Behavioral Despair Research Articles

Early life adversity accelerates epileptogenesis and enhances depression-like behaviors in rats

ObjectiveEarly life stressors are well-established risk factors for psychiatric disorders, and evidence also suggests that these promote vulnerability to epilepsy. Given the high prevalence of psychiatric disorders in epilepsy, early life stress may represent a common driver for these comorbidities. We used animal modelling to investigate the effects of early life stress on epileptogenesis and depressive behaviors, also exploring HPA axis programming as a potential associative mechanism. MethodsFrom post-natal day 2–9, Wistar rat dams (n = 3) and their offspring were exposed to the Limited Bedding and Nesting (LBN) model of early life adversity. Control dams (n = 3) were undisturbed. Maternal care was video-recorded, and behavior scored. As adults, rats (n = 7/group) underwent kainic acid-induced status epilepticus (SE), to trigger epilepsy development. Spontaneous seizures, depression-like behavior and HPA axis function were quantified. ResultsLBN significantly altered aspects of maternal care, including markedly reducing the consistency of care (p < 0.05), compared to control conditions. Following SE, LBN rats exhibited significantly accelerated epileptogenesis (p = 0.01) and greater disease severity (p = 0.001), compared to control rats. Anhedonia and behavioral despair were observed in epileptic rats exposed to LBN. LBN rats showed significantly dampened HPA axis responsivity, but epileptic rats showed greater corticosterone responses to CRH administration (all p < 0.05). SignificanceEarly life adversity promotes a vulnerability to experimental epileptogenesis. These two ‘hits’ (early life stress and epilepsy) interact to create a depressive-like phenotype, but effects on HPA axis are complex and contrasting. This has implications for the mechanisms underpinning the increased prevalence of psychiatric disorders observed in people with epilepsy.

Memantine Disrupts Motor Coordination through Anxiety-like Behavior in CD1 Mice

Memantine is an FDA approved drug for the treatment of Alzheimer’s disease. It reduces neurodegeneration in the hippocampus and cerebral cortex through the inhibition of extrasynaptic NMDA receptors in patients and mouse models. Potentially, it could prevent neurodegeneration in other brain areas and caused by other diseases. We previously used memantine to prevent functional damage and to retain morphology of cerebellar neurons and Bergmann glia in an optogenetic mouse model of spinocerebellar ataxia type-1 (SCA1). However, before suggesting wider use of memantine in clinics, its side effects must be carefully evaluated. Blockers of NMDA receptors are controversial in terms of their effects on anxiety. Here, we investigated the effects of chronic application of memantine over 9 weeks to CD1 mice and examined rotarod performance and anxiety-related behaviors. Memantine-treated mice exhibited an inability to adapt to anxiety-causing conditions which strongly affected their rotarod performance. A tail suspension test revealed increased signs of behavioral despair. These data provide further insights into the potential deleterious effects of memantine which may result from the lack of adaptation to novel, stressful conditions. This effect of memantine may affect the results of tests used to assess motor performance and should be considered during clinical trials of memantine in patients.

Involvement of Mice Hippocampus Brain-derived Neurotrophic Factor in Diazinon-induced Depressive Behavior in Mice

