Behavior In Female Mice Research Articles

E-vaping and high-fat diet consumption: It’s all a hazy memory

The central signaling actions of cytokines are mediated by signal transducer and activator of transcription (STAT3). STAT3 activation plays a pivotal role in the behavioral responses to the adiposity hormone leptin, including in midbrain dopamine (DA) neurons where it mediates the influence of leptin to diminish physical activity and running reward in male mice. Leptin also has anxiolytic effects which have been tied to the mesolimbic DA system. To assess the contribution of STAT3 signaling in mesolimbic DA neurons on feeding, mesolimbic DA tone and anxiodepressive behaviors in female mice, we generated DA-specific STAT3 knockout mice by crossing mice expressing Cre under the control of the dopamine transporter with STAT3-LoxP mice. Feeding, locomotion, wheel running, conditioned place preference for palatable food and amphetamine locomotor sensitization were unaffected by DA-specific STAT3 deletion. Conversely, knockout mice exhibited heightened anxiety-like behavior (open field test and elevated plus maze) along with increased basal and stress-induced plasma corticosterone, whereas indices of behavioral despair (forced swim and tail-suspension tasks) were unchanged. In accordance with biochemical evidence of increased D1 receptor signaling (phospho-DARPP32Thr34) in the central nucleus of the amygdala (CeA) of knockout mice, local microinjections of a D1 receptor antagonist reversed the anxiogenic phenotype of knockout mice. In addition to alluding to sex differences in the signaling mechanisms mediating anxiety-like behavior, our findings suggest that activation of STAT3 in midbrain dopamine neurons projecting to the CeA dampens anxiety in a D1R-dependent manner in female mice.

Effects of Long-Term Exposure of Intermediate Frequency Magnetic Fields (20 kHz, 360 µT) on the Development, Pathological Findings, and Behavior of Female Mice.

The use of magnetic fields in the intermediate-frequency (IF) range to wirelessly charge electric cars with power transfer in the kilowatt range has become increasingly widespread, leading to unavoidable stray fields in the microtesla range. Only a handful of studies have assessed the potential biological risks associated with exposure to such fields. We exposed female mice (n = 80 per group) to either 20 kHz, 360 µT (rms), or sham in Helmholtz coils to conduct a blind design study. Exposure started at 3 months of age (24 h/day). Body mass was recorded every 1-2 weeks. At 10 months of age, three behavioral tests were performed on 24 animals per group. Three months later, the mice were sacrificed and organs (brain, liver, kidney, spleen, and lung) were removed and prepared for microscopic analysis. Our findings demonstrate no differences in the development of body mass and survival rates (96% and 89%, respectively). Similarly, no significant differences were observed in tumor incidence rates. When it comes to behavioral tests, the 8-arm maze results revealed no significant differences. In contrast, the Rotarod data were significantly (P < 0.001) different with longer retention times seen in the exposed mice. In the open field, the number of supported rears was significantly lower (P < 0.01), whereas the other endpoints did not show any differences. Overall, our data reveal no adverse effects of exposure to 20 kHz, 360 µTon the development and tumor incidences, while the significant differences in the behavioral tests may indicate higher levels of alertness in mice.

Early estradiol exposure masculinizes disease-relevant behaviors in female mice.

Most psychiatric disorders show a sex bias in incidence, symptomatology, and/or response to treatment. Males are more susceptible to neurodevelopmental disorders including autism spectrum disorder and attention-deficit activity disorder, while women are more prone to major depressive disorder and anxiety disorders after puberty. A striking difference between males and females in humans and other mammals is that males undergo a process of brain masculinization due to the early exposure to gonadal hormones. In rodents, this developmental organization of the brain is essential for adult males to express the appropriate sexual behaviors in the presence of a receptive female. Our goal was to determine whether this process of brain masculinization influences behaviors relevant to psychiatric disorders. To this aim, we studied sex differences and the effect of neonatal 17β-estradiol benzoate treatment of female mice on different disease-relevant behaviors. Our analysis includes postnatal behavior, juvenile play, and adult tests for sociability, repetitive behaviors, anxiety, and depression. Our results show that the sex differences observed in exploration, repetitive behaviors, and depression-related behaviors are largely reduced when females are neonatally treated with 17β-estradiol benzoate. These results suggest a role of neonatal sex steroids in the development of disease-relevant behaviors and provide evidence supporting a role for perinatal exposure to estrogens and androgens on the development and manifestation of psychiatric disorders.

