Postovulatory Aging of Mouse Oocytes Impairs Offspring Behavior by Causing Oxidative Stress and Damaging Mitochondria.

Information on long-term effects of postovulatory oocyte aging (POA) on offspring is limited. Whether POA affects offspring by causing oxidative stress (OS) and mitochondrial damage is unknown. Here, in vivo-aged (IVA) mouse oocytes were collected 9 h after ovulation, while in vitro-aged (ITA) oocytes were obtained by culturing freshly ovulated oocytes for 9 h in media with low, moderate, or high antioxidant potential. Oocytes were fertilized in vitro and blastocysts transferred to produce F1 offspring. F1 mice were mated with naturally bred mice to generate F2 offspring. Both IVA and the ITA groups in low antioxidant medium showed significantly increased anxiety-like behavior and impaired spatial and fear learning/memory and hippocampal expression of anxiolytic and learning/memory-beneficial genes in both male and female F1 offspring. Furthermore, the aging in both groups increased OS and impaired mitochondrial function in oocytes, blastocysts, and hippocampus of F1 offspring; however, it did not affect the behavior of F2 offspring. It is concluded that POA caused OS and damaged mitochondria in aged oocytes, leading to defects in anxiety-like behavior and learning/memory of F1 offspring. Thus, POA is a crucial factor that causes psychological problems in offspring, and antioxidant measures may be taken to ameliorate the detrimental effects of POA on offspring.

Hyperexcitation of ovBNST CRF neurons during stress contributes to female-biased expression of anxiety-like avoidance behaviors.

Corticotropin releasing factor (CRF) network in the oval nucleus of bed nuclei of the stria terminalis (ovBNST) is generally indicated in stress, but its role in female-biased susceptibility to anxiety is unknown. Here, we established a female-biased stress paradigm. We found that the CRF release in ovBNST during stress showed female-biased pattern, and ovBNST CRF neurons were more prone to be hyperexcited in female mice during stress in both in vitro and in vivo studies. Moreover, optogenetic modulation to exchange the activation pattern of ovBNST CRF neurons during stress between female and male mice could reverse their susceptibility to anxiety. Last, CRF receptor type 1 (CRFR1) mediated the CRF-induced excitation of ovBNST CRF neurons and showed female-biased expression. Specific knockdown of the CRFR1 level in ovBNST CRF neurons in female or overexpression that in male could reverse their susceptibility to anxiety. Therefore, we identify that CRFR1-mediated hyperexcitation of ovBNST CRF neurons in female mice encode the female-biased susceptibility to anxiety.

Pesticide-Induced Alterations in Locomotor Activity, Anxiety, and Depression-like Behavior Are Mediated through Oxidative Stress-Related Autophagy: A Persistent Developmental Study in Mice.

Chlorpyrifos (CPF), dichlorvos (DDV), and cypermethrin (CP), as commonly used pesticides, have been implicated in inducing neuropsychiatric disorders, such as anxiety, depression-like behaviors, and locomotor activity impairment. However, the exact molecular mechanisms of these adverse effects, particularly in both sexes and their next-generation effects, remain unclear. In this study, we conducted behavioral analysis, along with cellular assays (monodansylcadaverine staining) and molecular investigations (qRT-PCR and western blotting of mTOR, P62, and Beclin-1) to clear the potential role of autophagy in pesticide-induced behavioral alterations. For this purpose, 42 adult female and 21 male inbred ICR mice (F0) were distributed into seven groups. Maternal mice (F0) and 112 F1 offspring were exposed to 0.5 and 1 ppm of CPF, DDV, and CP through drinking water. F1 male and female animals were studied to assess the sex-specific effects of pesticides on brain tissue. Our findings revealed pronounced anxiogenic effects and impaired locomotor activity in mice. F1 males exposed to CPF (1 ppm) exhibited significantly elevated depression-like behaviors compared to other groups. Moreover, pesticide exposure reduced mTOR and P62 levels, while enhancing the Beclin-1 gene and protein expression. These changes in autophagy signaling pathways, coupled with oxidative and neurogenic damage in the cerebral cortex and hippocampus, potentially contribute to heightened locomotor activity, anxiety, and depression-like behaviors following pesticide exposure. This study underscores the substantial impact of pesticides on both physiological and behavioral aspects, emphasizing the necessity for comprehensive assessments and regulatory considerations for pesticide use. Additionally, the identification of sex-specific responses presents a crucial dimension for pharmaceutical sciences, highlighting the need for tailored therapeutic interventions and further research in this field.

