New combinations or alternative therapies for major depressive disorder (MDD) are necessary. Intradermal acupuncture (IA) shows promise but requires further investigation regarding its efficacy, safety, and mechanisms. Conducted across 3 centers from November 2022 to January 2024, our randomized controlled trial included 120 participants with moderate to severe MDD, divided into the selective serotonin reuptake inhibitors (SSRIs), SSRIs plus sham IA (SSRIs + SIA), and SSRIs plus active IA (SSRIs + AIA) groups. Acupuncture groups received 10 sessions over 6 weeks at Shenmen (HT7), Neiguan (PC6), Sanyinjiao (SP6) and Taichong (LR3) bilaterally, followed by a 4-week follow-up. The primary outcome was changes in Hamilton Depression Rating Scale-17 (HAMD-17) scores at week 6. Furthermore, healthy controls (HCs) and MDD patients underwent magnetic resonance imaging (MRI) scans for functional connectivity (FC) analysis. After 6 weeks of treatment, the SSRIs + AIA group showed a greater reduction in HAMD-17 score than the SSRIs + SIA group (MD, -4.9 [CI, -7.6 to -2.2], P < 0.001) and SSRIs group (MD, -5.1 [CI, -7.8 to -2.3], P < 0.001). No serious adverse events occurred. SSRIs + AIA resulted in lower incidences of palpitations (vs.SSRIs + SIA: OR, 0.1% [CI, 0.0-1.0%]; vs. SSRIs: OR, 0.1% [CI, 0.0-0.7%]; P < 0.05), somnolence (vs.SSRIs + SIA: OR, 0.1% [CI, 0.0-0.9%]; vs.SSRIs: OR, 0.1% [CI, 0.0-0.7%]; P < 0.05), and nausea (vs.SSRIs + SIA: OR, 0.1% [CI, 0.0-1.0%]; vs. SSRIs: OR, 0.1% [CI, 0.0-0.9%]; P < 0.05). MDD patients showed abnormal FCs, and IA enhanced FCs between striatum and frontal_inf_tri, and striatum and cerebellum in the MRI study. Overall, IA as adjunctive therapy provides clinical efficacy and safety for MDD, and it may exert antidepressant effects by modulating striatal FCs.

In this review, a hypothesis explaining the origin and genesis of depression development from the perspective of a holistic functional system of behavioral control is proposed. The core of the functional system is the memory apparatus, on which all other key components of the behavioral control system (sensory information, motivation, reinforcement, and motor activity) are interlocked. In the organization of memory traces (engrams) there are two inputs, sensory and motivational, through which the stimulus-stimulus (S-S) and stimulus-motor (S-R) engrams are formed. These engrams are organized and actualized by means of forward and backward conditional connections between cortical representations of sensory information and motivational structures of the brain. Through feedback connections from reinforcing (emotional) input to the memory apparatus, the S-S and S-R engrams are consolidated or weakened depending on the strength of reward or negative events. Depression begins with a breakdown in memory mechanisms. These breakdowns are related to problems with the three mentioned memory inputs: sensory, motivational, and reinforcing (emotional). Disruptions in sensory and motivational input lead to an inability to form new memory engrams, their actualization and retrieval. This creates difficulty in solving current and past unresolved problems, eliciting more accumulation and increasing difficulties in their solving. Unresolved tasks lead to weakening of the reinforcing input, and further impairment of consolidation of the acting engrams. Another reason for the weakening of reinforcing input is excessive action of directly harmful events or constant chronic stress. The review presents the current literature and some data from our laboratory in favor of each memory input's contribution and their impact on the development of depression, when they are problematic.

Major Depressive Disorder (MDD) is a devastating, multifactorial disease with limited pharmacological treatment options. Patients with MDD exhibit alterations in their dopamine (DA) signaling pathways through the midbrain ventral tegmental area (VTA). A similar observation is also detected in preclinical models of stress - mice exhibit behavioral and physiological impairments following chronic social defeat stress (CSDS). Prior studies demonstrate that CSDS-susceptible mice have increased VTA DA neuronal excitability, in part driven by an upregulation in hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels. Inhibiting HCN channels with known inhibitors such as Cilobradine alleviates the negative behavioral effects of CSDS. Here, we aimed to identify Cilobradine analogs with improved neural tropism and inhibitory efficacy. Two compounds, MS7710 and MS7712, differing by their left-hand side moieties, have a similar, potent inhibitory effect on VTA DA Ih currents as compared to Cilobradine, and a greater inhibitory effect than Cilobradine on VTA DA firing rate. We demonstrate that MS7710 and MS7712 have superior brain/plasma concentration ratios as compared to Cilobradine. They were efficacious at inhibiting VTA DA neuron firing rate and bursting activity in CSDS-susceptible male mice at lower doses than Cilobradine, which was recapitulated in female CSDS-susceptible mice with MS7710. Finally, we define that a single intraperitoneal injection of MS7710 ameliorates CSDS-induced social interaction deficits and reward-associated cognitive inflexibility for at least two weeks in male and female mice. These findings yield a novel HCN channel inhibitor with improved neural tropism and stress-alleviating effects that could provide a basis for future antidepressant drug discovery.