Sensory Detection by the Vomeronasal Organ Modulates Experience-Dependent Social Behaviors in Female Mice.

In mice, social behaviors are largely controlled by the olfactory system. Pheromone detection induces naïve virgin females to retrieve isolated pups to the nest and to be sexually receptive to males, but social experience increases the performance of both types of innate behaviors. Whether animals are intrinsically sensitive to the smell of conspecifics, or the detection of olfactory cues modulates experience for the display of social responses is currently unclear. Here, we employed mice with an olfactory-specific deletion of the G protein Gαi2, which partially eliminates sensory function in the vomeronasal organ (VNO), to show that social behavior in female mice results from interactions between intrinsic mechanisms in the vomeronasal system and experience-dependent plasticity. In pup- and sexually-naïve females, Gαi2 deletion elicited a reduction in pup retrieval behavior, but not in sexual receptivity. By contrast, experienced animals showed normal maternal behavior, but the experience-dependent increase in sexual receptivity was incomplete. Further, lower receptivity was accompanied by reduced neuronal activity in the anterior accessory olfactory bulb and the rostral periventricular area of the third ventricle. Therefore, neural mechanisms utilize intrinsic sensitivity in the mouse vomeronasal system and enable plasticity to display consistent social behavior.

Hyperlipidic diet affects body composition and induces anxiety-like behaviour in intrauterine growth-restricted adult mice.

What is the central question of this study? What is the effect in male and female offspring of a protein-deficient diet producing intrauterine growth restriction (IUGR) in maternal mice on morphometric, metabolic and behavioural parameters before and after a challenge with a fat diet? What is the main finding and its importance? Male and female mice presented different growth trajectories after birth. IUGR favoured increased adiposity in male mice, and high-fat diet-induced anxiety-like behaviour in female mice. As there is sexual dimorphism in the response to maternal manipulations, we aimed to analyse the effects of intrauterine growth restriction (IUGR) in both sexes on morphometric, metabolic and behavioural parameters throughout postnatal development, and after challenge with a hyperlipidic diet. Female Swiss mice (n=59) were distributed into two groups (SD: standard diet, n=26; and PDD: isocaloric protein-deficient diet, n=33), 2weeks before mating and during the gestational period. After birth, offspring from SD and PDD dams were cross-fostered and nurtured by SD dams until postnatal day (PND) 28. At PND 60 all animals were challenged with a hypercaloric diet for 4weeks. Offspring birth weight was significantly reduced in the PDD group compared to the SD group (P=0.0001), but only male offspring presented a rapid catch-up during the first 21days of development. Although no differences in body weight were observed between groups after the challenge with the hyperlipidic diet, an increase in the relative perigonadal white adipose tissue (P=0.009) and a decrease in gross gastrocnemius muscle weight (P=0.010) were observed in the PDD males. In relation to behavioural tests, there was an increase in locomotion in both sexes (P=0.0001), and a decrease in female grooming (P=0.006) in the PDD group. Additionally, females from the PDD group showed increased hyperlipidic food intake. In conclusion, IUGR affected both sexes, with females showing prominent behavioural modifications and males presenting altered body composition elicited by a hyperlipidic diet.

Sex-specific peripheral and central responses to stress-induced depression and treatment in a mouse model.