A vasopressin circuit that modulates mouse social investigation and anxiety-like behavior in a sex-specific manner.

One of the largest sex differences in brain neurochemistry is the expression of the neuropeptide arginine vasopressin (AVP) within the vertebrate brain, with males having more AVP cells in the bed nucleus of the stria terminalis (BNST) than females. Despite the long-standing implication of AVP in social and anxiety-like behaviors, the circuitry underlying AVP's control of these behaviors is still not well defined. Using optogenetic approaches, we show that inhibiting AVP BNST cells reduces social investigation in males, but not in females, whereas stimulating these cells increases social investigation in both sexes, but more so in males. These cells may facilitate male social investigation through their projections to the lateral septum (LS), an area with the highest density of sexually differentiated AVP innervation in the brain, as optogenetic stimulation of BNST AVP → LS increased social investigation and anxiety-like behavior in males but not in females; the same stimulation also caused a biphasic response of LS cells ex vivo. Blocking the vasopressin 1a receptor (V1aR) in the LS eliminated all these responses. Together, these findings establish a sexually differentiated role for BNST AVP cells in the control of social investigation and anxiety-like behavior, likely mediated by their projections to the LS.

Changes in the hippocampal level of tau but not beta-amyloid may mediate anxiety-like behavior improvement ensuing from exercise in diabetic female rats.

BACKGROUND: In the present study, we investigated the effect of high-intensity interval training (HIIT) on cognitive behaviors in female rats with a high-fat diet + streptozotocin (STZ)-induced type 2 diabetes. METHODS: Twenty-four female rats were divided into four groups randomly (n = 6): control (C), control + exercise (Co + EX), diabetes mellitus (type 2) (T2D), and diabetes mellitus + exercise (T2D + EX). Diabetes was induced by a two-month high-fat diet and a single dose of STZ (35 mg/kg) in the T2D and T2D + EX groups. The Co + EX and T2D + EX groups performed HIIT for eight weeks (five sessions per week, running on a treadmill at 80-100% of VMax, 4-10 intervals). Elevated plus maze (EPM) and open field test (OFT) were used for assessing anxiety-like behaviors, and passive avoidance test (PAT) and Morris water maze (MWM) were applied for evaluating learning and memory. The hippocampal levels of beta-amyloid (Aß) and Tau were also assessed using Western blot. RESULTS: An increase in fasting blood glucose (FBG), hippocampal level of Tau, and a decrease in the percentage of open arm time (%OAT) as an index of anxiety-like behavior were seen in the female diabetic rats which could be reversed by HIIT. In addition, T2D led to a significant decrease in rearing and grooming in the OFT. No significant difference among groups was seen for the latency time in the PAT and learning and memory in the MWM. CONCLUSIONS: HIIT could improve anxiety-like behavior at least in part through changes in hippocampal levels of Tau.

PM2.5 exposure contributes to anxiety and depression-like behaviors via phenyl-containing compounds interfering with dopamine receptor.

As a global problem, fine particulate matter (PM2.5) really needs local fixes. Considering the increasing epidemiological relevance to anxiety and depression but inconsistent toxicological results, the most important question is to clarify whether and how PM2.5 causally contributes to these mental disorders and which components are the most dangerous for crucial mitigation in a particular place. In the present study, we chronically subjected male mice to a real-world PM2.5 exposure system throughout the winter heating period in a coal combustion area and revealed that PM2.5 caused anxiety and depression-like behaviors in adults such as restricted activity, diminished exploratory interest, enhanced repetitive stereotypy, and elevated acquired immobility, through behavioral tests including open field, elevated plus maze, marble-burying, and forced swimming tests. Importantly, we found that dopamine signaling was perturbed using mRNA transcriptional profile and bioinformatics analysis, with Drd1 as a potential target. Subsequently, we developed the Drd1 expression-directed multifraction isolating and nontarget identifying framework and identified a total of 209 compounds in PM2.5 organic extracts capable of reducing Drd1 expression. Furthermore, by applying hierarchical characteristic fragment analysis and molecular docking and dynamics simulation, we clarified that phenyl-containing compounds competitively bound to DRD1 and interfered with dopamine signaling, thereby contributing to mental disorders. Taken together, this work provides experimental evidence for researchers and clinicians to identify hazardous factors in PM2.5 and prevent adverse health outcomes and for local governments and municipalities to control source emissions for diminishing specific disease burdens.