Background: Diazinon (Dzn), an Organophosphorus (OP) pesticide, is extensively used in agriculture. Acetylcholinesterase inhibition is linked to OP toxicity, and there are major mental health concerns associated with the use of pesticides. The objective of this study was to assess the depressive behavior in an animal model following their exposure to Dzn and the effect on the Brain-Derived Neurotrophic Factor (BDNF) as a critical neurotropic factor. Methods: Male Swiss mice (N=42; 25±3g each) were used and their behaviors were eamined on including the locomotor, Forced Swimming (FST), and Sucrose Preference (SP) tests. These tests were performed the day after a single daily Dzn administration by gavage (2.5-20 mg/kg). Specific animal groups were exposed to Dzn daily (2.5-10 mg/kg) for 14 days, and a test was performed on days 7 and 15. Results: Following the acute exposure to Dzn, the animals’ locomotor activity did not change significantly. During the FST, Dzn at 20 mg/kg significantly increased the animals’ immobility time, indicating despair behavior. Imipramine, injected intraperitoneally at 10 mg/kg, did not cause the depressive behavior. The subacute exposure to Dzn induced less locomotor activity than that of the controls. The 7-day exposure to Dzn at 10 mg/kg significantly prolonged the immobility period compared to that of the controls. The 14-day Dzn exposure at 2.5, 5, or 10 mg/kg increased the immobility time significantly compared to that of the controls. None of the treatment groups showed SP, clearly showing animal anhedonia. The BDNF levels significantly decreased not only by subacute exposures to Dzn but also following a single exposure to this this pesticide. Conclusion: The acute and subacute exposure to Dzn induced depressive behavior and increased the BDNF levels in the hippocampus of Swiss male mice following exposure to Dzn at varying doses of 2.5, 5, or 10 mg/kg.

Investigations of the Activity of Phenobarbitone in Mice Models of Depression

Background: Depression is a severe neurological condition that interferes with the brain neurochemistry and downstream signaling pathways that are involved in the regulation of mood and behavior. Studies have highlighted the antidepressant potential of GABA mimetics such as Barbiturates and Benzodiazepines. Objective: This study investigated the activities of Phenobarbitone in acute and chronic mice models of depression. Methodology: The experimental animals received a single intraperitoneal injection of Phenobarbitone 10mg/kg, 5mg/kg, 2.5mg/kg and 0.5mg/kg respectively. Imipramine 20mg/kg was used as a positive control and 0.1mg/kg of distilled water was used as the negative control. The experimental animals were subjected to a series of stressors using neurobehavioral assays in the Forced swimming test (FST), Tail suspension test (TST), and Chronic mild stress (CMS) models of depression. The duration of immobility in the TST and FST were taken as an index of behavioral despair which is a core index of depression, while aversion to consumption of palatable solution containing 2% sucrose was also taken as index anhedonia, a symptom of depression. Result: A statistically significant decrease in the immobility time was observed in the highest dose tested i.e., 10 mg/kg Phenobarbitone (P&lt;0.05) in both phases of the study when compared to control. There was no statistically significant decrease in the immobility time in the 5mg/kg, 2.5mg/kg, and 0.5mg/kg groups in both phases of the experiment when compared to the control. Mice subjected to the Sucrose preference test showed an increase in sucrose preference at the highest dose tested, while mice subjected to the Open field test (OFT) following exposure to CMS paradigms did not show any statistically significant increase in locomotory activity (line crossings) when compared to control. Conclusion: The result of the study indicates that Phenobarbitone possesses antidepressant activity at the highest dose tested (10mg/kg).

Knockdown of FSTL1 inhibits microglia activation and alleviates depressive-like symptoms through modulating TLR4/MyD88/NF-κB pathway in CUMS mice

Inflammatory processes play a pivotal role in the development and progression of depression. Since Follistatin-like protein 1 (FSTL1) has been identified as a novel inflammatory protein, a variety of studies suggest that targeting FSTL1 may be useful in the treatment of diseases in which inflammation plays a central role. In the study, we aimed to investigate the causal relationship between FSTL1 signaling and the development of depression. To explore the effect and mechanism of FSTL1 on chronic stress-induced depression, the chronic unpredictable mild stress (CUMS) paradigm was used. Animals subjected to CUMS for 4 weeks exhibited depressive-like symptoms, including decreased sucrose preference and obvious behavioral despair, concomitantly with increased FSTL1 level in the hippocampus. In contrast, mice with FSTL1 knockdown abolished CUMS induced depression-like and anxiety-like behaviors. Moreover, FSTL1 knockdown reversed CUMS induced synaptic plasticity deficits in the PP-DG pathway of the hippocampus and increased the expression of synaptic associated proteins in the hippocampus of CUMS exposed mice. Microglia activation induced by CUMS paradigm could be significantly inhibited by FSTL1 knockdown. Furthermore, Western blot revealed that FSTL1 knockdown considerably decreased the expression of indicated molecules TLR4/MyD88/NF-κB signaling pathway in CUMS exposed mice. In conclusion, our data implies that FSTL1 may modulate the microglial activation through TLR4/MyD88/NF-κB signaling, which affects depression-like behaviors and synaptic function deficits induced by CUMS in mice. These results suggested that the role of FSTL1 in mediating microglia-related mechanisms in depression may shed light on developing new therapeutic strategies to treat this prevalent disease.

