animal models used in anxiety studies and their associated molecular mechanisms, while also summarizing the brain circuitry related to anxiety. In conclusion, this article provides a valuable foundation for future anxiolytic drug discovery efforts.

The posterior medial (POm) thalamus is heavily interconnected with sensory and motor circuitry and is likely involved in behavioral modulation and sensorimotor integration. POm provides axonal projections to the dorsal striatum, a hotspot of sensorimotor processing, yet the role of POm-striatal projections has remained undetermined. Using optogenetics with slice electrophysiology, we found that POm provides robust synaptic input to direct and indirect pathway striatal spiny projection neurons (D1- and D2-SPNs, respectively) and parvalbumin-expressing fast spiking interneurons (PVs). During the performance of a whisker-based tactile discrimination task, POm-striatal projections displayed learning-related activation correlating with anticipatory, but not reward-related, pupil dilation. Inhibition of POm-striatal axons across learning caused slower reaction times and an increase in the number of training sessions for expert performance. Our data indicate that POm-striatal inputs provide a behaviorally relevant arousal-related signal, which may prime striatal circuitry for efficient integration of subsequent choice-related inputs.

Emotional stress is a significant environmental risk factor for various mental health disabilities, such as anxiety. Electroacupuncture (EA) has been demonstrated to have pronounced anxiolytic effects. However, the neural mechanisms underlying these effects and their contribution to behavioral deficits remain poorly understood. Here, we addressed these issues using a classical mouse anxiety model induced by chronic restraint stress (CRS).Anxiety-like behaviors were evaluated with the open field test and elevated plus maze. Neuronal activation in various brain regions was marked using c-Fos, followed by calculations of interregional correlation to characterize a network that became functionally active following EA at the HT7 acupoint (EA-HT7). We selected the hub regions and further investigated their functions and connections in regulating anxiety-like behaviors by using a combination of chemogenetic manipulations and behavioral testing. CRS exposure induced anxiety-like behaviors. Interestingly, EA-HT7 mitigated these behavioral abnormalities. The c-Fos expression in 30 brain areas revealed a vital brain network for acupuncture responsiveness in naïve mice. Neural activity in the NAcSh (nucleus accumbens shell), BNST (bed nucleus of the stria terminalis), VMH (Ventromedial Hypothalamus), ARC (arcuate nucleus), dDG (dorsal dentate gyrus), and VTA (ventral tegmental area) was significantly altered following acupuncture. Notably, both c-Fos immunostaining and brain functional connectivity analysis revealed the significant activation of VTA following EA-HT7. Interestingly, blocking the VTA eliminated the anxiolytic effects of EA-HT7, whereas chemogenetic activation of the VTA replicated the therapeutic effects of EA-HT7. EA-HT7 has demonstrated benefits in treating anxiety and enhances brain functional connectivity. The VTA is functionally associated with the anxiolytic effects of EA-HT7.

Bipolar disorder is a psychiatric condition characterized by the coexistence of depression and mania. Diagnosis of this disorder can be challenging due to limited pathologic and experimental tools. Treatment compliance is often poor due to medication side effects. Although cathepsin is known to play a significant role in diseases such as tumors and osteoporosis, its role in psychiatric disorders is not yet fully understood.

The aim of this study was to investigate the relationship between cathepsin in the blood circulation and bipolar disorder.

The causal relationship between cathepsin and different subtypes of bipolar affective disorder was explored using bidirectional Mendelian randomization analysis and multivariate analysis.

It was found that cathepsin H level was a protective factor for type II bipolar disorder. No potential causal relationship was found between cathepsin H and type I bipolar disorder, but cathepsin B changes with the development of type I bipolar disorder. A causal relationship was found between cathepsin H and cerebral dopamine neurotrophic factor.

In conclusion, cathepsin H may be a diagnostic target for bipolar II disorder and may play a guiding role in clinical diagnosis. Cathepsin H may have an effect on BD through cerebral dopamine neurotrophic factor.