Major depressive disorder affects ~20% of the world population and is characterized by strong sexual dimorphism with females being two to three times more likely to develop this disorder. Previously, we demonstrated that a combination therapy with dihydrocaffeic acid and malvidin-glucoside to synergistically target peripheral inflammation and stress-induced synaptic maladaptation in the brain was effective in alleviating chronic social defeat stress (CSDS)-induced depression-like phenotype in male mice. Here, we test the combination therapy in a female CSDS model for depression and compared sex-specific responses to stress in the periphery and the central nervous system. Similar to male mice, the combination treatment is also effective in promoting resilience against the CSDS-induced depression-like behavior in female mice. However, there are sex-specific differences in peripheral immune responses and differential gene regulation in the prefrontal cortex to chronic stress and to the treatment. These data indicate that while therapeutic approaches to combat stress-related disorders may be effective in both sexes, the mechanisms underlying these effects differ, emphasizing the need for inclusion of both sexes in preclinical studies using animal models.

Becoming a better parent: Mice learn sounds that improve a stereotyped maternal behavior

While mothering is often instinctive and stereotyped in species-specific ways, evolution can favor genetically “open” behavior programs that allow experience to shape infant care. Among experience-dependent maternal behavioral mechanisms, sensory learning about infants has been hard to separate from motivational changes arising from sensitization with infants. We developed a paradigm in which sensory learning of an infant-associated cue improves a stereotypical maternal behavior in female mice. Mice instinctively employed a spatial memory-based strategy when engaged repetitively in a pup search and retrieval task. However, by playing a sound from a T-maze arm to signal where a pup will be delivered for retrieval, mice learned within 7 days and retained for at least 2 weeks the ability to use this specific cue to guide a more efficient search strategy. The motivation to retrieve pups also increased with learning on average, but their correlation did not explain performance at the trial level. Bilaterally silencing auditory cortical activity significantly impaired the utilization of new strategy without changing the motivation to retrieve pups. Finally, motherhood as compared to infant-care experience alone accelerated how quickly the new sensory-based strategy was acquired, suggesting a role for the maternal hormonal state. By rigorously establishing that newly formed sensory associations can improve the performance of a natural maternal behavior, this work facilitates future studies into the neurochemical and circuit mechanisms that mediate novel sensory learning in the maternal context, as well as more learning-based mechanisms of parental behavior in rodents.

Overexpression of angiotensin converting enzyme 2 reduces anxiety-like behavior in female mice.

Accumulating evidence has revealed an intricate role for the renin-angiotensin system (RAS) in the progression or alleviation of stress-related disorders. Along these lines, the ‘pro-stress’ actions of angiotensin-II (Ang-II) are largely thought to be mediated by the angiotensin type-1a receptor (AT1aR). On the other hand, a counter regulatory limb of the RAS that depends on the conversion of Ang-II to angiotensin-(1–7) by angiotensin-converting enzyme 2 (ACE2) has been postulated to exert stress-dampening actions. We have previously found that augmenting ACE2 activity is potently anxiolytic and blunts stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis in male mice. Whether increasing ACE2 activity also relieves stress and anxiety in females has not yet been determined. Consequently, this series of experiments tests the hypothesis that augmenting ACE2 expression is anxiolytic and dampens the activity of the HPA axis in female mice. Using the Cre-LoxP system, we generated female mice that were homo-, heterozygous or wild-type for a mutated allele resulting in ubiquitous overexpression of ACE2. Next, we used qPCR to determine that levels of ACE2 mRNA isolated from central and peripheral tissues was dependent on genotype. That is, mice homo- and heterozygous for the ACE2 overexpression had significantly greater levels of ACE2 mRNA relative to littermate matched wild-type controls. Interestingly, anxiety-like behavior as determined by the elevated plus maze, light-dark box and novelty-induced hypophagia tests was also affected by genotype. Specifically, ACE2 overexpression significantly decreased anxiety-like behavior in paradigms dependent on approach-avoidance conflict and novelty; however, locomotor activity was similar amongst the genotypes. Final experiments measured plasma corticosterone to evaluate whether increasing ACE2 alters basal and/or stress-induced HPA axis activity. In contrast to what was previously found in males, increasing ACE2 expression had no effect on plasma corticosterone under basal conditions or subsequent to an acute restraint challenge. Collectively, these results suggest that increasing ACE2 expression potently elicits anxiolysis in female mice without altering HPA axis activity.