Nicotinic receptor signaling is influential in modulating appropriate responses to salient stimuli within a complex environment. The cholinergic neurotransmitter system drives attention to salient stimuli such as stressors, and aids in orchestrating the proper neural and behavioral responses. Dysregulation of this system, however, has been implicated in altered anxiety regulation and mood disorders. Among the multiple layers of regulation are protein modulators such as Lynx2/Lypd1, which provides negative nicotinic acetylcholine receptor regulation within anxiety-related circuits, such as the amygdala and medial prefrontal cortex, among other brain regions. Mice null for Lynx2/Lypd1 (Lynx2 KO) show elevated basal anxiety-like behavior in tests such as elevated plus maze, light-dark box and social interaction assays. Here, we queried how a line predisposed to basal anxiety-like behavior would respond to specific stressors, using validated models of experiential-based affective disorders such as fear extinction, acute and chronic social defeat stress assays. We discovered that Lynx2 KO mice demonstrate an inability to extinguish learned fear during fear extinction tests even during milder stress conditions. In social defeat studies, contrary to our predictions, the Lynx2 KO mice switched from a socially avoidant phenotype (which could be considered susceptible) before defeat to a social approach/resilient phenotype after defeat. Consistent with reports of the inverse relationship between resilience and BDNF levels, we observed reduced BDNF levels in the VTA of Lynx2 KO mice. Furthermore, we provide evidence for the functional role of α7 nicotinic receptor subtypes by phenotypic rescue of fear extinction and social defeat phenotypes by MLA antagonism of α7 nicotinic acetylcholine receptors, or by crossing with α7 nicotinic acetylcholine receptor null mutant mice. A stable physical interaction between LYNX2 and α7 nAChRs was observed by co-immunoprecipitation of complexes from mouse amygdalae extracts. Together, these data indicate that responses to specific stressors can become aberrant when baseline genetic factors predispose animals to anxiety dysregulation. These studies underscore the critical nature of well-regulated nicotinic receptor function in the adaptive response to environmental stressors.

Anhedonia is a core feature of depression. It contains a consummatory and a motivational aspect. Whilst much neuroimaging research in patients with depression focused on the consummatory aspect of anhedonia, less is known about its motivational aspect. This study aimed to explore the neurobiology of networks related to motivational anhedonia. Thirty-eight patients with major depressive disorder (MDD) and 19 healthy controls underwent diffusion-weighted and resting state functional magnetic resonance imaging (rs-fMRI). For assessment of motivational anhedonia, we summed the values of the CORE non-interactiveness score, and the items 1 (hopelessness) and 7 (work and activities) of the Hamilton Depression Rating Scale. Whole-brain voxel-wise statistical analysis of fractional anisotropy (FA) data was performed using Tract-Based Spatial Statistics (TBSS). Additionally, we performed a whole-brain comparison of integrated local correlation of rs-fMRI signal (LCOR), to investigate regional functional differences between patients and healthy controls. Whole brain correlations between motivational anhedonia and measures of structural and functional connectivity (FA, and LCOR) were calculated. TBSS-analyses revealed reduced FA in the left superior longitudinal fasciculus (SLF) in patients with MDD. LCOR was reduced in patients with depression in an adjacent cluster localized in bilateral precunei. Within patients, there was a positive correlation between motivational anhedonia and LCOR in the precunei and a negative correlation in bilateral sensorimotor areas. FA-values did not show significant correlations. These findings suggest that motivational anhedonia in depression is linked to alterations of functional connectivity within bilateral precunei. Observed white matter microstructural alterations in the SLF do not show such an association.

Up to half of individuals with depression do not respond to first-line treatments, possibly due to a lack of treatment interventions informed by neurobiology. A novel therapeutic approach for depression has recently emerged from translational work targeting aberrant activity of ventral tegmental area (VTA) dopamine neurons via modulation of the KCNQ voltage-gated potassium channels. In this study, individuals with major depressive disorder (MDD) with elevated anhedonia were randomized to five weeks of the KCNQ channel opener, ezogabine (up to 900 mg/day) or placebo. Participants completed functional MRI during a monetary anticipation task and resting-state at baseline and at end-of-treatment. The clinical results were reported previously. Here, we examined VTA activity during monetary anticipation and resting-state functional connectivity between the VTA and the ventromedial prefrontal cortex (mesocortical pathway) and ventral striatum (mesolimbic pathway) at baseline and end-of-treatment. Results indicated a significant drug-by-time interaction in VTA activation during anticipation (F(1,34) = 4.36, p = 0.044), where VTA activation was reduced from pre-to-post ezogabine, compared to placebo. Mesocortical functional connectivity was also higher in depressed participants at baseline compared to a healthy control group (t(56) = 2.68, p = 0.01) and associated with VTA hyper-activity during task-based functional MRI at baseline (R = 0.352, p = 0.033). Mesocortical connectivity was also reduced from pre-to-post ezogabine, compared to placebo (significant drug-by-time interaction, F(1,33) = 4.317, p = 0.046). Together this translational work is consistent with preclinical findings highlighting VTA hyper-activity in depression, and suggesting a mechanism of action for KCNQ channel openers in normalizing this hyper-activity in individuals with both depression and anhedonia.

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.

Ketamine, a rapid-acting antidepressant, has undesirable psychotomimetic effects, including a dissociative effect. There is currently no effective strategy to suppress these side effects while preserving its antidepressant effect. Here, we investigated the effects of a D2/D3 receptor antagonist and partial agonists on the psychotomimetic and antidepressant effects of ketamine in mice and humans. Aripiprazole, a partial agonist, attenuated the psychotomimetic effect, but maintaining and even enhancing the antidepressant-like effect of ketamine in the forced swim test, whereas raclopride, an antagonist, suppressed both effects in mice. Brain-wide Fos mapping and its network analysis suggested the ventral tegmental area (VTA) as a critical region for distinguishing the effects of aripiprazole and raclopride. In the chronic stress model, local infusion of raclopride into the VTA inhibited ketamine's antidepressant-like effect, accompanied by activation of dopaminergic neurons, suggesting the inhibitory effect of VTA activation on the antidepressant-like effect of ketamine. Consistently, systemic injections of raclopride and brexpiprazole, a partial agonist similar to aripiprazole but closer to an antagonist (lower Emax), activated dopaminergic neurons in the VTA and suppressed ketamine's antidepressant-like effect in the model when co-administered with ketamine, whereas aripiprazole didn't. In line with these results, in a single-arm, double-blinded clinical study of sequential treatments in depressed patients (N = 9), co-administration of 12 mg of aripiprazole suppressed the dissociative symptoms induced by ketamine while maintaining its antidepressant effects. Together, these findings suggest that fine-tuning dopamine receptor signaling with aripiprazole allows selective suppression of ketamine-induced dissociation preserving its antidepressant effects, and that the combined use of aripiprazole and ketamine may be a preferred therapy for treatment-resistant depression.

