Burying Behavior Research Articles

Novel aspect of oxytocin neurons mediating parental behavior and aversive burying behavior under the control of melanin-concentrating hormone neurons.

Parental behavior comprises a set of crucial actions essential for offspring survival. In this study, a double transgenic mouse model engineered to specifically express channelrhodopsin-2 (ChR2) in paraventricular hypothalamic nucleus (PVN)-oxytocin neurons and ablate lateral hypothalamic area (LHA)-melanin-concentrating hormone (MCH) neurons was used to determine the relationship between PVN-oxytocin neurons and LHA-MCH neurons associated with parental behavior. Optogenetic stimulation of ChR2-expressing PVN-oxytocin neurons induces typical parental behavior with intact LHA-MCH neurons. However, after the partial ablation of LHA-MCH neurons, even optogenetic stimulation of PVN-oxytocin neurons failed to induce parental behavior in virgin male mice, resulting in neglect rather than parental behavior. Furthermore, approximately half of the subjects exhibited burying behavior toward pups, suggesting that pups became aversive stimuli, and male mice actively performed burying behavior to avoid these aversive stimuli. This study emphasizes the novel aspect of oxytocin neurons that could result in neglect in the absence of LHA-MCH neurons regulation.

Maternal fluoxetine impairs synaptic transmission and plasticity in the medial prefrontal cortex and alters the structure and function of dorsal raphe nucleus neurons in offspring mice

Selective serotonin (5-HT) reuptake inhibitors (SSRIs) are commonly prescribed to women during pregnancy and breastfeeding despite posing a risk of adverse cognitive outcomes and affective disorders for the child. The consequences of SSRI-induced excess of 5-HT during development for the brain neuromodulatory 5-HT system remain largely unexplored. In this study, an SSRI - fluoxetine (FLX) - was administered to C57BL/6 J mouse dams during pregnancy and lactation to assess its effects on the offspring. We found that maternal FLX decreased field potentials, impaired long-term potentiation, facilitated long-term depression and tended to increase the density of 5-HTergic fibers in the medial prefrontal cortex (mPFC) of female but not male adolescent offspring. These effects were accompanied by deteriorated performance in the temporal order memory task and reduced sucrose preference with no change in marble burying behavior in FLX-exposed female offspring. We also found that maternal FLX reduced the axodendritic tree complexity of 5-HT dorsal raphe nucleus (DRN) neurons in female but not male offspring, with no changes in the excitability of DRN neurons of either sex. While no effects of maternal FLX on inhibitory postsynaptic currents (sIPSCs) in DRN neurons were found, we observed a significant influence of FLX exposure on kinetics of spontaneous excitatory postsynaptic currents (sEPSCs) in DRN neurons. Finally, we report that no changes in field potentials and synaptic plasticity were evident in the mPFC of the offspring after maternal exposure during pregnancy and lactation to a new antidepressant, vortioxetine. These findings show that in contrast to the mPFC, long-term consequences of maternal FLX exposure on the structure and function of DRN 5-HT neurons are mild and suggest a sex-dependent, distinct sensitivity of cortical and brainstem neurons to FLX exposure in early life. Vortioxetine appears to exert fewer side effects with regards to the mPFC when compared with FLX.

Chronic caffeine decreases anxiety-like behavior in the marble burying task in adolescent rats.

Exposure to chronic caffeine during adolescence has been shown to produce decreased anxiety-like behaviors in rats as well as decreased immobility in the forced swim test (FST) suggesting an antidepressant-like effect. The effects of chronic caffeine on anxiety, however, have been found to be test-dependent and sexually dimorphic. In addition, decreased immobility in the FST has been argued to reflect a shift toward active coping behavior as opposed to an antidepressant-like effect. In order to further characterize the effects of adolescent caffeine exposure, the present experiment assessed the effects of caffeine on marble burying behavior in a two-zone marble burying task. There was no difference in the amount of time rats spent in the two zones failing to support a shift in coping strategy. Caffeine-exposed rats spent less time engaged in marble burying activity and buried slightly fewer marbles, suggesting an anxiolytic effect of caffeine. In addition, caffeine treated rats spent less time engaged in nondirected burying and slightly more time actively engaging with the marbles; however, these effects appeared to be sexually dimorphic as they were driven by larger changes in the females. Overall, these results support an anxiolytic effect of adolescent caffeine, with female behavior appearing to be more affected by caffeine than males.