Sex Differences in Depression-Like Behaviors in Adult Mice Depend on Endophenotype and Strain.

Depression affects women nearly twice as frequently as men. In contrast, rodent models of depression have shown inconsistent results regarding sex bias, often reporting more depression-like behaviors in males. This sex discrepancy in rodents modeling depression may rely on differences in the baseline activity of males and females in depression-related behavioral tests. We previously showed that the baseline despair and anhedonia behaviors, major endophenotypes of depression, are not sex biased in young adolescent wild-type mice of C57BL/6N, DBA/2, and FVB/N strains. Since the prevalence of depression in women peaks in their reproductive years, we here investigated sex differences of the baseline depression-like behaviors in adult mice using these three strains. Similar to the results in young mice, no difference was found between adult male and female mice in behavioral tests measuring despair in both tail suspension and forced swim tests, and anhedonia in the sucrose preference test. We then extended our study and tested apathy, another endophenotype of depression, using the splash test. Adult male and female mice showed significantly different results in the baseline apathy-like behaviors depending on the investigated strain. This study dissects the complex sex effects of different depression endophenotypes, stresses the importance of considering strain, and puts forward a hypothesis of the inconsistency of results between different laboratories investigating rodent models of depression.

Prophylactic (R,S)-Ketamine Is Effective Against Stress-Induced Behaviors in Adolescent but Not Aged Mice.

Background(R,S)-ketamine, an N-methyl-D-aspartate receptor antagonist, is frequently used as an anesthetic and as a rapid-acting antidepressant. We and others have reported that (R,S)-ketamine is prophylactic against stress in adult mice but have yet to test its efficacy in adolescent or aged populations.MethodsHere, we administered saline or (R,S)-ketamine as a prophylactic at varying doses to adolescent (5-week-old) and aged (24-month-old) 129S6/SvEv mice of both sexes 1 week before a 3-shock contextual fear-conditioning (CFC) stressor. Following CFC, we assessed behavioral despair, avoidance, perseverative behavior, locomotion, and contextual fear discrimination. To assess whether the prophylactic effect could persist into adulthood, adolescent mice were injected with saline or varying doses of (R,S)-ketamine and administered a 3-shock CFC as a stressor 1 month later. Mice were then re-exposed to the aversive context 5 days later and administered behavioral tests as aforementioned. Brains were also processed to quantify Cyclooxygenase 2 expression as a proxy for inflammation to determine whether the prophylactic effects of (R,S)-ketamine were partially due to changes in brain inflammation.ResultsOur data indicate that (R,S)-ketamine is prophylactic at sex-specific doses in adolescent but not aged mice. (R,S)-ketamine attenuated learned fear and perseverative behavior in females, reduced behavioral despair in males, and facilitated contextual fear discrimination in both sexes. (R,S)-ketamine reduced Cyclooxygenase 2 expression specifically in ventral Cornu Ammonis region 3 of male mice.ConclusionsThese findings demonstrate that prophylactic (R,S)-ketamine efficacy is sex, dose, and age dependent and will inform future studies investigating (R,S)-ketamine efficacy across the lifespan.