CD300f immunoreceptor is associated with major depressive disorder and decreased microglial metabolic fitness

A role for microglia in neuropsychiatric diseases, including major depressive disorder (MDD), has been postulated. Regulation of microglial phenotype by immune receptors has become a central topic in many neurological conditions. We explored preclinical and clinical evidence for the role of the CD300f immune receptor in the fine regulation of microglial phenotype and its contribution to MDD. We found that a prevalent nonsynonymous single-nucleotide polymorphism (C/T, rs2034310) of the human CD300f receptor cytoplasmic tail inhibits the protein kinase C phosphorylation of a threonine and is associated with protection against MDD, mainly in women. Interestingly, CD300f-/- mice displayed several characteristic MDD traits such as augmented microglial numbers, increased interleukin 6 and interleukin 1 receptor antagonist messenger RNA, alterations in synaptic strength, and noradrenaline-dependent and persistent depressive-like and anhedonic behaviors in females. This behavioral phenotype could be potentiated inducing the lipopolysaccharide depression model. RNA sequencing and biochemical studies revealed an association with impaired microglial metabolic fitness. In conclusion, we report a clear association that links the function of the CD300f immune receptor with MDD in humans, depressive-like and anhedonic behaviors in female mice, and altered microglial metabolic reprogramming.

Maternal Separation Early in Life Alters the Expression of Genes Npas4 and Nr1d1 in Adult Female Mice: Correlation with Social Behavior

Early-life stress affects neuronal plasticity of the brain regions participating in the implementation of social behavior. Our previous studies have shown that brief and prolonged separation of pups from their mothers leads to enhanced social behavior in adult female mice. The goal of the present study was to characterize the expression of genes (which are engaged in synaptic plasticity) Egr1, Npas4, Arc, and Homer1 in the prefrontal cortex and dorsal hippocampus of adult female mice with a history of early-life stress. In addition, we evaluated the expression of stress-related genes: glucocorticoid and mineralocorticoid receptors (Nr3c1 and Nr3c2) and Nr1d1, which encodes a transcription factor (also known as REVERBα) modulating sociability and anxiety-related behavior. C57Bl/6 mice were exposed to either maternal separation (MS, 3 h once a day) or handling (HD, 15 min once a day) on postnatal days 2 through 14. In adulthood, the behavior of female mice was analyzed by some behavioral tests, and on the day after the testing of social behavior, we measured the gene expression. We found increased Npas4 expression only in the prefrontal cortex and higher Nr1d1 expression in both the prefrontal cortex and dorsal hippocampus of adult female mice with a history of MS. The expression of the studied genes did not change in HD female mice. The expression of stress-related genes Nr3c1 and Nr3c2 was unaltered in both groups. We propose that the upregulation of Npas4 and Nr1d1 in females with a history of early-life stress and the corresponding enhancement of social behavior may be regarded as an adaptation mechanism reversing possible aberrations caused by early-life stress.

Heterozygous mutation of sonic hedgehog receptor (Ptch1) drives cerebellar overgrowth and sex-specifically alters hippocampal and cortical layer structure, activity, and social behavior in female mice

Sonic hedgehog (SHH) signaling is essential for the differentiation and migration of early stem cell populations during cerebellar development. Dysregulation of SHH-signaling can result in cerebellar overgrowth and the formation of the brain tumor medulloblastoma. Treatment for medulloblastoma is extremely aggressive and patients suffer life-long side effects including behavioral deficits. Considering that other behavioral disorders including autism spectrum disorders, holoprosencephaly, and basal cell nevus syndrome are known to present with cerebellar abnormalities, it is proposed that some behavioral abnormalities could be inherent to the medulloblastoma sequalae rather than treatment. Using a haploinsufficient SHH receptor knockout mouse model (Ptch1+/−), a partner preference task was used to explore activity, social behavior and neuroanatomical changes resulting from dysregulated SHH signaling. Compared to wild-type, Ptch1+/− females displayed increased activity by traveling a greater distance in both open-field and partner preference tasks. Social behavior was also sex-specifically modified in Ptch1+/− females that interacted more with both novel and familiar animals in the partner preference task compared to same-sex wild-type controls. Haploinsufficiency of PTCH1 resulted in cerebellar overgrowth in lobules IV/V and IX of both sexes, and female-specific decreases in hippocampal size and isocortical layer thickness. Taken together, neuroanatomical changes related to deficient SHH signaling may alter social behavior.

