Early postnatal whisker deprivation cross-modally modulates prefrontal cortex myelination and leads to social novelty deficit.

Sensory experience affects not only the corresponding primary sensory cortex, but also synaptic and neural circuit functions in other brain regions in a cross-modal manner. However, it remains unclear whether oligodendrocyte (OL) generation and myelination can also undergo cross-modal modulation. Here, we report that while early life short-term whisker deprivation from birth significantly reduces in the number of mature of OLs and the degree of myelination in the primary somatosensory cortex(S1) at postnatal day 14 (P14), it also simultaneously affects the primary visual cortex (V1), but not the medial prefrontal cortex (mPFC) with a similar reduction. Interestingly, when mice were subjected to long-term early whisker deprivation from birth (P0) to P35, they exhibited dramatically impaired myelination and a deduced number of differentiated OLs in regions including the S1, V1, and mPFC, as detected at P60. Meanwhile, the process complexity of OL precursor cells (OPCs) was also rduced, as detected in the mPFC. However, when whisker deprivation occurred during the mid-late postnatal period (P35 to P50), myelination was unaffected in both V1 and mPFC brain regions at P60. In addition to impaired OL and myelin development in the mPFC, long-term early whisker-deprived mice also showed deficits in social novelty, accompanied by abnormal activation of c-Fos in the mPFC. Thus, our results reveal a novel form of cross-modal modulation of myelination by sensory experience that can lead to abnormalities in social behavioral, suggesting a possible similar mechanism underlying brain pathological conditions that suffer from both sensory and social behavioral deficits, such as autism spectrum disorders.

Serine racemase deletion alters adolescent social behavior and whole-brain cFos activation.

Background: Neurodevelopmental disorders (NDDs) can cause debilitating impairments in social cognition and aberrant functional connectivity in large-scale brain networks, leading to social isolation and diminished everyday functioning. To facilitate the treatment of social impairments, animal models of NDDs that link N- methyl-D-aspartate receptor (NMDAR) hypofunction to social deficits in adulthood have been used. However, understanding the etiology of social impairments in NDDs requires investigating social changes during sensitive windows during development. Methods: We examine social behavior during adolescence using a translational mouse model of NMDAR hypofunction (SR-/-) caused by knocking out serine racemase (SR), the enzyme needed to make D-serine, a key NMDAR coagonist. Species-typical social interactions are maintained through brain-wide neural activation patterns; therefore, we employed whole-brain cFos activity mapping to examine network-level connectivity changes caused by SR deletion. Results: In adolescent SR-/- mice, we observed disinhibited social behavior toward a novel conspecific and rapid social habituation toward familiar social partners. SR-/- mice also spent more time in the open arm of the elevated plus maze which classically points to an anxiolytic behavioral phenotype. These behavioral findings point to a generalized reduction in anxiety-like behavior in both social and non-social contexts in SR-/- mice; importantly, these findings were not associated with diminished working memory. Inter-regional patterns of cFos activation revealed greater connectivity and network density in SR-/- mice compared to controls. Discussion: These results suggest that NMDAR hypofunction - a potential biomarker for NDDs - can lead to generalized behavioral disinhibition in adolescence, potentially arising from disrupted communication between and within salience and default mode networks.

Mouse Model of Parkinson's Disease with Bilateral Dorsal Striatum Lesion with 6-Hydroxydopamine Exhibits Cognitive Apathy-like Behavior.

Among the symptoms of Parkinson's disease (PD), apathy comprises a set of behavioral, affective, and cognitive features that can be classified into several subtypes. However, the pathophysiology and brain regions that are involved in these different apathy subtypes are still poorly characterized. We examined which subtype of apathy is elicited in a mouse model of PD with 6-hydroxydopamine (6-OHDA) lesions and the behavioral symptoms that are exhibited. Male C57/BL6J mice were allocated to sham (n = 8) and 6-OHDA (n = 13) groups and locally injected with saline or 4 µg 6-OHDA bilaterally in the dorsal striatum. We then conducted motor performance tests and apathy-related behavioral experiments. We then pathologically evaluated tyrosine hydroxylase (TH) immunostaining. The 6-OHDA group exhibited significant impairments in motor function. In the behavioral tests of apathy, significant differences were observed between the sham and 6-OHDA groups in the hole-board test and novelty-suppressed feeding test. The 6-OHDA group exhibited impairments in inanimate novel object preference, whereas social preference was maintained in the three-chamber test. The number of TH+ pixels in the caudate putamen and substantia nigra compacta was significantly reduced in the 6-OHDA group. The present mouse model of PD predominantly showed dorsal striatum dopaminergic neuronal loss and a decrease in novelty seeking as a symptom that is related to the cognitive apathy component.