Behavioral and Molecular Characterization of Prenatal Stress Effects on the C57BL/6J Genetic Background for the Study of Autism Spectrum Disorder.

Stress-inducing events during pregnancy are associated with aberrant neurodevelopment resulting in adverse psychiatric outcomes, including autism spectrum disorder (ASD). While numerous preclinical models for the study of ASD are frequently generated using C57BL/6J mice, few studies have investigated the effects of prenatal stress on this genetic background. In the current manuscript, we stressed C57BL/6 dams during gestation and examined numerous behavioral and molecular endophenotypes in the adult male and female offspring to characterize the resultant phenotype as compared with offspring born from nonstressed (NS) dams. Adult mice born from prenatal restraint stressed (PRS) dams demonstrated reduced sociability and reciprocal social interaction along with increased marble burying behaviors relative to mice born from nonstressed control dams. Differential expression of genes related to excitatory and inhibitory neurotransmission was evaluated in the medial prefrontal cortex, amygdala, hippocampus, nucleus accumbens and caudate putamen via qRT-PCR. The male PRS mouse behavioral phenotype coincided with aberrant expression of glutamate and GABA marker genes (e.g., Grin1, Grin2b, Gls, Gat1, Reln) in neural substrates of social behavior. Rescue of the male PRS sociability deficit by a known antipsychotic with epigenetic properties (i.e., clozapine (5 mg/kg) + 18 hr washout) indicated possible epigenetic regulation of genes that govern sociability. Clozapine treatment increased the expression levels of genes involved in DNA methylation, histone methylation, and histone acetylation in the nucleus accumbens. Identification of etiology-specific mechanisms underlying clinically relevant behavioral phenotypes may ultimately provide novel therapeutic interventions for the treatment of psychiatric disorders including ASD.

Communal nesting differentially attenuates the impact of pre-weaning social isolation on behavior in male and female rats during adolescence and adulthood.

Early social isolation (ESI) disrupts neurodevelopmental processes, potentially leading to long-lasting emotional and cognitive changes in adulthood. Communal nesting (CN), i.e., the sharing of parental responsibilities between multiple individuals in a nest, creates a socially enriching environment known to impact social and anxiety-related behaviors. This study examines the effects of (i) the CN condition and of (ii) ESI during the 3rd week of life (i.e., pre-weaning ESI) on motor, cognitive, and emotional domains during adolescence and adulthood in male and female rats reared in the two different housing conditions, as well as (iii) the potential of CN to mitigate the impact of ESI on offspring. We found that in a spontaneous locomotor activity test, females exhibited higher activity levels compared to males. In female groups, adolescents reared in standard housing (SH) condition spent less time in the center of the arena, suggestive of increased anxiety levels, while the CN condition increased the time spent in the center during adolescence, but not adulthood, independently from ESI. The prepulse inhibition (PPI) test showed a reduced PPI in ESI adolescent animals of both sexes and in adult males (but not in adult females), with CN restoring PPI in males, but not in adolescent females. Further, in the marble burying test SH-ESI adolescent males exhibited higher marble burying behavior than all other groups, suggestive of obsessive-compulsive traits. CN completely reversed this stress-induced effect. Interestingly, ESI and CN did not have a significant impact on burying behavior in adult animals of both sexes. Overall, our findings (i) assess the effects of ESI on locomotion, sensorimotor gating, and compulsive-like behaviors, (ii) reveal distinct vulnerabilities of males and females within these domains, and (iii) show how early-life social enrichment may successfully counteract some of the behavioral alterations induced by early-life social stress in a sex-dependent manner. This study strengthens the notion that social experiences during early-life can shape emotional and cognitive outcomes in adulthood, and points to the importance of social enrichment interventions for mitigating the negative effects of early social stress on neurodevelopment.