How nicotine acts on developing neurocircuitry in adolescence to promote later addiction vulnerability remains largely unknown, but may hold the key for informing more effective intervention efforts. We found transient nicotine exposure in early adolescent (PND 21-28) male mice was sufficient to produce a marked vulnerability to nicotine in adulthood (PND 60 + ), associated with disrupted functional connectivity in dopaminergic circuits. These mice showed persistent adolescent-like behavioral and physiological responses to nicotine, suggesting that nicotine exposure in adolescence prolongs an immature, imbalanced state in the function of these circuits. Chemogenetically resetting the balance between the underlying dopamine circuits unmasked the mature behavioral response to acute nicotine in adolescent-exposed mice. Together, our results suggest that the perseverance of a developmental imbalance between dopamine pathways may alter vulnerability profiles for later dopamine-dependent psychopathologies.

Generalized fear is a maladaptive behavior in which non-threatening stimuli elicit a fearful response. The ventral tegmental area (VTA) has been demonstrated to play important roles in fear response and fear memory generalization, but the precious neural circuit mechanism is still unclear. Here, we demonstrated that VTA-zona incerta (ZI) glutamatergic projection is involved in regulating high-intensity threatening training induced generalization and anxiety. Combining calcium signal recording and chemogentics, our work reveals that VTA glutamatergic neurons respond to closed arm entering in the model of PTSD. Inhibition of VTA glutamatergic neurons or the glutamatergic projection to ZI could both relieve fear generalization and anxiety. Together, our study proves the VTA - ZI glutamatergic circuit is involved in mediating fear generalization and anxiety, and provides a potential target for treating post-traumatic stress disorder.

Dopamine (DA) neurons in the ventral tegmental area (VTA) respond to motivationally relevant cues, and circuit-specific signaling drives different aspects of motivated behavior. Orexin (ox; also known as hypocretin) and dynorphin (dyn) are coexpressed lateral hypothalamic (LH) neuropeptides that project to the VTA. These peptides have opposing effects on the firing activity of VTADA neurons via orexin 1 (Ox1R) or kappa opioid (KOR) receptors. Given that Ox1R activation increases VTADA firing, and KOR decreases firing, it is unclear how the coreleased peptides contribute to the net activity of DA neurons. We tested if optical stimulation of LHox/dyn neuromodulates VTADA neuronal activity via peptide release and if the effects of optically driven LHox/dyn release segregate based on VTADA projection targets including the basolateral amygdala (BLA) or the lateral or medial shell of the nucleus accumbens (lAcbSh, mAchSh). Using a combination of circuit tracing, optogenetics, and patch-clamp electrophysiology in male and female orexincre mice, we showed a diverse response of LHox/dyn optical stimulation on VTADA neuronal firing, which is not mediated by fast transmitter release and is blocked by antagonists to KOR and Ox1R signaling. Additionally, where optical stimulation of LHox/dyn inputs in the VTA inhibited firing of the majority of BLA-projecting VTADA neurons, optical stimulation of LHox/dyn inputs in the VTA bidirectionally affects firing of either lAcbSh- or mAchSh-projecting VTADA neurons. These findings indicate that LHox/dyn corelease may influence the output of the VTA by balancing ensembles of neurons within each population which contribute to different aspects of reward seeking.

The occurrence of postoperative depression and anxiety in patients with endometriosis (EMS) not only causes psychological distress, but may also harm their physical health.

To explore the postoperative depression status, and its influencing factors, of EMS patients with reproductive intention.

A total of 321 EMS patients with reproductive intent were included. Using the self-rating anxiety scale and self-rating depression scale, EMS patients with anxiety or depression were distinguished. A clinical model for predicting anxiety or depression in EMS patients was constructed and evaluated using a nomogram, receiver operating characteristic curve, and calibration curve.

