Anxiety-like Behavior Research Articles

Additive effect of clove essential oil combined with hydrogen inhalation improves psychological harm caused by lipopolysaccharide in mice.

Psychological anxiety and depression, as well as memory impairment, are frequently linked to inflammation. Clove essential oil (CEO) administration and hydrogen (H2) inhalation have been proven to have anti-inflammatory and alleviating effects on related psychological disorders in the past. The current study investigated the potential to improve anxiety-like behaviors and cognitive function by a combination of CEO and H2 treatment. The mice were administered lipopolysaccharide (LPS) to induce inflammation and oxidative stress response and cause psychological disorders. Using this animal model, we conducted experiments to test whether essential oil and H2 inhalation could improve the psychological damage in behavior caused by LPS. Subsequently, elevated plus maze (EPM), forced swimming test (FST), and passive avoidance (PA) test were performed for evaluation of mice anxiety, depression, and response to electric shock, respectively. Furthermore, the biochemical analysis was used to examine the expression levels of inflammatory and oxidative stress markers. Our results showed that CEO administration and H2 inhalation alone or in combination positively improved inflammation-induced anxiety, depression, and cognitive memory deficits in the mice. In the single treatment groups, CEO demonstrated better results than H2 inhalation in the elevated plus maze, forced swimming, and passive avoidance tests, while combined treatment with both provided a further improved enhancement effect. Biochemical analysis of the cerebral cortex revealed that CEO and H2 therapy reversed the LPS-induced inflammation and oxidative stress response. Our results suggest that a combination of CEO and H2 has the potential to treat psychological disorders or neuropsychiatric disorders.

Lactobacillus Helveticus Improves Controlled Cortical Impact Injury-Generated Neurological Aberrations by Remodeling of Gut-Brain Axis Mediators.

Considerable studies augured the potential of gut microbiota-based interventions in brain injury-associated complications. Based on our earlier study results, we envisaged the sex-specific neuroprotective effect of Lactobacillus helveticus by remodeling of gut-brain axis. In this study, we investigated the effect of L. helveticus on neurological complications in a mouse model of controlled cortical impact (CCI). Adult, male and female, C57BL/6 mice underwent CCI surgery and received L. helveticus treatment for six weeks. Sensorimotor function was evaluated via neurological severity score and rotarod test. Long-term effects on anxiety-like behavior and cognition were assessed using the elevated-zero maze (EZM) and novel object recognition test (NORT). Brain perilesional area, blood, colon, and fecal samples were collected post-CCI for molecular biology analysis. CCI-operated mice displayed significant neurological impairments at 1-, 3-, 5-, and 7-days post-injury (dpi) and exhibited altered behavior in EZM and NORT compared to sham-operated mice. However, these behavioral changes were ameliorated in mice receiving L. helveticus. GFAP, Iba-1, TNF-α, and IL-1β expressions and corticotrophin-releasing hormone (CRH) levels were elevated in the perilesional cortex of CCI-operated male/female mice. These elevated biomarkers and decreased BDNF levels in both male/female mice were modified by L. helveticus treatment. Additionally, L. helveticus treatment restored altered short-chain fatty acids (SCFAs) levels in fecal samples and improved intestinal integrity but did not affect decreased plasma levels of progesterone and testosterone in CCI mice. These results indicate that L. helveticus exerts beneficial effects in the CCI mouse model by mitigating inflammation and remodeling of gut microbiota-brain mediators.

The novel estrogen receptor beta agonist EGX358 and APOE genotype influence memory, vasomotor, and anxiety outcomes in an Alzheimer’s mouse model