Gestational paracetamol exposure induces core behaviors of neurodevelopmental disorders in infant rats and modifies response to a cannabinoid agonist in females

Paracetamol (PAR) is an over-the-counter analgesic/antipyretic used during pregnancy worldwide. Epidemiological studies have been associating gestational PAR exposure with neurobehavioral alterations in the progeny resembling autism spectrum disorders and attention-deficit hyperactivity disorder symptoms. The endocannabinoid (eCB) dysfunction was previously hypothesized as one of the modes of action by which PAR may harm the developing nervous system. We aimed to evaluate possible effects of gestational exposure to PAR on male and female rat's offspring behavior and if an acute injection of WIN 55,212–2 (WIN, 0.3 mg/kg), a non-specific cannabinoid agonist, prior to behavioral tests, would induce different effects in PAR exposed and non-exposed animals. Pregnant Wistar rats were gavaged with PAR (350 mg/kg/day) or water from gestational day 6 until delivery. Nest-seeking, open field, apomorphine-induced stereotypy, marble burying and three-chamber tests were conducted in 10-, 24-, 25- or 30-days-old rats, respectively. PAR exposure resulted in increased apomorphine-induced stereotyped behavior and time spent in the central area of the open field in exposed female pups. Additionally, it induced hyperactivity in the open field and increased marble burying behavior in both male and female pups. WIN injection modified the behavioral response only in the nest seeking test, and opposite effects were observed in control and PAR-exposed neonate females. Reported alterations are relevant for the neurodevelopmental disorders that have been associated with maternal PAR exposure and suggest that eCB dysfunction may play a role in the action by which PAR may harm the developing brain.

Early prenatal and late prenatal escitalopram exposure differentially impacts behavioral flexibility and anxiety-related behaviors in adulthood

Selective serotonin reuptake inhibitors (SSRIs) are medications commonly used by pregnant women. While SSRIs have been considered safe during pregnancy, there is limited understanding of the long-term consequences of prenatal SSRI exposure on adult behavioral processes. Recent human studies have demonstrated prenatal exposure to some SSRIs in humans may increase susceptibility to autism spectrum disorder (ASD) and developmental delays. While escitalopram is one of the most effective antidepressants, it is also one of the newer available SSRIs, resulting in less information on its safety profile during pregnancy. The current study administered escitalopram (0 or 10 mg/kg, s.c.) to nulliparous female Long-Evans rats for the first (G1–10) or last half (G11–20) of the gestational period. Young adult male and female offspring were subsequently tested on a battery of behavioral tasks consisting of probabilistic reversal learning task, open field conflict, marble burying and social approach tasks. Results demonstrate that escitalopram exposure during the first half of pregnancy resulted in reduced anxiety-like behavior (disinhibition) on the modified open field and enhanced flexibility on the probabilistic reversal learning task. Exposure to escitalopram later in pregnancy resulted in an increase in marble burying behavior, but no differences were found with the other measures. These results suggest that exposure to escitalopram during the first half of prenatal development can have long lasting changes on adult behavior demonstrating better behavioral flexibility and lower anxiety-like behavior compared to non-exposed controls.

Loss of CAMK2G affects intrinsic and motor behavior but has minimal impact on cognitive behavior.

The gamma subunit of calcium/calmodulin-dependent protein kinase 2 (CAMK2G) is expressed throughout the brain and is associated with neurodevelopmental disorders. Research on the role of CAMK2G is limited and attributes different functions to specific cell types. To further expand on the role of CAMK2G in brain functioning, we performed extensive phenotypic characterization of a Camk2g knockout mouse. We found different CAMK2G isoforms that show a distinct spatial expression pattern in the brain. Additionally, based on our behavioral characterization, we conclude that CAMK2G plays a minor role in hippocampus-dependent learning and synaptic plasticity. Rather, we show that CAMK2G is required for motor function and that the loss of CAMK2G results in impaired nest-building and marble burying behavior, which are innate behaviors that are associated with impaired neurodevelopment. Taken together, our results provide evidence for a unique function of this specific CAMK2 isozyme in the brain and further support the role of CAMK2G in neurodevelopment.

