Elevated Plus-maze Test Research Articles

Varenicline improves cognitive impairment in a mouse model of mPFC ischemia: The possible roles of inflammation, apoptosis, and synaptic factors

Ischemia in the medial prefrontal cortex (mPFC) causes cognitive impairment in stroke cases. This study aimed to examine the effects of varenicline as α7 and α4β2 nicotine acetylcholine receptors (nAChRs) agonist, on cognitive impairment, inflammation, apoptosis, and synaptic dysfunction in mPFC ischemia. Mice were divided to three groups of control, sham, or photothrombotic mPFC ischemia model. The control and sham groups received 2 ml/kg of normal saline for a 14-day period. As well, the animals in the ischemia groups received normal saline (2 ml/kg) or varenicline at 0.1, 1, and 3 mg/kg doses for a 14-day period. Anxiety-like behaviors were then assessed by open field (OFT) and elevated plus-maze (EPM) tests. Memory was also evaluated using Morris water maze (MWM) and novel object recognition (NOR) tests. The levels of inflammatory (IL-1β, TNF-α), apoptotic (Bax, caspase3, BCL-2), and synaptic (SYP, PSD-95, and GAP-43) proteins were examined using the western blot method. In addition, the histological evaluation was performed to assess tissue damage. The administration of Varenicline at the dose of 3 mg/kg reduced the IL-1β, TNF-α, Bax, and caspase3 levels. Moreover, it increased BCL-2, SYP, PSD-95, and GAP-43 levels at the same dose and ameliorated memory impairment and anxiety-like behaviors in mPFC ischemic mice. Varenicline improved cognitive impairment by blocking inflammation and apoptosis, improving synaptic factors, and diminishing tissue damage in the mPFC ischemic mice.

Neuropsychopharmacological profiling of scoparone in mice

Scoparone (6,7-dimethoxycoumarin) is a simple coumarin from botanical drugs of Artemisia species used in Traditional Chinese Medicine and Génépi liquor. However, its bioavailability to the brain and potential central effects remain unexplored. We profiled the neuropharmacological effects of scoparone upon acute and subchronic intraperitoneal administration (2.5–25 mg/kg) in Swiss mice and determined its brain concentrations and its effects on the endocannabinoid system (ECS) and related lipids using LC–ESI–MS/MS. Scoparone showed no effect in the forced swimming test (FST) but, administered acutely, led to a bell-shaped anxiogenic-like behavior in the elevated plus-maze test and bell-shaped procognitive effects in the passive avoidance test when given subchronically and acutely. Scoparone rapidly but moderately accumulated in the brain (Cmax < 15 min) with an apparent first-order elimination (95% eliminated at 1 h). Acute scoparone administration (5 mg/kg) significantly increased brain arachidonic acid, prostaglandins, and N-acylethanolamines (NAEs) in the FST. Conversely, subchronic scoparone treatment (2.5 mg/kg) decreased NAEs and increased 2-arachidonoylglycerol. Scoparone differentially impacted ECS lipid remodeling in the brain independent of serine hydrolase modulation. Overall, the unexpectedly potent central effects of scoparone observed in mice could have toxicopharmacological implications for humans.

Environmental Enrichment Facilitates Anxiety in Conflict-Based Tests but Inhibits Predator Threat-Induced Defensive Behaviour in Male Mice

Introduction: Environmental enrichment (EE) is a useful and sophisticated tool that improves rodents’ well-being by stimulating social behaviour and cognitive, motor, and sensory functions. Exposure to EE induces neuroplasticity in different brain areas, including the limbic system, which has been implicated in the control of anxiety and fear. However, the effects of EE on ethologically relevant naturalistic behaviours, such as those displayed by prey in the presence of predators, remain largely unexplored. Material and Methods: In the present study, we investigated anxiety- and panic attack-like behaviours in a predator (cat)-prey confrontation paradigm and compared them with those in classical assays, such as the elevated plus-maze (EPM), marble-burying, and open field tests (OFTs), using C57BL/6J male mice housed in enriched or standard environments for 6 weeks. Results: We observed that EE exposure caused enhancement of the levels of anxiety-like behaviours in the EPM and OFTs, increasing risk assessment (an anxiety-related response), and decreasing escape (a panic attack-like response) behaviours during exposure to the predator versus prey confrontation paradigm. Conclusion: Taken together, our findings suggest that enriched external environments can modify the processing of fear- and anxiety-related stimuli in dangerous situations, changing the decision-making defensive strategy.