IntroductionAlzheimer’s disease (AD) prevalence and severity are associated with increased age, female sex, and apolipoprotein E4 (APOE4) genotype. Although estrogen therapy (ET) effectively reduces symptoms of menopause including hot flashes and anxiety, and can reduce dementia risk, it is associated with increased risks of breast and uterine cancer due to estrogen receptor alpha (ERβ)-mediated increases in cancer cell proliferation. Because ERβ activation reduces this cell proliferation, selective targeting of ERβ may provide a safer method of improving memory and reducing hot flashes in menopausal women, including those with AD. APOE genotype influences the response to ET, although it is unknown whether effects of ERβ activation vary by genotype.MethodsHere, we tested the ability of long-term oral treatment with a novel highly selective ERβ agonist, EGX358, to enhance object recognition and spatial recognition memory, reduce drug-induced hot flashes, and influence anxiety-like behaviors in female mice expressing 5 familial AD mutations (5xFAD-Tg) and human APOE3 (E3FAD) or APOE3 and APOE4 (E3/4FAD). Mice were ovariectomized at 5 months of age and were then treated orally with vehicle (DMSO) or EGX358 (10 mg/kg/day) via hydrogel for 8 weeks. Spatial and object recognition memory were tested in object placement (OP) and object recognition (OR) tasks, respectively, and anxiety-like behaviors were tested in the open field (OF) and elevated plus maze (EPM). Hot flash-like symptoms (change in tail skin temperature) were measured following injection of the neurokinin receptor agonist senktide (0.5 mg/kg).ResultsEGX358 enhanced object recognition memory in E3FAD and E3/4FAD mice but did not affect spatial recognition memory. EGX358 also reduced senktide-induced tail temperature elevations in E3FAD, but not E3/4FAD, females. EGX358 did not influence anxiety-like behaviors or body weight.DiscussionThese data indicate that highly selective ERβ agonism can facilitate object recognition memory in both APOE3 homozygotes and APOE3/4 heterozygotes, but only reduce the magnitude of a drug-induced hot flash in APOE3 homozygotes, suggesting that APOE4 genotype may blunt the beneficial effects of ET on hot flashes. Collectively, these data suggest a potentially beneficial effect of selective ERβ agonism for memory and hot flashes in females with AD-like pathology, but that APOE genotype plays an important role in responsiveness.

ACSL3 is a promising therapeutic target for alleviating anxiety and depression in Alzheimer's disease.

Alzheimer's disease (AD), the leading cause of dementia, affects over 55 million people worldwide and is often accompanied by depression and anxiety. Both significantly impact patients' quality of life and impose substantial societal and economic burdens on healthcare systems. Identifying the complex regulatory mechanisms that contribute to the psychological and emotional deficits in AD will provide promising therapeutic targets. Biosynthesis of omega-3 (ω3) and omega-6 fatty acids (ω6-FA) through long-chain acyl-CoA synthetases (ACSL) is crucial for cell function and survival. This is due to ω3/6-FA's imperative role in modulating the plasma membrane, energy production, and inflammation. While ACSL dysfunction is known to cause heart, liver, and kidney diseases, the role of ACSL in pathological conditions in the central nervous system (e.g., depression and anxiety) remains largely unexplored. The impact of ACSLs on AD-related depression and anxiety was investigated in a mouse model of Alzheimer's disease (3xTg-AD). ACSL3 levels were significantly reduced in the hippocampus of aged 3xTg-AD mice (via capillary-based immunoassay). This reduction in ACAL3 was closely associated with increased depression and anxiety-like behavior (via forced swim, tail suspension, elevated plus maze, and sucrose preference test). Upregulation of ACSL3 via adenovirus in aged 3xTg-AD mice led to increased protein levels of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor C (VEGF-C) (via brain histology, capillary-based immunoassay), resulting in alleviation of depression and anxiety symptoms. The present study highlights a novel neuroprotective role of ACSL3 in the brain. Targeting ACSL3 will offer an innovative approach for treating AD-related depression and anxiety.

Mapping of c-Fos Expression in Rat Brain Sub/Regions Following Chronic Social Isolation: Effective Treatments of Olanzapine, Clozapine or Fluoxetine

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.

Sex-dependent effects of early life sensory overstimulation on later life behavioral function in rats.

Children today are immersed in electronic technology shortly after birth as they now begin regularly watching television earlier than they did in the past. Many new programs geared towards infants contain lots of lights, color, and sounds, which may constitute a form of sensory overstimulation (SOS) that leads to cognitive and behavioral changes in children and adolescents. Here, we examined the impact of early life SOS exposure on later life behavioral and cognitive function in rodents by exposing developing male and female rats to excessive audiovisual stimulation from postnatal days (PND) 10-40 and assessing anxiety-like behavior, social motivation, compulsive behavior, and spatial learning/cognition from PND 50-60. To evaluate potential SOS effects on hypothalamic-pituitary-adrenal (HPA)-axis function, levels of the stress hormone corticosterone (CORT) were measured at 3 timepoints (e.g., PND 23, 41, 61) post-SOS exposure. Sensory overstimulated males exhibited reduced anxiety-like and compulsive behavior compared to controls, whereas females exhibited reduced social motivation but enhanced spatial learning/cognition compared to controls. No differences in baseline CORT levels were found at any age tested, suggesting no impact of early life SOS on later life basal HPA-axis function. Our results demonstrate sex-specific effects of early life SOS on distinct behavioral domains in early adult rats.