Lead (Pb) exposure exacerbates behavioral and immune abnormalities by upregulating Th17 and NF-κB-related signaling in BTBR T+ Itpr3tf/J autistic mouse model

Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder that are characterized by abnormal social interaction impairments in communication and repetitive and restricted activities or interests. Even though the exact etiology of ASD remains unknown. Lead (Pb) is a toxin known to harm many organs in the body, it is one of the most ubiquitous metal exposures which is associated with neurological deficits. Previous studies have shown that the exposure to Pb may play a role in ASD. BTBR T+ Itpr3tf/J (BTBR) mouse model is commonly used as a preclinical model for ASD. In this study, we investigated the effects of Pb exposure on sociability, self-grooming and marble burying behaviors tests in BTBR mice. We further examined the effects of Pb on IL-17A- RORγT-, STAT3-, NF-κB p65-, iNOS-, TLR-2- and TLR-4-producing CD45+ cells in spleen using flow cytometry. We also explored the effects of Pb on IL-17A, RORγT, STAT3, NF-κB p65, and TLR-2 mRNA expression in the brain tissue using RT-PCR analysis. Our results demonstrated that Pb exposure substantially increased repetitive behavior, marble burying and decrease social interactions in BTBR mice. In addition, in spleen cells, Pb exposure exaggerated CD45+IL-17A+, CD45+RORγT+, CD45+STAT3+, CD45+NF-κB p65+, CD45+iNOS+, CD45+TLR-2+ and CD45+TLR-4+ in BTBR mice. We also found that Pb significantly increased IL-17A, RORγT, STAT3, NF-κB p65, and TLR-2 mRNA in the brain tissue. Therefore, Pb exposure exacerbates behavioral and neuroimmune function in BTBR mice, suggesting a potentially strong role for Pb in ASD.

A Novel Automated Approach for Improving Standardization of the Marble Burying Test Enables Quantification of Burying Bouts and Activity Characteristics.

The marble burying test is a commonly used paradigm to describe phenotypes in mouse models of neurodevelopmental and psychiatric disorders. The current methodological approach relies predominantly on reporting the number of buried marbles at the end of the test. By measuring the proxy of the behavior (buried marbles), many important characteristics regarding the temporal aspect of this assay are lost. Here, we introduce a novel, automated method to quantify mouse behavior during the marble burying test with the focus on the burying bouts and movement dynamics. Using open-source software packages, we trained a supervised machine learning algorithm (the “classifier”) to distinguish burying behavior in freely moving mice. In order to confirm the classifier’s accuracy and characterize burying events in high detail, we performed the marble burying test in three mouse models: Ube3am-/p+ [Angelman syndrome (AS) model], Shank2−/− (autism model), and Sapap3−/− [obsessive-compulsive disorder (OCD) model] mice. The classifier scored burying behavior accurately and consistent with the previously reported phenotype of the Ube3am-/p+ mice, which showed decreased levels of burying compared with controls. Shank2−/− mice showed a similar pattern of decreased burying behavior, which was not found in Sapap3−/− mice. Tracking mouse behavior throughout the test revealed hypoactivity in Ube3am-/p+ and hyperactivity in the Shank2−/− mice, indicating that mouse activity is unrelated to burying behavior. Reducing activity with midazolam in Shank2−/− mice did not alter the burying behavior. Together, we demonstrate that our classifier is an accurate method for the analysis of the marble burying test, providing more information than currently used methods.

Antidepressant and anxiolytic activities of Cochlospermum religiosum leaf extract, synergism with antidepressants, and molecular docking studies

