Swim Stress Research Articles

Blockade of nociceptin/orphanin FQ signaling facilitates an active copying strategy due to acute and repeated stressful stimuli in mice

The role of stress in the etiology of depression has been largely reported. In this line, exogenous glucocorticoids are employed to mimic the influence of stress on the development of depression. The N/OFQ-NOP receptor system has been implicated in the modulation of stress and emotional behaviors. In fact, the blockade of NOP receptors induces antidepressant effects and increases resilience to acute stress. This study investigated the effects of the NOP receptor blockade on dexamethasone-treated mice exposed to acute and prolonged swimming stress. Swiss and NOP(+/+) and NOP(−/−) mice were treated with dexamethasone, and the protective effects of the NOP antagonist SB-612111 (10 mg/kg, ip) or imipramine (20 mg/kg, ip) were investigated in three swimming sessions. The re-exposure to swim stress increased immobility time in Swiss and NOP(+/+), but not in NOP(−/−) mice. Acute and repeated dexamethasone administration induced a further increase in the immobility time, and facilitated body weight loss in Swiss mice. Single administration of SB-612111, but not imipramine, prevented swimming stress- and dexamethasone-induced increase in the immobility time. Repeated administrations of SB-612111 prevented the deleterious effects of 5 days of dexamethasone treatment. Imipramine also partially prevented the effects of repeated glucocorticoid administration on the immobility time, but did not affect the body weight loss. NOP(−/−) mice were more resistant than NOP(+/+) mice to inescapable swimming stress, but not dexamethasone-induced increase in the immobility time and body weight loss. In conclusion, the blockade of the NOP receptor facilitates an active stress copying response and attenuates body weight loss due to repeated stress.

Behavioral and neuroendocrine consequences of disrupting a long-term monogamous social bond in aging prairie voles

Social support from a spouse, long-term partner, or someone who provides emotional or instrumental support may protect against consequences of aging, including mediating behavioral stress reactivity and altering neurobiological process that underlie short-term stress responses. Therefore, long-term social bonding may have behavioral and neurobiological benefits. The socially monogamous prairie vole provides a valuable experimental model for investigating the benefits of long-term social bonds on short-term stress reactivity in aging animals, given their unique social structure of forming enduring opposite-sex bonds, living in family groups, and bi-parental rearing strategies. Male-female pairs of long-term, cohabitating prairie voles were investigated for short-term behavioral and neuroendocrine stress reactivity following either long-term social pairing (control), or a period of social isolation. In Experiment 1, social isolation was associated with altered behavioral reactivity to an acute swim stressor, and greater neural activation in the hypothalamic paraventricular nucleus, as well as specifically the parvocellular region, following the swim stressor (vs. control). In Experiment 2, social isolation was associated with greater corticosterone reactivity following an acute restraint stressor (vs. control). No sex differences were observed. Exploratory correlation and subgroup analyses revealed systematic relationships among various demographic variables (such as age of the subjects, amount of time the pair cohabitated together, and number of litters the pair reared together) and the behavioral and neuroendocrine outcome measures. These findings may inform our understanding of the benefits of long-term social bonding on modulating short-term behavioral and neuroendocrine responses to stress. LAY SUMMARY Receiving social support from a long-term spouse or partner, or having a strong support network from friends, may have important health benefits as people age. In aging monogamous prairie voles, social isolation from a long-term social partner disrupted behaviors and short-term stress responses, whereas living with a long-term partner protected against these disruptions. This research is important for our understanding of the benefits of social support on stress responses as we age.

Short- and Long-Term Repeated Forced Swim Stress Induce Depressive-Like Phenotype in Mice: Effectiveness of 3-[(4-Chlorophenyl)Selanyl]-1-Methyl-1H-Indole.