The results of the single factor analysis showed that smoking, coffee, EMS stage, chronic pelvic pain, and sexual discomfort may be related to anxiety. Further, smoking, drinking, spouse, annual household income and EMS stage may be related to depression in EMS patients. Multivariate logistic regression illustrated that smoking, coffee, chronic pelvic pain and sexual discomfort may be independent risk factors for anxiety in EMS patients, while smoking, EMS stage (Phase III and Phase IV), spouse and high annual household income may be independent risk factors for depression in EMS patients. Additionally, the models used to predict the risk of anxiety or depression in EMS patients have good predictive value.

The anxiety and depression of EMS patients may be related to many factors. In clinical treatment, additional attention should be paid to the psychological status of EMS patients.

The association between tobacco smoke exposure and sleep has been widely discussed, but the correlation between serum cotinine levels and sleep health outcomes in adolescents has not been well described. This study aimed to further evaluate the association between serum cotinine levels and sleep health outcomes in adolescents using data from the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2018. This cross-sectional study included participants aged 16-19 years from the NHANES 2005-2018. A weighted multivariate logistic regression model was used for the primary analysis. A restricted cubic spline (RCS) model was employed to investigate the non-linear association between serum cotinine levels and trouble sleeping. Subgroup analyses based on population characteristics were also conducted. In total, 2630 participants were included, which are representative of the 11.5 million US adolescents. Higher serum cotinine levels (≥ 3 ng/ml) were significantly associated with trouble sleeping in the fully adjusted model (odds ratio [OR] 1.817). The RCS model revealed a non-linear relationship between serum cotinine levels and trouble sleeping. Subgroup analyses indicated that this relationship was consistent and stable across various population characteristics. Serum cotinine levels are associated with sleep health outcomes in adolescents, with high serum cotinine levels being linked to increased trouble sleeping and longer or shorter sleep duration.

Depressive disorders are a common and debilitating form of mental illness with significant impacts on individuals and society. Despite the high prevalence, the underlying causes and mechanisms of depressive disorders are still poorly understood. Neurochemical systems, including serotonin, norepinephrine, and dopamine, have been implicated in the development and perpetuation of depressive symptoms. Current treatments for depression target these neuromodulator systems, but there is a need for a better understanding of their role in order to develop more effective treatments. Monitoring neurochemical dynamics during depressive symptoms is crucial for gaining a better a understanding of their involvement in depressive disorders. Genetically encoded sensors have emerged recently that offer high spatial-temporal resolution and the ability to monitor neurochemical dynamics in real time. This review explores the neurochemical systems involved in depression and discusses the applications and limitations of current monitoring tools for neurochemical dynamics. It also highlights the potential of genetically encoded sensors for better characterizing neurochemical dynamics in depression-related behaviors. Furthermore, potential improvements to current sensors are discussed in order to meet the requirements of depression research.

Biological sex disparities manifest at various stages of drug addiction, including craving, substance abuse, abstinence, and relapse. These discrepancies are underpinned by notable distinctions in neurobiological substrates, encompassing brain structures, functions, and neurotransmitter systems implicated in drug addiction. Neuronal biomarkers, such as neurotransmitters, signaling proteins, and genes may be associated with the diagnosis, prognosis, and treatment outcomes in both biological sexes afflicted by drug abuse. Sex differences in the neural reward system, mainly through dopaminergic transmission during drug abuse, can be attributed to modifications in neurotransmitter systems and signaling pathways. This results in distinct patterns of neural activation and responsiveness to addictive substances in males and females. Sex hormones, the estrus/menstrual cycle, and cerebral neurochemistry contribute to the progression of psychological and physiological dependence in both male and female individuals grappling with addiction. Moreover, the alteration of sex hormone balance and neurotransmitter release plays a pivotal role in substance use disorders, subsequently modulating cognitive functions pertinent to reward, including memory formation, decision-making, and locomotor activity. Comparative investigations reveal distinctions in brain region volume, gene expression, neuronal firing, and circuitry in substance use disorders affecting individuals of both biological sexes. This review examines prevalent substance use disorders to elucidate the impact of sex hormones as therapeutic biomarkers on the mesocorticolimbic neurotransmitter systems via diverse mechanisms within the addicted brain. We underscore the imperative necessity of considering these variations to gain a deeper comprehension of addiction mechanisms and potentially discern sex-specific neuronal biomarkers for tailored therapeutic interventions.