Affective disorders, such as depression, are commonly associated with the development of chronic pain, but the underlying mechanisms still remain unclear. The dopaminergic system, located in the midbrain, is considered one of the regions where algesia and emotional processing overlap. This suggests a structural basis hypothesis for the comorbidity of chronic pain and depression, highlighting the interplay between nociceptive and affective processing. But there are more and more evidences show that somatic and head/facial pain involve different neuronal overlap. In previous study, the research show that VTA dopaminergic system involved in pIONT surgery induced depressive-like behaviors in mice. But there still no evidence shows if chronic somatic pain will induce depressive-like behaviors and which neuronal circle pathway is underly. In this study, we assessed depressive-like behaviors and performed artificial interference of VTA (ventral tegmental area) dopaminergic neurons in a mouse model of chronic peripheral neuropathic pain induced by the spared nerve injury (SNI) model. After a 4-week duration of hyperalgesia and allodynia resulting from SNI surgery, social withdraw and other depressive-like behaviors were observed in the SNI group. Furthermore, the dopaminergic cells' excitability in VTA were significantly increased in SNI mice. The excitability alteration was improved play a key role in the development and modulation of the chronic peripheral neuropathic pain-induced depressive-like behaviors. It has been shown pain and affections have structural and functional circuits to interact with each other, therefore the neuroplastic changes and functional role of VTA dopaminergic neurons within these circuits may serve as potential targets for understanding and therapeutically addressing the development of depressive-like symptoms accompanied by prolonged pain syndromes in humans.

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.

During GABAergic synaptic transmission, G protein-coupled GABAB receptors (GBRs) activate K+ channels that prolong the duration of inhibitory postsynaptic potentials (IPSPs). We now show that KCTD16, an auxiliary GBR subunit, anchors hyperpolarization-activated cyclic nucleotide-gated (HCN) channels containing HCN2/HCN3 subunits to GBRs. In dopamine neurons of the VTA (DAVTA neurons), this interaction facilitates activation of HCN channels via hyperpolarization during IPSPs, counteracting the GBR-mediated late phase of these IPSPs. Consequently, disruption of the GBR/HCN complex in KCTD16-/- mice leads to prolonged optogenetic inhibition of DAVTA neuron firing. KCTD16-/- mice exhibit increased anxiety-like behavior in response to stress - a behavior replicated by CRISPR/Cas9-mediated KCTD16 ablation in DAVTA neurons or by intra-VTA infusion of an HCN antagonist in wild-type mice. Our findings support that the retention of HCN channels at GABAergic synapses by GBRs in DAVTA neurons provides a negative feedback mechanism that restricts IPSP duration and mitigates the development of anxiety.

Deep brain stimulation (DBS) of the medial forebrain bundle (mfb) demonstrated anti-depressant effects both clinically and experimentally. Modulation of mesocorticolimbic dopaminergic (DA) activity could contribute-in part-to the therapeutic effects. By comparing selective and pathway specific midbrain DA optogenetic stimulation with the global, non-pathway specific mfb-DBS, the study explored changes in gene-expression of key biomarkers associated with neurocircuitry of depression. Rats received either optogenetic DAergic or mfb-DBS, delivered as acute/single or chronic/repeated stimulation. Micro-dissected regions were prepared for in situ hybridization targeting biomarkers of GABAergic, glutamatergic, and dopaminergic systems. Mfb-DBS mediated DA independent pathway increased GABAergic biomarkers (GABAA, GAD1) in frontal and accumbal regions, not in midbrain. The combinations of low frequency/high pulse width and high frequency/low pulse width stimulation generally increased biomarker expression similarly, but chronic/repetitive stimulation had no accumulative effect. Interestingly, unilateral stimulation had bilateral effects, but stimulation modalities had little impact on DAT and Vglut2 expression. In conclusion, both low and high frequency, acute/single and chronic/repetitive mfb-DBS-but not selective optogenetic stimulation -activated gene expression of biomarkers associated with GABAergic transmission. The increased expression was transitory and less chronic than predicted. Importantly, the study provides evidence that the anti-depressant therapeutic effects of clinical medial forebrain bundle DBS occurs-in part-be via modulation of GABAergic signalling which in turn could regulate the release of dopamine in frontal and accumbal regions. In addition, clinical implication of the data is that unilateral stimulation had bilateral consequences on the gene expression, although the physiological and functional sequelae of this are yet unknown.

Optogenetics and chemogenetics are emerging neuromodulation techniques that have attracted significant attention in recent years. These techniques enable the precise control of specific neuronal types and neural circuits, allowing researchers to investigate the cellular mechanisms underlying depression. The advancement in these techniques has significantly contributed to the understanding of the neural circuits involved in depression; when combined with other emerging technologies, they provide novel therapeutic targets and diagnostic tools for the clinical treatment of depression. Additionally, these techniques have provided theoretical support for the development of novel antidepressants. This review primarily focuses on the application of optogenetics and chemogenetics in several brain regions closely associated with depressive-like behaviors in rodent models, such as the ventral tegmental area, nucleus accumbens, prefrontal cortex, hippocampus, dorsal raphe nucleus, and lateral habenula and discusses the potential and challenges of optogenetics and chemogenetics in future research. Furthermore, this review discusses the potential and challenges these techniques pose for future research and describes the current state of research on sonogenetics and odourgenetics developed based on optogenetics and chemogenetics. Specifically, this study aimed to provide reliable insights and directions for future research on the role of optogenetics and chemogenetics in the neural circuits of depressive rodent models.