Antidepressant-Like Effect and Mechanism of Ginsenoside Rd on Rodent Models of Depression.

BackgroundThere is growing evidence to suggest that ginsenoside Rd (GRd) has a therapeutic effect on depression, but the specific mechanisms behind its activity require further study.ObjectiveThis study is designed to investigate the antidepressant-like effect and underlying mechanisms of GRd.MethodsIn this study, the behavioral despair mouse model of depression and chronic unpredictable mild stress (CUMS) rat model of depression were established to explore the effects of GRd on depression-like behavior and its underlying mechanisms. Behavioral tests were used to evaluate the replication of animal models and depression-like behaviors. The hypoxia-inducible factor-1α (HIF-1α) blocker 2-methoxyestradiol (2-ME) was injected to determine the role of HIF-1α in the antidepressant-like effect of GRd. In addition, molecular biology techniques were used to determine the mRNA and protein expression of HIF-1ɑ signaling pathway and synaptic plasticity-related regulators, that is synapsin 1 (SYN 1) and postsynaptic density protein 95 (PSD 95). In silico binding interaction studies of GRd with focused target proteins were performed using molecular docking to predict the affinity and optimal binding mode between ligands and receptors.ResultsOur data show that GRd significantly reversed depression-like behavior and promoted mRNA and protein expression of HIF-1ɑ signaling pathway and synaptic plasticity-related regulators. However, the antidepressant-like effect of GRd disappeared upon inhibition of HIF-1α expression following administration of 2-ME. Furthermore, molecular docking results showed that GRd possessed significant binding affinity for HIF-1α, VEGF, and VEGFR-2.ConclusionOur results show that GRd exhibits significant antidepressant-like effect and that HIF-1α signaling pathway is a promising target for the treatment of depression.

The differential effects of brief environmental enrichment following social isolation in rats.

Environmental enrichment (EE) in rodents is associated with a wide range of physiological, affective, and cognitive benefits. A seemingly opposite housing condition, social isolation (SI), is used as a rodent model of stress, negatively affecting several neurobiological mechanisms and hampering cognitive performance. Experimental designs that involve switching between these housing conditions produced mixed results. We evaluated different behavioral and cognitive effects of brief EE following long-term, SI-induced stress. We revealed the influence of enrichment after 30 days of isolation on behavioral despair, anxiety-like behavior, and spatial working memory in adult male Wistar rats and found a substantial anxiolytic effect in the experimental (SI to EE) group. Interestingly, rats exposed to EE also showed increased behavioral despair compared with the control (continuous SI) group. There was no difference in spatial working memory performance at the end of a 5-day water Y-maze (WYM) test. However, the SI to EE animals displayed better memory performance in the first 2 days of the WYM, indicating faster learning. In line with this difference, we recorded significantly more c-Fos-immunopositive (c-Fos+) cells in the retrosplenial and perirhinal cortices of the SI to EE animals. The lateral and basolateral nuclei of the amygdala showed no such difference. These results suggest that brief enrichment following isolation stress leads to differential results in affective and cognitive systems.

Hippocampal Over-Expression of Cyclooxygenase-2 (COX-2) Is Associated with Susceptibility to Stress-Induced Anhedonia in Mice.