Median raphe serotonin neurons promote anxiety-like behavior via inputs to the dorsal hippocampus

Anxiety disorders may be mediated in part by disruptions in serotonin (5-hydroxytryptamine, 5-HT) system function. Behavioral measures of approach-avoidance conflict suggest that serotonin neurons within the median raphe nucleus (MRN) promote an anxiogenic state, and some evidence indicates this may be mediated by serotonergic signaling within the dorsal hippocampus. Here, we test this hypothesis using an optogenetic approach to examine the contribution of MRN 5-HT neurons and 5-HT innervation of the dorsal hippocampus (dHC) to anxiety-like behaviours in female mice. Mice expressing the excitatory opsin ChR2 were generated by crossing the ePet-cre serotonergic cre-driver line with the conditional Ai32 ChR2 reporter line, resulting in selective expression of ChR2 in 5-HT neurons. Electrophysiological recordings confirmed that this approach enabled reliable optogenetic stimulation of MRN 5-HT neurons, and this stimulation produced downstream 5-HT release in the dHC as measured by in vivo microdialysis. Optogenetic stimulation of the MRN elicited behavioral responses indicative of an anxiogenic effect in three behavioural tests: novelty-suppressed feeding, marble burying and exploration on the elevated-plus maze. These effects were shown to be behaviourally-specific. Stimulation of 5-HT terminals in the dHC recapitulated the anxiety-like behaviour in the novelty-suppressed feeding and marble burying tests. These results show that activation of 5-HT efferents from the MRN rapidly induces expression of anxiety-like behaviour, in part via projections to the dHC. These findings reveal an important neural circuit implicated in the expression of anxiety in female mice.

Chronic repeated predatory stress induces resistance to quinine adulteration of ethanol in male mice

BackgroundTrauma related psychiatric disorders, such as posttraumatic stress disorder (PTSD), and alcohol use disorder (AUD) are highly comorbid illnesses that separately present an opposing, sex-specific pattern, with increased prevalence of PTSD in females and increased prevalence of AUD diagnoses in males. Likewise, PTSD is a risk factor in the development of AUD, with conflicting data on the impact of sex in the comorbid development of both disorders. Because the likelihood of experiencing more than one traumatic event is high, we aim to utilize chronic repeated predatory stress (CRPS) to query the extent to which sex interacts with CRPS to influence alcohol consumption, or cessation of consumption. MethodsMale (n = 16) and female (n = 15) C57BL/6 J mice underwent CRPS or daily handling for two weeks during adolescence (P35-P49) and two weeks during adulthood (P65-P79). Following the conclusion of two rounds of repeated stress, behavior was assessed in the open field. Mice subsequently underwent a two-bottle choice intermittent ethanol access (IEA) assessment (P90-131) with the options of 20 % ethanol or water. After establishing drinking behavior, increasing concentrations of quinine were added to the ethanol to assess the drinking response to adulteration of the alcohol. ResultsCRPS increased fecal corticosterone concentrations and anxiety-like behaviors in the open field in both male and female mice as compared to control mice that had not been exposed to CRPS. Consistent with previous reports, we observed a sex difference in alcohol consumption such that females consumed more ethanol per gram of body mass than males. In addition, CRPS reduced alcohol aversion in male mice such that higher concentrations of quinine were necessary to reduce alcohol intake as compared to control mice. CRPS did not alter alcohol-related behaviors in female mice. ConclusionCollectively, we demonstrate that repeated CRPS can induce anxiety-like behavior in both sexes but selectively influences the response to ethanol adulteration in males.