Chronic stress is a causal antecedent condition for major depressive disorder and associates with altered patterns of neural connectivity. There are nevertheless important individual differences in susceptibility to chronic stress. How functional connectivity (FC) amongst interconnected, depression-related brain regions associates with resilience and susceptibility to chronic stress is largely unknown. We used resting-state functional magnetic resonance imaging (rs-fMRI) to examine FC between established depression-related regions in susceptible (SUS) and resilient (RES) adult mice following chronic social defeat stress (CSDS). Seed-seed FC analysis revealed that the ventral dentate gyrus (vDG) exhibited the greatest number of FC group differences with other stress-related limbic brain regions. SUS mice showed greater FC between the vDG and subcortical regions compared to both control (CON) or RES groups. Whole brain vDG seed-voxel analysis supported seed-seed findings in SUS mice but also indicated significantly decreased FC between the vDG and anterior cingulate area compared to CON mice. Interestingly, RES mice exhibited enhanced FC between the vDG and anterior cingulate area compared to SUS mice. Moreover, RES mice showed greater FC between the infralimbic prefrontal cortex and the nucleus accumbens shell compared to CON mice. These findings indicate unique differences in FC patterns in phenotypically distinct SUS and RES mice that could represent a neurobiological basis for depression, anxiety, and negative-coping behaviors that are associated with exposure to chronic stress.

The field of psychoneuroimmunology (PNI) aims to uncover the processes and consequences of nervous, immune, and endocrine system relationships. Behavior is a consequence of such interactions and manifests from a complex interweave of factors including immune-to-neural and neural-to-immune communication. Often the signaling molecules involved during a particular episode of neuroimmune activation are not known, but behavioral response provides evidence that bioactives such as neurotransmitters and cytokines are perturbed. Immunobehavioral phenotyping is a first-line approach when examining the neuroimmune system and its reaction to immune stimulation or suppression. Behavioral response is significantly more sensitive than direct measurement of a single specific bioactive and can quickly and efficiently rule in or out relevance of a particular immune challenge or therapeutic to neuroimmunity. Classically, immunobehavioral research was focused on sickness symptoms related to bacterial infection, but neuroimmune activation is now a recognized complication of diseases and disorders ranging from cancer to diabesity to Alzheimer's. Immunobehaviors include lethargy, loss of appetite, and disinterest in social activity/surrounding environment. In addition, neuroimmune activation can diminish physical activity, precipitate feelings of depression and anxiety, and impair cognitive and executive function. Provided is a detailed overview of behavioral tests frequently used to examine neuroimmune activation in mice with a special emphasis on pre-experimental conditions that can confound or prevent successful immunobehavioral experimentation.

Although clinically relevant, evidence for a protective effect of early secure attachment against the development of depressive symptoms in adulthood is still inconsistent. This study used a translational approach to overcome this limitation. The analysis of a non-clinical adult population revealed a moderating effect of secure attachment on depressive symptoms in women only. Thus, we tested the causal link between early attachment with caregiver and adult depressive-like phenotypes in a mouse model of early adversities that is especially effective in females. Repeated cross fostering (RCF) in the first postnatal days prevented the development of pups' secure attachment with the caregiver as tested in a rodent version of the "strange situation"-the standard human test-induced depressive-like behaviors and altered activity of the ventral tegmental area dopamine neurons in adulthood. Finally, a stable alternative caregiver during the RCF experience prevented all these effects, modeling human "earned attachment."

The slow-intrinsic-pacemaker dopaminergic (DA) neurons originating in the ventral tegmental area (VTA) are implicated in various mood- and emotion-related disorders, such as anxiety, fear, stress and depression. Abnormal activity of projection-specific VTA DA neurons is the key factor in the development of these disorders. Here, we describe the crucial role of the NALCN and TRPC6, non-selective cation channels in mediating the subthreshold inward depolarizing current and driving the firing of action potentials of VTA DA neurons in physiological conditions. Furthermore, we demonstrate that down-regulation of TRPC6 protein expression in the VTA DA neurons likely contributes to the reduced activity of projection-specific VTA DA neurons in chronic mild unpredictable stress (CMUS) depressive mice. In consistent with these, selective knockdown of TRPC6 channels in the VTA DA neurons conferred mice with depression-like behavior. This current study suggests down-regulation of TRPC6 expression/function is involved in reduced VTA DA neuron firing and chronic stress-induced depression-like behavior of mice.

Some individuals are susceptible to chronic stress, and others are more resilient. While many brain regions implicated in learning are dysregulated after stress, little is known about whether and how neural teaching signals during stress differ between susceptible and resilient individuals. Here, we seek to determine if activity in the lateral habenula (LHb), which encodes a negative teaching signal, differs between susceptible and resilient mice during stress to produce different outcomes. After (but not before) chronic social defeat stress, the LHb is active when susceptible mice are in proximity of the aggressor strain. During stress, activity is higher in susceptible mice during aggressor interactions, and activation biases mice toward susceptibility. This manipulation generates a persistent and widespread increase in the balance of subcortical vs. cortical activity in susceptible mice. Taken together, our results indicate that heightened activity in the LHb during stress produces lasting brainwide and behavioral substrates of susceptibility.