Effects of Shugan Tiaoshen acupuncture on anxiety-like behavior and PKC/ERK/CREB pathway in the bed nucleus of the stria terminalis in rats with post-traumatic stress disorder

To observe the effect of Shugan Tiaoshen acupuncture (acupuncture for soothing the liver and regulating the spirit) on the protein kinase C/extracellular signal-regulated kinase/cAMP response element-binding protein (PKC/ERK/CREB) signaling pathway in the bed nucleus of the stria terminalis (BNST) of rats with post-traumatic stress disorder (PTSD), and to explore the mechanism of acupuncture on alleviating anxiety and fear in PTSD. Fifty SPF-grade male SD rats were randomly divided into a blank group (10 rats) and a PTSD model group (40 rats). The PTSD model was induced by using a combination of closed electric shock and forced exhaustive swimming. Thirty successfully modeled rats were randomly assigned to a model group, a medication group, and an acupuncture group, with 10 rats in each group. The rats in the medication group were treated with paroxetine hydrochloride solution by gavage, once daily for 12 consecutive days. The rats in the acupuncture group were treated with acupuncture at "Baihui" (GV 20) and bilateral "Neiguan" (PC 6), "Shenmen" (HT 7), "Taichong" (LR 3). "Baihui" (GV 20) was needled daily, while the other acupoints were alternately needled on the left side on odd days and the right side on even days, once daily for 12 consecutive days. Anxiety and fear behaviors changes were assessed by using the open field test and elevated plus maze test. Histological changes in the BNST were observed by using HE staining and Nissl staining. The expression of PKC, phosphorylated PKC (p-PKC), ERK1/2, phosphorylated ERK1/2 (p-ERK1/2), and p-CREB proteins in the BNST were detected by using Western blot. Compared with the blank group, the model group showed decreased time and total distance spent in the center of the open field and on the open arms of the elevated plus maze (P<0.05); the BNST tissues in the model group exhibited a reduced number of neurons, disorganized cell arrangement, cell shrinkage, nuclear condensation, abnormal neuronal structure, uneven Nissl staining, and reduced Nissl bodies. The model group showed increased protein expression of p-PKC and p-PKC/PKC ratio (P<0.05) and decreased protein expression of p-ERK1/2, p-CREB, and p-ERK1/2/ERK1/2 ratio (P<0.05). Compared with the model group, the medication group and the acupuncture group showed increased time and total distance spent in the center of the open field and on the open arms of the elevated plus maze (P<0.05); the BNST tissues showed increased number of neurons, more organized cell arrangement, improved neuronal structure, and increased Nissl bodies; the medication group and the acupuncture group also showed decreased p-PKC protein expression and p-PKC/PKC ratio (P<0.05) and increased p-ERK1/2, p-CREB protein expression, and p-ERK1/2/ERK1/2 ratio (P<0.05). Shugan Tiaoshen acupuncture could alleviate anxiety and fear behaviors in PTSD rats, and improve neuronal damage in the BNST. The mechanism may be related to the regulation of the PKC/ERK/CREB signaling pathway in the BNST.

Impaired oxytocin signalling in the central amygdala in rats with chronic heart failure.