The leaves of Cochlospermum religiosum were investigated for the antidepressant and anxiolytic activities in mice using behavioural models like spontaneous locomotor activity, forced swim test, tail suspension test, elevated plus maze and marble burying behaviour. The mechanism was studied using Reserpine-induced hypothermia (RIH) model and in silico molecular docking. The leaf extract exhibited significant antidepressant and anxiolytic effects ( P <0.05 for 50 mg/kgb.w.,p.o./ P <0.01 for 100 mg/kgb.w., p.o.) in mice without an impact on baseline locomotor activity. The result from Reserpine-induced hypothermia rat model revealed that the leaf extract (50 mg/kgb.w., p.o.) significantly antagonized the effect ( P <0.05) of Reserpine. Furthermore, synergistic effect was evaluated by coadministration of the leaf extracts with fluoxetine (10 mg/kg, i.p.) and imipramine (10 mg/kg, i.p.) at sub-therapeutic dose levels. Synergistic effect of the leaf extract was significant ( P <0.05) for both antidepressant and anxiolytic activities as compared to therapeutic doses of extract, imipramine, and fluoxetine. The molecular docking studies for the chemical constituents of the leaves on 5HT1B, 5HT2A, β1 and β2 crystal structures revealed that pentagalloyl glucose showed typical binding with higher affinity on 5HT1B (-10.79) and 5HT2A(-10.33) than fluoxetine and imipramine. Cynarine docked on β-2 receptor with score of -13.582 at binding site of timolol, and similarly, it binds with 5HT1B and 5HT2A at serotonin binding site.

Genetic disruption of Grm5 causes complex alterations in motor activity, anxiety and social behaviors

Autism is a neurodevelopmental disorder characterized by impaired social interactions and restricted and repetitive behaviors. Although group 1 metabotropic glutamate receptors (mGluRs), and in particular mGluR5, have been extensively proposed as potential targets for intervention in autism and other neurodevelopmental disorders, there has not been a comprehensive analysis of the effect of mGluR5 loss on behaviors typically assessed in autism mouse models thought to be correlates of behavioral symptoms of human disorders. Here we present a behavioral characterization of mice with complete or partial loss of mGluR5 (homozygous or heterozygous null mutations in Grm5 gene). We tested several autism related behaviors including social interaction, repetitive grooming, digging and locomotor behaviors. We found that digging and marble burying behaviors were almost completely abolished in mGluR5 ko mice, although self-grooming was not altered. Social interaction was impaired in ko but not in heterozygote (het) mice. In tests of locomotor activity and anxiety related behaviors, mGluR5 ko mice exhibited hyperactivity and reduced anxiety in the open field test but unexpectedly, showed hypoactivity in the elevated zero-maze test. There was no impairment in motor learning in the accelerating rotarod in both ko and het mutant. Together these results provide support for the importance of mGluR5 in motor and social behaviors that are specifically affected in autism disorders.

Prolonged Alteration of Neonate Traits Following Maternal Exposure to Fishing-Capture Stress During Late Pregnancy in a Chondrichthyan Species

For animals discarded after fishing capture (unwanted bycatch), the effects of fishing-capture stress can extend beyond immediate or delayed death, causing long-term, sub-lethal effects such as injuries and physiological, behavioral, immune, energetic, and reproductive consequences. Given the importance of successful reproduction for population recruitment, investigating reproductive impairment is essential, even more so for animals with low reproductive rates such as chondrichthyans. However, data for these species are lacking, even though the poor conservation status of many chondrichthyan populations and the threats from overexploitation and discard require a better understanding of fishing-capture stress consequences. In this study, we investigated the reproductive consequences of trawling and air exposure stress when experienced by southern fiddler rays (Trygonorrhina dumerilii) during late pregnancy, with a focus on neonatal traits. Compared with neonates from unstressed mothers, neonates born from mothers subjected to capture simulation had significantly lower body mass and yolk sac volume at birth, showed a granulocyte-to-lymphocyte ratio indicative of a stressed condition, reduced growth, altered burying behavior, reduced boldness, and swam for shorter distances after a simulated predator attack. Smaller size and lower growth rate might expose neonates to a higher rate of predation, and similarly, the altered burying and swimming behaviors may reduce their ability to escape from predators. Decreased boldness could impact neonate survival by reducing their ability to compete and obtain food and resources. Further investigations are needed, but these initial results suggest that capture stress suffered by pregnant rays may alter traits and survival of their offspring with consequences for recruitment and population abundance.