Parkinson's disease (PD) is a prevalent neurodegenerative condition for which there are symptomatic treatments but no disease-modifying therapies (DMTs). Extensive research over the years has highlighted the need for a multi-target DMT approach in PD that recognizes the various risk factors and their intricate interplay in contributing to PD-related neurodegeneration. Widespread risk factors, such as emotional stress and metabolic factors, have increasingly become focal points of exploration. Our review aims to summarize interactions between emotional stress and selected key players in metabolism, such as insulin, as potential mechanisms underlying neurodegeneration in PD.

The c-Fos as a marker of cell activation is used to identify brain regions involved in stimuli processing. This review summarizes a pattern of c-Fos immunoreactivity and the overlapping brain sub/regions which may provide hints for the identification of neural circuits that underlie depressive- and anxiety-like behaviors of adult male rats following three and six weeks of chronic social isolation (CSIS), relative to controls, as well as the antipsychotic-like effects of olanzapine (Olz), and clozapine (Clz), and the antidepressant-like effect of fluoxetine (Flx) in CSIS relative to CSIS alone. Additionally, drug-treated controls relative to control rats were also characterized. The overlapping rat brain sub/regions with increased expression of c-Fos immunoreactivity following three or six weeks of CSIS were the retrosplenial granular cortex, c subregion, retrosplenial dysgranular cortex, dorsal dentate gyrus, paraventricular nucleus of the thalamus (posterior part, PVP), lateral/basolateral (LA/BL) complex of the amygdala, caudate putamen, and nucleus accumbens shell. Increased activity of the nucleus accumbens core following exposure of CSIS rats either to Olz, Clz, and Flx treatments was found, whereas these treatments in controls activated the LA/BL complex of the amygdala and PVP. We also outline sub/regions that might represent potential neuroanatomical targets for the aforementioned antipsychotics or antidepressant treatments.

Social stress is the most significant source of chronic stress in humans and is commonly associated with health impairment. Individual differences in the behavioral coping responses to stress have been proposed to mediate the negative effects of stress on physical, behavioral and mental health. Animal models, particularly mice, offer valuable insights into the physiological and neurobiological correlates of behavioral coping strategies in response to chronic social stress. Here we aim to identify differences and similarities among stress protocols in mice, with particular attention to how neuroendocrine and/or behavioral responses vary according to different coping strategies, while highlighting the need for standardized approaches in future research. A systematic review was undertaken following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA statement). A total of 213 references were identified by electronic search, and after the screening, 18 articles were found to meet all the established criteria. We analyzed differences in the stress protocol, the characterization and classification of coping strategies and the physiological and behavioral differences according to coping. The results show that differences in behavioural expression under chronic social stress (coping) may also be associated with physiological differences and differential susceptibility to disease. However, this review also underlines the importance of a cautious interpretation of the results obtained. The lack of consistency in the nomenclature and procedures associated with the study of coping strategies for social stress, as well as the absence of a uniform classification, highlight the importance of using a common language when approaching the study of coping strategies. Thereby, this review encourages the development of a more defined method and criteria for assessing coping strategies, based on both behavioral and biological indicators.

Some individuals are susceptible to the experience of chronic stress and others are more resilient. While many brain regions implicated in learning are dysregulated after stress, little is known about whether and how neural teaching signals during stress differ between susceptible and resilient individuals. Here, we seek to determine if activity in the lateral habenula (LHb), which encodes a negative teaching signal, differs between susceptible and resilient mice during stress to produce different outcomes. After, but not before, chronic social defeat stress (CSDS), the LHb is active when susceptible mice are in the proximity of the aggressor strain. During stress itself, LHb activity is higher in susceptible mice during aggressor proximity, and activation of the LHb during stress biases mice towards susceptibility. This manipulation generates a persistent and widespread increase in the balance of subcortical versus cortical activity in susceptible mice. Taken together, our results indicate that heightened activity in the LHb during stress produces lasting brainwide and behavioral substrates of susceptibility.

Robust epidemiological evidence of risk and protective factors for psychosis is essential to inform preventive interventions. Previous evidence syntheses have classified these risk and protective factors according to their strength of association with psychosis. In this critical review we appraise the distinct and overlapping mechanisms of 25 key environmental risk factors for psychosis, and link these to mechanistic pathways that may contribute to neurochemical alterations hypothesised to underlie psychotic symptoms. We then discuss the implications of our findings for future research, specifically considering interactions between factors, exploring universal and subgroup-specific factors, improving understanding of temporality and risk dynamics, standardising operationalisation and measurement of risk and protective factors, and developing preventive interventions targeting risk and protective factors.

Peri-operative hemorrhagic shock and resuscitation (HSR), a severe traumatic stress, is closely associated with post-operative anxiety, depression, and cognitive dysfunction, subsequently causing a serious burden on families and society. Following the co-release of corticotropin-releasing factor and catecholamine, traumatic stress activates dopaminergic neurons, increasing the addictive behavior and neurocognitive impairment risks. This study investigates the association between cognitive dysfunction and dopaminergic neurons in the mPFC under HSR conditions. This study established an HSR model by bleeding and re-transfusion in the mice. After HSR exposure, a dopamine D1 receptor antagonist, SKF-83566, was administered intraperitoneally for three consecutive days. Novel object recognition (NOR), conditioned fearing (FC), and conditioned place preference (CPP) were used to assess cognitive changes 16 days after HSR exposure. Local field potential (LFP) in the mPFC was also investigated during the novel object exploration. Compared with the mice exposed to sham, there was a significant decrease in the object recognition index, a reduction in context- and tone-related freezing time, an increase in CPP values, a downregulation of β-power but upregulation of γ-power in the mPFC in the mice exposed to HSR. Moreover, the mice exposed to HSR showed significantly upregulated TH-positive cell number, cleaved caspase-1- and TH-positive cells, and interleukin (IL)-1β/18 expression in the mPFC compared with sham; SKF-83566 could partially reverse these alternations. The HSR caused excessive dopaminergic signaling and cognitive dysfunction in the mPFC, a condition that might be ameliorated using a dopamine D1 receptor inhibitor.