The phenomenon of individual variability in susceptibility/resilience to stress and depression, in which the hippocampus plays a pivotal role, is attracting increasing attention. We investigated the potential role of hippocampal cyclooxygenase-2 (COX-2), which regulates plasticity, neuroimmune function, and stress responses that are all linked to this risk dichotomy. We used a four-week-long chronic mild stress (CMS) paradigm, in which mice could be stratified according to their susceptibility/resilience to anhedonia, a key feature of depression, to investigate hippocampal expression of COX-2, a marker of microglial activation Iba-1, and the proliferation marker Ki67. Rat exposure, social defeat, restraints, and tail suspension were used as stressors. We compared the effects of treatment with either the selective COX-2 inhibitor celecoxib (30 mg/kg/day) or citalopram (15 mg/kg/day). For the celecoxib and vehicle-treated mice, the Porsolt test was used. Anhedonic (susceptible) but not non-anhedonic (resilient) animals exhibited elevated COX-2 mRNA levels, increased numbers of COX-2 and Iba-1-positive cells in the dentate gyrus and the CA1 area, and decreased numbers of Ki67-positive cells in the subgranular zone of the hippocampus. Drug treatment decreased the percentage of anhedonic mice, normalized swimming activity, reduced behavioral despair, and improved conditioned fear memory. Hippocampal over-expression of COX-2 is associated with susceptibility to stress-induced anhedonia, and its pharmacological inhibition with celecoxib has antidepressant effects that are similar in size to those of citalopram.

C1q deletion exacerbates stress-induced learned helplessness behavior and induces neuroinflammation in mice

Increased levels of pro-inflammatory cytokines have been reported in postmortem brain samples and in the blood of depressed subjects. However, the inflammatory pathways that lead to depressive-like symptoms are not well understood. Using the learned helplessness (LH) model of depression, we examined the role of C1q, the initiator of classical complement pathway in mediating stress-induced depressive-like behavior in mice. We observed no significant changes in social behavior, despair behavior, spatial memory, and aggressive behavior between the wild type (WT) and C1q knockout (KO) mice. However, C1q deletion exacerbated the inescapable electric foot shock-induced learned helplessness behavior in mice. We found significant reductions in C1q mRNA levels in the prefrontal cortex (PFC) of WT helpless mice as compared to the naïve mice. Increased levels of pro-inflammatory cytokines were found in the PFC of C1q KO mice. These findings suggest that classical complement pathway-mediated learned helplessness behavior is accompanied by neuroinflammatory changes under stressful conditions.

Female-specific role of ciliary neurotrophic factor in the medial amygdala in promoting stress responses

Ciliary neurotrophic factor (CNTF) is produced by astrocytes which have been implicated in regulating stress responses. We found that CNTF in the medial amygdala (MeA) promotes despair or passive coping, i.e., immobility in an acute forced swim stress, in female mice, while having no effect in males. Neutralizing CNTF antibody injected into the MeA of wildtype females reduced activation of downstream STAT3 (Y705) 24 and 48 h later. In concert, the antibody reduced immobility in the swim test in females and only after MeA injection, but not when injected in the central or basolateral amygdala. Antibody injected into the male MeA did not affect immobility. These data reveal a unique role of CNTF in female MeA in promoting despair or passive coping behavior. Moreover, 4 weeks of chronic unpredictable stress (CUS) increased immobility in the swim test and reduced sucrose preference in wildtype CNTF+/+, but not CNTF−/− littermate, females. Following CUS, 10 min of restraint stress increased plasma corticosterone levels only in CNTF+/+ females. In males, the CUS effects were present in both genotypes. Further, CUS increased CNTF expression in the MeA of female, but not male, mice. CUS did not alter CNTF in the female hippocampus, hypothalamus and bed nucleus of stria terminalis. This suggests that MeA CNTF has a female-specific role in promoting CUS-induced despair or passive coping, behavioral anhedonia and neuroendocrine responses. Compared to CNTF+/+ mice, CNTF−/− mice did not show differences in CUS-induced anxiety-like behavior and sensorimotor gating function as measured by elevated T-Maze, open field and pre-pulse inhibition of the acoustic startle response. Together, this study reveals a novel CNTF-mediated female-specific mechanism in stress responses and points to opportunities for developing treatments for stress-related disorders in women.

The Suprachiasmatic Nucleus Regulates Anxiety-Like Behavior in Mice.