Repeated allergic asthma in early versus late pregnancy differentially impacts offspring brain and behavior development

BackgroundStress during pregnancy and maternal inflammation are two common prenatal factors that impact offspring development. Asthma is the leading chronic condition complicating pregnancy and a common source of prenatal stress and inflammation. ObjectiveThe goal of this study was to characterize the developmental impact of repeated allergic asthma inflammation during pregnancy on offspring behavioral outcomes and brain inflammation. MethodsPregnant female C57BL/6 mice were sensitized with ovalbumin (OVA) or PBS vehicle control and then randomly assigned to receive daily aerosol exposures to the same OVA or PBS treatment during early, gestational days (GD) 2-GD9, or late pregnancy, GD10-GD17. Maternal sera were collected after the first and last aerosol induction regimen and measured for concentrations of corticosterone, anti-OVA IgE, and cytokine profiles. Juvenile male and female offspring were assessed for locomotor and social behaviors and later as adults assessed for anxiety-like, and marble burying behaviors using a series of behavioral tasks. Offspring brains were evaluated for region-specific differences in cytokine concentrations. ResultsIn early gestation, both PBS and OVA-exposed dams had similar serum corticosterone concentration at the start (GD2) and end (GD9) of daily aerosol inductions. Only OVA-exposed dams showed elevations in cytokines that imply a diverse and robust T helper cell-mediated immune response. Male offspring of early OVA-exposed dams showed decreases in open-arm exploration in the elevated plus maze and increased marble burying without concomitant changes in locomotor activity or social interactions. These behavioral deficits in early OVA-exposed male offspring were associated with lower concentrations of G-CSF, IL-4, IL-7, IFNγ, and TNFα in the hypothalamus. In late gestation, both PBS and OVA-exposed dams had increased corticosterone levels at the end of daily aerosol inductions (GD17) compared to at the start of inductions (GD10). Male offspring from both PBS and OVA-exposed dams in late gestation showed similar decreases in open arm exploration on the elevated plus maze compared to OVA male offspring exposed in early gestation. No behavioral differences were present in female offspring across all treatment groups. However, females of dams exposed to OVA during early gestation displayed similar reductions as males in hypothalamic G-CSF, IL-7, IL-4, and IFNγ. DiscussionThe inflammatory responses from maternal allergic asthma in early gestation and resulting increases in anxiety-like behavior in males support a link between the timing of prenatal insults and sex-specific developmental outcomes. Moreover, the heightened stress responses in late gestation and concomitant dampened inflammatory response to allergic asthma suggest that interactions between the maternal immune and stress-response systems shape early life fetal programming.

Ethologically based behavioural and neurochemical characterisation of mice with isoform-specific loss of dysbindin-1A in the context of schizophrenia

Dysbindin-1 is implicated in several aspects of schizophrenia, including cognition and both glutamatergic and dopaminergic neurotransmission. Targeted knockout of dysbindin-1A (Dys-1A KO), the most abundant and widely expressed isoform in the brain, is associated with deficits in delay/interference-dependent working memory. Using an ethologically based approach, the following behavioural phenotypes were examined in Dys-1A KO mice: exploratory activity, social interaction, anxiety and problem-solving ability. Levels of monoamines and their metabolites were measured in striatum, hippocampus and prefrontal cortex using high-performance liquid chromatography with electrochemical detection. The ethogram of initial exploration in Dys-1A KO mice was characterised by increased rearing from a seated position; over subsequent habituation, stillness was decreased relative to wildtype. In a test of dyadic social interaction with an unfamiliar conspecific in a novel environment, female KO mice showed an increase in investigative social behaviours. Marble burying behaviour was unchanged. Using the puzzle-box test to measure general problem-solving performance, no effect of genotype was observed across nine trials of increasing complexity. Dys-1A KO demonstrated lower levels of 5-HT in ratio to its metabolite 5-HIAA in the prefrontal cortex. These studies elaborate the behavioural and neurochemical phenotype of Dys-1A KO mice, revealing subtle genotype-related differences in non-social and social exploratory behaviours and habituation of exploration in a novel environment, as well as changes in 5-HT activity in brain areas related to schizophrenia.