The potential brain mechanism underlying resilience to socially transferred allodynia remains unknown. Here, we utilize a well-established socially transferred allodynia paradigm to segregate male mice into pain-susceptible and pain-resilient subgroups. Brain screening results show that ventral tegmental area glutamatergic neurons are selectively activated in pain-resilient mice as compared to control and pain-susceptible mice. Chemogenetic manipulations demonstrate that activation and inhibition of ventral tegmental area glutamatergic neurons bi-directionally regulate resilience to socially transferred allodynia. Moreover, ventral tegmental area glutamatergic neurons that project specifically to the nucleus accumbens shell and lateral habenula regulate the development and maintenance of the pain-resilient phenotype, respectively. Together, we establish an approach to explore individual variations in pain response and identify ventral tegmental area glutamatergic neurons and related downstream circuits as critical targets for resilience to socially transferred allodynia and the development of conceptually innovative analgesics.

Accompanied by a rapid and effective antidepressant effect, electroconvulsive shock (ECS) can also induce learning and memory impairment. Our previous research reported that metaplasticity is involved in this process. However, the mechanisms still remain unclear. This study investigated the role of I h current in the metaplastic changes and learning and memory impairment induced by ECS in depressive rats.

Depressive rats received ECS after modelling using chronic unpredictable. ZD7288, a type of I h current inhibitor was used to verify the effect of I h current. The sucrose preference test and Morris water maze were used for behavior testing. Changes in metaplasticity was assessed with the LTD/LTP threshold by stimulation at different frequencies. Spontaneous and evoked action potentials (APs) were measured to confirm difference of neuronal excitability. Additionally, the amplitude of I h current was analyzed.

ECS exerts antidepressant effect, but also induce spatial learning and memory dysfunction. ECS up-regulates the LTD/LTP threshold. In rats treated with ECS, the frequency of spontaneous and evoked APs is significantly reduced. In addition, ECS induces changes in the intrinsic properties of AP, including a decrease of AP-half width and peak amplitude, and an increase in AP time to peak and post-hyperpolarization potential amplitude. In particular, ECS increases both instantaneous and steady-state I h currents. However, Inhibition of I h current with ZD7288 results in a relief of learning and memory impairment and a decrease in threshold, as well as a significant reversal of whole-cell electrophysiological changes.

ECS-induced learning and memory impairment is caused by neuronal hypoexcitability mediated metaplasticity, and upregulation of LTD/LTP threshold by an increase in I h current.

Social behaviour is essential for animal survival, and the hypothalamic neuropeptide oxytocin (OXT) critically impacts bonding, parenting, and decision-making. Dopamine (DA), is released by ventral tegmental area (VTA) dopaminergic neurons, regulating social cues in the mesolimbic system. Despite extensive exploration of OXT and DA roles in social behaviour independently, limited studies investigate their interplay. This narrative review integrates insights from human and animal studies, particularly rodents, emphasising recent research on pharmacological manipulations of OXT or DA systems in social behaviour. Additionally, we review studies correlating social behaviour with blood/cerebral OXT and DA levels. Behavioural facets include sociability, cooperation, pair bonding and parental care. In addition, we provide insights into OXT-DA interplay in animal models of social stress, autism, and schizophrenia. Emphasis is placed on the complex relationship between the OXT and DA systems and their collective influence on social behaviour across physiological and pathological conditions. Understanding OXT and DA imbalance is fundamental for unravelling the neurobiological underpinnings of social interaction and reward processing deficits observed in psychiatric conditions.

Ghrelin, a hormone secreted by the stomach, binds to the growth hormone secretagogue receptor (GHSR) in various brain regions to produce a number of behavioral effects that include increased feeding motivation. During social defeat stress, ghrelin levels rise in correlation with increased feeding and potentially play a role in attenuating the anxiogenic effects of social defeat. One region implicated in the feeding effects of ghrelin is the ventral tegmental area (VTA), a region implicated in reward seeking behaviors, and linked to social defeat in mice. Here we examined the role of GHSR signaling in the VTA in feeding behavior in mice exposed to social defeat stress. Male C57BL/J6 mice that were socially defeated once daily for 3 weeks ate more, had higher plasma ghrelin level and increased GHSR expression in the VTA compared to non-stressed mice. Socially defeated GHSR KO mice failed to increase their caloric intake in response to this stressor but rescue of GHSR expression in the VTA restored feeding responses. Finally, we pharmacologically blocked VTA GHSR signalling with JMV2959 infused via an indwelling VTA cannula connected to a minipump. Vehicle-treated mice increased their caloric intake during social defeat, but JMV2959-infusions attenuated feeding responses and increased anxiety-like behaviors. The data suggest that GHSR signalling in the VTA is critical for the increases in appetite observed during chronic social defeat stress. Furthermore, these data support the idea that GHSR signaling in the VTA may also have anxiolytic effects, and blocking GHSR in this region may result in an anxiety-like phenotype.

Optogenetics has made substantial contributions to our understanding of the mechanistic underpinnings of depression. This systematic review employs quantitative analysis to investigate the impact of optogenetic stimulation in mice and rats on behavioral alterations in social interaction, sucrose consumption, and mobility. The review analyses optogenetic behavioral studies using standardized behavioral tests to detect behavioral changes induced via optogenetic stimulation in stressed or stress-naive mice and rats. Behavioral changes were evaluated as either positive, negative, or not effective. The analysis comprises the outcomes of 248 behavioral tests of 168 studies described in 37 articles, including negative and null results. Test outcomes were compared for each behavior, depending on the animal cohort, applied type of stimulation and the stimulated neuronal circuit and cell type. The presented synthesis contributes toward a comprehensive picture of optogenetic behavioral research in the context of depression.

