Distinct Gut Microbial Enterotypes and Functional Dynamics in Wild Striped Field Mice (Apodemus agrarius) across Diverse Populations.

Rodents, including the striped field mouse (Apodemus agrarius), play vital roles in ecosystem functioning, with their gut microbiota contributing significantly to various ecological processes. Here, we investigated the structure and function of 94 wild A. agrarius individuals from 7 geographic populations (45°57' N, 126°48' E; 45°87' N, 126°37' E; 45°50' N, 125°31' E; 45°59' N, 124°37' E; 46°01' N, 124°88' E; 46°01' N, 124°88' E; 46°01' N, 124°88' E), revealing two distinct enterotypes (Type1 and Type2) for the first time. Each enterotype showed unique microbial diversity, functions, and assembly processes. Firmicutes and Bacteroidetes dominated, with a significant presence of Lactobacillus and Muribaculaceae. Functional analysis highlighted metabolic differences, with Type1 emphasizing nutrient processing and Type2 showing higher energy production capacity. The analysis of the neutral model and the null model revealed a mix of stochastic (drift and homogenizing dispersal) and deterministic processes (homogenous selection) that shape the assembly of the microbiota, with subtle differences in the assembly processes between the two enterotypes. Correlation analysis showed that elevation and BMI were associated with the phylogenetic turnover of microbial communities, suggesting that variations in these factors may influence the composition and diversity of the gut microbiota in A. agrarius. Our study sheds light on gut microbial dynamics in wild A. agrarius populations, highlighting the importance of considering ecological and physiological factors in understanding host-microbiota interactions.

Continuous oral olanzapine or clozapine treatment initiated in adolescence has differential short- and long-term impacts on antipsychotic sensitivity than those initiated in adulthood.

One of the major discoveries in recent research on antipsychotic drugs is that antipsychotic treatment in adolescence could induce robust long-term alterations in antipsychotic sensitivity that persist into adulthood. These long-term impacts are likely influenced by various factors, including the "diseased" state of animals, sex, type of drugs, mode of drug administration, and age of treatment onset. In this study we compared the short- and long-term behavioral effects of 21-day continuous oral olanzapine (7.5 mg/kg/day) or clozapine (30.0 mg/kg/day) administration in heathy or maternal immune activated adolescent (33-53 days old) or adult (80-100 days old) rats of both sexes. We used a conditioned avoidance response model to assess the drug-induced alterations in antipsychotic sensitivity. Here, we report that while under the chronic drug treatment period, olanzapine progressively increased its suppression of avoidance responding over time, especially when treatment was initiated in adulthood. Clozapine's suppression depended on the age of drug exposure, with treatment initiated in adulthood showing a suppression while that initiated in adolescent did not. After a 17-day drug-free interval, in a drug challenge test, olanzapine treatment initiated in adolescence caused a decrease in drug sensitivity, as reflected by less avoidance suppression (a tolerance effect); whereas that initiated in adulthood appeared to cause an increase (more avoidance suppression, a sensitization effect). Clozapine treatments initiated in both adolescence and adulthood caused a similar tolerance effect. Our findings indicate that the same chronic antipsychotic treatment regimen initiated in adolescence or adulthood can have differential short- and long-term impacts on drug sensitivity.

Geographical distribution and species variation of gut microbiota in small rodents from the agro-pastoral transition ecotone in northern China.

The gut microbiota of rodents is essential for survival and adaptation and is susceptible to various factors, ranging from environmental conditions to genetic predispositions. Nevertheless, few comparative studies have considered the contribution of species identity and geographic spatial distance to variations in the gut microbiota. In this study, a random sampling survey encompassing four rodent species (Apodemus agrarius, Cricetulus barabensis, Tscherskia triton and Rattus norvegicus) was conducted at five sites in northern China's farming-pastoral ecotone. Through a cross-factorial comparison, we aimed to discern whether belonging to the same species or sharing the same capture site predominantly influences the composition of gut microbiota. Notably, the observed variations in microbiome composition among these four rodent species match the host phylogeny at the family level but not at the species level. The gut microbiota of these four rodent species exhibited typical mammalian characteristics, predominantly characterized by the Firmicutes and Bacteroidetes phyla. As the geographic distance between populations increased, the number of shared microbial taxa among conspecific populations decreased. We observed that within a relatively small geographical range, even different species exhibited convergent α-diversity due to their inhabitation within the same environmental microbial pool. In contrast, the composition and structure of the intestinal microbiota in the allopatric populations of A. agrarius demonstrated marked differences, similar to those of C. barabensis. Additionally, geographical environmental elements exhibited significant correlations with diversity indices. Conversely, host-related factors had minimal influence on microbial abundance. Our findings indicated that the similarity of the microbial compositions was not determined primarily by the host species, and the location of the sampling explained a greater amount of variation in the microbial composition, indicating that the local environment played a crucial role in shaping the microbial composition.