Individuals suffering from mood and anxiety disorders often show significant disturbances in sleep and circadian rhythms. Animal studies indicate that circadian rhythm disruption can cause increased depressive- and anxiety-like behavior, but the underlying mechanisms are unclear. One potential mechanism to explain how circadian rhythms are contributing to mood and anxiety disorders is through dysregulation of the suprachiasmatic nucleus (SCN) of the hypothalamus, known as the “central pacemaker.” To investigate the role of the SCN in regulating depressive- and anxiety-like behavior in mice, we chronically manipulated the neural activity of the SCN using two optogenetic stimulation paradigms. As expected, chronic stimulation of the SCN late in the active phase (circadian time 21, CT21) resulted in a shortened period and dampened amplitude of homecage activity rhythms. We also repeatedly stimulated the SCN at unpredictable times during the active phase of mice when SCN firing rates are normally low. This resulted in dampened, fragmented, and unstable homecage activity rhythms. In both chronic SCN optogenetic stimulation paradigms, dampened homecage activity rhythms (decreased amplitude) were directly correlated with increased measures of anxiety-like behavior. In contrast, we only observed a correlation between behavioral despair and homecage activity amplitude in mice stimulated at CT21. Surprisingly, the change in period of homecage activity rhythms was not directly associated with anxiety- or depressive-like behavior. Finally, to determine if anxiety-like behavior is affected during a single SCN stimulation session, we acutely stimulated the SCN in the active phase (zeitgeber time 14-16, ZT14-16) during behavioral testing. Unexpectedly this also resulted in increased anxiety-like behavior. Taken together, these results indicate that SCN-mediated dampening of rhythms is directly correlated with increased anxiety-like behavior. This work is an important step in understanding how specific SCN neural activity disruptions affect depressive- and anxiety-related behavior.

Thermoregulatory significance of immobility in the forced swim test

The forced swim test (FST) is a widely used animal model of depression and antidepressant drug screen. Rats are forced to swim on two test days in a restricted space from which there is no escape. On the first test day the rats attempt to escape and then become largely immobile; on the second test day the onset of immobility is more rapid. Immobility is said to reflect a state of lowered mood or “behavioral despair”, but the validity of the FST as a model of depression has been questioned. We show here that whatever psychological states the FST may induce, immobility is water temperature dependent and thermoregulatory. In Experiment 1, separate groups of rats were first tested in water of 15, 20, 22, 25, 30, 35, 37, or 40 °C. When retested at the same temperature, reduced activity was evident only in those groups tested above 20 °C and below 37 °C. On a third test, rats previously tested in 35 °C water failed to show reduced activity in 15 °C water, whereas rats previously tested at 15 °C water did exhibit reduced activity when tested in 35 °C water. Thus, activity was dependent on current water temperature rather than prior experience. In Experiment 2, activity and body temperature were monitored during 30 min swim tests in 27 °C water. The more the animals moved, the greater the loss of body temperature. The results are consistent with a hypothesis that immobility in the FST is an adaptive thermoregulatory response that increases survival by minimizing convective heat loss. This interpretation is also aligned with best practices for survival of humans in water that is below thermoneutral.

Xiaoyaosan ethyl acetate fraction alleviates depression-like behaviors in CUMS mice by promoting hippocampal neurogenesis via modulating the IGF-1Rβ/PI3K/Akt signaling pathway