Peripheral inflammation triggering central anxiety through the hippocampal glutamate metabolized receptor 1.

AIMS: This study aimed to investigate the relationship between ulcerative colitis (UC) and anxiety and explore its central mechanisms using colitis mice. METHODS: Anxiety-like behavior was assessed in mice induced by 3% dextran sodium sulfate (DSS) using the elevated plus maze and open-field test. The spatial transcriptome of the hippocampus was analyzed to assess the distribution of excitatory and inhibitory synapses, and Toll-like receptor 4 (TLR4) inhibitor TAK-242 (10 mg/kg) and AAV virus interference were used to examine the role of peripheral inflammation and central molecules such as Glutamate Receptor Metabotropic 1 (GRM1) in mediating anxiety behavior in colitis mice. RESULTS: DSS-induced colitis increased anxiety-like behaviors, which was reduced by TAK-242. Spatial transcriptome analysis of the hippocampus showed an excitatory-inhibitory imbalance mediated by glutamatergic synapses, and GRM1 in hippocampus was identified as a critical mediator of anxiety behavior in colitis mice via differential gene screening and AAV virus interference. CONCLUSION: Our work suggests that the hippocampus plays an important role in brain anxiety caused by peripheral inflammation, and over-excitation of hippocampal glutamate synapses by GRM1 activation induces anxiety-like behavior in colitis mice. These findings provide new insights into the central mechanisms underlying anxiety in UC and may contribute to the development of novel therapeutic strategies for UC-associated anxiety.

Neurocircuitry underlying the actions of glucagon-like peptide 1 and peptide YY3-36 in the suppression of food, drug-seeking, and anxiogenesis.

Obesity is a critical health condition worldwide that increases the risks of comorbid chronic diseases, but it can be managed with weight loss. However, conventional interventions relying on diet and exercise are inadequate for achieving and maintaining weight loss, thus there is significant market interest for pharmaceutical anti-obesity agents. For decades, receptor agonists for the gut peptide glucagon-like peptide 1 (GLP-1) featured prominently in anti-obesity medications by suppressing appetite and food reward to elicit rapid weight loss. As the neurocircuitry underlying food motivation overlaps with that for drugs of abuse, GLP-1 receptor agonism has also been shown to decrease substance use and relapse, thus its therapeutic potential may extend beyond weight management to treat addictions. However, as prolonged use of anti-obesity drugs may increase the risk of mood-related disorders like anxiety and depression, and individuals taking GLP-1-based medication commonly report feeling demotivated, the long-term safety of such drugs is an ongoing concern. Interestingly, current research now focuses on dual agonist approaches that include GLP-1 receptor agonism to enable synergistic effects on weight loss or associated functions. GLP-1 is secreted from the same intestinal cells as the anorectic gut peptide, Peptide YY3-36 (PYY3-36), thus this review assessed the therapeutic potential and underlying neural circuits targeted by PYY3-36 when administered independently or in combination with GLP-1 to curb the appetite for food or drugs of abuse like opiates, alcohol, and nicotine. Additionally, we also reviewed animal and human studies to assess the impact, if any, for GLP-1 and/or PYY3-36 on mood-related behaviors in relation to anxiety and depression. As dual agonists targeting GLP-1 and PYY3-36 may produce synergistic effects, they can be effective at lower doses and offer an alternative approach for therapeutic benefits while mitigating undesirable side effects.

Medicinal cannabis oil improves anxiety-like and depressive-like behaviors in CCS mice via the BDNF/TRPC6 signaling pathway.

