Changes in SLITRK1 Level in the Amygdala Mediate Chronic Neuropathic Pain-Induced Anxio-Depressive Behaviors in Mice.

BACKGROUND: Comorbid chronic neuropathic pain (NPP) and anxio-depressive disorders (ADD) have become a serious global public-health problem. The SLIT and NTRK-like 1 (SLITRK1) protein is important for synaptic remodeling and is highly expressed in the amygdala, an important brain region involved in various emotional behaviors. We examined whether SLITRK1 protein in the amygdala participates in NPP and comorbid ADD. METHODS: A chronic NPP mouse model was constructed by L5 spinal nerve ligation; changes in chronic pain and ADD-like behaviors were measured in behavioral tests. Changes in SLITRK1 protein and excitatory synaptic functional proteins in the amygdala were measured by immunofluorescence and Western blot. Adeno-associated virus was transfected into excitatory synaptic neurons in the amygdala to up-regulate the expression of SLITRK1. RESULTS: Chronic NPP-related ADD-like behavior was successfully produced in mice by L5 ligation. We found that chronic NPP and related ADD decreased amygdalar expression of SLITRK1 and proteins important for excitatory synaptic function, including Homer1, postsynaptic density protein 95 (PSD95), and synaptophysin. Virally-mediated SLITRK1 overexpression in the amygdala produced a significant easing of chronic NPP and ADD, and restored the expression levels of Homer1, PSD95, and synaptophysin. CONCLUSION: Our findings indicated that SLITRK1 in the amygdala plays an important role in chronic pain and related ADD, and may prove to be a potential therapeutic target for chronic NPP-ADD comorbidity.

The relationship between anxiety symptoms and disturbances in biological rhythms in patients with depression.

BACKGROUND: Biological rhythms denote the cyclical patterns of life activities anchored to a 24-hour cycle. Research shows that depression exhibits disturbances in biological rhythms. Yet, the relationship between these biological rhythms and concomitant anxiety symptoms is insufficiently investigated in structured clinical assessments. METHODS: This multicenter study, carried out in four Chinese hospitals, comprehensively examined the relationship between anxiety and disruptions in biological rhythms among patients with depression. The study encompassed 218 patients diagnosed with depression and 205 matched healthy controls. The Chinese version of the Biological Rhythms Interview of Assessment in Neuropsychiatry was utilized to evaluate the participants' biological rhythms, focusing on four dimensions: sleep, activity, social, and diet. RESULTS: In patients with depression, there is a significant positive correlation between the severity of anxiety symptoms and the disturbances in biological rhythms. The severity of anxiety and depression, along with the quality of life, are independently associated with disruptions in biological rhythms. The mediation model reveals that anxiety symptoms mediate the relationship between depressive symptoms and biological rhythms. CONCLUSION: This research highlights the role of anxiety within the spectrum of depressive disorders and the associated disturbances in biological rhythms. Our findings shed light on potential pathways towards more targeted preventive strategies and therapeutic interventions for individuals battling depression and anxiety.

Static and dynamic functional connectivity of the habenula in late-life depression patient with suicidal ideation.

BACKGROUND: Suicide is one of the most lethal complications of late-life depression (LLD), and habenular dysfunction may be involved in depression-related suicidality and may serve as a potential target for alleviating suicidal ideation. This study aimed to investigate abnormal functional connectivity of the habenula in LLD patients with suicidal ideation. METHODS: One hundred twenty-seven patients with LLD (51 with suicidal ideation (LLD-S) and 76 without suicidal ideation (LLD-NS)) and 75 healthy controls (HCs) were recruited. The static functional connectivity (sFC) and dynamic functional connectivity (dFC) between the habenula and the whole brain were compared among the three groups, and correlation and moderation analyses were applied to investigate whether suicidal ideation moderated the relationships of habenular FC with depressive symptoms and cognitive impairment. RESULTS: The dFC between the right habenula and the left orbitofrontal cortex (OFC) increased in the following order: LLD-S > LLD-NS > control. No significant difference in the habenular sFC was found among the LLD-S, LLD-NS and control groups. The dFC between the right habenula and the left OFC was positively associated with global cognitive function and visuospatial skills, and the association between this dFC and visuospatial skills was moderated by suicidal ideation in patients with LLD. CONCLUSION: The increased variability in dFC between the right habenula and left OFC was more pronounced in the LLD-S group than in the LLD-NS group, and the association between habenular-OFC dFC and visuospatial skills was moderated by suicidal ideation in patients with LLD.