Ethnopharmacological relevanceXiaoyaosan (XYS), a representative and classic traditional Chinese medicine (TCM) prescription with function of dispersing stagnated liver and strengthening spleen, has been used for thousands of years to treat depression. XYS’ anti-depression effect has been demonstrated both clinically and experimentally; however, the material basis for this effect has yet to be elucidated. Aim of the studyThis study aimed to evaluate the impact and underlying action mechanism of XYS’ antidepressant active component (Xiaoyaosan ethyl acetate fraction, XYSEF) against chronic unpredictable mild stress (CUMS)-induced depression-like behavior in mice. Materials and methodsFirst, we established a behavioral despair depression mouse model to preliminarily determine the effective antidepressant dose of XYSEF. Then, we created a CUMS mouse model and used various classic behavioral tests, including SPT, ST, NFST, and TST, to assess XYSEF's antidepressant properties. IGF-1 levels in mouse serum and hippocampus were quantified using ELISA. The average optical density of Nissl bodies in the mouse hippocampal CA3 region was determined utilizing toluidine blue staining. Brdu and DCX expression in the hippocampal dentate gyrus (DG) was assayed using the immunofluorescence method. IGF-1Rβ, PI3K, p-PI3K, Akt, p-Akt, Caspase-3, and cleaved Caspase-3 protein levels in the hippocampus were determined with Western blot. ResultsThe behavioral despair mouse model findings showed that 9.1 and 40 g/kg of XYSEF both significantly shortened the immobility time of mice, suggesting that the effective dose range was 9.1–40 g/kg. Compared to the CUMS mouse model, XYSEF at 20 and 40 g/kg markedly increased the sucrose preference percentage in the SPT and grooming time in the ST, shortened the immobility time in the TST and the feeding latency in the NSFT, and reversed the downregulated IGF-1 content in mouse serum and hippocampus. In addition, XYSEF amplified the average optical density of Nissl bodies in the hippocampal CA3 region, promoted Brdu and DCX expression in DG, and diminished IGF-1Rβ, p-PI3K/PI3K, p-Akt/Akt, and cleaved Caspase-3/Caspase-3 protein levels in the hippocampi of CUMS mice. ConclusionXYSEF acted as an antidepressant in mice exhibiting CUMS-induced depression-like behaviors, possibly by promoting hippocampal neurogenesis, reducing neuronal apoptosis, and inhibiting the over-activation of the IGF-1Rβ/PI3K/Akt pathway.

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.

Periaqueductal gray is required for controlling chronic stress-induced depression-like behavior

BackgroundEnduring exposure to psychological stress is associated with an elevated risk of major depressive disorder (MDD). There is an enormous need to investigate the unexplored mechanisms of MDD. We examined whether pain-free stress alters synaptic transmission, causing depression-like behaviors in the ventrolateral periaqueductal gray (vlPAG), a brain stem nucleus that controls stress-related depression-like behavior. MethodsIn the current study, we studied neuronal changes in the vlPAG and behavioral transforms using electrophysiological recordings, behavioral tests, and pharmacological approaches. ResultsWe found that chronic restraint stress (CRS) diminished glutamatergic transmission in the vlPAG, leading to maladaptive behavioral despair and anhedonia in mice demonstrated by the forced swimming test (FST), tail suspension test (TST) and female urine sniffing test (FUST). Moreover, CRS increased behavioral hypersensitivity shown by the von Frey test. Bath perfusion with the rapid-acting antidepressant (2R,6R)-hydroxynorketamine (HNK) increased both the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs) in vlPAG neurons in the CRS and control groups. Functionally, (2R,6R)-HNK directly enhanced the action potential firing rate in vlPAG neurons. Behaviorally, intravlPAG microinjection of (2R,6R)-HNK alleviated chronic restraint stress-induced depression-like behaviors and behavioral hypersensitivity. ConclusionsThese results demonstrate that psychological stress-elicited depression-like behavior is related to a remarkable decrease in glutamatergic transmission in the vlPAG. The maladaptive behaviors are attributed to hypoactivity of glutamatergic neurons in the vlPAG, and direct enhancement of glutamatergic neuronal activity in the vlPAG rescues depression-like behaviors. The present results prove that vlPAG is critical for controlling stress-induced depression-like behaviors through alteration of glutamatergic transmission.

A systematic review of studies investigating the acute effects of N-methyl-D-aspartate receptor antagonists on behavioural despair in normal animals suggests poor predictive validity.