Long-term impacts of prenatal maternal immune activation and postnatal maternal separation on maternal behavior in adult female rats: Relevance to postpartum mental disorders.

Early life adversities are known to exert long-term negative impacts on psychological and brain functions in adulthood. The present work examined how a prenatal brain insult and a postnatal stressor independently or interactively influence the quality of maternal care of postpartum female rats and their cognitive and emotional functions, as a way to identify the behavioral dysfunctions underlying childhood trauma-induced postpartum mental disorders (as indexed by impaired maternal care). Sprague-Dawley female offspring born from mother rats exposed to polyinosinic:polycytidylic acid (PolyI:C, 4.0-6.0 mg/kg) intended to cause gestational maternal immune activation (MIA) or saline were subjected to a repeated maternal separation stress (RMS, 3 h/day) or no separation for 9 days in the first two weeks of life (a 2 × 2 design). When these offspring became mothers, their attentional filtering ability (as measured in the prepulse inhibition of acoustic startle reflex test), positive hedonic response (as measured in the sucrose preference test), and negative emotional response (as measured in the startle reflex and fear-potentiated startle test) were examined, along with their home-cage maternal behavior. Virgin littermates served as controls in all the behavioral tests except in maternal behavior. Results showed that mother rats who experienced RMS displayed impaired nest building and crouching/nursing activities. RMS also interacted with MIA to alter pup retrieval latency and startle reactivity, such that MIA-RMS dams demonstrated significantly slower pup retrieval latency and higher startle magnitude compared to either RMS-only and MIA-only mothers. MIA also disrupted attentional filtering ability, with significantly lower prepulse inhibition. However, neither prenatal MIA nor postnatal RMS impaired sucrose preference or the acquisition of fear-potentiated startle. These results indicate that prenatal stress and postnatal adversity could impair maternal behavior individually, and interact with each other, causing impairments in attention, emotion and maternal motivation.

Providing or receiving alloparental care promote partner preference and alter central oxytocin and dopamine systems in adult mandarin voles.

Juveniles of cooperative breeding species usually remain in the natal area and provide care to younger siblings, a behavior considered one form of alloparenting in the natural condition. Previous studies have demonstrated the effects of providing or receiving alloparental care on adult behaviors, including anxiety-like behavior, social interaction, and parental behavior, but little is known about the influences on species-typical bonding behaviors, such as pair-bond formation. In this study, we explored this concept using socially monogamous mandarin voles (Lasiopodomys mandarinus). As the oxytocin (OT) and dopamine systems are involved in alloparental and pair-bonding behaviors, we also examined the levels of central OT and tyrosine hydroxylase (TH), as well as OT receptor (OTR) and dopamine D1-type and D2-type receptors (D1R and D2R) mRNA expression in the nucleus accumbens (NAcc) and amygdala to investigate the underlying mechanisms. Our results show that mandarin voles providing alloparental care to younger siblings displayed facilitation of partner preference formation, lower levels of OT expression in the paraventricular nucleus of the hypothalamus (PVN) and lateral hypothalamus (LH), and increased OTR and D2R mRNA expression in the NAcc compared to controls. Individuals receiving alloparental care also demonstrated facilitation of partner preference formation in adult voles. Additionally, alloparental care enhanced OT expression in the PVN, anterior medial preoptic nucleus (MPOAa), medial amygdala (MeA), and TH expression in the ventral tegmental area (VTA) and zona incerta (ZI). Furthermore, males displayed decreased D1R mRNA expression in the NAcc, whereas females showed slightly increased D2R expression in the amygdala. These results demonstrate that providing or received alloparental care can promote partner preference formation in monogamous species and that these changes are associated with altered OT and dopamine levels and their receptors in specific brain regions.

Adolescence Predatory Risk Alters Social Behaviors and Cognitive Ability and Central Oxytocin and Vasopressin Expression in Adult Brandt's Voles.