Liquiritin Alleviates Depression-Like Behavior in CUMS Mice by Inhibiting Oxidative Stress and NLRP3 Inflammasome in Hippocampus.

Objective Central inflammation is generally accepted to be involved in the pathology of depression. We investigated whether liquiritin exerts antidepressant effects by inhibiting central NLRP3 inflammasomes. Results The behavioral despair model and chronic unpredictable mild stress (CUMS) model in mice were established to evaluate the antidepressant action of liquiritin. In the despair model study, liquiritin (40 mg/kg) administration reduced immobility time in tail suspension test (TST) and forced swimming test (FST) without affecting locomotion activity. In CUMS model study, liquiritin (40 mg/kg, once daily for 4 weeks) significantly increased sucrose consumption and body weight of CUMS mice. The behavioral experiment results showed that liquiritin reduced the immobile time of CUMS mice in TST and FST, respectively, and increased the time spent and open arm entries in the elevated plus-maze (EPM) test. Further, the hippocampal superoxide dismutase (SOD) activity was increased in liquiritin-treated group, while malonaldehyde (MDA) decreased. Additionally, the hippocampal cytokines interleukin-18 (IL-18) and interleukin-1 beta (IL-1β) contents were reduced in the liquiritin-treated group. Further, liquiritin downregulated the expression of NLRP3 in the hippocampus of CUMS mice rather than TLR4. Besides, NLRP3 inflammasome-associated proteins caspase-1 and ASC were also downregulated. However, liquiritin did not alter the thermal stability of NLRP3 in the cellular thermal shift assay (CETSA), suggesting that its inhibition of NLPR3 was not by direct targeting of NLRP3 protein. Conclusions Liquiritin attenuates depression-like behavior of CUMS mice and inhibited cytokines levels triggered by NLRP3 inflammasome, suggesting the antidepressant action is, at least partially, associated with antioxidant stress and inhibition of NLRP3 inflammasome activation.

Social isolation induces neuroinflammation and microglia overactivation, while dihydromyricetin prevents and improves them

BackgroundAnxiety disorders are the most prevalent mental illnesses in the U.S. and are estimated to consume one-third of the country’s mental health treatment cost. Although anxiolytic therapies are available, many patients still exhibit treatment resistance, relapse, or substantial side effects. Further, due to the COVID-19 pandemic and stay-at-home order, social isolation, fear of the pandemic, and unprecedented times, the incidence of anxiety has dramatically increased. Previously, we have demonstrated dihydromyricetin (DHM), the major bioactive flavonoid extracted from Ampelopsis grossedentata, exhibits anxiolytic properties in a mouse model of social isolation-induced anxiety. Because GABAergic transmission modulates the immune system in addition to the inhibitory signal transmission, we investigated the effects of short-term social isolation on the neuroimmune system.MethodsEight-week-old male C57BL/6 mice were housed under absolute social isolation for 4 weeks. The anxiety-like behaviors after DHM treatment were examined using elevated plus-maze and open field behavioral tests. Gephyrin protein expression, microglial profile changes, NF-κB pathway activation, cytokine level, and serum corticosterone were measured.ResultsSocially isolated mice showed increased anxiety levels, reduced exploratory behaviors, and reduced gephyrin levels. Also, a dynamic alteration in hippocampal microglia were detected illustrated as a decline in microglia number and overactivation as determined by significant morphological changes including decreases in lacunarity, perimeter, and cell size and increase in cell density. Moreover, social isolation induced an increase in serum corticosterone level and activation in NF-κB pathway. Notably, DHM treatment counteracted these changes.ConclusionThe results suggest that social isolation contributes to neuroinflammation, while DHM has the ability to improve neuroinflammation induced by anxiety.