Exposure to stress highly correlates with the emergence of mood-related illnesses. Therefore, the present study was designed to characterize the acute and chronic effects of 3-((4-chlorophenyl)selanyl)-1-methyl-1H-indole (CMI) on depressive-like behavior induced by repeated forced swim stress (FSS) in male adult Swiss mice. In the repeated FSS, mice were placed in water to swim for a single trial during a 15-min period. Twenty-four hours after the first FSS, the animals were placed in water to swim through a series of four trials, and each of them swam for 6 min long; between each trial, mice were towel dried and returned to their home cage for 6 min. In addition, the oxidative stress in the prefrontal cortex and hippocampus and corticosterone levels of plasma of mice were investigated. The animals exposed to FSS were treated with CM in two different protocols. In protocol 1, CMI [1 and 10 mg/kg, intragastric (i.g.) route] or fluoxetine, a positive control (10 mg/kg, i.g. route), were administered 30 min before of sections of repeated FSS in both days of stress. After the last section of repeated FSS, the mice performed first the spontaneous locomotor activity and after the tail suspension test. In protocol 2, CMI or fluoxetine (1 mg/kg, i.g. route) was administered for 20 days after the exposition of repeated FSS. The spontaneous locomotor activity, tail suspension, and forced swimming tests were performed in this order after 24 h of last administration of CMI or fluoxetine. The euthanasia of animals was performed after the behavioral tests. CMI and fluoxetine abolished the depressive-like behavior induced by repeated FSS in mice in the two different treatments. CMI modulated the oxidative stress in the prefrontal cortices and hippocampi of mice subjected to repeated FSS. Mice subjected to repeated FSS had an increase in the corticosterone levels and CMI regulated the levels of this glucocorticoid. These findings demonstrate that CMI was effective to abolish the depressive-like behavior induced by repeated FSS, which was accompanied by changes in the corticosterone levels and oxidative stress of prefrontal cortices and hippocampi of mice.

Effects of forced swimming stress on expression and phosphorylation of PI3K/Akt signal pathway in pancreas of type 2 diabetic rats.

BackgroundTo study the effects of forced swimming stress on blood glucose and insulin levels and the expression and phosphorylation of pancreatic PI3K/Akt signal pathway in type 2 diabetic rats.MethodsThirty adult SD rats (8-week-old, male) were randomly divided into three groups: control group, diabetic model group, and diabetic model stress group. The diabetic model group was established by feeding with the high-fat and high-glucose diet for four weeks, and then the rats were injected with low-dose streptozotocin (STZ, 25 mg/kg, once a day for 2 days). The rats in the diabetic model group were subjected to forced swimming stress for seven days, which was a diabetic model stress group. Twenty-four hours after the last forced swimming stress, the rats fasted, and blood samples were collected to detect blood glucose, insulin, triglycerides (TGs), free fatty acids (FFAs), high- and low-density lipoprotein cholesterol (HDLC and LDLC) levels. The western blot was applied to detect the expression of PI3K, Akt, p-Akt, and mTOR in the pancreas of rats in each group.ResultsBlood glucose and insulin levels in the diabetic model stress group were significantly lower than those in the diabetic model group, and the protein levels of PI3K, p-AKT, and mTOR in the pancreas of the diabetic model stress group were significantly higher than those of the diabetic model group.ConclusionsOne-week swimming stress can decrease the blood glucose level and improve insulin indexes in type 2 diabetic rats and increase the expression and phosphorylation of pancreatic PI3K/Akt signal pathway proteins.

Contribution of central sensitization to stress-induced spreading hyperalgesia in rats with orofacial inflammation

Temporomandibular disorder (TMD) is commonly comorbid with fibromyalgia syndrome (FMS). The incidence of these pain conditions is prevalent in women and prone to mental stress. Chronic pain symptoms in patients with FMS and myofascial TMD (mTMD) are severe and debilitating. In the present study, we developed a new animal model to mimic the comorbidity of TMD and FMS. In ovariectomized female rats, repeated forced swim (FS) stress induced mechanical allodynia and thermal hyperalgesia in the hindpaws of the 17β-estradiol (E2) treated rats with orofacial inflammation. Subcutaneous injection of E2, injection of complete Freund’s adjuvant (CFA) into masseter muscles or FS alone did not induce somatic hyperalgesia. We also found that the somatic hyperalgesia was accompanied by upregulation of GluN1 receptor and serotonin (5-hydroxytryptamine, 5-HT)3A receptor expression in the dorsal horn of spinal cord at L4-L5 segments. Intrathecal injection of N-methyl-D-aspartic acid receptor (NMDAR) antagonist 2-amino-5-phosphonovaleric acid (APV) or 5-HT3 receptor antagonist Y-25130 blocked stress-induced wide-spreading hyperalgesia. These results suggest that NMDAR-dependent central sensitization in the spinal dorsal horn and 5-HT-dependent descending facilitation contribute to the development of wide-spreading hyperalgesia in this comorbid pain model.