BACKGROUND: Post-traumatic stress disorder (PTSD) refers to a chronic impairing psychiatric disorder occurring after exposure to the severe traumatic event. Studies have demonstrated that medicinal cannabis oil plays an important role in neuroprotection, but the mechanism by which it exerts anti-PTSD effects remains unclear. METHODS: The chronic complex stress (CCS) simulating the conditions of long voyage stress for 4 weeks was used to establish the PTSD mice model. After that, behavioral tests were used to evaluate PTSD-like behaviors in mice. Mouse brain tissue index was detected and hematoxylin-eosin staining was used to assess pathological changes in the hippocampus. The indicators of cell apoptosis and the BDNF/TRPC6 signaling activation in the mice hippocampus were detected by western blotting or real-time quantitative reverse transcription PCR experiments. RESULTS: We established the PTSD mice model induced by CCS, which exhibited significant PTSD-like phenotypes, including increased anxiety-like and depression-like behaviors. Medicinal cannabis oil treatment significantly ameliorated PTSD-like behaviors and improved brain histomorphological abnormalities in CCS mice. Mechanistically, medicinal cannabis oil reduced CCS-induced cell apoptosis and enhanced the activation of BDNF/TRPC6 signaling pathway. CONCLUSIONS: We constructed a PTSD model with CCS and medicinal cannabis oil that significantly improved anxiety-like and depressive-like behaviors in CCS mice, which may play an anti-PTSD role by stimulating the BDNF/TRPC6 signaling pathway.

A TNF-α inhibitor abolishes sepsis-induced cognitive impairment in mice by modulating acetylcholine and nitric oxide homeostasis, BDNF release, and neuroinflammation.

Neurodegenerative disorders have a pathophysiology that heavily involves neuroinflammation. In this study, we used lipopolysaccharide (LPS) to create a model of cognitive impairment by inducing systemic and neuroinflammation in experimental animals. LPS was injected intraperitoneally at a dose of 0.5 mg/kg during the last seven days of the study. Adalimumab (ADA), a TNF-α inhibitor, was injected at a dose of 10 mg/kg a total of 3 times throughout the study. On the last two days of the experiment, 50 mg/kg of curcumin was administered orally as a positive control group. Open field (OF) and elevated plus maze tests (EPM) were used to measure anxiety-like behaviors. The tail suspension test (TST) was used to measure depression-like behaviors, while the novel object recognition test (NOR) was used to measure learning and memory activities. Blood and hippocampal TNF α and nitric oxide (NO) levels, hippocampal BDNF, CREB, and ACh levels, and AChE activity were measured by ELISA. LPS increased anxiety and depression-like behaviors while decreasing the activity of the learning-memory system. LPS exerted this effect by causing systemic and neuroinflammation, cholinergic dysfunction, and impaired BDNF release. ADA controlled LPS-induced behavioral changes and improved biochemical markers. ADA prevented cognitive impairment induced by LPS by inhibiting inflammation and regulating the release of BDNF and the cholinergic pathway.

EZH2-dependent epigenetic reprogramming in the central nucleus of amygdala regulates adult anxiety in both sexes after adolescent alcohol exposure.

Alcohol use and anxiety disorders occur in both males and females, but despite sharing similar presentation and classical symptoms, the prevalence of alcohol use disorder (AUD) is lower in females. While anxiety is a symptom and comorbidity shared by both sexes, the common underlying mechanism that leads to AUD and the subsequent development of anxiety is still understudied. Using a rodent model of adolescent intermittent ethanol (AIE) exposure in both sexes, we investigated the epigenetic mechanism mediated by enhancer of zeste 2 (EZH2), a histone methyltransferase, in regulating both the expression of activity-regulated cytoskeleton-associated protein (Arc) and an anxiety-like phenotype in adulthood. Here, we report that EZH2 protein levels were significantly higher in PKC-δ positive GABAergic neurons in the central nucleus of amygdala (CeA) of adult male and female rats after AIE. Reducing protein and mRNA levels of EZH2 using siRNA infusion in the CeA prevented AIE-induced anxiety-like behavior, increased H3K27me3, decreased H3K27ac at the Arc synaptic activity response element (SARE) site, and restored deficits in Arc mRNA and protein expression in both male and female adult rats. Our data indicate that an EZH2-mediated epigenetic mechanism in the CeA plays an important role in regulating anxiety-like behavior and Arc expression after AIE in both male and female rats in adulthood. This study suggests that EZH2 may serve as a tractable drug target for the treatment of adult psychopathology after adolescent alcohol exposure.