The objective of this study is to assess the impact of smoking on stroke prevalence and to delineate the relationship between smoking-related factors and the risk of stroke, incorporating an analysis of demographic variations influencing this association.

Our analysis encompassed 9,176 participants, evaluating clinical attributes alongside smoking-related characteristics such as duration of cigarette consumption, and levels of nicotine, tar, and carbon monoxide. We employed weighted univariate logistic regression and restricted cubic splines to examine the association between smoking indicators and stroke risk, complemented by subgroup analyses for demographic differentiation.

The overall prevalence of stroke in our cohort was 3.4%. Statistically significant associations were found between stroke incidence and factors such as age, gender, education, and marital status (p < 0.05). Adjusted logistic regression models showed increased odds ratios (ORs) for stroke with higher nicotine and carbon monoxide levels across progressively adjusted models: Model 1 (unadjusted), Model 2 (adjusted for age, gender), Model 3 (further adjusted for education, marital status, BMI, PIR), and Model 4 (fully adjusted for additional factors including hypertension, hyperlipidemia, diabetes, and drinking). Specifically, ORs for nicotine increased from 2.39 in Model 1 to 2.64 in Model 4; for carbon monoxide, from 1.10 to 1.11 over the same models.​The threshold analysis using restricted cubic splines revealed critical points for stroke risk increase at smoke exposure levels of 410 units, tar 12 mg, nicotine 1.1 mg, and carbon monoxide 12 ppm. Above these thresholds, stroke risk escalates significantly. Additionally, the presence of family smoking history was associated with higher stroke risks compared to those without such history.

This study confirms that smoking significantly contributes to increased stroke risk, particularly through exposure to nicotine and carbon monoxide. The findings emphasize the necessity for tailored stroke prevention strategies that specifically address smoking behaviors and consider demographic susceptibilities. Incorporating smoking-related indicators into risk assessment models could enhance the precision of stroke prevention efforts.

Nicotine intake is linked to the maintenance and development of anxiety disorders and impairs adaptive discrimination of threat and safety in rodents and humans. Yet, it is unclear if nicotine exerts a causal pharmacological effect on the affective and neural mechanisms that underlie aversive learning. We conducted a pre-registered, pseudo-randomly and double-blinded pharmacological fMRI study to investigate the effect of acute nicotine on Fear Acquisition and Extinction in non-smokers (n = 88). Our results show that nicotine administration led to decreased discrimination between threat and safety in subjective fear. Nicotine furthermore decreased differential (threat vs. safety) activation in the hippocampus, which was functionally coupled with Nucleus Accumbens and amygdala, compared to placebo controls. Additionally, nicotine led to enhanced physiological arousal to learned threats and overactivation of the ventral tegmental area. This study provides mechanistic evidence that single doses of nicotine impair neural substrates of adaptive aversive learning in line with the risk for the development of pathological anxiety.

Stress and trauma are significant risk factors for many neuropsychiatric disorders and diseases, including anxiety disorders. Stress-induced anxiety symptoms have been attributed to enhanced excitability in circuits controlling fear, anxiety, and aversion. A growing body of evidence has implicated GABAergic neurons of the ventral tegmental area (VTA) in aversion processing and affective behavior.

We used an unpredictable footshock (uFS) model, together with electrophysiological and behavioral approaches, to investigate the role of VTA GABA neurons in anxiety-related behavior in mice.

One day after a single uFS session, C57BL/6J mice exhibited elevated anxiety-related behavior and VTA GABA neuron excitability. The enhanced excitability of VTA GABA neurons was correlated with increased glutamatergic input and a reduction in postsynaptic signaling mediated via GABAA and GABAB receptors. Chemogenetic activation of VTA GABA neurons was sufficient to increase anxiety-related behavior in stress-naïve mice. In addition, chemogenetic inhibition of VTA GABA neurons suppressed anxiety-related behavior in mice exposed to uFS.