Evaluation of the effect of doxasozin and zonisamide on voluntary ethanol intake in mice that experienced chronic intermittent ethanol exposure and stress.

The comorbidity between alcohol use disorder and post-traumatic stress disorder represents a serious health care burden with few effective treatment options. The current study was designed to evaluate the effect of an alpha 1 receptor antagonist (doxazosin) and a novel anticonvulsant (zonisamide) in a model of alcohol (ethanol) dependence and stress exposure. The main dependent variable was voluntary ethanol intake in mice that experienced chronic intermittent ethanol (CIE) exposure and forced swim stress (FSS) alone, and in combination. Adult male and female C57BL/6J mice had access to a single bottle of 15% (v/v) ethanol for 1-hr in the home cage, 3-hr into the dark phase of the light/dark cycle. Once stable ethanol intake was established (~4 weeks), mice were separated into four groups (CTL, CIE, FSS, CIE+FSS). Mice in the FSS condition received 10-min FSS exposure 4-hr prior to drinking sessions (remaining mice were not disturbed). During baseline and the first two test cycles, all mice received vehicle (saline) injections (IP) 30-min before ethanol access. As previously observed, FSS increased ethanol drinking in dependent (CIE-exposed) mice but not in nondependent control (CTL) mice. In the following test cycles mice were evaluated for ethanol intake after administration of doxazosin, zonisamide or their combination. Results indicated that the three doses of doxazosin evaluated significantly reduced voluntary ethanol intake in all mice. Zonisamide had a more modest effect and may require a more prolonged treatment regime. The combined administration of both compounds was not more effective than each drug alone. This study suggests that doxazosin is reliable at reducing voluntary ethanol intake in mice independently of their history of ethanol dependence and stress exposure.

Attenuation of stress-induced behavioral changes by activation of serotonin type 7 receptors in the median raphe nucleus of rats.

Exposure to stressful aversive situations induces physiological and behavioral changes. Serotonin has been suggested to mediate such changes, as well as adaptation to stressful events. Serotoninergic projections arising from the median raphe nucleus to the dorsal hippocampus have been suggested to promote adaptation to chronic aversive stimuli. Such pathway may involve serotonin type 1a receptor-mediated neurotransmission. However, the serotonin 7 receptor can also be found in the median raphe nucleus and may be involved in mechanisms underlying response to stress. In this work we sought to investigate if activation of serotonin type 7 receptors would attenuate stress-induced deficits in different animal models of depression. Male Wistar rats with a guide-cannula aimed to the median raphe nucleus were submitted to restraint or forced swim stress and were tested in an elevated plus maze or forced swim test, respectively, 24 h later. SB 258741 (serotonin type 7 receptor antagonist) and/or LP 44 (serotonin type 7 receptor agonist) were administered intra-median raphe nucleus immediately before or after exposure to stress or before test. Control groups received intra-median raphe nucleus treatment 24 h or immediately before test in the elevated plus maze or forced swim test. LP 44 attenuated restraint-induced exploratory deficits independently of the moment it was administered. Similar results were observed in the forced swim test, with the exception on post-stress condition. These effects on adaptation to stress induced by serotonin type 7 receptor activation were prevented by previous treatment with SB 258741. Our data support the idea that activation of median raphe nucleus serotonin 7 receptor is important to the development of adaptation to stress.

Noradrenergic tone mediates marble burying behavior after chronic stress and ethanol.