Heart failure (HF) patients suffer from cognitive decline and mood impairments, but the molecular signals and brain circuits underlying these effects remain elusive. The hypothalamic neuropeptide oxytocin (OT) is critically involved in regulating mood, and OTergic signalling in the central amygdala (CeA) is a key mechanism that controls emotional responses including anxiety-like behaviours. Still, whether an altered OTergic signalling contributes to mood disorders in HF remains unknown. To address this, we used an ischaemic rat HF model, along with a highly multidisciplinary approach, to mechanistically study multiple levels of the hypothalamus-to-CeA OTergic circuit in male rats with HF. We aimed to test the hypothesis that sustained activation of the OT system following an infarct leads to depletion of OT content in this pathway, with subsequent changes in OT receptor expression and blunted modulation of local GABAergic circuits. We found that most of OTergic innervation of the CeA originated from the supraoptic nucleus (SON). While no differences in the numbers of SON→CeA OTergic neurons was observed between sham and HF rats, we observed a blunted content and release of OT from axonal terminals within the CeA. Moreover, we report downregulation of neuronal and astrocytic OT receptors, and impaired OTR-driven GABAergic synaptic activity within the CeA microcircuit of HF rats. We provide the first evidence that male HF rats display perturbations in the hypothalamus-to-amygdala OTergic circuit, laying the foundation for future translational studies targeting either the OT system or GABAergic amygdalar microcircuit to ameliorate mood impairments in rats or patients with chronic HF. KEY POINTS: Heart failure patients suffer from cognitive decline, depression and mood impairments, but the underlying mechanisms remain elusive. Acting within the central amygdala, the neuropeptide oxytocin regulates emotional responses, including anxiety-like behaviours. However, whether changes in oxytocin signalling occurs during heart failure is unknown. In this study, we used an ischaemic rat heart failure model to mechanistically study multiple levels of the hypothalamus-to-amygdala oxytocinergic circuit in this disease. We report an overall blunted oxytocinergic signalling pathway in rats with heart failure, including blunted content and release of oxytocin from axonal terminals, downregulation of neuronal and astrocytic oxytocin receptors, and impaired oxytocin-driven GABAergic synaptic activity within the central amygdala microcircuit of HF rats. These studies shed light on mechanisms that contribute to mood disorders in cardiovascular disease states and help to identify potential molecular targets for their improved treatment.

Chronic corticosterone exposure causes anxiety- and depression-related behaviors with altered gut microbial and brain metabolomic profiles in adult male C57BL/6J mice

Chronic exposure to glucocorticoids in response to long-term stress is thought to be a risk factor for major depression. Depression is associated with disturbances in the gut microbiota composition and peripheral and central energy metabolism. However, the relationship between chronic glucocorticoid exposure, the gut microbiota, and brain metabolism remains largely unknown. In this study, we first investigated the effects of chronic corticosterone exposure on various domains of behavior in adult male C57BL/6J mice treated with the glucocorticoid corticosterone to evaluate them as an animal model of depression. We then examined the gut microbial composition and brain and plasma metabolome in corticosterone-treated mice. Chronic corticosterone treatment resulted in reduced locomotor activity, increased anxiety-like and depression-related behaviors, decreased rotarod latency, reduced acoustic startle response, decreased social behavior, working memory deficits, impaired contextual fear memory, and enhanced cued fear memory. Chronic corticosterone treatment also altered the composition of gut microbiota, which has been reported to be associated with depression, such as increased abundance of Bifidobacterium, Turicibacter, and Corynebacterium and decreased abundance of Barnesiella. Metabolomic data revealed that long-term exposure to corticosterone led to a decrease in brain neurotransmitter metabolites, such as serotonin, 5-hydroxyindoleacetic acid, acetylcholine, and gamma-aminobutyric acid, as well as changes in betaine and methionine metabolism, as indicated by decreased levels of adenosine, dimethylglycine, choline, and methionine in the brain. These results indicate that mice treated with corticosterone have good face and construct validity as an animal model for studying anxiety and depression with altered gut microbial composition and brain metabolism, offering new insights into the neurobiological basis of depression arising from gut-brain axis dysfunction caused by prolonged exposure to excessive glucocorticoids.

Methylphenidate differentially affects the social ultrasonic vocalizations of wild-type and prodromal Parkinsonian rats.

Prodromal signs of Parkinson's disease (PD), including vocal communication deficits, are poorly understood and do not respond adequately to current pharmacologic treatments. Norepinephrine dysfunction is involved early in PD; thus, drug therapies targeting norepinephrine may be useful as a treatment of prodromal signs. This study used a validated, translational rodent model of prodromal PD, the male Pink1-/- rat, which exhibits ultrasonic vocalization (USV) deficits as early as 2 months of age. The purpose of this preclinical study was to investigate a dose-dependent (2.5, 5.0, 7.5, 10 mg/kg) response of methylphenidate on USV parameters with the hypothesis that methylphenidate would increase vocalization output. Because methylphenidate is a psychostimulant with known adverse side effects, we also hypothesized that potential side effects including anxietylike behavior and spontaneous activity would be increased in a dose-dependent manner. To accomplish this, wild-type (WT) and Pink1-/- rats were administered a dose of a vehicle (saline) and a methylphenidate dose in a randomized within-subjects design and then assessed for USVs, anxiety behavior (open field), and limb motor (cylinder) activity. The results suggest that methylphenidate does not alter USV emissions in Pink1-/- rats; however, methylphenidate increased the total number of vocalizations and duration of frequency-modulated calls in WT rats. Methylphenidate dose dependently influenced spontaneous movements in both WT and Pink1-/- rats, as expected, while methylphenidate increased anxiety in Pink1-/- rats and not WT rats. This study demonstrates a difference in response to a psychostimulant between Pink1-/- rats and WT rats. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Single Intranasal Administration of Ucn3 Affects the Development of PTSD Symptoms in an Animal Model