These data show that VTA GABA neurons are an early substrate for stress-induced anxiety-related behavior in mice and suggest that approaches mitigating enhanced excitability of VTA GABA neurons may hold promise for the treatment of anxiety provoked by stress and trauma.

Comorbid anxiodepressive-like symptoms (CADS) in chronic pain are closely related to the overactivation of the lateral habenula (LHb). Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels have been implicated to play a key role in regulating neuronal excitability. However, the role of HCN channels in the LHb during CADS has not yet been characterized. This study aimed to investigate the effect of HCN channels in the LHb on CADS during chronic pain.

After chronic neuropathic pain induction by spared nerve injury (SNI), mice underwent a sucrose preference test, forced swimming test, tail suspension test, open-field test, and elevated plus maze test to evaluate their anxiodepressive-like behaviors. Electrophysiological recordings, immunohistochemistry, Western blotting, pharmacological experiments, and virus knockdown strategies were used to investigate the underlying mechanisms.

Evident anxiodepressive-like behaviors were observed 6w after the SNI surgery, accompanied by increased neuronal excitability, enhanced HCN channel function, and increased expression of HCN2 isoforms in the LHb. Either pharmacological inhibition or virus knockdown of HCN2 channels significantly reduced LHb neuronal excitability and ameliorated both pain and depressive-like behaviors.

Our results indicated that the LHb neurons were hyperactive under CADS in chronic pain, and this hyperactivation possibly resulted from the enhanced function of HCN channels and up-regulation of HCN2 isoforms.

The addictive use of nicotine contained in tobacco is associated with stressor-like emotional and cognitive effects such as anxiety and working memory impairment, and the involvement of epigenetic mechanisms such as histone acetylation has recently been reported. Although the precise nature of behavioural plasticity remains unclear, both anxiogenic- and working memory impairment-like effects were observed in the present experimental model of mice treated with repeated subcutaneous nicotine and/or immobilization stress, and these effects were commonly attenuated by the histone deacetylase (HDAC) inhibitors that induce histone acetylation. Such HDAC inhibitor-induced resilience was mimicked by ligands for the endocannabinoid (ECB) system, a neurotransmitter system that is closely associated with nicotine-induced addiction-related behaviours: the anxiogenic-like effects were mitigated by the cannabinoid type 1 (CB1) agonist arachidonylcyclopropylamide (ACPA), whereas the working memory impairment-like effects were mitigated by the CB1 antagonist SR 141716A. Moreover, the effects of the HDAC inhibitors were also mimicked by ligands for the endovanilloid (transient receptor potential vanilloid 1 [TRPV1]) system, a system that shares common characteristics with the ECB system: the anxiogenic-like effects were mitigated by the TRPV1 antagonist capsazepine, whereas the working memory impairment-like effects were mitigated by the TRPV1 agonist olvanil. Notably, the HDAC inhibitor-induced anxiolytic-like effects were attenuated by SR 141716A, which were further counteracted by capsazepine, whereas the working memory improvement-like effects were attenuated by capsazepine, which were further counteracted by SR 141716A. These results suggest the contribution of interrelated control of the ECB/TRPV1 systems and epigenetic processes such as histone acetylation to novel therapeutic approaches.

Elevated maternal psychological distress during pregnancy is associated with altered fetal brain development. During the COVID-19 pandemic, prenatal maternal psychological distress more than doubled.

To examine the association of the pandemic and rising maternal psychological distress with brain growth in newborns using quantitative 3-dimensional volumetric magnetic resonance imaging (MRI).