Stress plays a major role in the development of alcohol use disorder (AUD)-a history of chronic stress contributes to alcohol misuse, and withdrawal from alcohol elevates stress, perpetuating cycles of problematic drinking. Recent studies have shown that, in male mice, repeated chronic intermittent ethanol (CIE) and stress elevates alcohol use above either manipulation alone and impacts cognitive functions such as behavioral flexibility. Here, we investigated the impact of CIE and stress on anxiety in both sexes, and whether the norepinephrine (NE) system via locus coeruleus, which is implicated in both stress and alcohol motivation, is involved. Male and female mice received multiple cycles of CIE and/or repeated forced swim stress (FSS), producing elevated drinking in both sexes. CIE/FSS treatment increased anxiety, which was blocked by treatment with the α1-AR inverse agonist prazosin. In contrast, administration of the corticotropin releasing factor receptor antagonist CP376395 into locus coeruleus did not reduce CIE/FSS-elevated anxiety. We also observed sex differences in behavioral responses to a history of CIE or FSS alone as well as differential behavioral consequences of prazosin treatment. These data indicate that NE contributes to the development of anxiety following a history of alcohol and/or stress, and that the influence of both treatment history and NE signaling is sex dependent. These results argue for further investigation of the NE system in relation to disrupted behavior following chronic alcohol and stress, and support the assertion that treatments may differ across sex based on differential neural system engagement.

Changes in c-fos and p-CREB signaling following exposure to forced swim stress or exogenous corticosterone during morphine-induced place preference are dependent on glucocorticoid receptor in the basolateral amygdala.

Neural circuitry comprising the nucleus accumbens (NAc), prefrontal cortex (PFC), amygdala (AMY), and hippocampus (HIP) are the main components of the reward circuit. Our previous behavioral data showed that forced swim stress (FSS) and corticosterone administration could inhibit the acquisition of morphine-induced conditioned place preference (CPP), and this effect was blocked by intra-basolateral amygdala (BLA) administration of RU38486, glucocorticoid receptor (GR) antagonist. Therefore, we tried to evaluate the effect of intra-BLA administration of the GR antagonist during the conditioning phase on the c-fos and p-CREB/CREB ratio expression in the AMY, NAc, PFC, and HIP of rats that underwent FSS or received exogenous corticosterone (10 mg/kg; i.p.) before morphine injection (5 mg/kg; s.c.) during 3 conditioning days. Our results showed that morphine-induced CPP could increase c-fos level and p-CREB/CREB ratio in all regions (except in the HIP). In addition, c-fos expression was elevated by FSS in all regions and blockade of GR decreased this effect. In the PFC, in addition to FSS, corticosterone could raise c-fos expression, which was blocked by RU38486. In conclusion, it seems that the intra-BLA administration of RU38486 differently modulates the effect of morphine-induced CPP on the expression of c-fos and p-CREB/CREB ratio in animals that underwent FSS or corticosterone administration.

Long term transcriptional and behavioral effects in mice developmentally exposed to a mixture of endocrine disruptors associated with delayed human neurodevelopment

Accumulating evidence suggests that gestational exposure to endocrine disrupting chemicals (EDCs) may interfere with normal brain development and predispose for later dysfunctions. The current study focuses on the exposure impact of mixtures of EDCs that better mimics the real-life situation. We herein describe a mixture of phthalates, pesticides and bisphenol A (mixture N1) detected in pregnant women of the SELMA cohort and associated with language delay in their children. To study the long-term impact of developmental exposure to N1 on brain physiology and behavior we administered this mixture to mice throughout gestation at doses 0×, 0.5×, 10×, 100× and 500× the geometric mean of SELMA mothers’ concentrations, and examined their offspring in adulthood. Mixture N1 exposure increased active coping during swimming stress in both sexes, increased locomotion and reduced social interaction in male progeny. The expression of corticosterone receptors, their regulator Fkbp5, corticotropin releasing hormone and its receptor, oxytocin and its receptor, estrogen receptor beta, serotonin receptors (Htr1a, Htr2a) and glutamate receptor subunit Grin2b, were modified in the limbic system of adult animals, in a region-specific, sexually-dimorphic and experience-dependent manner. Principal component analysis revealed gene clusters associated with the observed behavioral responses, mostly related to the stress axis. This integration of epidemiology-based data with an experimental model increases the evidence that prenatal exposure to EDC mixtures impacts later life brain functions.

Forced swimming stress increases natatory activity of lead-exposed mice.