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.

Stress increases hepatic release of lipocalin 2 which contributes to anxiety-like behavior in mice.

Chronic stress induces anxiety disorders via both neural pathways and circulating factors. Although many studies have elucidated the neural circuits involved in stress-coping behaviors, the origin and regulatory mechanism of peripheral cytokines in behavioural regulation under stress conditions are not fully understood. Here, we identified a serum cytokine, lipocalin 2 (LCN2), that was upregulated in participants with anxiety disorders. Using a mouse model of chronic restraint stress (CRS), circulating LCN2 was found to be related to stress-induced anxiety-like behaviour via modulation of neural activity in the medial prefrontal cortex (mPFC). These results suggest that stress increases hepatic LCN2 via a neural pathway, leading to disrupted cortical functions and behaviour.

CGRP causes anxiety via HP1γ-KLF11-MAOB pathway and dopamine in the dorsal hippocampus.

Calcitonin gene-related peptide (CGRP) is a neuropeptide that causes anxiety behavior; however, the underlying mechanisms remain unclear. We found that CGRP modulates anxiety behavior by epigenetically regulating the HP1γ-KLF-11-MAOB pathway and depleting dopamine in the dorsal hippocampus. Intracerebroventricular administration of CGRP (0.5 nmol) elicited anxiety-like behaviors in open field, hole-board, and plus-maze tests. Additionally, we observed an increase in monoamine oxidase B (MAOB) levels and a concurrent decrease in dopamine levels in the dorsal hippocampus of mice following CGRP administration. Moreover, CGRP increased abundance the transcriptional regulator of MAOB, Krüppel-like factor 11 (KLF11), and increased levels of phosphorylated heterochromatin protein (p-HP1γ), which is involved in gene silencing, by methylating histone H3 in the dorsal hippocampus. Chromatin immunoprecipitation assay showed that HP1γ was recruited to the Klf11 enhancer by CGRP. Furthermore, infusion of CGRP (1 nmol) into the dorsal hippocampus significantly increased MAOB expression as well as anxiety-like behaviors, which were suppressed by the pharmacological inhibition or knockdown of MAOB. Together, these findings suggest that CGRP reduces dopamine levels and induces anxiety-like behavior through epigenetic regulation in the dorsal hippocampus.

Bright daylight produces negative effects on affective and cognitive outcomes in nocturnal rats.

The daily light/dark cycle affects animals' learning, memory, and cognition. Exposure to insufficient daylight illumination negatively impacts emotion and cognition, leading to seasonal affective disorder characterized by depression, anxiety, low motivation, and cognitive impairment in diurnal animals. However, how this affects memory, learning, and cognition in nocturnal rodents is largely unknown. Here, we studied the effect of daytime light illuminance on memory, learning, cognition, and expression of mRNA levels in the hippocampus, thalamus, and cortex, the higher-order learning centers. Two experiments were performed. In experiment one, rats were exposed to 12 L:12D (12 h light and 12 h dark) with a 10, 100, or 1000 lx daytime light illuminance. After 30 days, various behavioral tests (novel object recognition test, hole board test, elevated plus maze test, radial arm maze, and passive avoidance test) were performed. In experiment 2, rats since birth were raised either under constant bright light (250 lx; LL) or a daily light-dark cycle (12 L:12D). After four months, behavioral tests (novel object recognition test, hole board test, elevated plus maze test, radial arm maze, passive avoidance test, Morris water maze, and Y-maze tests) were performed. At the end of experiments, rats were sampled, and mRNA expression of Brain-Derived Neurotrophic Factor (Bdnf), Tyrosine kinase (Trk), microRNA132 (miR132), Neurogranin (Ng), Growth Associated Protein 43 (Gap-43), cAMP Response Element-Binding Protein (Crebp), Glycogen synthase kinase-3ß (Gsk3ß), and Tumour necrosis factor-α (Tnf-α) were measured in the hippocampus, cortex, and thalamus of individual rats. Our results show that exposure to bright daylight (100 and 1000 lx; experiment 1) or constant light (experiment 2) compromises memory, learning, and cognition. Suppressed expression levels of these mRNA were also observed in the hypothalamus, cortex, and thalamus. These results suggest that light affects differently to different groups of animals.