Frontal Theta Asymmetry may be a new target for reducing the severity of depression and improving cognitive function in depressed patients.

BACKGROUND: The prevalence of depressive disorder is increasing due to a variety of factors, which brings a huge strain on individuals, families and society. This study aims to investigate whether there is Frontal Theta Asymmetry (FTA) in depressed patients, and whether FTAs are related to depression severity and cognitive function changes in depressed patients. METHODS: Participants who met the inclusion criteria were enrolled in this study. Socio-demographic data of each participant were recorded. Zung's self-rating Depression Scale was used to assess the depression status of participants. P300 was used to evaluate the cognitive function of participants. EEG data from participants were collected by the NeuroScan SynAmps RT EEG system. t-test, Wilcoxon rank-sum test and Chi-square test were used to detect the differences of different variables between the two groups. Multiple linear regression analysis and multiple logistic regression analysis were used to analyze relationships between FTAs in different regions and participants' depression status and cognitive function. RESULTS: A total of 66 depressed participants and 47 healthy control participants were included in this study. The theta spectral power of the left frontal lobe was slightly stronger than that of the right frontal lobe in the depression group, while the opposite was true in the healthy control group. The FTA in F3/F4 had certain effects on the emergence of depression in participants, the emergence of depression in participants and Changes in cognitive function. CONCLUSIONS: FTAs are helpful to assess the severity of depression and early identify cognitive impairment in patients with depression.

Mood and physiological effects of visual stimulation with images of the natural environment in individuals with depressive and anxiety disorders.

BACKGROUND: Nature therapies are gaining attention as non-pharmacological treatments for depressive and anxiety disorders, but research on their effectiveness in patients is limited. This study investigates the mood-improving effects of visual stimulation with natural environmental images in patients with depressive and anxiety disorders. METHODS: We conducted a randomized crossover comparison trial involving 60 right-handed adult participants with depressive or anxiety disorders and receiving outpatient treatment. Visual stimuli of natural environments consisted of green-themed nature images, while the control stimuli featured urban scenes dominated by buildings. The stimulation lasted for 3 min, during which orbital prefrontal brain activity was measured using a 2-channel Near-infrared Spectroscopy (NIRS) system, and heart rate variability was assessed using fingertip accelerated plethysmography. RESULTS: Mood enhancement effects were observed in both the depressive and anxiety disorder groups following visual stimulation with nature images. In the depression group, orbital prefrontal oxygenated hemoglobin concentration significantly increased after visual stimulation with nature images, while there were no significant changes in the anxiety group. However, in the anxiety group, a correlation was found between reduced orbital prefrontal oxygenated hemoglobin in response to nature images and increased mood-enhancement. Furthermore, the severity of depressive symptoms did not significantly affect the intervention effects, whereas heightened anxiety symptoms was associated with a smaller mood enhancement effect. DISCUSSION: Our study demonstrates the benefits of nature image stimulation for patients with depressive and anxiety disorders. Differential orbital prefrontal brain activity impacts notwithstanding, both conditions exhibited mood enhancement, affirming the value of nature image stimulation.

Hippocampal MSK1 regulates the behavioral and biological responses of mice to chronic social defeat stress: Involving of the BDNF-CREB signaling and neurogenesis.