Recent evidence points to the relationship between lead toxicity and the function of the hypothalamic-pituitary-adrenal axis, which suggests that lead exposure could influence how an individual cope with stress. Here we test this hypothesis by investigating the behavioral effects of lead exposure in mice during the forced swimming test (FST), a parading in which animals are exposed to a stressful situation and environment. Swiss mice received either 180ppm or 540ppm of lead acetate (Pb) in their ad-lib water supply for 60-90days, starting at postnatal day 30. Control (Ctrl) mice drank tap water. At the end of the exposure period, mice were submitted to a 5-min session of FST or to an open-field session of the same duration. Data from naïve animals showed that corticosterone levels were higher for animals tested in the FST compared to animals tested in the open-field. Blood-lead levels (BLL) in Pb-exposed mice ranged from 14.3 to 106.9µg/dL. No differences were observed in spontaneous locomotion between Ctrl and Pb-exposed groups in the open-field. However, in the FST, Pb-treated mice displayed higher swimming activity than Ctrl ones and this effect was observed even for animals with BLL higher than 20µg/dL. Furthermore, significant differences in brain glutathione levels, used as an indicator of led toxicity, were only observed for BLL higher than 40µg/dL. Overall, these findings suggest that swimming activity in the FST is a good indicator of lead toxicity and confirm our prediction that lead toxicity influences behavioral responses associated to stress.

Down-regulation of Spinal 5-HT2A and 5-HT2C Receptors Contributes to Somatic Hyperalgesia induced by Orofacial Inflammation Combined with Stress

Patients suffering with functional somatic pain syndromes such as temporomandibular disorders (TMD) and fibromyalgia syndrome (FMS) have some similar symptoms, but the underlying cause is still unclear. The purpose of this study was to investigate whether 5-HT2A and 5-HT2C receptors in the spinal cord contribute to somatic hyperalgesia induced by orofacial inflammation combined with different modes of stress. Ovariectomized rats were injected subcutaneously with estradiol and bilateral masseter muscles were injected with complete Freund’s adjuvant followed by stress. Somatic sensitivity was assessed with thermal and mechanical stimulation. The anxiety- and depression-like behaviors were measured by immobility time, sucrose preference, elevated plus maze and open field tests. The expression of 5-HT2A and 5-HT2C receptors in the spinal cord was examined by Western blot. Orofacial inflammation combined with 11 day forced swim stress (FSS) induced persistent mechanical allodynia for 15 days and thermal hyperalgesia for 2 days. The mechanical and thermal hyperalgesia lasted for 43 days and 30 days respectively following orofacial inflammation combined with 11 day heterotypic stress. Orofacial inflammation combined with stress induced anxiety- and depression-like behaviors. The expression of 5-HT2A and 5-HT2C receptors significantly decreased in the orofacial inflammation combined with stress groups. Intrathecal injection of 5-HT2A or 5-HT2C receptor agonist reversed somatic hyperalgesia. The results suggest that down-regulation of 5-HT2A and 5-HT2C receptors in the spinal cord contributes to somatic hyperalgesia induced by orofacial inflammation combined with stress, indicating that 5-HT2A and 5-HT2C receptors may be potential targets in the treatment of TMD comorbid with FMS.

Anxiolytic Effects of 8-O-Acetyl Shanzhiside Methylester on Acute and Chronic Anxiety via Inflammatory Response Inhibition and Excitatory/Inhibitory Transmission Imbalance

Anxiety leads to a global decline in quality of life and increase in social burden. However, treatments are limited, because the molecular mechanisms underlying complex emotional disorders are poorly understood. We explored the anxiolytic effects of 8-O-acetyl shanzhiside methylester (8-OaS), an active component in Lamiophlomis rotata (L. rotata; Benth.) or Kudo, a traditional herb that has been shown to be effective in the clinical treatment of chronic pain syndromes in China. Two mouse anxiety models were used: forced swimming stress (FSS)–induced anxiety and complete Freund’s adjuvant (CFA)–induced chronic inflammatory pain. All animal behaviors were analyzed on the elevated plus maze and in the open-field test. 8-OaS significantly ameliorated anxiety-like behaviors in both anxiety models and inhibited the translation enhancement of GluN2A, GluN2B, and PSD95. Moreover, a reduction in GABA receptors disrupted the excitatory/inhibitory (E/I) balance in the basolateral amygdala (BLA), indicated by increased excitatory and decreased inhibitory presynaptic release. 8-OaS also blocked microglia activation and reduced the phosphorylation of p38, c-Jun N-terminal kinase (JNK), NF-κB p65, and tumor necrosis factor alpha (TNF-α) in the BLA of anxiety mice. 8-OaS exhibits obvious anxiolytic effects by regulating the excitatory/inhibitory (E/I) synaptic transmission and attenuating inflammatory responses in the BLA.