INTRODUCTION: Stress during adolescence causes long-term behavioral changes in adulthood. We previously found that adolescent exposure to predatory risk augments adolescent social contact and adult parental behavior in Brandt's voles (Lasiopodomys brandtii). METHODS: Here, we determined whether this experience alters sexual behavior, pair-bond formation, and recognition ability as well as basal HPA axis activity, central oxytocin (OT), and arginine-vasopressin (AVP) expression in adulthood. RESULTS: In the social interaction test, repeated cat odor (CO) exposure enhanced the frequency of lordosis by female voles toward an unfamiliar opposite-sex conspecific. CO voles preferred to engage with their partners after 48-h cohabitation whereas the control groups did not, which may reflect stable pair bonds in the CO treatment group. Furthermore, adolescent exposure to CO inhibited novel object recognition and place recognition ability, while it influenced social recognition only among adult males. No effect of adolescent CO exposure was observed for basal HPA axis activity, showing a habituation effect. Finally, we found that CO exposure increased OT and decreased AVP expression in the hypothalamus, including the paraventricular nucleus and anterior hypothalamus. The levels of OT in the medial amygdala were lower, and AVP in the lateral septum was higher in CO voles compared with the control. CONCLUSION: These findings demonstrate that adolescent exposure to predator risk promotes adult reproductive behavior of Brandt's voles. Deficits in recognition ability may necessitate alterations in reproductive strategies to enhance inclusive fitness. OT and AVP systems may play a modulatory role in the alteration of social behaviors elicited by adolescent predatory risk.

8-OH-DPAT enhances dopamine D2-induced maternal disruption in rats.

Recent evidence indicates that 5-HT1A receptors play a significant role in mediating maternal behavior in rats. Given that they also modulate the mesocortical dopamine system, we hypothesized that 5-HT1A receptors may mediate maternal behavior, possibly by interacting with the D2 receptor. To address this issue, we used a combination of 5-HT1A agonist (8-OH-DPAT, 0.5 mg/kg) and two D2 drugs (an agonist quinpirole, QUIN, 1.0 mg/kg; a potent D2 antagonist haloperidol, HAL, 0.1 mg/kg) on rat maternal behavior in the home-cage maternal behavior and pup preference tests. We replicated the findings that acute QUIN, HAL, and 8-OH-DPAT disrupted home-cage maternal behavior. When administered in combination, pretreatment with HAL and QUIN worsened 8-OH-DPAT-induced maternal disruption and induced a decrease in the pup preference ratio. Accordingly, 8-OH-DPAT enhanced QUIN' and HAL's disruption of pup retrieval and pup preference, reversed the increase in hovering over pups induced by HAL. These findings suggest that activation of 5-HT1A receptors enhances D2-mediated maternal disruption. Furthermore, given that the combination of D2 drugs and 5-HT1A agonists only produced an additive effect on maternal disruption, 5-HT1A receptors may have a direct effect on maternal behavior independent of their interaction with D2 receptors.

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.

Postpartum maternal exposure to predator odor alters offspring antipredator behavior, basal HPA axis activity and immunoglobulin levels in adult Brandt's voles.

Predation risk can program offspring behavior, physiology, and fitness through maternal effect, but most studies have mainly focused on this effect during pregnancy; little is known about the effect of postpartum predation risk on offspring's phenotype. Here, we compared the antipredator behaviors of adult offspring (approximately 90 days old) produced by female Brandt's voles (Lasiopodomys brandtii) exposed to one of three treatments: cat odor (CO), rabbit odor (RO), and distilled water (DW) for 60 min daily from postpartum day 1-18. Basal levels of plasma adrenocorticotropic hormone (ACTH) and corticosterone (CORT), hypothalamic corticotrophin releasing hormone (CRH), as well as spleen immunoglobulins (IgA, IgM, and IgG) were also measured. Our data showed that the offspring of CO-exposed mothers displayed less head-out behavior to acute 15-min CO exposure, and female offspring showed more freezing behavior. CO offspring showed significantly lower basal ACTH and CORT levels than the RO and DW offspring. Additionally, female but not male CO offspring had higher hypothalamic CRH expression and spleen IgG levels than controls, showing a sex-specific effect. These findings demonstrate that postpartum maternal predator risk exposure promotes a passive-avoidant response to these cues in adult offspring, showing a cross-generational maternal effect of postpartum predation risk. Further, these changes may be associated with alterations in the hypothalamic-pituitary-adrenal axis and immune function.