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.

How mood interacts with information processing in the brain is thought to mediate the maladaptive behaviors observed in depressed individuals. However, the neural mechanisms underlying impairments in emotion-cognition interactions are poorly understood. This includes influencing the balance between how past-sensitive vs. future-looking one is during decision-making. Recent insights from the field of neuroeconomics offer novel approaches to study changes in such valuation processes in a manner that is biologically tractable and readily translatable across species. We recently discovered that rodents are sensitive to "sunk costs" - a feature of higher cognition previously thought to be unique to humans. The sunk costs bias describes the phenomenon in which an individual overvalues and escalates commitment to continuing an ongoing endeavor, even if suboptimal, as a function of irrecoverable past (sunk) losses - information that, according to classic economic theory, should be ignored. In the present study, mice were exposed to chronic social defeat stress paradigm, a well-established animal model used for the study of depression. Mice were then tested on our longitudinal neuroeconomic foraging task, Restaurant Row. We found mice exposed to this severe stressor displayed an increased sensitivity to sunk costs, without altering overall willingness to wait. Mice were then randomly assigned to receive a single intraperitoneal injection of either saline or ketamine (20 mg/kg). We discovered that stress-induced hypersensitivity to sunk costs was renormalized following a single dose of ketamine. Interestingly, in non-defeated mice, ketamine treatment completely abolished sunk cost sensitivity, causing mice to no longer value irrecoverable losses during re-evaluation decisions who instead based choices solely on the future investment required to obtain a goal. These findings suggest that the antidepressant effects of ketamine may be mediated in part through changes in the processing of past-sensitive information during on-going decision-making, reducing its weight as a potential source of cognitive dissonance that could modulate behavior and instead promoting more future-thinking behavior.

The midbrain dopamine system is a sophisticated hub that integrates diverse inputs to control multiple physiological functions, including locomotion, motivation, cognition, reward, as well as maternal and reproductive behaviors. Dopamine is a neurotransmitter that binds to G-protein-coupled receptors. Dopamine also works together with other neurotransmitters and various neuropeptides to maintain the balance of synaptic functions. The dysfunction of the dopamine system leads to several conditions, including Parkinson's disease, Huntington's disease, major depression, schizophrenia, and drug addiction. The ventral tegmental area (VTA) has been identified as an important relay nucleus that modulates homeostatic plasticity in the midbrain dopamine system. Due to the complexity of synaptic transmissions and input-output connections in the VTA, the structure and function of this crucial brain region are still not fully understood. In this review article, we mainly focus on the cell types, neurotransmitters, neuropeptides, ion channels, receptors, and neural circuits of the VTA dopamine system, with the hope of obtaining new insight into the formation and function of this vital brain region.

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.

The integration of optogenetics in the trigeminal pain circuitry broadens and reinforces existing pain investigations. Similar to research on spinal neuropathic pain, the exploration of the underlying determinants of orofacial pain is expanding. Optogenetics facilitates more direct, specific, and subtle investigations of the neuronal circuits involved in orofacial pain. One of the most significant concerns of both dentistry and medicine is trigeminal neuralgia (TN) management due to its substantial impact on a patient's quality of life. Our objective is to gather insights from preclinical studies conducted in TN employing an optogenetic paradigm, thereby extending the prospects for in-depth neurobiological research. This review highlights optogenetic research in trigeminal pain circuitry involving TN. We outline the central and peripheral regions associated with pain-that have been investigated using optogenetics in the trigeminal pain circuitry. The study further reports its scope and limitations as well as its potential for future applications from bench to bedside.

Persistent stress increases the probability for developing depression significantly thereafter. Repeated social defeat stress is a widely used model to investigate depressive-like behavior in preclinical models. Hence, the repeated social defeat stress model provided an ideal animal model, through which the hypotheses of prevention and treatment can be investigated. We have successfully induced depressive-like behavior for male C57BL/6J mice with this model. Here, we reported that certain level of during-stress social interactions with single female or multiple male peer(s) exerted a positive role in preventing the development of depressive-like behavior induced by repeated social defeat stress. Our data suggested that the stress-susceptible mice may benefit from positive social interaction, which reduces the chance for depressive-like behavior development. Since numerous studies indicate that the metabotropic glutamate receptor 5 (mGluR5) plays an important role in various cognitive functions, we further investigate the treatment effect of 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) benzamide (CDPPB) on the depressive-like behavior induced by repeated social defeat stress. Most importantly, robust anti-depressant effects have been achieved through modulating the mGluR5 function. We found that single oral dose administration of CDPPB (20 mg/kg), to some extent, alleviated the social avoidance behaviors for the stress-susceptible mice. Our data implies that the CDPPB, a positive allosteric modulator of mGluR5, is a promising anti-depressant candidate with limited side effect.

Melancholic depression, marked by typical symptoms of anhedonia, is regarded as a homogeneous subtype of major depressive disorder (MDD). However, little attention was paid to underlying mechanisms of melancholic depression. This study aims to examine functional connectivity of the reward circuit associated with anhedonia symptoms in melancholic depression.

Fifty-nine patients with first-episode drug- naive MDD, including 31 melancholic patients and 28 non-melancholic patients, were recruited and underwent resting-state functional magnetic resonance imaging (rs-fMRI). Thirty-two healthy volunteers were recruited as controls. Bilateral nucleus accumbens (NAc) were selected as seed points to form functional NAc network. Then support vector machine (SVM) was used to distinguish melancholic patients from non-melancholic patients.