Sequencing the serotonergic neuron translatome reveals a new role for Fkbp5 in stress.

Serotonin is a key mediator of stress, anxiety, and depression, and novel therapeutic targets within serotonin neurons are needed to combat these disorders. To determine how stress alters the translational profile of serotonin neurons, we sequenced ribosome associated RNA from these neurons after repeated stress in male and female mice. We identified numerous sex- and stress-regulated genes. In particular, Fkbp5 mRNA, which codes for the glucocorticoid receptor co-chaperone protein FKBP51, was consistently upregulated in male and female mice following stress. Pretreatment with a selective FKBP51 inhibitor into the dorsal raphe prior to repeated forced swim stress decreased resulting stress-induced anhedonia. Our results support previous findings linking FKBP51 to stress-related disorders and provide the first evidence suggesting that FKBP51 function may be an important regulatory node integrating circulating stress hormones and serotonergic regulation of stress responses.

Transcriptome Analysis of Alcohol Drinking in Non-Dependent and Dependent Mice Following Repeated Cycles of Forced Swim Stress Exposure.

Chronic stress is a known contributing factor to the development of drug and alcohol addiction. Animal models have previously shown that repeated forced swim stress promotes escalated alcohol consumption in dependent animals. To investigate the underlying molecular adaptations associated with stress and chronic alcohol exposure, RNA-sequencing and bioinformatics analyses were conducted on the prefrontal cortex (CTX) of male C57BL/6J mice that were behaviorally tested for either non-dependent alcohol consumption (CTL), chronic intermittent ethanol (CIE) vapor dependent alcohol consumption, repeated bouts of forced swim stress alone (FSS), and chronic intermittent ethanol with forced swim stress (CIE + FSS). Brain tissue from each group was collected at 0-h, 72-h, and 168-h following the final test to determine long-lasting molecular changes associated with maladaptive behavior. Our results demonstrate unique temporal patterns and persistent changes in coordinately regulated gene expression systems with respect to the tested behavioral group. For example, increased expression of genes involved in “transmitter-gated ion channel activity” was only determined for CIE + FSS. Overall, our results provide a summary of transcriptomic adaptations across time within the CTX that are relevant to understanding the neurobiology of chronic alcohol exposure and stress.

Methanol extracts of Basella alba leaves alleviate stress in rats

ObjectiveStress is becoming an unavoidable threat in recent times, there has been increasing interest by researchers in the use of naturally occurring biologically active compounds with medicinal value to cure body ailments. The present work was carried out to investigate the effect of methanol extract of Basella alba leaves on stress in Wistar rats (Rattus norvegicus). MethodsA total of 35 male rats were used in this study. They were grouped into seven groups of five rats each. Group 1 (normal control) was received 10 mL/kg normal saline. Group 2 contained restraint stress rats only. Group 3 contained forced swim stress rats only. Group 4 and 5 were treated with 60 mg/kg of B. alba extract (BAE) thereafter subjected to restraint and forced swim stresses respectively. Group 6 and 7 were treated with 120 mg/kg of BAE thereafter subjected to restraint and forced swim stresses respectively. Stress procedures were carried out at the end of first and third weeks. ResultsIn the stressed rats, there were significant increases (P < 0.05) in fasting blood glucose and white blood cell count while there were significant decreases in superoxide dismutase activity and glutathione concentration when compared to group 1. There were significant decreases (P < 0.05) in blood glucose and white blood cell count and significant increases in superoxide dismutase and glutathione concentrations in BAE treated rats when compared to group 2 and 3. Some of the significant differences were either dose or duration dependent. ConclusionIn conclusion, results from this research suggest that BAE alleviates hyperglycaemia, chronic activation of immune system and generation of free radicals due to stress in Wistar rats.