Prefrontal parvalbumin cells are sensitive to stress and mediate anxiety-related behaviors in female mice

Reduced activity of the prefrontal cortex (PFC) is seen in mood disorders including depression and anxiety. The mechanisms of this hypofrontality remain unclear. Because of their specific physiological properties, parvalbumin-expressing (PV+) inhibitory interneurons contribute to the overall activity of the PFC. Our recent work using a chronic stress mouse model showed that stress-induced increases in prefrontal PV expression correlates with increased anxiety-like behaviors in female mice. Our goal is now to provide a causal relationship between changes in prefrontal PV+ cells and changes in emotional behaviors in mice. We first show that, in addition to increasing overall level of PV expression, chronic stress increases the activity of prefrontal PV+ cells. We then used a chemogenetic approach to mimic the effects of chronic stress and specifically increase the activity of prefrontal PV+ cells. We observed that chemogenetic activation of PV+ cells caused an overall reduction in prefrontal activity, and that chronic activation of PV+ cells lead to increased anxiety-related behaviors in female mice only. These results demonstrate that activity of prefrontal PV+ cells could represent a novel sex-specific modulator of anxiety-related behaviors, potentially through changes in overall prefrontal activity. The findings also support the idea that prefrontal PV+ cells are worth further investigation to better understand mood disorders that are more prevalent in female populations.

Effects of Soy isoflavones on depression like behavior in female mice and mechanism of estrogen receptor β

Effects of Soy isoflavones on depression like behavior in female mice and mechanism of estrogen receptor β

Granulocyte-Colony Stimulating Factor-Induced Neutrophil Recruitment Provides Opioid-Mediated Endogenous Anti-nociception in Female Mice With Oral Squamous Cell Carcinoma.

Oral cancer patients report severe function-induced pain; severity is greater in females. We hypothesize that a neutrophil-mediated endogenous analgesic mechanism is responsible for sex differences in nociception secondary to oral squamous cell carcinoma (SCC). Neutrophils isolated from the cancer-induced inflammatory microenvironment contain β-endorphin protein and are identified by the Ly6G+ immune marker. We previously demonstrated that male mice with carcinogen-induced oral SCC exhibit less nociceptive behavior and a higher concentration of neutrophils in the cancer microenvironment compared to female mice with oral SCC. Oral cancer cells secrete granulocyte colony stimulating factor (G-CSF), a growth factor that recruits neutrophils from bone marrow to the cancer microenvironment. We found that recombinant G-CSF (rG-CSF, 5 μg/mouse, intraperitoneal) significantly increased circulating Ly6G+ neutrophils in the blood of male and female mice within 24 h of administration. In an oral cancer supernatant mouse model, rG-CSF treatment increased cancer-recruited Ly6G+ neutrophil infiltration and abolished orofacial nociceptive behavior evoked in response to oral cancer supernatant in both male and female mice. Local naloxone treatment restored the cancer mediator-induced nociceptive behavior. We infer that rG-CSF-induced Ly6G+ neutrophils drive an endogenous analgesic mechanism. We then evaluated the efficacy of chronic rG-CSF administration to attenuate oral cancer-induced nociception using a tongue xenograft cancer model with the HSC-3 human oral cancer cell line. Saline-treated male mice with HSC-3 tumors exhibited less oral cancer-induced nociceptive behavior and had more β-endorphin protein in the cancer microenvironment than saline-treated female mice with HSC-3 tumors. Chronic rG-CSF treatment (2.5 μg/mouse, every 72 h) increased the HSC-3 recruited Ly6G+ neutrophils, increased β-endorphin protein content in the tongue and attenuated nociceptive behavior in female mice with HSC-3 tumors. From these data, we conclude that neutrophil-mediated endogenous opioids warrant further investigation as a potential strategy for oral cancer pain treatment.