Relative to non-melancholic patients, melancholic patients displayed increased functional connectivity (FC) between bilateral NAc and right middle frontal gyrus (MFG) and between right NAc and left cerebellum lobule VIII. Compared to healthy controls, melancholic patients showed increased FC between right NAc and right lingual gyrus and between left NAc and left postcentral gyrus; non-melancholic patients had increased FC between bilateral NAc and right lingual gyrus. No significant correlations were observed between altered FC and clinical variables in melancholic patients. SVM results showed that FC between left NAc and right MFG could accurately distinguish melancholic patients from non-melancholic patients.

Melancholic depression exhibited different patterns of functional connectivity of the reward circuit relative to non-melancholic patients. This study highlights the significance of the reward circuit in the neuropathology of melancholic depression.

Migraine is a highly prevalent neurological disorder. Among the risk factors identified, psychiatric comorbidities, such as depression, seem to play an important role in its onset and clinical course. Patients with migraine are 2.5 times more likely to develop a depressive disorder; this risk becomes even higher in patients suffering from chronic migraine or migraine with aura. This relationship is bidirectional, since depression also predicts an earlier/worse onset of migraine, increasing the risk of migraine chronicity and, consequently, requiring a higher healthcare expenditure compared to migraine alone. All these data suggest that migraine and depression may share overlapping biological mechanisms. Herein, this review explores this topic in further detail: firstly, by introducing the common epidemiological and risk factors for this comorbidity; secondly, by focusing on providing the cumulative evidence of common biological aspects, with a particular emphasis on the serotoninergic system, neuropeptides such as calcitonin-gene-related peptide (CGRP), pituitary adenylate cyclase-activating polypeptide (PACAP), substance P, neuropeptide Y and orexins, sexual hormones, and the immune system; lastly, by remarking on the future challenges required to elucidate the etiopathological mechanisms of migraine and depression and providing updated information regarding new key targets for the pharmacological treatment of these clinical entities.

Despite women representing most of those affected by major depression, preclinical studies have focused almost exclusively on male subjects, partially due to a lack of ideal animal paradigms. As the persistent need regarding the sex balance of neuroscience research and female-specific pathology of mental disorders surges, the establishment of natural etiology-based and systematically validated animal paradigms for depression with female subjects becomes an urgent scientific problem. This study aims to establish, characterize, and validate a "Multiple Integrated Social Stress (MISS)" model of depression in female C57BL/6J mice by manipulating and integrating daily social stressors that females are experiencing. Female C57BL/6J mice randomly experienced social competition failure in tube test, modified vicarious social defeat stress, unescapable overcrowding stress followed by social isolation on each day, for ten consecutive days. Compared with their controls, female MISS mice exhibited a relatively decreased preference for social interaction and sucrose, along with increased immobility in the tail suspension test, which could last for at least one month. These MISS mice also exhibited increased levels of blood serum corticosterone, interleukin-6 L and 1β. In the pharmacological experiment, MISS-induced dysfunctions in social interaction, sucrose preference, and tail suspension tests were amended by systematically administrating a single dose of sub-anesthetic ketamine, a rapid-onset antidepressant. Compared with controls, MISS females exhibited decreased c-Fos activation in their anterior cingulate cortex, prefrontal cortex, nucleus accumbens and some other depression-related brain regions. Furthermore, 24 h after the last exposure to the paradigm, MISS mice demonstrated a decreased center zone time in the open field test and decreased open arm time in the elevated plus-maze test, indicating anxiety-like behavioral phenotypes. Interestingly, MISS mice developed an excessive nesting ability, suggesting a likely behavioral phenotype of obsessive-compulsive disorder. These data showed that the MISS paradigm was sufficient to generate pathological profiles in female mice to mimic core symptoms, serum biochemistry and neural adaptations of depression in clinical patients. The present study offers a multiple integrated natural etiology-based animal model tool for studying female stress susceptibility.

Chronic pain and negative emotions are often linked, and both can impact the reward circuit. The use of electroacupuncture (EA) has been found to regulate and improve these conditions. This study explores the potential mechanism of chronic pain relief by adding acupoints with emotional regulation effect to the basis of routine EA analgesia, to optimize the acupoint compatibility scheme of EA in the treatment of analgesia.

For this study, 42 male Wistar rats were used. Recombinant adeno-associated viruses were used to label and regulate the activity of dopamine (DA) neurons. The rat model was established by complete Freund's adjuvant (CFA). Lower limb electroacupuncture (LEA) was applied to the ST36 and BL60 acupoints. In addition, LEA + scalp EA (SEA) was given using the GV20 and GV24+ acupoints besides ST36 and BL60. To evaluate the pain threshold, we measured 50% paw withdrawal thresholds and thermal paw withdrawal latencies. Negative emotions were evaluated through the open field test, marble-burying test, sucrose preference test, and forced swimming test. Moreover, the conditional place preference test was conducted to measure the reward behavior in response to pain relief. Immunofluorescence staining, Western blotting, and qPCR were used to detect the activity of the VTADA-NAc reward circuit.

The injection of CFA significantly lowered the pain threshold. As the pain persisted, the anxiety and depression-like behaviors escalated while the response to reward reduced. Meanwhile, the VTADA-NAc pathway was suppressed with pain chronification. However, activating DA neurons in VTA attenuated the effects induced by CFA. LEA could relieve chronic pain, negative emotions, and reward disorders, while also activating the VTADA-NAc pathway. In addition, LEA + SEA exhibited a more pronounced effect compared with LEA alone. Nevertheless, chemogenetic inhibition of DA neurons decreased the efficacy of LEA + SEA in the treatment of chronic pain and associated comorbidities.

Adding SEA to conventional LEA effectively alleviates negative emotions and chronic pain, potentially due to the activation of the VTADA-NAc reward neural circuit. Thus, LEA + SEA is a more effective treatment for hyperalgesia and associated negative emotions compared with LEA alone.