Predator odor exposure increases social contact in adolescents and parental behavior in adulthood in Brandt's voles.

Research suggests that predation risk during adolescence can program adult stress response and emotional behavior; however, little is known about the short-term and lasting residual effects of this experience on social behavior. We explored this concept in social Brandt's voles (Lasiopodomys brandtii). Adolescent male and female voles were exposed to distilled water, rabbit urine (as a non-predator stimulus), and cat urine for 60 min daily from postnatal day (PND) 28-49. Social play tests were conducted immediately following exposure on PND 28, 35, 42, and 49. In the social play test, repeated cat odor (CO) exposure enhanced the contact behavior of voles with their cagemate. Adolescent exposure to CO did not affect behavioral responses toward unrelated pups in the alloparental behavior test or same-sex individuals in the social interaction test. However, exposure to CO significantly enhanced the licking/grooming behavior of voles towards their own pups in the home cage parental behavior test. Repeated CO exposure significantly inhibited weight gain in male voles during adolescence. This effect was transmitted to the next generation, with lower weight gain in offspring before weaning. Following repeated CO exposure, males tended to have more female offspring whereas females produced more offspring, suggesting an adaptive strategy to increase inclusive fitness under predatory risk. These findings demonstrate that adolescent exposure to predatory risk augments adolescent social contact and adult parental behavior and suggest a role for improved inclusive fitness in mediating long-term outcomes.

Repeated predator odor exposure alters maternal behavior of postpartum Brandt's voles and offspring's locomotor activity.

Recent evidence indicates that predation risk plays a special role in the rodent behavior of dams and offspring, but little is known about the effect of maternal exposure to the predator cues in the absence of pups. Here, we assessed the effects of repeated predator odor exposure on various maternal responses in postpartum Brandt's voles (Lasiopodomys brandtii). We also examined offspring's behavioral response to a novel environment. Only mother voles were exposed to distilled water, rabbit urine and cat urine for 60 min daily from postpartum day (PP) 1-18. Maternal behavior was immediately tested after these exposures on PP1, 3, 6, 9 and 18. Repeated cat odor (CO) and rabbit odor (RO) exposure disrupted hovering over pups in a time-dependent fashion. Repeated CO exposure also time-dependently disrupted pup retrieval, whereas RO exposure induced long-term reduction in pup licking. Juvenile offspring of CO-exposed mothers showed increased locomotor activity and decreased rearing in the open field at postnatal day 30. These findings demonstrated that maternal exposure to predator or non-predator odors had a disruptive effect on the maternal behavior of Brandt's voles when only the mother was exposed to these odors, and that the adversity experience with predation risk significantly impacted the behavioral development of offspring. Future work should explore possible behavioral mechanisms, such as the effect of predation risk, on the dams' emotional processing or pup preference.

Parent-offspring cohabitation after weaning inhibits partner preference and alters central oxytocin and dopamine systems in adult mandarin vole.

In some mammals, offspring may live with their parents for a very long time after weaning, but little is known about the effect of post-weaning parent-offspring cohabitation on the behavioral and neurobiological development of offspring. Here, we explored the effect of this experience on partner preference in adult mandarin vole (Microtus mandarinus). Levels of central oxytocin (OT), tyrosine hydroxylase (TH), as well as OT receptor (OTR), dopamine D1-type and D2-type receptors (D1R and D2R) mRNA expression in the nucleus accumbens (NAcc) and medial amygdala (MeA) were also measured. Our data showed that post-weaning living with parents inhibited the preference to partner over an unfamiliar opposite-sex conspecific. Voles with this experience possessed more OT-but less TH-immunoreactive neurons as compared to the control. Additionally, males with this experience had less D2R and OTR mRNA expression in the NAcc than the control while females had less D2R mRNA expression in the NAcc, but more OTR mRNA expression in the MeA. These findings demonstrate that post-weaning parent-offspring cohabitation inhibits the partner preference formation at adulthood, and these changes may be associated with alterations in the levels of central OT and DA, and their receptor mRNA expression in specific brain regions.

Behavioral mechanisms underlying the maternal disruptive effect of serotonin 5-HT2A receptor activation in Sprague-Dawley rats.