Post-traumatic stress disorder (PTSD) is a multifactorial psychological disorder that affects different neurotransmitter systems, including the central CRH system. CRH acts via the CRHR1 and CRHR2 receptors, which exert opposite effects, i.e., anxiogenic or anxiolytic. The aim of this work was to investigate how intranasal administration of the CRHR2-specific agonist urocortin 2 (Ucn2) or urocortin 3 (Ucn3) affects manifestations of PTSD in a single prolonged stress (SPS) animal model of PTSD. Elevated plus maze (EPM) and open field (OF) tests were used to assess anxiety-like behavior. Changes in the gene expressions of CRH, CRHR1, CRHR2, glucocorticoid receptor (GR), and FKBP5 were measured in brain regions (BNST, amygdala, and PVN) responsible for modulating the stress response. The SPS animals spent less time in the OF central zone and were less mobile than the controls; however, the Ucn3 treatment reversed this effect. SPS decreased the GR and FKPB5 mRNA levels in the PVN. Ucn3 suppressed the effect of SPS on FKBP5 mRNA expression in the PVN and increased FKBP5 mRNA in the BNST and PVN compared to the stressed animals. We demonstrate that Ucn3 has the potential to ameliorate anxiety-like behavior in SPS animals and also to affect the neuroendocrine system in the BNST and PVN. In addition, we confirm the important role of CRHR2 signaling in mediating the stress response.

Perinatal bisphenol A exposure has an age- and dose-dependent association with thyroid allostasis adaptive response, as well as anxiogenic-depressive-like and asocial behaviors in juvenile and adult male rats

Thyroid hormones are essential for brain development, and a shortage throughout the fetal and postnatal periods can result in mood disorders. Perinatal exposure to bisphenol A (BPA) affects thyroid activity and dependent processes indirectly during pregnancy or early postnatal life. This is particularly important because it may cause changes in tissue ontogeny, increasing the risk of developing disorders later in life. The study aimed to investigate the consequences of thyroid hormone deficiency on anxiety, social, and depressive behaviors, as well as disruption in thyroid peroxidase (TPO) gene expression, which influences the NF-κB/Nrf-2/HO-1/iNOS signaling pathway, leading to oxidative stress, inflammation, and DNA fragmentation in perinatal BPA exposure (PND18), and whether these effects can be observed in juvenile (PND60) and adult (PND95) male offspring rats. BPA increased anxiety-like behavior while decreasing sucrose preference and sociability on a choice task between novel conspecific male rats and enhanced immobility on the forced swim test. Perinatal exposure to BPA causes thyroid insult by overproducing ROS, increasing iNOS, and NF-κB levels—these effects, in turn, down-regulate Nrf-2/HO-1 signaling, resulting in DNA fragmentation within thyroid tissues. Furthermore, perinatal BPA exposure for 60 and 95 days resulted in a significant fold decrease in TPO mRNA levels in the thyroid tissues, with an insignificant fold rise in TPO expression levels in BPA 50–60. In conclusion, the present study found that perinatal BPA exposure induced thyroid allostasis-adaptive response by inhibiting the NF-κB/Nrf-2/HO-1/iNOS signaling pathway and altering the transcriptional expression of TPO, where TSH reinforced a possible association with TPO activity, disrupting thyroid hormone synthesis in juvenile rats and gradual deterioration reaching the adult stage.

The protective effect of DMI on hippocampus EEG, behavioral and biochemical parameters in hypoxia-induced seizure on neonatal period.