This prospective cross-sectional study recruited mother-infant dyads at Children's National Hospital, Washington, DC, during the COVID-19 pandemic (June 1, 2020, to June 30, 2022) into a longitudinal infant brain development study and compared them with an existing normative healthy cohort (recruited March 1, 2014, to December 31, 2019). Exclusion criteria included multiple gestation pregnancy, known or suspected congenital infection, documented chromosomal abnormalities, or any maternal contraindication to MRI, as well as prenatal COVID-19 exposure. Infants with structural brain abnormalities or a postnatal confirmation of a genetic syndrome were excluded.

Psychological distress during COVID-19 pandemic.

Prenatal maternal mental health was evaluated using the Spielberger State-Trait Anxiety Inventory and the Perceived Stress Scale. Neonates underwent nonsedated brain MRI. An ordinary least squares linear regression model was used to measure the differences in regional brain volumes of neonates born before vs during the pandemic with and without exposure to elevated prenatal maternal psychological distress after adjustment for neonatal sex and gestational age at MRI and maternal age and educational level.

A total of 159 mother-infant dyads were included in the analysis: 103 before and 56 during the pandemic (median gestational age of infants, 39.6 [IQR, 38.4-40.4] weeks; median maternal age, 34.5 [IQR, 31.0-37.0] years). Eighty-three infants (52.2%) were female. Among the mothers, 130 (81.8%) had a college degree and 87 (54.7%) had a graduate degree. Forty-four mothers (27.7%) identified as Asian, Hispanic, or multiracial; 27 (17.0%), as Black; and 88 (55.3%), as White. Scores on anxiety and stress measures were significantly increased in the pandemic cohort. Infants of mothers with elevated maternal distress showed median reductions in white matter (-0.36 [95% CI, -0.61 to -0.11] cm3; Q < .001), right hippocampal (-0.35 [95% CI, -0.65 to -0.06] cm3; Q = .04), and left amygdala (-0.49 [95% CI, -0.84 to -0.13] cm3; Q = .03) volumes compared with infants of mothers with low distress levels. After adjusting for the cohort effect of the pandemic, elevated trait anxiety remained significantly associated with decreased left amygdalar volumes (-0.71 [95% CI, -1.12 to -0.29]; Q < .001).

In this cross-sectional study of maternal-infant dyads prior to and during the COVID-19 pandemic, regional neonatal brain volumes were associated with elevated maternal psychological distress.

Nicotinic acetylcholine receptors (nAChRs) are widely expressed in the central nervous system and play an important role in the control of neural functions including neuronal activity, transmitter release and synaptic plasticity. Although the common subtypes of nAChRs are abundantly expressed throughout the brain, their expression in different brain regions and by individual neuronal types is not homogeneous or incidental. In recent years, several studies have emerged showing that particular subtypes of nAChRs are expressed by specific neuronal populations in which they have major influence on the activity of local circuits and behavior. It has been demonstrated that even nAChRs expressed by relatively rare neuronal types can induce significant changes in behavior and contribute to pathological processes. Depending on the identity and connectivity of the particular nAChRs-expressing neuronal populations, the activation of nAChRs can have distinct or even opposing effects on local neuronal signaling. In this review, we will summarize the available literature describing the expression of individual nicotinic subunits by different neuronal types in two crucial brain regions, the striatum and the prefrontal cortex. The review will also briefly discuss nicotinic expression in non-neuronal, glial cells, as they cannot be ignored as potential targets of nAChRs-modulating drugs. The final section will discuss options that could allow us to target nAChRs in a neuronal-type-specific manner, not only in the experimental field, but also eventually in clinical practice.

Individual variability in response to rewarding stimuli is a striking but understudied phenomenon. The mesolimbic dopamine system is critical in encoding the reinforcing properties of both natural reward and alcohol; however, how innate or baseline differences in the response dynamics of this circuit define individual behavior and shape future vulnerability to alcohol remain unknown.

Using naturalistic behavioral assays, a voluntary alcohol drinking paradigm, in vivo fiber photometry, in vivo electrophysiology, and chemogenetics, we investigated how differences in mesolimbic neural circuit activity contribute to the individual variability seen in reward processing and, by proxy, alcohol drinking.