The ability of the N-methyl- D -aspartate receptor antagonist ketamine to induce a rapid and sustained antidepressant effect has led to a surge in pre-clinical studies investigating underlying mechanisms and seeking novel treatments. Animal models are key to this research as they can provide a behavioural readout linking underlying mechanisms to clinical benefits. However, quantifying depression-related behaviours in rodents represents a major challenge with the validity of traditional methods such as models of behavioural despair (forced swim test and tail suspension test) a topic of debate. While there is good evidence to support the value of using these behavioural readouts to study the effects of stress, these approaches have largely failed to detect reliable phenotypic effects in other disease models. In this systematic review, we identified publications which had tested N-methyl- D -aspartate receptor antagonists in normal animals using either the forced swim test or tail suspension test. We compared findings for different doses and time points and also drugs with different clinical profiles to investigate how well the outcomes in the rodent model predicted their effects in the clinic. Despite clear evidence that N-methyl- D -aspartate receptor antagonists reduce immobility time and hence exhibit an antidepressant profile in these tasks, we found similar effects with both clinically effective drugs as well as those which have failed to show efficacy in clinical trials. These findings suggest that behavioural despair tests in normal animals do not provide a good method to predict clinical efficacy of N-methyl- D -aspartate receptor antagonists.

REPEATED COLLECTION OF VAGINAL SMEAR CAUSES STRESS IN MICE

Women are more likely to be misdiagnosed in many neuropsychiatric disorders than men. One of the possible underlying reasons for this disparity may be more frequent use of male mice than female mice in neuroscience studies. With the increasing realization of the shortcomings of this approach in understanding the neurobiological basis of these disorders, many funding agencies mandate the inclusion of both male and female subjects in study design. As the behaviors vary with the stage of the estrous cycle, the collection of vaginal smears to identify the estrous stage becomes a widely used procedure. Here we tested whether vaginal smear collection causes similar effects to that of stress by evaluating an increase in depression-like behavior and impairment in memory. Vaginal smear was collected from Swiss albino mice twice a day for 10 days. In order to test depression-like behavior tail suspension, sucrose preference and splash tests were conducted. Novel object recognition and novel object location tests were performed 1 hour and 24 hours after training to evaluate short-and long-term memory respectively. The female mice whose vaginal smears were collected demonstrated increased behavioral despair and anhedonia. Vaginal smear group showed deficits in both short-term and long-term memory when compared to the control group. Our results indicate that the collection of vaginal smear not only increased depression-like behaviors in mice, but also impaired short-term and long-term memory, indicating that the procedure of vaginal smear collection was stressful. We recommend to consider other ways of estrous cycle staging when studying behavior.

Study of the emotional state of the offspring of rats treated with aqueous plant extracts

The influence of biologically active compounds on the functional state of the central nervous system and the emotional component in rats can be evaluated by using behavioral methods, which are based on studying the exploratory behavior of animals in an environment new to them. One such method is the study of animal behavior in an elevated cross-shaped maze with open and closed arms and the Porsolt "despair" test. The aim of our study was to investigate the emotional state of the offspring of rats treated with aqueous plant extracts of Centella asiatica, Ginkgo biloba, Eleuterococcus and a mixture of aqueous extracts of Centella asiatica and Ginkgo biloba. The study of the emotional state of the offspring of rats treated with aqueous plant extracts was performed on 3 month old animals obtained in the experiment from males (20 animals) and females (50 animals), which received aqueous plant extracts at a dose of 30 mg/100 g of the animal body weight, in the volume of 1 ml for 30 days. Conclusions: Aqueous extracts of Centella asiatica, Ginkgo biloba and Eleutherococcus have pronounced nootropic activity, as the evaluation of animal anxiety level in the Elevated Cross Maze test and depression level in the Porsolt Despair Behavior test show a significant difference in the behavior of intact rats and offspring rats, receiving aqueous plant extracts as an additional load and the most pronounced effect is observed with the complex application of extracts of Centella asiatica and Ginkgo biloba.