Hypoxia-Induced Neonatal Seizure (HINS) is a prevalent type of seizure in infants caused by hypoxic conditions, which can lead to an increased risk of epilepsy, learning disabilities, and cognitive impairments later in life. This study focuses on examining the effects of dimethyl itaconate (DMI) on cognition, motor coordination, and anxiety-like behavior in male rats that have experienced HINS. 42 male Wistar newborn rats (PND10) were randomly divided into six groups (n = 7). 1) Control (Vehicle only); received DMI solvent (0.1ml) without applying hypoxia. 2-3) DMI; receiving (20 and 50 mg/kg; i.p). 4) HINS; they were placed in a hypoxia chamber with 7% oxygen and 93% nitrogen concentration for 15 minutes. 5-6) DMI+HINS; received DMI (20 and 50 mg/kg; i.p) 24h before hypoxia. Behavioral tests including; Novel object recognition test, Rotarod, Parallel bar, Open field and elevated plus maze (EPM); started at age 45 after birth. After behavioral tests, the hippocampal CA1 region local EEG was recorded in all groups. Then the brain hippocampus tissue was isolated and the amount of MDA, SOD, NO, and Thiol was measured by ELISA method. Data showed that the administration of DMI improved motor symptoms, anxiety-like behaviors, and cognition in HINS rats (p<0.05). EEG power in the HINS group decreased significantly compared to other experimental groups (p<0.05). Biochemical observations showed that DMI significantly reduced oxidative stress and inflammation in the hippocampal tissue of HINS rats (p<0.05). Increased hippocampal oxidative stress and inflammation can be effective in the occurrence of behavioral disorders observed in HINS rats. While DMI improved these behavioral impairments by reducing oxidative stress and inflammation.

Neuroprotective Roles of Daidzein Through Extracellular Signal-Regulated Kinases Dependent Pathway In Chronic Unpredictable Mild Stress Mouse Model.

Depression is a stress-related neuropsychiatric disorder causing behavioural, biochemical, molecular dysfunctions and cognitive impairments. Previous studies suggested connection between neuropsychiatric diseases like depression with estrogen and estrogen receptors (ER). Daidzein is a phytoestrogen that functions as mammalian estrogen and regulates gene expressions through extracellular signal-regulated kinases (ERKs) dependent pathway by activating ERβ. ERβ modulates stress responses, physiological processes by activating protein kinases and plays a significant role in various neurological diseases like depression. However, significant roles of daidzein in depression involving ERK1/2, pERK1/2, and mTOR still unknown. Herein, we examined neuroprotective role of daidzein in chronic unpredictable mild stress (CUMS) mouse model. CUMS model was prepared, and placed in six groups namely, control, CUMS, CUMS vehicle, CUMS DZ (Daidzein 1mg/kgbw, orally), CUMS PHTPP (ERβ blocker, 0.3mg/kgbw, i..p.) and CUMS Untreated. Supplementation of daidzein to CUMS mice exhibits decrease depressive and anxiety-like behaviour, improved motor coordination and memory. Further, immunofluorescence results showed daidzein improved ERK1/2, pERK1/2 and mTOR expressions in the cortex, hippocampus and medulla of stressed mice. SOD, catalase and acetylcholinesterase levels were also improved. Blocking of ERβ with PHTPP stressed mice showed deficits in behaviour, low expression of ERK1/2, pERK1/2 and mTOR, and no significant changes in SOD, catalase and acetylcholinesterase level. Collectively, this study suggests that daidzein may ameliorate depressive and anxiety-like behaviour through ERK downregulating pathway by activating ERβ through ERK1/2, pERK1/2 and mTOR. Such study may be useful to understand daidzein dependent neuroprotection through ERβ in depression.

The role of vitamin D: a promising pathway to combat neuropsychiatric lupus disorders.

To evaluate neuropsychiatric manifestations in the pristane-induced lupus (PIL) model, as well as to evaluate immunoregulatory effects of vitamin D (vit-D) in the brain of mice with PIL. Eighty female BALB/c mice were divided into six groups with 90 (3 months) and 180 (6 months) days of experimentation: CO3, CO6 (controls), PIL3, PIL6 (pristane-induced lupus), VD3 and VD6 (PIL supplemented with 1,25-dihydroxyvitamin D). Forced-swim, elevated plus maze and Barnes maze were the behavioral tests performed. Expression of pVDR was assessed by immunofluorescence. Brain IgM and IgG deposits were evaluated by double staining fluorescence. Serum IL-6 and IFN-α1 were quantified by ELISA. AUC-ROC curve was also performed for immunoglobulins. PIL and VD showed depressive-like behavior in the forced-swim test and anxious-like behavior in the elevated plus maze test. PIL also presented cognitive and memory impairment in the Barnes maze test. Additionally, PIL and VD presented higher levels of serum IFN-α1, but not IL-6. Mice supplemented with vit-D had reduced IgM and IgG deposits and increased pVDR expression in the brain after 180 days. The AUC-ROC curve demonstrated high sensitivity and specificity for IgM and IgG in the brain. We observed neuropsychiatric manifestations in this model of systemic lupus erythematosus (SLE), strongly corroborating to PIL model being suitable as a neuropsychiatric lupus (NPSLE) model. Vit-D was able to reduce immunoglobulin deposits in the brain and influenced the levels of serum IL-6 in the animals assessed. Also, it improved memory, but it had no effect on depressive and anxious-like behavior.