Glyphosate-based herbicide exposure affects cognitive flexibility and social cognition in adult mice.

Glyphosate (Gly) is the active ingredient of several widely used herbicide formulations. Studies on Gly and glyphosate-based herbicide (GBH) exposure in different experimental models have suggested that the nervous system represented a key target for its toxicity, especially the prefrontal cortex (PFC). However, it is still unknown whether exposure to GBH affects higher brain functions dependent on PFC circuitry. The present work aimed to examine the effects of subtoxic doses of GBH on social cognition and cognitive flexibility as two functions belonging to higher brain function in mice. To do so, adult male mice were exposed daily to GBH by gavage at doses of 250 or 500 mg/kg for a sub-chronic period lasting 6 weeks. Then, mice were subjected to behavioral testing using the three-chamber and the Barnes maze paradigms. Our results indicate that GBH did not affect sociability. However, we found that GBH affects social cognition expressed by a lower discrimination index in the three-chamber test. Moreover, spatial memories evaluated during the probe trial, and cognitive flexibility evaluated during the reversal probe, were affected in mice exposed to GBH. Based on these results, exposure to subtoxic doses of GBH led to neurobehavioral alterations affecting the integrity of social cognition and cognitive flexibility functions. Finally, these data urge a thorough investigation of the cellular and molecular mechanisms underlying these alterations.

Efr3b is essential for social recognition by modulating the excitability of CA2 pyramidal neurons.

CA2 pyramidal neurons (PNs) are associated with social behaviors. The mechanisms, however, remain to be fully investigated. Here, we report that Efr3b, a protein essential for phospholipid metabolism at the plasma membrane, is widely expressed in the brain, especially in the hippocampal CA2/CA3 areas. To assess the functional significance of Efr3b in the brain, we generated Efr3bf/f mice and crossed them with Nestin-cre mice to delete Efr3b specifically in the brain. We find that Efr3b deficiency in the brain leads to deficits of social novelty recognition and hypoexcitability of CA2 PNs. We then knocked down the expression of Efr3b specifically in CA2 PNs of C57BL/6J mice, and our results showed that reducing Efr3b in CA2 PNs also resulted in deficits of social novelty recognition and hypoexcitability of CA2 PNs. More interestingly, restoring the expression of Efr3b in CA2 PNs enhances their excitability and improves social novelty recognition in Efr3b-deficient mice. Furthermore, direct activation of CA2 PNs with chemogenetics improves social behaviors in Efr3b-deficient mice. Together, our data suggest that Efr3b is essential for social novelty by modulating the excitability of CA2 PNs.

Maternal exposure to polystyrene microplastics impairs social behavior in mouse offspring with a potential neurotoxicity.

As plastic production has been increasing steadily, environmental pollution resulting from microplastics (MPs) continues to draw considerable attention of the researchers. Several studies have reported that MPs are risk factors for various cellular and systemic dysfunctions. However, the effects of chronic MP exposure from the embryonic stage to adulthood on mouse brain remain unclear. Accordingly, determining the impacts of maternal exposure to MPs on mouse offspring was the main goal of this study. To this end, single cells of primary cortical neurons were isolated from mouse embryos. Subsequently, the cells were exposed to 2 µm polystyrene microplastics (PS-MPs), which resulted in a notable reduction in dendritic length, and PS-MPs cannot pass through the cellular membrane of neurons. Moreover, exposure to PS-MPs caused the proliferation increase and apoptosis in primary cortical neuronal cells. We then evaluated the neurotoxicity associated with chronic PS-MP exposure from the embryonic stage to adulthood in C57BL/6 J mouse offspring. PS-MPs were found to accumulate in the digestive and excretory organs of the offspring but not in the brain tissue. However, offspring exposed to PS-MPs exhibited no differences in the levels of expression of genes related to brain cell markers or synaptic organization. Nevertheless, PS-MP-exposed mice exhibited impaired social novelty preferences; however, no changes were observed in the emotional, compulsive, or cognitive behaviors. Taken together, these results demonstrate the potential neurotoxic effects of chronic exposure to PS-MPs in mouse offspring.