Recent evidence indicates that acute activation of 5-HT2A receptors causes a disruption of maternal behavior in rats. However, the behavioral mechanisms underlying such a disruption are not known. We addressed this issue using two behavioral approaches targeting the maternal motivational and emotional processing systems. First, we used the pup-separation technique to increase maternal motivation to see whether pup separation is capable of reducing the maternal disruptive effect of TCB-2 (a high-affinity 5-HT2A agonist) treatment. On postpartum days 4 and 6, different groups of Sprague-Dawley dams were treated with the TCB-2 (5.0 mg/kg, sc) or vehicle and their maternal behaviors were tested after either a 4-h pup-separation or no-pup-separation condition. Although acute TCB-2 injection disrupted maternal behavior, this disruption was not attenuated by pup separation, even after we optimized the timing of separation to maximize its increase on maternal motivation. Acute TCB-2 also impaired the retrieval of food pellets, suggesting a general effect on motivated behaviors. Next, we used a pup preference test and found that dams treated with TCB-2 exhibited an even stronger preference to pups over a male conspecific than vehicle-treated dams, indicating an enhanced motivational and emotional processing of the rewarding property of pups. These findings suggest that TCB-2 has a disruptive effect on rat maternal behavior, and this disruption is not likely due to the drug's effect on mothers' motivational and emotional processing of the incentive salience of pups, although this motivational suppression account cannot be completely ruled out. Future work could explore other possible behavioral mechanisms, such as the drug's effect on executive function.

A behavioral mechanistic investigation of the role of 5-HT1A receptors in the mediation of rat maternal behavior.

Previous work suggests that 5-HT1A receptors play a special role in rodent maternal aggression, but not in other aspects of maternal care (e.g. pup retrieval and nest building). The present study re-assessed the basic effects of 5-HT1A activation or blockade on various maternal responses in postpartum female rats. We also examined the possible behavioral mechanisms underlying the maternal effects of 5-HT1A. Sprague-Dawley mother rats were injected with a 5-HT1A agonist 8-OH-DPAT (0.1, 0.5 or 1.0 mg/kg, sc), a 5-HT1A antagonist WAY-101405 (0.1, 0.5 or 1.0 mg/kg, sc) or 0.9% saline solution on postpartum days 3, 5, and 7. Maternal behavior was tested 30 min before, 30 min, 120 min, and 240 min after the injection. Acute and repeated 8-OH-DPAT treatment significantly disrupted pup retrieval, pup licking, nursing, and nest building in a dose-dependent fashion, whereas WAY-101405 had no effect at the tested doses. The 5-HT1A receptor specificity of 8-OH-DPAT's action was confirmed as its maternal disruption effect was reversed by pretreatment of WAY-100635 (a highly selective 5-HT1A receptor antagonist). Subsequent pup preference test found that 8-OH-DPAT did not decrease the pup preference over a novel object, thus no inhibition on maternal motivation or maternal affect. The pup separation test and pup retrieval on an elevated plus maze test also failed to find any motivational and motor impairment effect with 8-OH-DPAT. However, 8-OH-DPAT at the maternal disruptive dose did disrupt the prepulse inhibition (a measure of attentional function) of acoustic startle response and enhanced the basal startle response. These findings suggest that stimulation of 5-HT1A receptors by 8-OH-DPAT impairs maternal care by partially interfering with the attentional processing or basal anxiety. More work is needed to further delineate the psychological and neuronal mechanisms underlying the maternal disruptive effect of 5-HT1A receptor activation.

Activation of 5-HT2A receptor disrupts rat maternal behavior.