Ethanolamine and Vinyl–Ether Moieties in Brain Phospholipids Modulate Behavior in Rats

Plasmalogens are brain-enriched phospholipids with a vinyl–ether bond at the sn-1 position between the glycerol backbone and the alkyl chain. Previous studies have suggested that plasmalogens modulate locomotor activity, anxiety-like behavior, and cognitive functions in rodents; however, the specific moieties contributing to behavioral regulation are unknown. In this study, we examined the behavioral modulation induced by specific phospholipid moieties. To confirm the permeability of phospholipids in injected liposomes, we measured the fluorescence intensity following intravenous injection of liposomes containing ATTO 740-labeled dioleoylphosphatidylethanolamine. Then, we compared the behavioral effects following injection of liposomes composed of egg phosphatidylcholine (PC) and 1-stearoyl-2-docosahexaenoyl-sn-glycero-3-phosphoethanolamine (PE 18:0/22:6), PC 18:0/22:6, 1-(1Z-octadecenyl)-2-docosahexaenoyl-sn-glycero-3-phosphoethanolamine (PE P-18:0/22:6), or PC P-18:0/22:6, into the tail vein of male rats. The time spent in the central region of the open field was significantly reduced after injection of PE 18:0/22:6, harboring an ester bond at sn-1 compared to controls. Furthermore, the discrimination ratio in the novel object recognition test was significantly higher in PC 18:0/22:6 compared to PE 18:0/22:6, suggesting that the substitution of ethanolamine with choline can enhance recognition memory. We demonstrate that the structures of the sn-1 bond and the hydrophilic moiety in the phospholipids can modulate exploratory behaviors and recognition memory in rodents.

Experimental Periodontitis Increases Anxious Behavior and Worsens Cognitive Aspects and Systemic Oxidative Stress in Wistar Rats.

Periodontitis (PD) has the potential to induce systemic changes that affect both physical and behavioral aspects. These alterations may be associated with changes in both the inflammatory profile and the oxidative stress status of individuals with PD. Therefore, we aimed to evaluate the effects of PD on oxidative stress, as well as on behavioral parameters and cognitive impairment, in a preclinical model. Twenty-four male Wistar rats were randomly assigned to PD and sham groups. PD was induced by the ligature protocol for 14 days. Behavioral tests were initiated on the 9th day of the experiment to evaluate anxious behavior and cognition (learning and memory). After euthanasia, oxidative stress was evaluated in the gums, blood, hippocampus, and amygdala. Alveolar bone loss, bone microstructure, and elemental compositions of the mandibular bone were also assessed. PD increased alveolar bone loss, reduced the calcium and phosphorus content in the mandibular bone, and increased anxiety-like behavior and cognitive decline (p < 0.05). Furthermore, PD significantly affected the redox balance, as evidenced by increased total antioxidant capacity (TAC) in the gingiva and hippocampus (p < 0.05). It also led to increased lipid peroxidation in the gingiva and erythrocytes (p < 0.05), decreased antioxidant defenses in erythrocytes (superoxide dismutase) and the hippocampus (catalase), and increased antioxidant activity (catalase) in the amygdala (p < 0.05). PD resulted in cognitive alterations, including impairments in spatial learning and memory, as well as increased anxious behavior, likely due to redox imbalance in rats.

Non-coding RNA alterations in occlusal disharmony-induced anxiety-like behaviour.