Corticotropin-releasing hormone signaling from prefrontal cortex to lateral septum suppresses interaction with familiar mice.

Social preference, the decision to interact with one member of the same species over another, is critical to optimize social interactions. Thus, adult rodents favor interacting with novel conspecifics over familiar ones, but whether this social preference stems from neural circuits facilitating interactions with novel individuals or suppressing interactions with familiar ones remains unknown. Here, we identify neurons in the infra-limbic area (ILA) of the mouse prefrontal cortex that express the neuropeptide corticotropin-releasing hormone (CRH) and project to the dorsal region of the rostral lateral septum (rLS). We show how release of CRH during familiar encounters disinhibits rLS neurons, thereby suppressing social interactions with familiar mice and contributing to social novelty preference. We further demonstrate how the maturation of CRH expression in ILA during the first 2 post-natal weeks enables the developmental shift from a preference for littermates in juveniles to a preference for novel mice in adults.

Sericin improves memory and sociability impairments evoked by transient global cerebral ischemia through suppression of hippocampal oxidative stress, inflammation, and apoptosis.

Sericin (Ser) is a natural neuroactive macromolecule with diverse pharmacological properties, and our previous findings have shown its neuroprotective potentials. This study aimed to investigate the therapeutic potential of Ser on cognitive dysfunction induced by transient global cerebral ischemia/reperfusion (tGI/R) and its mechanism of action. The tGI/R was induced in BALB/c mice by bilateral occlusion of the common carotid arteries for two 5 min followed by a 10-min reperfusion period. After 24 h, mice were treated with normal saline or different doses of Ser (100, 200, and 300 mg/kg) for 10 days. Cognitive performances were assessed using the Barnes maze and social interaction tasks. Oxidative stress markers including superoxide dismutase (SOD), glutathione peroxidase (GPx), total antioxidant capacity (TAC), and malondialdehyde (MDA) as well as pro-inflammatory cytokines (interleukin (IL)-6 and tumor necrosis factor-alpha) and anti-inflammatory cytokine (IL-10) were assessed in the hippocampus. Markers of apoptosis (pro- and cleaved caspase-9 and 3, Bax, and Bcl-2) were assessed by Western blotting. Besides, transferase-mediated dUTP nick end-labeling assay was used to detect apoptotic cell death. We show here that Ser administration improved tGI/R-induced cognitive deficits, enhanced the activity of SOD and GPx, increased TAC levels, while reduced MDA levels. Notably, Ser decreased neuronal apoptotic cell death in the hippocampal dentate gyrus (DG) region, accompanied by suppression of neuroinflammation, downregulation of pro-apoptotic proteins (caspase-9, caspases-3, and Bax), and upregulation of anti-apoptotic protein, Bcl-2. Taken together, Ser administration protected hippocampal neurons from apoptotic cell death by impeding oxidative stress and inflammatory responses and, in turn, improved cognitive function in the tGI/R mice.

Microbial metabolites regulate social novelty via CaMKII neurons in the BNST.

Social novelty is a cognitive process that is essential for animals to interact strategically with conspecifics based on their prior experiences. The commensal microbiome in the gut modulates social behavior through various routes, including microbe-derived metabolite signaling. Short-chain fatty acids (SCFAs), metabolites derived from bacterial fermentation in the gastrointestinal tract, have been previously shown to impact host behavior. Herein, we demonstrate that the delivery of SCFAs directly into the brain disrupts social novelty through distinct neuronal populations. We are the first to observe that infusion of SCFAs into the lateral ventricle disrupted social novelty in microbiome-depleted mice without affecting brain inflammatory responses. The deficit in social novelty can be recapitulated by activating calcium/calmodulin-dependent protein kinase II (CaMKII)-labeled neurons in the bed nucleus of the stria terminalis (BNST). Conversely, chemogenetic silencing of the CaMKII-labeled neurons and pharmacological inhibition of fatty acid oxidation in the BNST reversed the SCFAs-induced deficit in social novelty. Our findings suggest that microbial metabolites impact social novelty through a distinct neuron population in the BNST.

Social investigation and social novelty in zebrafish: Roles of salience and novelty.