Depression is one of the most common psychiatric diseases in the 21st century, while its pathogenesis is not yet fully understood. Currently, besides to the monoaminergic system, the brain-derived neurotrophic factor (BDNF)-cAMP response element-binding protein (CREB) signaling is one of the most attractive signaling pathways for treating depression. Mitogen and stress-activated kinase (MSK) 1 and 2 are nuclear proteins activated downstream of the ERK1/2 or p38 MAPK pathways, and it has been demonstrated that MSKs are involved in the BDNF-CREB signaling. Here we assumed that MSKs may play a role in depression, and various methods including the chronic social defeat stress (CSDS) model of depression, western blotting, immunofluorescence and virus-mediated gene transfer were used together. It was found that CSDS fully enhanced the expression of both phosphorylated MSK1 and total MSK1 in the hippocampus but not the medial prefrontal cortex (mPFC). CSDS did not influence the expression of phosphorylated MSK2 and total MSK2 in the two brain regions. Genetic over-expression of hippocampal MSK1 fully prevented not only the CSDS-induced depressive-like behaviors but also the CSDS-induced dysfunction in the hippocampal BDNF-CREB signaling and neurogenesis in mice, while genetic knockdown of hippocampal MSK1 aggravated the CSDS-induced depressive-like symptomatology in mice. Our results collectively suggest that although CSDS evidently enhances the activity of hippocampal MSK1, it is not a contributor to the CSDS-induced dysfunction in the brain but a defensive feedback regulator which protects against CSDS. Therefore, hippocampal MSK1 participates in the pathogenesis of depression and is a feasible and potential antidepressant target.

Resting-state functional connectivity in adolescents experiencing subclinical and clinical symptoms of depression: a mini-review of recent evidence.

Adolescence is a developmental period associated with major neural reorganization and the onset of many psychological disorders. Depression in particular is prevalent and impairing in adolescents and rates have been rising in recent years. Recent advances in the neurobiology of adolescent depression contribute to a better understanding of functional connectivity among neural networks and represent a promising start for determining biomarkers of depression and potential areas of intervention.

Identifying subtypes of depression in clinician-annotated text: a retrospective cohort study.

Current criteria for depression are imprecise and do not accurately characterize its distinct clinical presentations. As a result, its diagnosis lacks clinical utility in both treatment and research settings. Data-driven efforts to refine criteria have typically focused on a limited set of symptoms that do not reflect the disorder's heterogeneity. By contrast, clinicians often write about patients in depth, creating descriptions that may better characterize depression. However, clinical text is not commonly used to this end. Here we show that clinically relevant depressive subtypes can be derived from unstructured electronic health records. Five subtypes were identified amongst 18,314 patients with depression treated at a large mental healthcare provider by using unsupervised machine learning: severe-typical, psychotic, mild-typical, agitated, and anergic-apathetic. Subtypes were used to place patients in groups for validation; groups were found to be associated with future outcomes and characteristics that were consistent with the subtypes. These associations suggest that these categorizations are actionable due to their validity with respect to disease prognosis. Moreover, they were derived with automated techniques that might theoretically be widely implemented, allowing for future analyses in more varied populations and settings. Additional research, especially with respect to treatment response, may prove useful in further evaluation.

Repeated exposure with short-term behavioral stress resolves pre-existing stress-induced depressive-like behavior in mice.

Chronic stress induces adaptive changes in the brain via the cumulative action of glucocorticoids, which is associated with mood disorders. Here we show that repeated daily five-minute restraint resolves pre-existing stress-induced depressive-like behavior in mice. Repeated injection of glucocorticoids in low doses mimics the anti-depressive effects of short-term stress. Repeated exposure to short-term stress and injection of glucocorticoids activate neurons in largely overlapping regions of the brain, as shown by c-Fos staining, and reverse distinct stress-induced gene expression profiles. Chemogenetic inhibition of neurons in the prelimbic cortex projecting to the nucleus accumbens, basolateral amygdala, or bed nucleus of the stria terminalis results in anti-depressive effects similarly to short-term stress exposure, while only inhibition of neurons in the prelimbic cortex projecting to the bed nucleus of the stria terminalis rescues defective glucocorticoid release. In summary, we show that short-term stress can reverse adaptively altered stress gains and resolve stress-induced depressive-like behavior.

Comparing underlying mechanisms of depression in multiple sclerosis and rheumatoid arthritis.

Multiple Sclerosis (MS) and Rheumatoid Arthritis (RA) are common, chronic, autoimmune diseases affecting many people worldwide. While clinically very different in their phenotype, both diseases are thought to have an autoimmune-mediated origin. MS and RA share genetic similarities, and in both diseases, antibodies against host antigens can be found. Aside from the well-known somatic symptoms, many RA patients also show signs and symptoms of psychiatric illnesses, of which depression is the most common diagnosis. In this commentary, both diseases will be introduced and briefly characterized individually and then compared. Depression will be introduced as one of the most frequent psychiatric diseases in the general population. This paper focuses on presenting the possible causes, including psychosocial factors, genetics, and immunologic mechanisms. Hypotheses aimed to explain the higher incidence of depression in these two seemingly different autoimmune diseases will be discussed.