Behavioral assessment of rimonabant under acute and chronic conditions

Cannabinoid subtype 1 receptor (CB1R) antagonists were originally developed as anti-obesity agents. Unfortunately, SR1417116A (rimonabant), the first marketed inverse agonist of CB1R, produced CNS-related adverse effects including depression and suicidal ideation, and thus it was withdrawn from the market. These effects of rimonabant became evident in patients following chronic dosing. Standard preclinical toxicity studies failed to detect these adverse effects. The goal of these studies was to perform an integrated battery of behavioral assays to better understand the behavioral effects of rimonabant following both acute and chronic administration. In the present study, acute dosing with rimonabant in rats significantly decreased food consumption; decreased measures of locomotor activity; increased scratching, grooming and wet-dog shakes; and increased defecation. Subsequently, animals were tested using a chronic dosing regimen but prior to drug administration for that day. The highest dose of rimonabant tested significantly decreased marble burying behavior, presumably anxiolysis. There were also significant effects in social interaction after chronic dosing. Our results did not reveal significant rimonabant-induced anxiogenic behaviors. Future studies to characterize behavioral screens for anxiogenic effects of CB1 antagonists in rodents should further explore social interaction paradigms and potential comorbid factors of rimonabant dosing such as sex, age, and obesity.

5-aminoisoquinolinone attenuates social behavior deficits and immune abnormalities in the BTBR T+ Itpr3tf/J mouse model for autism

Autism spectrum disorder (ASD) is diagnosed by core symptoms including impaired social communication and the presence of repetitive and stereotypical behaviors. There is also evidence for immune dysfunction in individuals with ASD, but it is a disease that is still insufficiently controlled by current treatment strategies. The use of 5-aminoisoquinolinone (5-AIQ) ameliorates several immune-mediated symptoms including rheumatoid arthritis and colitis, and has neuroprotective properties; however, its role in ASD is not yet characterized. In this study, we investigated the effect of 5-AIQ on sociability tests, self-grooming, marble burying, and locomotor activities in BTBR T+ Itpr3tf/J (BTBR) mice, which serve as an ASD animal model. We further investigated the possible molecular mechanism of 5-AIQ administration on CXCR4-, CXCR6-, IFN-γ-, IL-22-, NOS2-, STAT1-, T-bet-, and RORγT-producing CD3+ T cells isolated from the spleens of treated mice. We also explored its effects on mRNA expression in brain tissue. Our results showed that in BTBR mice, 5-AIQ treatment significantly prevented self-grooming and marble burying behaviors and enhanced social interactions without any adverse effects on locomotor activity/anxiety level. Additionally, 5-AIQ treatment substantially decreased CXCR4-, CXCR6-, IFN-γ-, IL-22-, NOS2-, STAT1-, T-bet-, and RORγT-producing CD3+ T cells in the spleen. Furthermore, 5-AIQ treatment decreased CXCR4, IFN-γ, IL-22, STAT1, and RORγT mRNA expression levels in brain tissue. Our findings demonstrated that 5-AIQ improved behavioral and immune abnormalities associated with ASD, which supports the hypothesis that 5-AIQ has important therapeutic potential for the treatment of behavioral and neuroimmune dysfunctions in ASD.

Adolescent behavioral abnormalities in a Scn1a+/− mouse model of Dravet syndrome

Dravet syndrome is an intractable pediatric epilepsy associated with SCN1A mutations. In addition to having a large seizure burden and a reduced lifespan, patients with Dravet syndrome also exhibit delays in reaching normal developmental milestones in attentional, emotional, and cognitive function. These developmental delays manifest in autistic-like social withdrawal and compulsive behavior. Additionally, cognitive impairments including deficits in sensorimotor processing and memory function are present. Several mouse models utilizing heterozygous deletion of Scn1a (Scn1a+/− mice) have been generated that recapitulate many aspects of Dravet syndrome. Studies in these mouse models of Dravet syndrome have characterized behavioral phenotypes in adult mice. In the present study, we characterized the behavioral phenotype of Scn1a+/− mice generated by targeted deletion of Scn1a exon 1 (Scn1atm1Kea) during adolescence. Identifying behavioral deficits in adolescent mice would more closely model the early onset of attentional, emotional, and cognitive delays observed in patients with Dravet syndrome. The behaviors of adolescent Scn1a+/− and wildtype (WT) mice were compared across several behavioral domains. We assessed motor function (open-field test), sociability and social recognition memory (three-chambered social preference and social interaction tests), memory function (novel object recognition, Barnes maze, fear conditioning paradigm), anxiety-related behavior (elevated plus maze and open-field thigmotaxis), startle reflex and sensorimotor gating (prepulse inhibition of startle (PPI) tests), and repetitive compulsive behavior (marble burying test). Adolescent Scn1a+/− mice exhibited normal locomotor activity, marble burying behavior, sociability, and sensorimotor gating. However, adolescent Scn1a+/− mice displayed increased anxiety-related thigmotactic behavior, atypical fear expression, blunted acoustic startle responses, and impaired social recognition and spatial memory. Our results show that Scn1a+/− mice display various behavioral impairments during adolescence, which provides a foundation for testing early intervention therapies targeting developmental delays modeled in Dravet syndrome mice.