Social preference tests can be used to analyze variables that influence and modify social behaviors, and to investigate effects of substances such as medications, drugs, and hormones. They may become important tools for finding a valid model to study neuropsychiatric changes and to study human neurodevelopmental processes that have been impaired by social events. While a preference for conspecifics has been shown for different species, social novelty has been used as a model for anxiety-like behavior in rodents. The goal of this research was to understand the roles of stimulus salience (numerousness) and novelty in social investigation and social novelty tests in zebrafish (Danio rerio Hamilton 1822). We used a sequential design, in which animals are exposed first to a social investigation test (with dichotomous presentation of novel conspecifics vs. empty tank) and then to a social novelty test (with dichotomous presentation of the already known conspecific and a novel conspecific). In experiment 1, animals were presented to either 1 or 3 (vs. an empty tank) conspecifics as stimuli. In experiment 2, animals were presented to 1 vs. 3 conspecifics as stimuli. In experiment 3, animals were observed in the social investigation and social novelty tests for 3 consecutive days. The results showed equivalence between 1 or 3 conspecifics in the social investigation and social novelty tests, although animals were able to discriminate between different shoal sizes. These preferences do not change with repeated test exposure, suggesting novelty to be a minor contributor to social investigation and social novelty in zebrafish.

Adolescent sleep defects and dopaminergic hyperactivity in mice with a schizophrenia-linked Shank3 mutation.

Shank3 is a shared risk gene for autism spectrum disorders and schizophrenia. Sleep defects have been characterized for autism models with Shank3 mutations; however, evidence has been lacking for the potential sleep defects caused by Shank3 mutation associated with schizophrenia and how early in development these defects may occur. Here we characterized the sleep architecture of adolescent mice carrying a schizophrenia-linked, R1117X mutation in Shank3. We further employed GRABDA dopamine sensor and fiber photometry to record dopamine release in the nucleus accumbens during sleep/wake states. Our results show that homozygous mutant R1117X mice have significantly reduced sleep in the dark phase during adolescence, altered electroencephalogram power, especially during the rapid-eye-movement sleep, and dopamine hyperactivity during sleep but not during wakefulness. Further analyses suggest that these adolescent defects in sleep architecture and dopaminergic neuromodulation tightly correlate with the social novelty preference later in adulthood and predict adult social performance during same-sex social interactions. Our results provide novel insights into the sleep phenotypes in mouse models of schizophrenia and the potential use of developmental sleep as a predictive metric for adult social symptoms. Together with recent studies in other Shank3 models, our work underscores the idea that Shank3-involved circuit disruptions may be one of the shared pathologies in certain types of schizophrenia and autism. Future research is needed to establish the causal relationship among adolescent sleep defects, dopaminergic dysregulation, and adult behavioral changes in Shank3 mutation animals and other models.

Roles of the 5-HT2C receptor on zebrafish sociality.

Serotonin (5-HT) receptors have been implicated in social behavior in vertebrates. Zebrafish (Danio rerio) have been increasingly being used behavioral neuroscience to study the neurobiological correlates of behavior, including sociality. Nonetheless, the role of 5-HT2C receptors in different social functions were not yet studied in this species. Zebrafish were treated with the agonist MK-212 (2 mg/kg) or the antagonist RS-102221 (2 mg/kg) and tested in the social interaction and social novelty tests, conditional approach test, or mirror-induced aggressive displays. MK-212 increased preference for an unknown conspecific in the social investigation test, but also increased preference for the known conspecific in the social novelty test; RS-102221, on the other hand, decreased preference in the social investigation test but increased preference for the novel conspecific in the social novelty test. MK-212 also decreased predator inspection in the conditional approach test. While RS-102221 decreased time in the display zone in the mirror-induced aggressive display test, it increased display duration. Overall, these results demonstrate the complex role of 5-HT2C receptors in different social contexts in zebrafish, revealing a participation in social plasticity in vertebrates.

Changes in Sociability and Preference for Social Novelty in Female Rats in Prolonged Social Isolation.