Correlation of Antibodies to Neurotransmitters in the Sera of Women with Alcohol Dependence and Depressive Disorders.

Comparative analysis of blood sera from women with alcohol dependence and depressive disorders or from conditionally healthy women revealed reduced level of antibodies to dopamine, norepinephrine, serotonin, glutamate, and GABA in blood serum in women with dysthymic disorder and a depressive episode and their increased content in women with alcohol dependence in combination with depressive disorders.

Assessing the effect of interaction between C-reactive protein and gut microbiome on the risks of anxiety and depression.

Cumulative evidence shows that gut microbiome can influence brain function and behavior via the inflammatory processes. However, the role of interaction between gut dysbiosis and C-reactive protein (CRP) in the development of anxiety and depression remains to be elucidated. In this study, a total of 3321 independent single nucleotide polymorphism (SNP) loci associated with gut microbiome were driven from genome-wide association study (GWAS). Using individual level genotype data from UK Biobank, we then calculated the polygenetic risk scoring (PRS) of 114 gut microbiome related traits. Moreover, regression analysis was conducted to evaluate the possible effect of interaction between gut microbiome and CRP on the risks of Patient Health Questionnaire-9 (PHQ-9) (N = 113,693) and Generalized Anxiety Disorder-7 (GAD-7) (N = 114,219). At last, 11 candidate CRP × gut microbiome interaction with suggestive significance was detected for PHQ-9 score, such as F_Ruminococcaceae (ß = - 0.009, P = 2.2 × 10-3), G_Akkermansia (ß = - 0.008, P = 7.60 × 10-3), F_Acidaminococcaceae (ß = 0.008, P = 1.22 × 10-2), G_Holdemanella (ß = - 0.007, P = 1.39 × 10-2) and O_Lactobacillales (ß = 0.006, P = 1.79× 10-2). 16 candidate CRP × gut microbiome interaction with suggestive significance was detected for GAD-7 score, such as O_Bacteroidales (ß = 0.010, P = 4.00× 10-4), O_Selenomonadales (ß = - 0.010, P = 1.20 × 10-3), O_Clostridiales (ß = 0.009, P = 2.70 × 10-3) and G_Holdemanella (ß = - 0.008, P = 4.20 × 10-3). Our results support the significant effect of interaction between CRP and gut microbiome on the risks of anxiety and depression, and identified several candidate gut microbiomes for them.

Tianeptine modulates synaptic vesicle dynamics and favors synaptic mitochondria processes in socially isolated rats.

Deregulation of synaptic function and neurotransmission has been linked with the development of major depression disorder (MDD). Tianeptine (Tian) has been used as antidepressant with anxiolytic properties and recently as a nootropic to improve cognitive performance, but its mechanism of action is unknown. We conducted a proteomic study on the hippocampal synaptosomal fractions of adult male Wistar rats exposed to chronic social isolation (CSIS, 6 weeks), an animal model of depression and after chronic Tian treatment in controls (nootropic effect) and CSIS-exposed rats (lasting 3 weeks of 6-week CSIS) (therapeutic effect). Increased expression of Syn1 and Camk2-related neurotransmission, vesicle transport and energy processes in Tian-treated controls were found. CSIS led to upregulation of proteins associated with actin cytoskeleton, signaling transduction and glucose metabolism. In CSIS rats, Tian up-regulated proteins involved in mitochondrial energy production, mitochondrial transport and dynamics, antioxidative defense and glutamate clearance, while attenuating the CSIS-increased glycolytic pathway and cytoskeleton organization proteins expression and decreased the expression of proteins involved in V-ATPase and vesicle endocytosis. Our overall findings revealed that synaptic vesicle dynamics, specifically exocytosis, and mitochondria-related energy processes might be key biological pathways modulated by the effective nootropic and antidepressant treatment with Tian and be a potential target for therapeutic efficacy of the stress-related mood disorders.

Neuronal Nsun2 deficiency produces tRNA epitranscriptomic alterations and proteomic shifts impacting synaptic signaling and behavior.