Growth and morphometric relationships of the bean clam Donax punctatostriatus Hanley, 1843 in a sandy beach of southern Sinaloa, Mexico

There have been no published studies of the genus Donax in the eastern tropical Pacific. This work describes the morphometric relationships, growth and mortality of the bean clam Donax punctatostriatus Hanley, 1843 in the sandy beach of Isla de la Piedra, south of Mazatlan Bay, Mexico. Direct collections by hand were performed during 20 monthly sample periods (November 2008 to June 2010) in the intertidal zone of the beach. A total of 2,324 clams of different sizes were removed from the sand, then measured and weighed in the laboratory. The length range of the shells was 2.78-25.64 mm (mean = 12.61 ± 4.04 mm). The length-weight relationship of the total sample indicated isometric growth ( a = 0.0002 g; b = 3.0 g mm -1 , R 2 = 0.97); there was positive allometric growth in the recruits (<6.99 mm) ( b = 3.4) and in juveniles ( b = 3.2); in adults there was negative allometric growth ( b = 2.6). Negative allometry of the length/width (log Wd = -0.239 + 0.922 log L) and height/width (log Wd = -0.054 + 0.900 log H) ratio of adults is consistent with a more compressed form of their shell, which assists rapid burying behavior in the sand. The maximum-recorded size of an empty shell (39 mm) was used to set the value of L ∞ and to estimate K with the Shepherd (SLCA) method. The average growth rate during the life cycle was 0.43 mm yr -1 . Values of L ∞ between 29.16 and 34.22 mm were estimated with the Powell-Wetherall method using different class intervals. The mortality coefficient estimated with various methods was variable (0.84-1.15 yr -1 ). The growth of the clam is rapid and the mortality high, probably because of the characteristics of the habitat, in a subtropical region with high hydrodynamics and sediment transport.

Parental morphine exposure affects repetitive grooming actions and marble burying behavior in the offspring: Potential relevance for obsessive-compulsive like behavior

Family, adoption and twin studies have highlighted the significant role of heritable influences on individual differences in opioid addiction. Meanwhile, obsessive-compulsive disorder (OCD) is a disorder wherein the individual experiences recurring thoughts that cause irrational fears and anxiety. In the present study, adult male and female rats received morphine solution for 21 days and were drug-free for 10 days. Offspring were used in 4 distinct groups; (1) paternal morphine-exposed, (2) maternal morphine-exposed, (3) maternal and paternal morphine-exposed, and (4) drug-naïve subjects. We assessed the grooming behavior and marble burying test as an indicator of obsessive-compulsive behavior. To clarify the mechanisms underlying these changes, the mRNA level of BDNF, the phosphorylation level of CREB and the protein level of D2 dopamine receptor (DR) were evaluated in the nucleus accumbens (NAc). The grooming behavior in male offspring with one or two morphine-abstinent parent(s) increased compared with the offspring of drug naïve rats. In addition, the offspring of morphine-exposed parents buried more marbles when compared with the offspring of drug-naïve parents. Also, the BDNF mRNA was down-regulated in the NAC. However, the levels of phospho-CREB and D2 DR were elevated. Previous studies indicated that exposure to morphine in adulthood enhances the risk of psychiatric disorders in offspring. OCD is one the comorbid disorders with addiction and increases the risk of substance abuse disorder in patients. In this survey, we found that morphine exposure in parents before gestation can encourage obsessive-compulsive behavior in offspring.