Chronic stress due to social isolation (SI) can lead to distress with negative consequences for both humans and animals. Numerous disorders caused by SI include disorders in the emotional-motivational domain and cognitive functions, as well as changes in social behavior. There are currently no data identifying the sequelae of SI when its duration is significantly increased. Although female rats have been shown to be highly sensitive to stress, research on them is lacking. The present study assessed sociability and preference for "social novelty" in a three-chamber social test in female Wistar rats in two series of experiments at different time points during prolonged SI, which began at adolescence and continued to ages 5.5 and 9.5 months. At two months of SI, rats showed an increased preference for a social object over a non-social object (increased sociability) simultaneously with the appearance of signs of a decrease in the preference for a new social object over an already familiar social object (signs of a decrease in the preference for social novelty). In a social interaction test, the rats also displayed increases in the durations of social contacts, including aggressive interactions; they showed a decrease in exploratory risk assessments (head dips from the open arms) in the elevated plus maze test and a decrease in exploratory activity. After SI lasting 8.5 months, the rats showed signs of social deficit and a marked decrease in the preference for social novelty. No signs of increased aggressiveness were found. Thus, the impact of SI on social behavior depended on its duration and, we believe, was accompanied by a change in coping strategies.

A circuit from dorsal hippocampal CA3 to parvafox nucleus mediates social novelty preference deficits induced by chronic social defeat stress / 中国药理学与毒理学杂志

OBJECTIVE The preference for social novelty is crucial to the social life of humans and rodents.However,the neural mechanisms underlying social novelty preference are poorly understood.Dorsal hippocampal CA3(dCA3)is an important brain area that responds to social defeat stress,and the neural circuitry of dCA3→lat-eral septum(LS)participates in the context-associated memory.Meanwhile,the parvafox nucleus(PFN)Foxb1+ neurons regulate the defensive reaction to life-threaten-ing situations.Therefore,we investigate a cell-specific cir-cuit of dCA3CaMKⅡα+→dorsal LSGABA+→PFNFoxb1+ in social novelty preference.METHODS Chronic social defeat stress(CSDS)and three-chamber social interaction test were performed in adult male C57BL/6J mice to detect social behaviors.Optogenetic and chemical-genetic experiments were conducted to regulate the circuit.RESULTS CSDS reduced the preference for social nov-elty in mice and the response of dCA3CaMKⅡα+ neurons dur-ing approach to an unfamiliar mouse was impaired by CSDS.Optogenetic inhibition of dCA3CaMKⅡα+→dLS pro-jection reduced the preference for the unfamiliar mouse versus a familiar mouse.Meanwhile,optogenetic activa-tion of dCA3CaMKⅡα+→dLS projection rescued the prefer-ence for social novelty of CSDS-treated mice.Manipula-tions dLSGABA+→PFN projection activation regulated the preference for social novelty in mice.Optogenetic activa-tion of PFNFoxb1+→lPAG projection reduced the prefer-ence for a familiar C57BL/6J mouse versus a novel object in control mice.CSDS decreased the excitability of dCA3CaMKⅡα+ neurons by up-regulation of Kir2.4(Kcnj14)expression.CONCLUSION Our present study suggest-ed that activation of a cell-specific circuit of dCA3CaMKⅡα+→dLSGABA+→PFNFoxb1+→lPAG reverses the deficits of social novelty preference in defeated mice,and inhibition of this circuit reduces the preference for social novelty.The cir-cuit that regulates the preference for social novelty deficits may provide a new information for the potential therapeu-tic targets for neuropsychiatric diseases.

eEF2 in the prefrontal cortex promotes excitatory synaptic transmission and social novelty behavior.

Regulation of mRNA translation is essential for brain development and function. Translation elongation factor eEF2 acts as a molecular hub orchestrating various synaptic signals to protein synthesis control and participates in hippocampus-dependent cognitive functions. However, whether eEF2 regulates other behaviors in different brain regions has been unknown. Here, we construct a line of Eef2 heterozygous (HET) mice, which show a reduction in eEF2 and protein synthesis mainly in excitatory neurons of the prefrontal cortex. The mice also show lower spine density, reduced excitability, and AMPAR-mediated synaptic transmission in pyramidal neurons of the medial prefrontal cortex (mPFC). While HET mice exhibit normal learning and memory, they show defective social behavior and elevated anxiety. Knockdown of Eef2 in excitatory neurons of the mPFC specifically is sufficient to impair social novelty preference. Either chemogenetic activation of excitatory neurons in the mPFC or mPFC local infusion of the AMPAR potentiator PF-4778574 corrects the social novelty deficit of HET mice. Collectively, we identify a novel role for eEF2 in promoting prefrontal AMPAR-mediated synaptic transmission underlying social novelty behavior.

Effect of social instability stress in adolescence or adulthood on sensitivity to sucrose concentration in a social context in male and female Long-Evans rats.