Global Cerebral Ischemia in Male Long Evans Rats Impairs Dopaminergic/ΔFosB Signalling in the Mesocorticolimbic Pathway Without Altering Delay Discounting Rates.

Global cerebral ischemia (GCI) in rats has been shown to promote exploration of anxiogenic zones of the Elevated-Plus Maze (EPM) and Open Field Test (OFT). This study investigated changes in impulsive choice and/or defensive responses as possible contributors of heightened anxiogenic exploration observed after ischemia. Impulsivity was assessed using delay discounting (DD) paradigms, while the Predator Odour Test (PO) served to assess changes in defensive responses towards a naturally aversive stimulus. Male Long Evans rats underwent 9 days of autoshaping training and 24 days of DD training prior to GCI or sham surgery (n = 9/group). Post-surgery, rats completed the OFT, EPM, and PO, followed by 6 days of DD sessions. Blood droplets served to evaluate corticosterone secretion associated with PO exposure. With impulsivity being regulated through mesocorticolimbic monoaminergic pathways, we also characterised post-ischemic changes in the expression of dopamine D2 receptors (DRD2), dopamine transporters (DAT), and 1FosB in the basolateral amygdala (BLA), nucleus accumbens core (NAcC) and shell (NAcS), and ventromedial prefrontal cortex (vmPFC) using immunohistofluorescence. Our findings revealed no impact of GCI on delay discounting rates, while PO approach behaviours were minimally affected. Nonetheless, GCI significantly reduced DRD2 and ΔFosB-ir in the NAcS and NAcC, respectively, while DAT-ir was diminished in both NAc subregions. Collectively, our findings refine the understanding of cognitive-behavioural and biochemical responses following stroke or cardiac arrest. They support significant alterations to the dopaminergic mesocorticolimbic pathway after ischemia, which are not associated with altered impulsive choice in a DD task but may influence locomotor exploration of the OFT and EPM.

Phytoestrogen genistein modulates neuron–microglia signaling in a mouse model of chronic social defeat stress

Microglia, resident immune cells in the brain, are shown to mediate the crosstalk between psychological stress and depression. Interestingly, increasing evidence indicates that sex hormones, particularly estrogen, are involved in the regulation of immune system. In this study, we aimed to understand the potential effects of chronic social defeat stress (CSDS) and genistein (GEN), an estrogenic compound of the plant origin, on neuron–microglia interactions in the mouse hippocampus. The time spent in the avoidance zone in the social interaction test was increased by CSDS 1 day after the exposure, while the avoidance behavior returned to control levels 14 days after the CSDS exposure. Similar results were obtained from the elevated plus-maze test. However, the immobility time in the forced swim test was increased by CSDS 14 days after the exposure, and the depression-related behavior was in part alleviated by GEN. The numerical densities of microglia in the hippocampus were increased by CSDS, and they were decreased by GEN. The voxel densities of synaptic structures and synaptic puncta colocalized with microglia were decreased by CSDS, and they were increased by GEN. Neither CSDS nor GEN affected the gene expressions of major pro-inflammatory cytokines. Conversely, the expression levels of genes related to neurotrophic factors were decreased by CSDS, and they were partially reversed by GEN. These findings show that GEN may in part alleviate stress-related symptoms, and the effects of GEN may be associated with the modulation of neuron–microglia signaling via chemokines and neurotrophic factors in the hippocampus.