Effects of neuromedin U-8 on stress responsiveness and hypothalamus-pituitary-adrenal axis activity in male C57BL/6J mice

Neuromedin U (NMU) is a highly conserved neuropeptide that has been implicated in the stress response. To better understand how it influences various aspects of the stress response, we studied the effects of intracerebroventricular NMU-8 administration on stress-related behavior and activity of the hypothalamus-pituitary-adrenal (HPA) axis in male C57BL/6J mice. We investigated these NMU-8 effects when mice remained in their home cage and when they were challenged by exposure to forced swim stress. NMU-8 administration resulted in increased grooming behavior in mice that remained in their home cage and in a significant increase in c-Fos immunoreactivity in the paraventricular hypothalamus (PVH) and arcuate nucleus (ARC). Surprisingly, NMU-8 administration significantly decreased plasma corticosterone concentrations. Furthermore, NMU-8 administration increased immobility in the forced swim test in both naïve mice and mice that were previously exposed to swim stress. The effect of NMU-8 on c-Fos immunoreactivity in the PVH was dependent on previous exposure to swim stress given that we observed no significant changes in mice exposed for the first time to swim stress. In contrast, in the ARC we observed a significant increase in c-Fos immunoreactivity regardless of previous stress exposure. Interestingly, NMU-8 administration also significantly decreased plasma corticosterone concentrations in mice that were exposed to single forced swim stress, while this effect was no longer observed when mice were exposed to forced swim stress for a second time. Taken together, our data indicate that NMU-8 regulates stress responsiveness and suggests that its effects depend on previous stress exposure.

Dipeptide tyrosyl-leucine exhibits antidepressant-like activity in mice

Depression is a worldwide health problem. In the present study, we found that a dipeptide, tyrosyl leucine (Tyr-Leu, YL), administered orally, intracerebroventricularly, or intraperitoneally exhibited a potent antidepressant-like activity in the forced swim and tail suspension tests in naïve mice. YL increased the amount of cells expressing c-Fos, a marker for neuronal activity, in the dentate gyrus of the hippocampus. YL increased bromo-2′-deoxyuridine-positive cells and doublecortin expression in the dentate gyrus of the hippocampus, suggesting that YL enhanced the proliferation of hippocampal progenitor cells in vivo and in vitro. YL did not affect hippocampal mRNA and protein expression of BDNF, which is a regulatory factor of both neurogenesis and depression-like behavior. Intriguingly, YL suppressed activation of the hypothalamo-pituitary-adrenal axis by forced swim stress. Moreover, other aromatic amino acid-leucines, Phe-Leu and Trp-Leu, also exhibited antidepressant-like activities, suggesting that the structure of aromatic amino acid-leucine may be important for antidepressant activity. In addition, bovine milk casein-derived peptide, Tyr-Leu-Gly (YLG), an anxiolytic peptide, exhibited an antidepressant-like activity. Our findings demonstrate that YL exhibits an antidepressant-like effect, moderates the stress response, and induces hippocampal neuronal proliferation through a signal pathway independent of BDNF.

The Effect of Hydro-alcoholic Extract of Lavandula Angustifolia on Purkinje Neurons Following Enforced Swimming Stress in Male Rats

The Effect of Hydro-alcoholic Extract of Lavandula Angustifolia on Purkinje Neurons Following Enforced Swimming Stress in Male Rats

New Biological Insights on X and Y Chromosome-Bearing Spermatozoa

A spermatozoon is a male germ cell capable of fertilizing an oocyte and carries genetic information for determining the sex of the offspring. It comprises autosomes and an X (X spermatozoa) or a Y chromosome (Y spermatozoa). The origin and maturation of both X and Y spermatozoa are the same, however, certain differences may exist. Previous studies proposed a substantial difference between X and Y spermatozoa, however, recent studies suggest negligible or no differences between these spermatozoa with respect to ratio, shape and size, motility and swimming pattern, strength, electric charge, pH, stress response, and aneuploidy. The only difference between X and Y spermatozoa lies in their DNA content. Moreover, recent proteomic and genomic studies have identified a set of proteins and genes that are differentially expressed between X and Y spermatozoa. Therefore, the difference in DNA content might be responsible for the differential expression of certain genes and proteins between these cells. In this review, we have compiled our present knowledge to compare X and Y spermatozoa with respect to their structural, functional, and molecular features. In addition, we have highlighted several areas that could be explored in future studies in this field.