Although there is evidence of sex differences in responding to social stress, and that age when stressed matters, females are understudied and adult-stress comparisons are few. Here, we investigated stress effects on reward sensitivity by examining rats' choice of social versus sucrose reward in a continuous spatial allocation design. We predicted social instability stress (SS) in adolescence would result in greater social discounting (spend less time near a novel peer when provided access to sucrose) relative to nonstressed controls (CTLs) and relative to SS in adulthood. All increased sucrose intake as the concentration increased, with no evidence of social discounting. SS males tested soon after the stress had a decrease in intake, whereas those tested long after had an increase in both time near the peer and in intake. CTL and SS females did not differ in intake, although their dose-response curves differed when tested soon after the SS. We also tested whether SS changed the stimulus value of the rat as a social peer; when tested in triads, CTL rats spent similar time in interaction with SS versus CTL rats. In sum, effects of SS on reward sensitivity were greater for males irrespective of administered in adolescence versus adulthood.

Interspecific differences in sociability, social novelty preference, anxiety- and depression-like behaviors between Brandt's voles and C57BL/6J mice.

The three-chamber test has been widely used to investigate social approach/novelty preference in rodents. Most studies have used the briefly familiar and unfamiliar individuals as stimuli to examine social recognition; however, little is known about the effects of long-term familiar peers in this paradigm. In the present study, we made a slight modification to it: the first phase measured preference for a cage-mate (not a novel individual) over an identical wire cage without an individual stimulus; the later phase measured preference for a novel individual placed in the previous empty wire cage compared to the cage-mate (not the briefly familiar individual). The present study aimed to compare differences in sociability and social recognition between Brandt's voles (Lasiopodomys brandtii) and C57BL/6J mice using this modified three-chamber test. The levels of anxiety-, depression-, and anhedonia-like behaviors were also examined in both species. We found that Brandt's voles preferred the cage-mate over the empty cage in phase 1 and showed a preference for the novel individual in phase 2. In C57BL/6J mice, males showed no preference for familiar peers in phase 1, whereas females failed to show a preference for the novel individual in phase 2, showing a sex-specific difference. Furthermore, Brandt's voles displayed higher levels of locomotor activity and sociability as well as lower levels of anxiety-, depression-, and anhedonia-like behaviors than C57BL/6J mice. Interestingly, sociability and social approach correlated with depression-like behavior, whereas social novelty preference correlated with anhedonia-like behavior. Together, these data indicate that Brandt's voles and C57BL/6J mice show significant differences in sociability, social recognition, and levels of anxiety- and depression-like behaviors. Furthermore, Brandt's voles are more suitable for the study of selective social relationships.

Neonatal exposure to sevoflurane impairs preference for social novelty in C57BL/6 female mice at early-adulthood.

Social interaction deficit is core symptom of children with autism, owing to interaction of genetic predisposition and environmental toxins. Sevoflurane could induce neurotoxicity in developing brain in rodent models. This study aims to investigate whether sevoflurane anesthesia in neonatal period could impair social behaviors in male and female mice. Twenty-eight male and thirty-one female mice were randomly assigned to receive 3.0% sevoflurane or 60% oxygen on postnatal day 6. They were tested for social interaction behaviors at one- and two-month-old. In addition, the cortex and hippocampus of neonatal mice undergoing sevoflurane anesthesia were harvested for immunoblotting analysis. As a result, both male and female mice undergoing sevoflurane anesthesia showed strong sociability and weak preference for social novelty at juvenile age. In addition, the male mice developed normal preference for social novelty at early-adulthood; However, the female mice remained weak preference for social novelty. Furthurmore, sevoflurane anesthesia could decrease the levels of PSD95 but not Neuroligin-1 in the hippocampus but not cortex of neonatal mice. In conclusion, sevoflurane anesthesia in neonatal period could disturb development of social memory and impair preference for social novelty in female mice at early-adulthood, with the potential mechanism of decreasing PSD95 expression in the hippocampus of C57BL/6 mice.