Effect of Ocimum sanctum leaf extract in animal models of anxiety

Background: Anxiety is one of the most prominent psychiatry disorders related to common stress. Approximately two-thirds of anxious patients respond to currently available treatments but the magnitude of problem is still disappointing. Ocimum sanctum (OS), a perennial shrub grown in India, has anti-stress activity. Yet, there is a paucity of data regarding this. Aims and Objectives: This study aims to evaluate the anti-anxiolytic effect of OS leaf extract (OSLE) in Swiss albino mice. Materials and Methods: Elevated plus maze (EPM) and open field test are standardized tests done for screening anxiolytic effects of drugs. The animals were grouped and the tests were conducted and the results were compared with the standard drug diazepam. Results: There was significant increase in the time spent in open arm and number of open arm entries in the diazepam group and group receiving OSLE at dose of 100 mg/kg and 200 mg/kg in EPM test. Furthermore, in the open field test, there was significant increase in the number of square crossed and rearing in the diazepam group and OSLE at dose of 100 mg/kg and 200 mg/kg. Conclusion: OSLE shows significant anxiolytic effect in EPM and open field test models in Swiss albino mice. This can be further studied to open up new possibilities for new drug development for anxiety.

Sex differences in behavioral, cognitive and voluntary ethanol-intake effects in Dexamethasone-induced depression-like state in Wistar rat

The stress response is attached to psychosomatic and psychiatric disorders. Therefore, it is important to comprehend the underlying mechanisms influencing this relationship. Moreover, men and women respond differently to stress–both psychologically and biologically. These differences should be studied to have an enhanced understanding of the gender difference. However, researches shedding light on sex dimorphism implication have historically been insufficient. Based on observations that advocate the inclusion of sex as a biological variable in stress response, the present study was designed to explore sex differences in (i) depressive-like, (ii) anxiety-like behaviors, (iii) cognitive-like performances, and (iv) voluntary ethanol intake (VEI) in Wistar rat submitted to dexamethasone (DEX)-stress simulation. Rats were administered daily with DEX (1.5 mg/kg, s.c., 21 days) or vehicle. Behavior, cognitive, and VEI states of rats were evaluated in the following paradigms: forced swimming test (FST); saccharin preference test (SPT); open field test (OFT); elevated plus-maze test (EPMT); novelty suppressed feeding test (NSFT); spatial learning and memory in Morris water maze test (MWMT); VEI in two-bottle choice paradigm. DEX-treated rats showed a set of depression-like behaviors: increased time of immobility; reduced preference for saccharin consumption; increased anxiety-like behavior; cognitive impairments; and enhanced VEI. Sexual dimorphism was recorded in this study. Females were more impaired in FST, SPT, EPMT, NSFT, and VEI. Results demonstrate that DEX-treatment induced a behavioral alterations related to anxiety-depressive-like state with learning and memory impairments; confirm the facilitatory role of glucocorticoids on VEI and reveal sexual dimorphism in stress response.

Behavioral, neurochemical, and neuroimmune changes associated with social buffering and stress contagion

Social buffering can provide protective effects on stress responses and their subsequent negative health outcomes. Although social buffering is beneficial for the recipient, it can also have anxiogenic effects on the provider of the social buffering – a phenomena referred to as stress contagion. Social buffering and stress contagion usually occur together, but they have traditionally been studied independently, thus limiting our understanding of this dyadic social interaction. In the present study, we examined the effects of preventative social buffering and stress contagion in socially monogamous prairie voles (Microtus ochrogaster). We tested the hypothesis that this dynamic social interaction is associated with coordinated alterations in behaviors, neurochemical activation, and neuroimmune responses. To do so, adult male prairie voles were stressed via an acute immobilization restraint tube (IMO) either alone (Alone) or with their previously pair-bonded female partner (Partner) in the cage for 1 h. In contrast, females were placed in a cage containing either an empty IMO tube (Empty) or one that contained their pair-bonded male (Partner). Anxiety-like behavior was tested on the elevated plus maze (EPM) following the 60-mins test and brain sections were processed for neurochemical/neuroimmune marker labeling for all subjects. Our data indicate that females in the Partner group were in contact with and sniffed the IMO tube more, showed fewer anxiety-like behaviors, and had a higher level of oxytocin expression in the paraventricular nucleus of the hypothalamus (PVN) compared to the Empty group females. Males in the Partner group had lower levels of anxiety-like behavior during the EPM test, greater activation of corticotropin-releasing hormone expressing neurons in the PVN, lower activation of serotonin neurons in the dorsal raphe, and lower levels of microgliosis in the nucleus accumbens. Taken together, these data suggest brain region- and neurochemical-specific alterations as well as neuroinflammatory changes that may be involved in the regulation of social buffering and stress contagion behaviors.