Serotonin 5-HT2A receptor is widely distributed in the central nervous system and plays an important role in sensorimotor function, emotion regulation, motivation, executive control, learning and memory. We investigated its role in rat maternal behavior, a naturalistic behavior encompassing many psychological functions that the 5-HT2A receptor is involved in. We first showed that activation of 5-HT2A receptor by TCB-2 (a highly selective 5-HT2A agonist, 1, 2.5 or 5.0 mg/kg) disrupted maternal behavior dose-dependently, and this effect was reduced by pretreatment with a 5-HT2A receptor antagonist MDL 100907, but exacerbated by pretreatment with a 5-HT2C receptor antagonist SB242084 and a 5-HT2C receptor agonist MK212, indicating that the maternal disruptive effect of 5-HT2A activation is receptor-specific and can be modulated by 5-HT2C receptor bidirectionally. We then microinjected TCB-2 into two brain regions important for the normal expression of maternal behavior: the medial prefrontal cortex (mPFC) and the medial preoptic area (mPOA) and found that only acute intra-mPFC infusion of TCB-2 suppressed pup retrieval, whereas intra-mPOA had no effect. Finally, using c-Fos immunohistochemistry, we identified that the ventral bed nucleus of stria terminalis (vBNST), the central amygdala (CeA), and the dorsal raphe (DR) were additionally involved in the maternal-disruptive effect of TCB-2. These findings suggest that the 5-HT2A receptor in the mPFC and other maternally related regions is required for the normal expression of maternal behavior through its intrinsic action or interactions with other receptors (e.g. 5-HT2C). Functional disruption of this neuroreceptor system might contribute to postpartum mental disorders (e.g. depression and psychosis) that impair the quality of maternal care.

Time-dependent sensitization of antipsychotic effect in adolescent male and female rats.

Many behavioral and biological effects of a psychoactive drug often undergo time-dependent change following even one single drug exposure. The present study examined whether one or two exposures of haloperidol, olanzapine or clozapine would also induce a time-dependent change in their behavioral effects in adolescent rats, and whether such a change vary between sexes. Adolescent Sprague-Dawley rats (<40days old) were first treated with one single injection of haloperidol (0.05 and 0.1mg/kg, sc), clozapine (10.0 and 20.0mg/kg, sc), 2 injections of olanzapine (1.0 and 2.0mg/kg, sc) or vehicle, and tested in a conditioned avoidance response (CAR) model or a PCP (3.20mg/kg, sc)-induced hyperlocomotion model to assess the drug's antipsychotic-like behavioral effects. One or three weeks later, rats were challenged with the drug and their avoidance responses and the PCP-induced hyperlocomotion were re-assessed. One-trial haloperidol and 2-trial olanzapine induced a sensitization, while 1-trial clozapine induced a tolerance effect. The 1-trial haloperidol sensitization was significantly higher at the 3-week time point than at 1-week point, especially in the females. Clozapine tolerance in the conditioned avoidance response model also exhibited the time-dependent increase in both sex groups. Olanzapine sensitization in the PCP model showed a time-dependent change in a sex-dependent fashion. Overall, the time-dependent antipsychotic sensitization and tolerance can be demonstrated in adolescent animals. Many pharmacological (e.g. specific drugs, drug doses), individual (e.g. male versus female) and environmental (e.g. specific behavioral models) factors play a role in the modulation of the strength of antipsychotic sensitization and tolerance.

Behavioral, pharmacological and neuroanatomical analysis of serotonin 2C receptor agonism on maternal behavior in rats.

As a highly motivated social behavior, maternal behavior in rats has been routinely used to study psychoactive drugs for clinical, neuroscience and pharmacological purposes. Recent evidence indicates that acute activation of serotonin 2C (5-HT2C) receptors causes a disruption of rat maternal behavior. The present study was designed to elucidate the behavioral, pharmacological mechanisms and neuroanatomical basis of this 5-HT2C effect. First, we replicated the finding that acute MK212 injection (2.0mg/kg, a highly selective 5-HT2C agonist) disrupts maternal behavior, especially on pup retrieval. Interestingly, this disruption was significantly attenuated by 4-h pup separation (a procedure putatively increased maternal motivation). MK212 also suppressed food retrieval, indicating that it has a general effect on motivated behaviors. Second, we showed that MK212 disrupts maternal behavior by specifically activating 5-HT2C receptor, as pretreatment with a 5-HT2C receptor antagonist SB242084 (0.6 and 1.0mg/kg) alleviated MK212-induced disruption on pup retrieval. Third, we microinjected MK212 into various brain regions implicated in the regulation of maternal behavior: nucleus accumbens shell (25, 75, 250ng/0.5µl/side), medial prefrontal cortex (25 and 250ng, 1, 2 and 5µg/0.5µl/side), and medial preoptic area (MPOA, 75ng, 1 and 5µg/0.5µl/side). Pup retrieval and other maternal responses were not affected by any of these manipulations. Finally, we used c-Fos immunohistochemistry to identify the central mechanisms of the acute and repeated MK212 effects on maternal behavior. Acute MK212 (2.0mg/kg) disrupted pup retrieval and concurrently decreased c-Fos expression in the ventral part of lateral septal nucleus (LSv), MPOA, dentate gyrus (DG) and dorsal raphe (DR), but increased it in the central amygdala (CeA). Five days of repeated MK212 (2.0mg/kg) treatment produced a persistent disruption of pup retrieval and only decreased c-Fos expression in the DR. These findings not only confirm a role of 5-HT2C receptor in rat maternal behavior, but also suggest that the coordinated 5-HT2C activity in various limbic (e.g., LSv, DG, CeA), hypothalamic regions (e.g., MPOA) and brainstem areas (e.g. DR), is likely involved in the mediation of important psychological processes (e.g. motor function, motivation) necessary for the normal expression of maternal behavior.