Epitranscriptomic mechanisms linking tRNA function and the brain proteome to cognition and complex behaviors are not well described. Here, we report bi-directional changes in depression-related behaviors after genetic disruption of neuronal tRNA cytosine methylation, including conditional ablation and transgene-derived overexpression of Nsun2 in the mouse prefrontal cortex (PFC). Neuronal Nsun2-deficiency was associated with a decrease in tRNA m5C levels, resulting in deficits in expression of 70% of tRNAGly isodecoders. Altogether, 1488/5820 proteins changed upon neuronal Nsun2-deficiency, in conjunction with glycine codon-specific defects in translational efficiencies. Loss of Gly-rich proteins critical for glutamatergic neurotransmission was associated with impaired synaptic signaling at PFC pyramidal neurons and defective contextual fear memory. Changes in the neuronal translatome were also associated with a 146% increase in glycine biosynthesis. These findings highlight the methylation sensitivity of glycinergic tRNAs in the adult PFC. Furthermore, they link synaptic plasticity and complex behaviors to epitranscriptomic modifications of cognate tRNAs and the proteomic homeostasis associated with specific amino acids.

Exploring grip strength as a predictor of depression in middle-aged and older adults.

Grip strength (GS) is an indicator of health and vulnerability and inversely associated with depressive symptoms. The aim of this study was to explore GS discrimination capacity for depression; and possible GS cut-off values for depression by sex and age group. Data from 2011 and 2015 on 20,598 (10,416 women) middle-aged and older adults from 14 European countries was analysed. GS was assessed by dynamometer, and depressive symptoms using the EURO-D scale. GS cut-off values for depression were calculated and logistic regression models were used to quantify the odds of having depression in 2011 and in 2015 according to being bellow or above the cut-off value. GS had a weak discriminant capacity for depression, with the area under the curve varying between 0.54 and 0.60 (p < 0.001). Sensitivity varied between 0.57 and 0.74; specificity varied between 0.46 and 0.66. GS cut-off values for discriminating depression were 43.5 kg for men and 29.5 kg for women aged 50-64 years, 39.5 kg for men and 22.5 kg for women aged ≥ 65 years. Having GS above the cut-off represents significant lower odds of depression in 2011 and 4 years later, in 2015. Healthcare practitioners and epidemiologic researchers may consider the low GS cut-off values to screen for potential depression risk. However, due to its weak discriminant values these cut-offs should not be used to identify depression.

Resilience and Hope Among Yazidi Women Released From ISIS Enslavement.

ABSTRACT: This study aimed to explore the levels of resilience and hope among Yazidi women who survived captivity by Islamic State of Iraq and Syria (ISIS) and to examine its relationship with posttraumatic stress disorder (PTSD), generalized anxiety, and depressive symptoms. In this cross-sectional study, 139 formerly enslaved Yazidi women were assessed. The mean scores of resilience and hope were below the suggested cutoff means (M = 2.47, SD = 0.48, R = 1-5) and (M = 31.6, SD = 11.7, R = 8-64), respectively. Sociodemographic variables were not related to resilience and hope, other than those women who stayed in captivity for more than a 3-year period who reported significantly lower levels of hope (M = 28.36, SD = 11.69). Formerly enslaved Yazidi women who display higher levels of PTSD, generalized anxiety, and depression exhibit significantly lower levels of resilience and hope. Resilience and hope are therefore important concepts to explore in traumatized populations.

Emerging Benefits: Pathophysiological Functions and Target Drugs of the Sigma-1 Receptor in Neurodegenerative Diseases.

The sigma-1 receptor (Sig-1R) is encoded by the SIGMAR1 gene and is a nonopioid transmembrane receptor located in the mitochondrial-associated endoplasmic reticulum membrane (MAM). It helps to locate endoplasmic reticulum calcium channels, regulates calcium homeostasis, and acts as a molecular chaperone to control cell fate and participate in signal transduction. It plays an important role in protecting neurons through a variety of signaling pathways and participates in the regulation of cognition and motor behavior closely related to neurodegenerative diseases. Based on its neuroprotective effects, Sig-1R has now become a breakthrough target for alleviating Alzheimer's disease and other neurodegenerative diseases. This article reviews the most cutting-edge research on the function of Sig-1R under normal or pathologic conditions and target drugs of the sigma-1 receptor in neurodegenerative diseases.