Effects of decoction products of Lavandula angustifolia, Laurus nobilis, and Artemisia herba-alba on depression and anxiety behaviors in Wistar rats

Medicinal and aromatic plants have very substantial emotional effects on rats, which is part of the current study. Decoction products of three Moroccan plants (Lavandula angustifolia L., Laurus nobilis L., and Artemisia herba-alba) were used to be tested on Wistar rats in the laboratory. The goal was to check if they had an anti-depressant and/or anti-anxiety action on the animals' tests. Wistar Rats were born and bred in the pet store of the Faculty of Science, Kenitra. The anti-depressant and anti-anxiety effects were assessed according to three animal models: Open Field, Elevated Plus-maze for anxiety, and the Forced Swimming animal model for depression. The results showed that drinking water containing plant extracts has anti-depressant and anti-anxiety effects. Rats have overcome depression by reducing downtime during forced swimming. Concerning anti-anxiety, the open-field test showed an increase in the rat’s locomotor activity, which indicates unhesitating exploratory behavior in the form of confident movement through the number of visits to the central part and the total distance crossed. The anxiety reduction was also corroborated by the elevated Plus-maze test, where the rats displayed no aversion to open spaces on account of the prolonged time they spent in the open arms and platform of the raised cross maze. In light of the findings from the experiments conducted in the study, the decoction products of the three plants appear to be viable candidates for the treatment of depression and anxiety.

Social housing promotes cognitive function and reduces anxiety and depressive-like behaviours in rats

The aim of the study was to assess the impact of social isolation of rats in the post-weaning period using behavioural tests aimed at assessing cognitive function, anxiety, and depressive-like behaviours. The monitoring was performed in male Wistar rats which were housed after weaning either individually (n = 8) or in pairs (n = 8) for 33 days. In the open field, rats kept in isolation reared less often (P &lt; 0.05) than pair-housed rats. In the elevated plus-maze test, pair-housed rats entered the open arm more frequently (P = 0.002) and stayed in the closed arm less often (P = 0.019) compared to rats housed in isolation. In the forced swim test, climbing was seen more frequently (P = 0.016) in pair-housed rats whereas immobility was more common (P = 0.006) in rats housed individually. In the novel object recognition test, the pair-housed rats preferred (P = 0.014) the novel object whereas there was no difference (P = 0.107) in time spent by exploring familiar and novel objects in rats housed in isolation. Furthermore, juvenile rats housed for 33 days in isolation showed higher (P = 0.003) body weight gain during the monitored period than rats housed for the same period in pairs. Our findings are important not only in terms of assessing the impact of rat housing on their mental and physical development but also in terms of the accurate interpretation of the results of other experiments where the rat is used as a model organism.

Studying some neuroprotective effects of Calotropis procera extracts against scopolamine- induced neuropschiatric comorbidities in a rodent model of epilepsy