Bilobalide alleviates depression-like behavior and cognitive deficit induced by chronic unpredictable mild stress in mice.

Bilobalide (BB), a unique constituent of Ginkgo biloba, has powerful neuroprotection and stress-alleviating properties. However, whether BB exerts a positive effect on depression and cognitive deficit induced by chronic stress is not known. The present study was designed to investigate the influence of BB on depression and cognitive impairments induced by chronic unpredictable mild stress (CUMS) in mice. During daily exposure to stressors for 5 consecutive weeks, mice were administered BB at the doses of 0, 3, or 6 mg/kg/day intraperitoneally. We replicated the finding that CUMS induced depression-like behavior and cognitive deficits as the CUMS+vehicle (VEH) group showed a significant increase in immobility in the tail suspension test, a decrease in the discrimination index of the novel object recognition task, and increased latency to platform and decreased number of platform crossings in the Morris water maze compared with the control+VEH group. Chronic administration of BB effectively reversed these alterations. In addition, the CUMS+VEH group showed significantly higher levels of baseline serum corticosterone than those of the control+VEH group and BB dose-dependently inhibited this effect. Our results suggest that BB may be useful for inhibition of depression-like behavior and cognitive deficits, and this protective effect was possibly exerted partly through an action on the hypothalamic-pituitary-adrenal axis.

Natural variation in paternal behavior is associated with central estrogen receptor alpha and oxytocin levels.

In monogamous mammals paternal care plays an important role in the neural and behavioral development of offspring. However, the neuroendocrine mechanisms underlying paternal behavior remain poorly understood. Here, we investigate the association between natural variation in paternal responsiveness and central levels of oxytocin (OT) and estrogen receptor alpha (ERα). We used the frequency of licking and grooming behavior to distinguish low paternal responsiveness and high paternal responsiveness in virgin mandarin voles (Microtus mandarinus). Males that engaged in high paternal behavior had elevated levels of OT immunoreactive neurons in the paraventricular nuclei of the hypothalamus and supraoptic nuclei of the hypothalamus compared with males that displayed low paternal behavior. Likewise, males of high paternal responsiveness had more ERα immunoreactive neurons in the medial preoptic area, bed nucleus of the stria terminalis, arcuate nucleus of the hypothalamus and medial amygdaloid nucleus compared to low responsive males. The level of ERα immunoreactive neurons in the ventromedial hypothalamic nucleus was lower in highly paternal males compared to less paternal males. These results suggest that natural variation in paternal responsiveness may be directly related to variation in central OT and ERα.

Postpartum repeated separation from pups affects the behavior and neuroendocrine parameters of mandarin vole fathers.

Repeated separation from pups results in anxiety and depression-like behaviors in mothers. This level of attachment has also been established between fathers and pups in monogamous rodents. We hypothesized that brief and lengthy separation from their pups would affect emotion, social behavior and neuroendocrine parameters in socially monogamous male mandarin voles (Microtus mandarinus). The results indicate that brief pup separation (BPS) of 15 min/day significantly reduced the percentage of time spent in the central area, total distance and total transition in open field tests. BPS resulted in increased sniffing and self-grooming in fathers, but reduced attacking and climbing. Long pup separation (LPS) of 3h/day suppressed attacking, sniffing, no-social investigating and digging in fathers, but increased time in immobile in social interaction and forced swimming tests. LPS upregulated levels of central oxytocin (OT) and vasopressin (AVP), serum corticosterone (CORT); BPS increased central OT and serum corticosterone only. These findings show that BPS and LPS are critical stressors for fathers and alter anxiety and depression-like and social behaviors in monogamous mandarin voles. These changes in behaviors may be associated with alteration in OT, AVP and CORT.