Occlusal disharmony (OD) may induce anxiety-like behaviours; however, the underlying mechanism remains unclear. Herein, we explored the expression profiles of non-coding RNAs (ncRNAs), along with their biological function and regulatory network, in anxiety-like behaviour induced by OD. Occlusal disharmony was produced by anterior crossbite of C57BL/6 mice. Behavioural tests, corticosterone (CORT) and serotonin (5-HT) levels were used to measure anxiety. In addition, RNA sequencing was used to screen all differentially expressed (DE) ncRNAs. Moreover, the RNA-binding proteins interacting with ncRNAs were predicted by the ENCORI database and confirmed using western blots. The significant differences in behavioural tests and CORT suggested the successful induction of anxiety-like behaviour by OD. In OD mice, ncRNAs were significantly dysregulated. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses suggested that the DE ncRNAs were enriched in anxiety-related pathways. CircRNA10039 was upregulated, and PTBP1 was predicted to interact with circRNA10039. In addition, KEGG pathway analysis showed that PTBP1 may be associated with messenger RNA biogenesis and spliceosomes. OD induced by anterior crossbite can lead to the anxiety-like behaviours. During this process, ncRNA also changes. CircRNA10039 and PTBP1 may play a role in OD-induced anxiety-like behaviours.

Comparison of forced and voluntary exercise types on male rat brain monoamine levels, anxiety-like behaviour, and physiological indexes under light and dark phases

PurposePhysical exercise improves physical and mental health; however, the differences between voluntary and forced exercise protocols are unclear. In addition, knowledge regarding the consequences of differences in testing timing, such as light and dark phases, in response to exercise type is limited. We investigated the effects of chronic forced and voluntary wheel running on the changes in brain monoamine levels (5-HT: serotonin, DA: dopamine, NA: noradrenaline), anxiety-like behaviours, and physiological stress responses in the light and dark phases. MethodsAdult male Wistar rats were equally and randomly assigned to four groups: sedentary control, voluntary exercise (free running on a wheel, V-EX), voluntary limited exercise (wheel available only 1h/day, VL-EX), and forced exercise (running on a motorised wheel, F-EX). Each group was further divided into dark- or light-experimental condition groups. After 4 weeks, the rats underwent an open-field test. The monoamines and their metabolite levels were measured in the major neural cell bodies and the projection areas related to behaviour, cognition, anxiety, and stress in the brain. ResultsAdrenal hypertrophy and elevated body temperature, except during the exercise period, were observed in the F-EX rats that exhibited anxiety-like behaviour. The levels of monoamines and their metabolites, particularly the 5-HTergic and DAergic systems, in specific areas, were significantly altered in the rats in the V-EX group compared to those in the VL-EX and other groups. These differences were observed only in the dark phase. ConclusionThe results suggest that V-EX mainly stimulates the 5-HTergic and DAergic systems, while F-EX induces physiological stress and increases anxiety-like behaviour during the dark phase. This study highlights the importance of accounting for exercise types and light/dark phases in behavioural neuroscience experiments.

Experimental colitis is comorbid with social interaction deficits and anxiety-like behaviors in mice: mechanistic intuitions into neuroinflammation and Claudin 5 expression in the hippocampus.

Inflammatory bowel disease (IBD) is accompanied by psychiatric disorders, including Schizophrenic-like manifestations. Although incompletely illustrated, intestinal mucosal membrane damage and blood-brain barrier (BBB) penetrability may have significant roles in psychiatric symptoms of IBD. This study aimed to investigate role of the Claudin-5 (CLDN5) (a regulator of the permeability of BBB) and neuroinflammatory response in the comorbid behavioral disorders in experimental colitis in mice. Acetic acid was used to induce colitis in mice. 7 days after induction of colitis, behaviors including social interaction and locomotor activity as well as anxiety-like behaviors were evaluated. Then, the colon was extracted for gross and microscopic evaluations. The expression of CLDN5, TNF-α, IL1β and IL23 was measured by RT-PCR in the colon and hippocampus. Histopathologic evaluations demonstrated mucosal, submucosal, and crypt-related damages in the colon. The negative and positive number of social interactions significantly increased in the colitis group. A considerable increase in locomotor activities (horizontal and vertical components) shown in the colitis group. Mice in colitis group spent less time in the central zone in the open field apparatus. Gene expressions of TNF-α, IL1β, and IL23 increased and CLDN5 decreased in the colitis group. The barrier function of the intestine and brain would be impaired, partially at least, following colitis (as we observed decrease in CLDN5 gene expression). Furthermore, we found that beside inflammatory response in the colon, a neuro-immune response triggered in the hippocampus following colitis. These alterations probably, mediated comorbid behavioral disorders in acetic acid-induced colitis in mice.