Many plants are largely used in alternative medicine of Burkina Faso for neuropsychiatric disorders treatment. However, their neuro-pharmacological properties are less evaluated through scientific studies. The present study aims to evaluate the neuroprotective effect of Calotropis procera leaves and root-bark aqueous extract, focusing on a scopolamine-induced model of epilepsy in rodents. In this study, we evaluated this plant extracts possible protective effects on the central nervous system, through the behavioral tests and the enzymes activity assays. Thus, elevated plus-maze test and Y-maze task were used to evaluate animals behavioral and UV/visible spectrophotometer methods were used to evaluate the enzyme’s activities in brain’s supernatant. Our results are showing no significant protective effects of leaves extract, but it revealed a significant neuroprotective effect of root-bark aqueous extract, as well as in the behavioral tests and the brain’s oxidative enzymes specific activity evaluation. Indeed, anti-amnesic and anxiolytic activities were observed through Y maze task and elevated plus maze tests for the groups of animals receiving root-bark extract (100 mg/kg b.w.). In these test, inhibition of disturbances of Time spent in Open Arms, Spontaneous Alternation, and Transfer Latency induced after scopolamine administration were recorded with animals received root-bark extract. Likewise, the superoxide dismutase and catalase activity disturbance induced by scopolamine were also inhibited in root-bark extract pre-administered group. Thus, our study provides biochemical and neuro-pharmacological data for traditional use of C. procera for neuropsychiatric disorders treatment, including scopolamine-induced epilepsy symptoms (mainly referring to the psychiatric comorbidities of this disorder).

Anti-depressant Activity of Hydroalcoholic Extract of Asperula odorata L. in Mice

Background: The relationship between the treatment of depression and plant-derived substances (e.g., flavonoids, coumarin, and scopoletin) has been demonstrated through interference with the monoamine system. The present study was planned to evaluate the anti-depressant effects of Asperula odorata L. plant through behavioral tests in mice. Material and Methods: In this experimental study, 35 male Syrian mice weighing 30-40 g were examined in five groups (n=7) as follow: received oral distilled water gavage (control), 10 mg/kg of fluoxetine solution gavage (reference standard), 10, 5, and 2.5 mg/kg of A. odorata L. extract gavage (treatment groups). After one week, all behavioral tests, including tail suspension test (TST), forced swimming test (FST), open field test (OFT), elevated plus maze test (EPMT), and fractionation tests were performed each morning for 4-6 h within five days. Results: The hydroalcoholic extract of A. odorata contained phenolic and flavonoid substances (Shinoda test confirmed flavonoid family). Administration of extract (10 and 5 mg/kg doses) versus fluoxetine (10 mg/kg dose) reduced the immobility of animals in both FST and TST (P&lt;0.05). At the OFT, the administered extract increased the number of central square entries of animals with higher mobility (P&lt;0.05). At a 10 mg/kg dose, the active flavonoid ingredients increased the mice's incline to entre and spent more time within no wall parts of EPMT (P&lt;0.05). Conclusion: Our study suggests that the hydroalcoholic extract of A. odorata L. could have significant anti-depressant activity. [GMJ.2021;10:e2206]

ELEVATED PLUS-MAZE AND THE HOLE BOARD TEST FOR USE AS A QUALITY CONTROL ASSAY OF HERBAL MEDICINES BASED ON PASSIFLORA INCARNATA LINNAEUS

In the search for the reduction of the side effects caused by allopathy, phytotherapeutic products are already on the veterinary market. This study aimed was to evaluate Elevated Plus-Maze and Hole Board test as an analytical methodology for quality control of anxiolytic medicines based on Passiflora incarnata . The efficacy of three brands commercial differents of Passiflora incarnata extracts was tested in the Elevated Plus-maze (for anxiolytic effect) and the Hole Board test (for locomotor and neophilia activity) in Wistar rats. Treatment with the P. incarnata brands revealed a significant 3-fold increase in the length of stay in the open arms in the LCE. In the ambulation, animals from bands 1 and 3 presented a significant increase, being brand 2 the only one that did not present this relevance. In the neophilia, Passiflora brand 1 presented a significant increase of 3 times and groups 2 and 3 an increase of approximately 2 times. The results showed that different brands of Passiflora have a satisfactory quality standard related to biological activity and showed that the use of Elevated plus-maze/Hole board test can be an effective tool in the quality control of herbal medicines with anxiolytic activity associated with the phytochemical analysis.