We first characterized heterogeneous behavioral and neural responses to natural reward and defined how these baseline responses predicted future individual alcohol-drinking phenotypes in male mice. We then determined spontaneous ventral tegmental area dopamine neuron firing profiles associated with responses to natural reward that predicted alcohol drinking. Using a dual chemogenetic approach, we mimicked specific mesolimbic dopamine neuron firing activity before or during voluntary alcohol drinking to link unique neurophysiological profiles to individual phenotype. We show that hyperdopaminergic individuals exhibit a lower neuronal response to both natural reward and alcohol that predicts lower levels of alcohol consumption in the future.

These findings reveal unique, circuit-specific neural signatures that predict future individual vulnerability or resistance to alcohol and expand the current knowledge base on how some individuals are able to titrate their alcohol consumption whereas others go on to engage in unhealthy alcohol-drinking behaviors.

Visceral hypersensitivity, a common clinical manifestation of irritable bowel syndrome, may contribute to the development of chronic visceral pain, which is a major challenge for both patients and health providers. Neural circuits in the brain encode, store, and transfer pain information across brain regions. In this review, we focus on the anterior cingulate cortex and paraventricular nucleus of the hypothalamus to highlight the progress in identifying the neural circuits involved in visceral pain. We also discuss several neural circuit mechanisms and emphasize the importance of cross-species, multiangle approaches and the identification of specific neurons in determining the neural circuits that control visceral pain.

Chronic stress is deemed a significant clinical contributor to depression. The use of animal models of chronic stress can fully reveal the complex pathological mechanisms and their changing trends in the pathogenesis of depression, which is crucial for both disease prevention and therapy. It is also unknown how various forms of stress differ in their impact on animal physiology and behavior. The nucleus accumbens (NAc), an essential brain area for the pathophysiology of depression, and its underlying neural mechanisms remain unclear. Here, we systematically compared transcriptional signatures in the NAc of four chronic stress models in rats: chronic unpredictable mild stress (CUMS), chronic social defeat stress (CSDS), learned helplessness (LH), chronic restraint stress (CRS). The majority of differentially expressed genes (DEGs) were unique to a single depression model, while the rank-rank hypergeometric overlap analysis showed that the CSDS and CRS models had the greatest overlap, and the CRS and CUMS models had the least. Then, we performed pathway analysis of the differential genes and found that the neuroactive ligand-receptor interaction pathway was significantly enriched not only in the LH, CRS and CSDS stress models, but also significantly enriched in stress genes that were also altered in at least two stress models. Finally, we found three hub genes (Dcx, Tnc and Wdfy4) by constructing co-expression networks for stress genes. In summary, our research has the potential to offer fresh insights into the molecular mechanisms underlying depression induced by different types of stress, highlighting both their similarities and differences. It may provide valuable clues for understanding the pathogenesis of depression.

Cigarette smoking is commonly reported among chronic pain patients in the clinic. Although chronic nicotine exposure is directly linked to nociceptive hypersensitivity in rodents, underlying neurobiological mechanisms remain unknown.

Multi-tetrode recordings in freely moving mice were used to test the activity of dopaminergic projections from the ventral tegmental area (VTA) to pyramidal neurones in the anterior cingulate cortex (ACC) in chronic nicotine-treated mice. The VTA→ACC dopaminergic pathway was inhibited by optogenetic manipulation to detect chronic nicotine-induced allodynia (pain attributable to a stimulus that does not normally provoke pain) assessed by von Frey monofilaments (force units in g).

Allodynia developed concurrently with chronic (28-day) nicotine exposure in mice (0.36 g [0.0141] vs 0.05 g [0.0018], P<0.0001). Chronic nicotine activated dopaminergic projections from the VTA to pyramidal neurones in the ACC, and optogenetic inhibition of VTA dopaminergic terminals in the ACC alleviated chronic nicotine-induced allodynia in mice (0.06 g [0.0064] vs 0.28 g [0.0428], P<0.0001). Moreover, optogenetic inhibition of Drd2 dopamine receptor signalling in the ACC attenuated nicotine-induced allodynia (0.07 g [0.0082] vs 0.27 g [0.0211], P<0.0001).