Rhesus infant nervous temperament predicts peri-adolescent central amygdala metabolism & behavioral inhibition measured by a machine-learning approach.

Anxiety disorders affect millions of people worldwide and impair health, happiness, and productivity on a massive scale. Developmental research points to a connection between early-life behavioral inhibition and the eventual development of these disorders. Our group has previously shown that measures of behavioral inhibition in young rhesus monkeys (Macaca mulatta) predict anxiety-like behavior later in life. In recent years, clinical and basic researchers have implicated the central extended amygdala (EAc)-a neuroanatomical concept that includes the central nucleus of the amygdala (Ce) and the bed nucleus of the stria terminalis (BST)-as a key neural substrate for the expression of anxious and inhibited behavior. An improved understanding of how early-life behavioral inhibition relates to an increased lifetime risk of anxiety disorders-and how this relationship is mediated by alterations in the EAc-could lead to improved treatments and preventive strategies. In this study, we explored the relationships between infant behavioral inhibition and peri-adolescent defensive behavior and brain metabolism in 18 female rhesus monkeys. We coupled a mildly threatening behavioral assay with concurrent multimodal neuroimaging, and related those findings to various measures of infant temperament. To score the behavioral assay, we developed and validated UC-Freeze, a semi-automated machine-learning (ML) tool that uses unsupervised clustering to quantify freezing. Consistent with previous work, we found that heightened Ce metabolism predicted elevated defensive behavior (i.e., more freezing) in the presence of an unfamiliar human intruder. Although we found no link between infant-inhibited temperament and peri-adolescent EAc metabolism or defensive behavior, we did identify infant nervous temperament as a significant predictor of peri-adolescent defensive behavior. Our findings suggest a connection between infant nervous temperament and the eventual development of anxiety and depressive disorders. Moreover, our approach highlights the potential for ML tools to augment existing behavioral neuroscience methods.

Activation of σ-1 receptor mitigates estrogen withdrawal-induced anxiety/depressive-like behavior in mice via restoration of GABA/glutamate signaling and neuroplasticity in the hippocampus.

Postpartum depression (PPD) is a significant contributor to maternal morbidity and mortality. The Sigma-1 (σ-1) receptor has received increasing attention in recent years because of its ability to link different signaling systems and exert its function in the brain through chaperone actions, especially in neuropsychiatric disorders. YL-0919, a novel σ-1 receptor agonist developed by our institute, has shown antidepressive and anxiolytic effects in a variety of animal models, but effects on PPD have not been revealed. In the present study, excitatory/inhibitory signaling in the hippocampus was reflected by GABA and glutamate and their associated excitatory-inhibitory receptor proteins, the HPA axis hormones in the hippocampus were assessed by ELISA. Finally, immunofluorescence for markers of newborn neuron were undertaken in the dentate gyri, along with dendritic spine staining and dendritic arborization tracing. YL-0919 rapidly improves anxiety and depressive-like behavior in PPD-like mice within one week, along with normalizing the excitation/inhibition signaling as well as the HPA axis activity. YL-0919 rescued the decrease in hippocampal dendritic complexity and spine density induced by estrogen withdrawal. The study results suggest that YL-0919 elicits a therapeutic effect on PPD-like mice; therefore, the σ-1 receptor may be a novel promising target for PPD treatment in the future.

Sex-specific effects of sucrose withdrawal on anxiety-like behavior and neuroimmune response.