Modulation of nociception and pain-evoked neurobehavioral responses by levetiracetam in a craniotomy pain model

Traditional and novel analgesic modalities have been extensively tested for post-craniotomy pain management, yet the role of newer antiepileptic drugs in this area remains obscure. This study investigates the impact of levetiracetam (LEV) on pain modulation and neurobehavioral performance in a craniotomy model. Fifty-six Wistar rats were randomly assigned into seven groups: no intervention (CTRL), administration of placebo or LEV with no further intervention (PBO and LEV, respectively), and sham-operation or craniotomy in placebo (PBO-SHAM and PBO-CR, respectively) or LEV-treated rats (LEV-SHAM and LEV-CR, respectively). Pain was assessed by the rat grimace scale before, and at 8 and 24 h after craniotomy, following intraperitoneal injections of LEV (100 mg/kg twice daily) or normal saline two consecutive days before and on the craniotomy day. Elevated plus-maze and olfactory social memory tests were performed at 24- and 48 h post-craniotomy, respectively. Upon testing conclusion blood samples were collected for cytokines estimation. Levetiracetam administration enhanced antinociception in sham and craniotomy groups. In the elevated plus-maze test, LEV-CR rats spent more time in investigating open arms and performed more open arm entries than PBO-SHAM and PBO-CR animals. The olfactory test revealed no between-groups difference in acquisition time during first contact with a juvenile rat, while LEV-CR rats spent less time to recognize the same juvenile rat compared to PBO-SHAM and PBO-CR groups. Furthermore, LEV-treatment attenuated cortisol, interleukin-6 and TNF-a release, in sham and craniotomy animals. In conclusion, preemptive use of LEV decreases nociception, improves pain-evoked behavior and attenuates stress response in rats subjected to craniotomy.

Daily Optogenetic Stimulation of the Left Infralimbic Cortex Reverses Extinction Impairments in Male Rats Exposed to Single Prolonged Stress.

Post-traumatic stress disorder (PTSD) is associated with decreased activity in the prefrontal cortex. PTSD-like pathophysiology and behaviors have been observed in rodents exposed to a single prolonged stress (SPS) procedure. When animals are left alone for 7 days after SPS treatment, they show increased anxiety-like behavior and impaired extinction of conditioned fear, and reduced activity in the prefrontal cortex. Here, we tested the hypothesis that daily optogenetic stimulation of the infralimbic region (IL) of the medial prefrontal cortex (mPFC) during the 7 days after SPS would reverse SPS effects on anxiety and fear extinction. Male Sprague-Dawley rats underwent SPS and then received daily optogenetic stimulation (20 Hz, 2 s trains, every 10 s for 15 min/day) of glutamatergic neurons of the left or right IL for seven days. After this incubation period, rats were tested in the elevated plus-maze (EPM). Twenty-four hours after the EPM test, rats underwent auditory fear conditioning (AFC), extinction training and a retention test. SPS increased anxiety-like behavior in the EPM task and produced a profound impairment in extinction of AFC. Optogenetic stimulation of the left IL, but not right, during the 7-day incubation period reversed the extinction impairment. Optogenetic stimulation did not reverse the increased anxiety-like behavior, suggesting that the extinction effects are not due to a treatment-induced reduction in anxiety. Results indicate that increased activity of the left IL after traumatic experiences can prevent development of extinction impairments. These findings suggest that non-invasive brain stimulation may be a useful tool for preventing maladaptive responses to trauma.

Neurobehavioral Toxicity of 4-methylimidazole on NMRI mice: Using Behavioral and Histopathology Methods

4-Methylimidazole (4-MEI) a toxic compound in humans and animal is formed as by product of the Maillard reaction. It is found in many foods and beverages and as an intermediate in the synthesis of different materials. Current study was conducted for evaluation the toxicity effects of 4-MEI (70,150,200 mg/kg) on behavioral changes using open field (OF), elevated plus maze (EPM), passive avoidance , Y-maze test and in the following, abnormalities in dentate gyrus cell of the hippocampus tissue using haematoxylin-eosin (HE ) staining. Our results showed that 4-MEI increased the total distance movement and decreased the time spent in central zone in the OF test while in the EPM test, in a dose-dependent manner decreased the time spent in the open arms. Also, 4-MEI led to different in size and density of dentate gyrus cell which was related with disruption obtained in passive avoidance test. Findings obtained indicated 4-MEI can induces neurobehavioral toxicity by increase in locomotor activity, anxiety and memory disorder in mice. Therefore it can be mentioned 4-MEI may have neurotoxicity and results of this study will be useful in order to investigation regarding probable mechanisms involved in neurobehavioral disorders in rats exposed 4-MEI.