Increased depression-related behavior during the postpartum period in inbred BALB/c and C57BL/6 strains

Pregnancy and lactation are characterized by dramatic changes in the endocrine system and brain in mammalian females. These changes, with stress before pregnancy, are potential risk factors for the development of postpartum depression (PPD). A valid animal model of PPD is needed to understand the neurobiological basis of the depressive state of females. To explore a mouse model of PPD, we first assessed anxiety-like and depression-related behaviors in nulliparous (virgin), nonlactating primiparous, and lactating primiparous females in four inbred strains of mice (C57BL/6J, C57BL/6JJcl, BALB/cAnNCrlCrlj, and BALB/cAJcl). Pups from the nonlactating female group were removed one day after parturition to examine the effects of physical interaction with pups on the postpartum behaviors. Second, we investigated the additional effects of prepregnancy stress (restraint stress for 6 h/day for 21 days) on postpartum behaviors in the BALB/cAJcl strain. We found that females of the two BALB/c substrains showed decreased locomotor activity and increased anxiety-like and depression-related behaviors compared with females of the two C57BL/6 substrains. Behavioral differences were also observed between the two substrains of each strain. Additionally, pregnancy- and lactation-dependent behavioral differences were found in some strains: lactating BALB/cAJcl females traveled shorter distance than the females of the other reproductive state groups, while nonlactating and lactating BALB/cAJcl and C57BL/6J females showed increased depression-related behavior compared with nulliparous females. Lactating BALB/cAJcl and C57BL/6JJcl females exhibited decreased sucrose preference or anhedonia-like behavior compared with nulliparous and nonlactating females, although these results did not reach statistical significance after correction for multiple testing. An additional independent experiment replicated the marked behavioral changes in lactating BALB/cAJcl females. Moreover, increased anxiety-like behavior was observed in lactating BALB/cAJcl females that experienced prepregnancy stress. These results suggest genetic contributions to the regulation of anxiety-like and depression-related behaviors in female mice. Furthermore, this study suggests that pregnancy and lactation cause decreased locomotor activity and increased depression-related behaviors, which was consistently found in our results, and that prepregnancy stress enhances anxiety-like behavior in the BALB/cAJcl strain. The inbred strain of female mice may be used as a potential model of PPD to further study the genetic and neurobiological mechanisms underlying the development of this disorder.

Probiotic consumption during puberty mitigates LPS-induced immune responses and protects against stress-induced depression- and anxiety-like behaviors in adulthood in a sex-specific manner

Puberty/adolescence is a significant period of development and a time with a high emergence of psychiatric disorders. During this period, there is increased neuroplasticity and heightened vulnerability to stress and inflammation. The gut microbiome regulates stress and inflammatory responses and can alter brain chemistry and behaviour. However, the role of the gut microbiota during pubertal development remains largely uninvestigated. The current study examined gut manipulation with probiotics during puberty in CD1 mice on lipopolysaccharide (LPS)-induced immune responses and enduring effects on anxiety- and depression-like behaviours and stress-reactivity in adulthood. Probiotics reduced LPS-induced sickness behaviour at 12 h in females and at 48 h following LPS treatment in males. Probiotics also reduced LPS-induced changes in body weight at 48 h post-treatment in females. Probiotic treatment also prevented LPS-induced increases in pro- and anti-inflammatory peripheral cytokines at 8 h following LPS treatment, reduced central cytokine mRNA expression in the hypothalamus, hippocampus and PFC, and prevented LPS-induced changes to in the gut microbiota. A single exposure to LPS during puberty resulted in enduring depression-like behaviour in female mice, and anxiety-like behaviour in male mice in adulthood. However, pubertal exposure to probiotics prevented enduring LPS-induced depression-like behaviour in females and anxiety-like behaviors in males. Moreover, probiotics altered toll-like receptor-4 activity in the paraventricular nucleus of the hypothalamus (PVN) in males in response to a novel stressor in adulthood. Our results suggest that the gut microbiome plays an important role in pubertal neurodevelopment. These findings indicate that exposure to probiotics during puberty mitigates inflammation and decreases stress-induced vulnerabilities to emotional behaviours later in life, in a sex-specific manner.