Sugar bingeing induces maladaptive neuroadaptations to decrease dietary control and promote withdrawal symptoms. This study investigated sex differences in sucrose bingeing, sucrose withdrawal-induced negative mood effects and underlying neuroimmune response in the prefrontal cortex (PFC) and nucleus accumbens (NAc) of C57BL/6J male and female mice. Two-bottle sucrose choice paradigm was used to develop sucrose dependence in mice. Female mice consumed more sucrose than male mice when given free access to water and 10% sucrose for four weeks. A significant increase in the mRNA expression of neuroinflammatory markers (Il1ß, Tnfα) was found in the PFC of males exposed to sucrose withdrawal. Sucrose bingeing and subsequent sucrose withdrawal showed elevated protein levels of pro-inflammatory cytokines/chemokines/growth factors in the PFC (IL-1ß, IL-6, TNFα, IFN-γ, IL-10, CCL5, VEGF) and NAc (IL-1ß, IL-6, IL-10, VEGF) of male mice as compared to their water controls. These effects were concurrent with reduced mRNA expression of neuronal activation marker (cFos) in the PFC of sucrose withdrawal males. One week of sucrose withdrawal after prolonged sucrose consumption showed anxiety-like behavior in male mice, not in females. In conclusion, this study demonstrates that repeated access to sucrose induces anxiety-like behavior when the sugar is no longer available in the diet and these effects are male-specific. Elevated neuroinflammation in reward neurocircuitry may underlie these sex-specific effects.

A role for the cerebellum in motor-triggered alleviation of anxiety.

Physical exercise is known to reduce anxiety, but the underlying brain mechanisms remain unclear. Here, we explore a hypothalamo-cerebello-amygdalar circuit that may mediate motor-dependent alleviation of anxiety. This three-neuron loop, in which the cerebellar dentate nucleus takes center stage, bridges the motor system with the emotional system. Subjecting animals to a constant rotarod engages glutamatergic cerebellar dentate neurons that drive PKCδ+ amygdalar neurons to elicit an anxiolytic effect. Moreover, challenging animals on an accelerated rather than a constant rotarod engages hypothalamic neurons that provide a superimposed anxiolytic effect via an orexinergic projection to the dentate neurons that activate the amygdala. Our findings reveal a cerebello-limbic pathway that may contribute to motor-triggered alleviation of anxiety and that may be optimally exploited during challenging physical exercise.

SCFAs Supplementation Rescues Anxiety- and Depression-like Phenotypes Generated by Fecal Engraftment of Treatment-Resistant Depression Rats.

Alteration of gut microbiota and microbial metabolites such as short-chain fatty acids (SCFAs) coexisted with stress-generated brain disorders, including depression. Herein, we investigated the effect of SCFAs in a treatment-resistant depression (TRD) model of rat. Rats were exposed to chronic-unpredictable mild stress (CUMS) and repeated adrenocorticotropic hormone (ACTH) injections to generate a TRD-like phenotype. The cecal contents of these animals were engrafted into healthy-recipient rats and allowed to colonize for 4 weeks (TRD-FMT group). Blood, brain, colon, fecal, and cecal samples were collected for molecular studies. Rats exposed to CUMS + ACTH showed TRD-like phenotypes in sucrose-preference (SPT), forced swim (FST), and elevated plus maze (EPM) tests. The TRD-FMT group also exhibited anxiety- and depression-like behaviors. Administration of SCFAs (acetate, propionate, and butyrate at 67.5, 25, and 40 mM, respectively) for 7 days exerted robust antidepressant and antianxiety effects by restoring the levels of SCFAs in plasma and fecal samples, and proinflammatory cytokines (TNF-α and IL-6), serotonin, GABA, norepinephrine, and dopamine in the hippocampus and/or frontal cortex of TRD and TRD-FMT animals. SCFAs treatment elevated the expression of free-fatty acid receptors 2/3, BDNF, doublecortin, and zonula-occludens, and reduced the elevated plasma levels of kynurenine and quinolinic acid and increased mucus-producing goblet cells in TRD and TRD-FMT animals. In 16S sequencing results, decreased microbial diversity in TRD rats corresponds with differences in the genus of Faecalibacterium, Anaerostipes, Allobaculum, Blautia, Peptococcus, Rombustia, Ruminococcaceae_UCG-014, Ruminococcaceae_UCG-002, Solobacterium, Subdolibacterium, and Eubacterium ventriosum. SCFAs may impart beneficial effects via modulation of tryptophan metabolism, inflammation, neurotransmitters, and microbiota-gut-brain axis in TRD rats.