A Rat Model of Post-Traumatic Stress Syndrome Causes Phenotype-Associated Morphological Changes and Hypofunction of the Adrenal Gland.

Background: Rats exposed to chronic predator scent stress mimic the phenotype of complex post-traumatic stress disorder (PTSD) in humans, including altered adrenal morphology and function. High- and low-anxiety phenotypes have been described in rats exposed to predator scent stress (PSS). This study aimed to determine whether these high- and low-anxiety phenotypes correlate with changes in adrenal histomorphology and corticosteroid production. Methods: Rats were exposed to PSS for ten days. Thirty days later, the rats’ anxiety index (AI) was assessed with an elevated plus-maze test. Based on differences in AI, the rats were segregated into low- (AI ≤ 0.8, n = 9) and high- (AI > 0.8, n = 10) anxiety phenotypes. Plasma corticosterone (CORT) concentrations were measured by ELISA. Adrenal CORT, desoxyCORT, and 11-dehydroCORT were measured by high-performance liquid chromatography. After staining with hematoxylin and eosin, adrenal histomorphometric changes were evaluated by measuring the thickness of the functional zones of the adrenal cortex. Results: Decreased plasma CORT concentrations, as well as decreased adrenal CORT, desoxyCORT and 11-dehydroCORT concentrations, were observed in high- but not in low-anxiety phenotypes. These decreases were associated with increases in AI. PSS led to a significant decrease in the thickness of the zona fasciculata and an increase in the thickness of the zona intermedia. The increase in the thickness of the zona intermedia was more pronounced in low-anxiety than in high-anxiety rats. A decrease in the adrenal capsule thickness was observed only in low-anxiety rats. The nucleus diameter of cells in the zona fasciculata of high-anxiety rats was significantly smaller than that of control or low-anxiety rats. Conclusion: Phenotype-associated changes in adrenal function and histomorphology were observed in a rat model of complex post-traumatic stress disorder.

Early environmental enrichment prevents cognitive impairments and developing addictive behaviours in a mouse model of prenatal psychological and physical stress.

Environmental enrichment (EE) has shown remarkable effects in improving cognition and addictive behaviour. We tested whether EE could help recover from prenatal stress exposure. Mature Swiss Webster male and virgin female mice were placed together until vaginal plugs were detectable. Next, pregnant rodents were randomized into the control, physically and psychologically stressed groups. The application of stress was initiated on the 10th day of pregnancy and persisted for a week to induce stress in the mice. Open field and elevated plus-maze (EPM) tests were utilized as explorative and anxiety assays, respectively. A passive avoidance shuttle-box test was carried out to check anxiety-modulated behaviour. Morris water maze (MWM) test was undertaken to evaluate spatial learning and memory. Conditioned place preference (CPP) test was selected for evaluation of tendency to morphine consumption. Our results showed that prenatal stress elevated anxiety-like behaviour in the offspring which EE could significantly alleviate after weaning. We also found a higher preference for morphine use in the physical stress and psychological stress offspring group. However, no difference was observed among the genders. Application of EE for the stress group improved several parameters of the cognitive behaviour significantly. Although prenatal stress can lead to detrimental behavioural and cognitive outcomes, it can in part be relieved by early exposure to EE. However, some outcomes linked to prenatal stress exposure may not be diminished by EE therapy. In light of such irreversible effects, large-scale preventive actions promoting avoidance from stress during pregnancy should be advised.