Circadian rhythm sleep-wake disturbances and depression in young people: implications for prevention and early intervention.

A rate-limiting step in the prevention and early intervention of depressive disorders in young people is our insufficient understanding of causal mechanisms. One plausible pathophysiological pathway is disturbance in the 24 h sleep-wake cycle and the underlying circadian system. Abnormalities in circadian rhythms are well documented in adults with various depressive disorders and have been linked to core clinical features, including unstable mood, daytime fatigue, non-restorative sleep, reduced motor activity, somatic symptoms, and appetite and weight change. In this Review, we summarise four areas of research: basic circadian biology and animal models of circadian disturbances; developmental changes in circadian rhythms during adolescence and implications for the emergence of adolescent-onset depressive syndromes; community and clinical studies linking 24 h sleep-wake cycle disturbances and depressive disorders; and clinical trials of circadian-based treatments. We present recommendations based on a highly personalised, early intervention model for circadian-linked depression in young people.

Depressive symptoms among cancer patients: Variation by gender, cancer type, and social engagement.

Prior literature has documented an association between cancer and depressive symptoms. There has been a limited understanding about whether the association between cancer and depressive symptoms varies by gender and whether social engagement moderates this association. Using seven waves of the Korean Longitudinal Study of Ageing (N = 10,055), we examine the association between cancer and depressive symptoms among middle- and older-aged adults in Korea. We conduct fixed-effects regression models to account for unobserved characteristics of individuals that may confound this association. We first investigate whether the association between cancer and depressive symptom differs by gender. We distinguish among cancer types to assess potentially distinctive mental health consequences of different types of cancer. Then, we explore whether social engagement moderates the cancer-depressive symptoms association. Naive OLS models yielded significant associations between cancer and depressive symptoms for both men and women. However, our preferred fixed effects estimates revealed that the association was statistically significant only for men, and not for women. This association was especially pronounced for lung cancer. We also found that one's level of social engagement including informal connections and formal social activities moderates the link between cancer and depressive symptoms. Cancer is not only a leading cause of death, but also a serious threat to one's mental health. This study sheds light on gender differences in psychological reactions to cancer among Korean adults. Findings of this study hold important implications for programs aiming to improve the mental health and quality of life of cancer patients.

Review of Allopregnanolone Agonist Therapy for the Treatment of Depressive Disorders.

OBJECTIVE: This paper reviews the current literature available for the efficacy and safety of allopregnanolone agonists and discusses considerations for their place in therapy. LITERATURE SEARCH: A literature search was conducted utilizing PubMed, clinicaltrials.gov, and the manufacturer's website. DATA SYNTHESIS: One phase II trial and two phase III trials evaluating the efficacy and safety of brexanolone were identified. Brexanolone demonstrated efficacy through significantly reduced Hamilton Depression Rating Scale (HAM-D) scores compared to placebo in the treatment of postpartum depression (PPD). Noted adverse effects were somnolence and dizziness, excessive sedation, and loss of consciousness. One published phase II study and the interim results of two phase III trials and one phase II trial on zuranolone were included in this review. Zuranolone, an oral allopregnanolone agonist, is given as a single, 14-day course. A significant reduction in HAM-D scores was demonstrated in patients with major depressive disorder (MDD) at 15 and 28 days compared to placebo. Interim results for zuranolone in PPD and bipolar disorder (BPD) show promising reductions in HAM-D scores. Adverse effects included sedation, dizziness, and headache. PLACE IN THERAPY: Allopregnanolone agonists seem to have a role in PPD when weighing the quick onset of action and potential risks of untreated PPD. The class of medications is limited by the single course for this indication and may fit as a bridge to maintenance therapy with selective serotonin reuptake inhibitors (SSRIs). Brexanolone, specifically, is hindered by the long infusion time, hospitalization associated with administration, and risk evaluation and mitigation strategy program. Zuranolone may also have a role in MDD or BPD, but more data are needed. CONCLUSION: Allopregnanolone agonists present a novel mechanism of action in the treatment of depressive disorders. Clinical trials and interim results support significant reductions in depression scores for brexanolone in PPD, and for zuranolone in PPD, MDD, and BPD.