Epstein-Barr Virus dUTPase Induces Neuroinflammatory Mediators: Implications for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

PurposeNeuroinflammation is a common feature in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), affecting 85%–90% of all patients, yet the underlying mechanism or mechanisms responsible for the initiation and/or promotion of this process is largely unknown. Multiple reports, however, have suggested a role for Epstein-Barr virus (EBV), in particular, in ME/CFS, but its potential role, if any, in the neuroinflammatory process has not been addressed. In support of this premise, studies by our group have found that the EBV protein deoxyuridine triphosphate nucleotidohydrolase (dUTPase) induces anxiety and sickness behaviors in female mice. We also found that a small subset of patients with ME/CFS exhibited prolonged and significantly elevated neutralizing antibodies against EBV dUTPase protein in serum, which inversely correlated with ME/CFS symptoms. A larger ME/CFS case–control cohort study further confirmed that a significant percentage of patients with ME/CFS (30.91%–52.7%) were simultaneously producing antibodies against multiple human herpesviruses-encoded dUTPases and/or human dUTPase. Altogether, these findings suggest that EBV dUTPase protein may be involved in the neuroinflammatory process observed in ME/CFS. Thus, the aim of the present study was to determine whether the EBV dUTPase protein could contribute to neuroinflammation by altering the expression of genes involved with maintaining blood–brain barrier (BBB) integrity and/or modulating synaptic plasticity. MethodsWith the use of human immortalized astrocytes, microglia, and cerebral microvascular endothelial cells, we conducted time-course (0–24 h) experiments with EBV dUTPase protein (10 μg/mL) to determine what effect(s) it may have on the expression of genes involved with BBB permeability, astrocytes and microglia cell function, tryptophan metabolism, and synaptic plasticity by quantitative reverse transcription polymerase chain reaction (qRT-PCR). In parallel, in vivo studies were conducted in female C57Bl/6 mice. Mice were injected by the intraperitoneal route with EBV dUTPase protein (10 μg) or vehicle daily for 5 days, and the brains were collected and processed for further qRT-PCR analysis of the in vivo effect of the dUTPase on the dopamine/serotonin and γ-aminobutyric acid/glutamate pathways, which are important for brain function, using RT2 Profiler PCR Arrays. FindingsEBV dUTPase protein altered the expression in vitro (12 of 15 genes and 32 of 1000 proteins examined) and in vivo (34 of 84 genes examined) of targets with central roles in BBB integrity/function, fatigue, pain synapse structure, and function, as well as tryptophan, dopamine, and serotonin metabolism. ImplicationsThe data suggest that in a subset of patients with ME/CFS, the EBV dUTPase could initiate a neuroinflammatory reaction, which contributes to the fatigue, excessive pain, and cognitive impairments observed in these patients.

Sex- and developmental stage-dependent effects of fluorene-9-bisphenol exposure on emotional behaviors in mice

Exposure to environmental endocrine disruptors (EEDs) could induce high risk of cancer, obesity and depression. Fluorene-9-bisphenol (BHPF), a widely used EED, has been reported to exhibit anti-estrogenic activity and induce insomnia-like behaviors. The potential effects of BHPF exposure on emotional behaviors are still elusive. The present study aimed to investigated the neurobehavioral effects of BHPF exposure intragastrically (0.5, 5 mg kg−1, i.g.) at different developmental stages by using behavioral tests, including open field test (OFT), novelty-suppressed feeding test (NSF), sucrose preference test (SPT), tail suspension test (TST) and forced swimming test (FST). The results showed that adulthood BHPF exposure significantly induced anxiety- and depression-like behaviors in adult male mice; exposure to BHPF during pregnancy could attenuate depression-like behaviors in female mice. Maternal BHPF exposure reduced spontaneous activity of both male and female adolescent offspring as well as male adult offspring. Besides, maternal BHPF exposure decreased depression-like behaviors in both male and female adolescent offspring, and the female adolescent offspring were more sensitive than male adolescent offspring. Maternal exposure to BHPF decreased depression-like behaviors in male adult offspring; increased depression- and anxiety-like behaviors in female adult offspring. In conclusion, these data indicated that exposure to BHPF could disrupt neurobehaviors to varying degrees at different stages in mice.