These findings implicate a role of Drd2-mediated dopaminergic VTA→ACC pathway signalling in chronic nicotine-elicited allodynia.

Phosphoinositides, including phosphatidylinositol-4,5-bisphosphate (PIP2), play a crucial role in controlling key cellular functions such as membrane and vesicle trafficking, ion channel, and transporter activity. Phosphatidylinositol 4-kinases (PI4K) are essential enzymes in regulating the turnover of phosphoinositides. However, the functional role of PI4Ks and mediated phosphoinositide metabolism in the central nervous system has not been fully revealed. In this study, we demonstrated that PI4KIIIβ, one of the four members of PI4Ks, is an important regulator of VTA dopaminergic neuronal activity and related depression-like behavior of mice by controlling phosphoinositide turnover. Our findings provide new insights into possible mechanisms and potential drug targets for neuropsychiatric diseases, including depression. Both sexes were studied in basic behavior tests, but only male mice could be used in the social defeat depression model.

Anxiety disorders, common symptoms during morphine withdrawal, are important negative reinforcement factors leading to relapse. Lateral habenula serves as a negative reinforcement center, however its role in morphine withdrawal-induced anxiety remains uncovered. The hyperpolarization activated cyclic nucleotide-gated (HCN) channels have been reported to be important in emotion processing and addiction, but the role of HCN in anxiety from drug protracted abstinence remains elusive. In this study, by using behavioral test, Western blot, immunofluorescence, electrophysiology and virus-mediated regulation of HCN, we found that: (1) Intra-LHb injection of selective HCN blocker ZD7288 alleviated anxiety-like behaviors in morphine protracted abstinent male mice. (2) The LHb neuronal activity was increased by morphine protracted abstinence. (3) LHb neurons were inhibited by ZD7288 and activated by 8-Br-cAMP respectively, which were enhanced by morphine withdrawal. (4) HCN1 in the LHb was upregulated by morphine withdrawal. (5) Virus-mediated overexpression of HCN1 in the LHb was sufficient to produce anxiety-like behaviors in male mice and virus-mediated knockdown of HCN1 in the LHb prevented the anxiety-like behaviors in male mice. The findings reveal that selective blockade of HCN1 channels in the LHb may represent a therapeutic approach to morphine withdrawal-induced anxiety.

The mesencephalic dopamine (DA) system is composed of neuronal subtypes that are molecularly and functionally distinct, are responsible for specific behaviors, and are closely associated with numerous brain disorders. Existing research has made significant advances in identifying the heterogeneity of mesencephalic DA neurons, which is necessary for understanding their diverse physiological functions and disease susceptibility. Moreover, there is a conflict regarding the electrophysiological properties of the distinct subsets of midbrain DA neurons. This review aimed to elucidate recent developments in the heterogeneity of midbrain DA neurons, including subpopulation categorization, electrophysiological characteristics, and functional connectivity to provide new strategies for accurately identifying distinct subtypes of midbrain DA neurons and investigating the underlying mechanisms of these neurons in various diseases.

Rearing environment plays a vital role in maintaining physical and mental health of both animals and humans. Plenty of studies have proved that physical environment enrichment in adolescence has protective effects on emotion, social behavior, learning and memory deficits. However, the following effects of social environment enrichment in adolescence remain largely elusive. Using the paradigm of companion rotation (CR), the present study found that social environment enrichment reduced anxiety-like behaviors of early adult male C57BL/6J mice. CR group also showed significantly higher expression of tyrosine hydroxylase in the ventral tegmental area and dopamine 1 receptor mRNA in the nucleus accumbens shell than control group. Taken together, these findings demonstrate that CR from adolescence to early adulthood can suppress the level of anxiety and upregulate dopaminergic neuron activity in early adult male C57BL/6J mice.