Bacteroides fragilis BF839 can improve learning, memory and social novelty of fragile X-mental retardation gene 1 knockout mice / 中华神经医学杂志

Objective:To observe the effect of bacteroides fragilis BF839 intervention on learning, memory and social novelty of fragile X-mental retardation gene 1 ( Fmr1) knockout (KO) mice. Methods:Thirty three-week-old Fmr1 KO mice were randomly divided into Fmr1 KO group ( n=15) and Fmr1 KO+BF839 group ( n=15). Mice in the Fmr1 KO group freely drank autoclaved tap water everyday; mice in the Fmr1 KO+BF839 group drank BF839 bacterial liquid (10 mL/d) everyday;11 wild-type mice freely drank autoclaved tap water everyday were set as controls (WT group). After 4 weeks of intervention, Morris water maze test was used to observe the differences in escape latency and frequencies of crossing the original platform among mice in each group; Three-chamber Social Interaction Test was used to observe the differences in contact frequencies and contact durations with unfamiliar mice among mice in each group. Results:On the 4 th d of experiment, the escape latency of mice in the Fmr1 KO group ([46.06±10.29] s) was significantly longer than that in the WT group ([33.39±12.02] s, P<0.05); the escape latency of mice in the Fmr1 KO+BF839 group ([28.39±9.07] s) was significantly shorter than that in the Fmr1 KO group ( P<0.05); the escape latency of mice in the Fmr1 KO+BF839 group was slightly shorter than that in the WT group without significant difference ( P>0.05). The frequencies of crossing through the original platform of mice in Fmr1 KO group (0.00[0.00, 1.00] time) was slightly less than that in WT group (1.00 [0.00, 1.00] time) without significant difference ( P>0.05); that in the Fmr1 KO+BF839 group (1.50[1.00, 2.00] times) was significantly larger than that in the Fmr1 KO group and WT group ( P<0.05). The contact frequencies of the mice in the Fmr1 KO group with unfamiliar mice (5.50[0.50, 12.75] times) was less than that in the WT group (7.00[4.00, 17.00] times) without significant difference ( P>0.05); that in the Fmr1 KO+BF839 group (23.00[16.00, 36.00] times) was significantly increased as compared with that in the Fmr1 KO group and WT group ( P<0.05). The contact duration of mice in the Fmr1 KO group with unfamiliar mice (9.50[0.50, 41.95] s) was significantly shorter than that in the WT group (142.00[65.00, 171.60] s, P<0.05); Fmr1 KO+BF839 group had significantly longer contact duration with unfamiliar mice (69.60 [50.40, 98.40] s) than Fmr1 KO group ( P<0.05); the contact duration of mice in Fmr1 KO+BF839 group with unfamiliar mice was shorter than that in WT group without significant difference ( P>0.05). Conclusion:Early BF839 intervention can significantly improve the learning, memory abilities and social novelty of Fmr1 KO mice, and even restore the Fmr1 KO mice to normal levels, which suggests that BF839 may become a new tool for treatment of fragile X syndrome and autism.

Maternal Separation Modifies the Activity of Social Processing Brain Nuclei Upon Social Novelty Exposure.

Maternal separation has been shown to disrupt proper brain development and maturation, having profound consequences on the neuroendocrine systems in charge of the stress response, and has been shown to induce behavioral and cognitive abnormalities. At the behavioral level, maternal separation has been shown to increase offensive play-fighting in juvenile individuals and reduce social interest in adulthood. Since most of the studies that have evaluated the consequences of maternal separation on social behavior have focused on behavioral analysis, there is a need for a further understanding of the neuronal mechanisms underlying the changes in social behavior induced by maternal separation. Therefore, the aim of the present research was to assess the long-term effects of maternal separation on social interaction behavior and to assess the activity of several brain regions involved in the processing of social cues and reward upon social novelty exposure, using c-Fos immunohistochemistry as a marker of neuronal activity. Male Wistar rats were subjected to 4 h maternal separation during the neonatal period, 9:00 h-13:00 h from postnatal day 1 to 21, and exposed to social novelty during adulthood. After social novelty exposure, brains were fixed and coronal sections of the medial amygdala, lateral septum (LS), paraventricular nucleus of the hypothalamus, nucleus accumbens, and medial prefrontal cortex were obtained for c-Fos immunohistochemistry. Maternally separated rats spent less time investigating the novel peer, suggesting that maternal separation reduces social approach motivation. Furthermore, maternal separation reduced the number of c-Fos positive cells of the medial amygdala, paraventricular nucleus of the hypothalamus, LS, nucleus accumbens, and medial prefrontal cortex upon social novelty exposure. These findings suggest that maternal separation can reduce the plastic capacity of several brain nuclei, which constitute a physiological basis for the emergence of behavioral disorders presented later in life reported to be linked to early life adversity.