Publications (16)66.62 Total impact
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Article: Low Home Cage Social Behaviors in BTBR T+tf/J Mice during Juvenile Development.
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ABSTRACT: BTBR T+tf/J (BTBR) is a genetically homogenous inbred strain of mice that displays abnormal social behaviors, deficits in vocalizations, and high levels of repetitive behaviors, relevant to the three diagnostic symptoms of autism spectrum disorder, leading to the use of this strain as a mouse model of autism. Comprehensive observations of BTBR social behaviors within the home cage during early stages of development have not been conducted. Here we evaluate the home cage behaviors of BTBR in two laboratory environments (NIMH, Bethesda, Maryland versus UC Davis, Davis, California), starting from the day of weaning and continuing into adulthood. Extensive ethogram parameters were scored for BTBR in home cages that contained four BTBR conspecifics, versus home cages that contained four C57BL/6J (B6) conspecifics. BTBR were considerably less interactive than B6 in the home cage at both sites, as measured during the early dark stage of their circadian cycle. A novel home cage behavioral measure, frequency of long interactions, was found to be more frequent and of longer duration in B6 versus BTBR home cages across experimental sites. Significant strain differences in the occurrence of investigative and affiliative behaviors were also seen, however these findings were not fully consistent across the two testing sites. At the end of the 30-day home cage observation period, each seven-week old subject mouse was tested in the three-chambered social approach task. BTBR displayed lack of sociability and B6 displayed significant sociability, consistent with previous reports. Our findings reveal that BTBR engaged in lower levels of some components of spontaneous conspecific social interactions in the home cage environment throughout juvenile development, consistent with their deficits in juvenile and adult sociability as measured in specialized social tasks.Physiology & Behavior 03/2013; · 2.87 Impact Factor -
Article: Absence of deficits in social behaviors and ultrasonic vocalizations in later generations of mice lacking neuroligin4.
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ABSTRACT: Mutations in NLGN4X have been identified in individuals with autism spectrum disorders and other neurodevelopmental disorders. A previous study reported that adult male mice lacking neuroligin4 (Nlgn4) displayed social approach deficits in the three-chambered test, altered aggressive behaviors and reduced ultrasonic vocalizations. To replicate and extend these findings, independent comprehensive analyses of autism-relevant behavioral phenotypes were conducted in later generations of the same line of Nlgn4 mutant mice at the National Institute of Mental Health in Bethesda, MD, USA and at the Institut Pasteur in Paris, France. Adult social approach was normal in all three genotypes of Nlgn4 mice tested at both sites. Reciprocal social interactions in juveniles were similarly normal across genotypes. No genotype differences were detected in ultrasonic vocalizations in pups separated from the nest or in adults during reciprocal social interactions. Anxiety-like behaviors, self-grooming, rotarod and open field exploration did not differ across genotypes, and measures of developmental milestones and general health were normal. Our findings indicate an absence of autism-relevant behavioral phenotypes in subsequent generations of Nlgn4 mice tested at two locations. Testing environment and methods differed from the original study in some aspects, although the presence of normal sociability was seen in all genotypes when methods taken from Jamain et al. (2008) were used. The divergent results obtained from this study indicate that phenotypes may not be replicable across breeding generations, and highlight the significant roles of environmental, generational and/or procedural factors on behavioral phenotypes.Genes Brain and Behavior 09/2012; · 3.48 Impact Factor -
Article: Reduced excitatory neurotransmission and mild autism-relevant phenotypes in adolescent Shank3 null mutant mice.
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ABSTRACT: Mutations in the synaptic scaffolding protein gene SHANK3 are strongly implicated in autism and Phelan-McDermid 22q13 deletion syndrome. The precise location of the mutation within the Shank3 gene is key to its phenotypic outcomes. Here, we report the physiological and behavioral consequences of null and heterozygous mutations in the ankyrin repeat domain in Shank3 mice. Both homozygous and heterozygous mice showed reduced glutamatergic transmission and long-term potentiation in the hippocampus with more severe deficits detected in the homozygous mice. Three independent cohorts were evaluated for magnitude and replicability of behavioral endophenotypes relevant to autism and Phelan-McDermid syndrome. Mild social impairments were detected, primarily in juveniles during reciprocal interactions, while all genotypes displayed normal adult sociability on the three-chambered task. Impaired novel object recognition and rotarod performance were consistent across cohorts of null mutants. Repetitive self-grooming, reduced ultrasonic vocalizations, and deficits in reversal of water maze learning were detected only in some cohorts, emphasizing the importance of replication analyses. These results demonstrate the exquisite specificity of deletions in discrete domains within the Shank3 gene in determining severity of symptoms.Journal of Neuroscience 05/2012; 32(19):6525-41. · 7.11 Impact Factor -
Article: Low sociability in BTBR T+tf/J mice is independent of partner strain.
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ABSTRACT: Inbred mouse strains differ greatly in social behaviors, making them a valuable resource to study genetic and non-genetic mechanisms underlying social deficits relevant to autism spectrum disorders. A hallmark symptom of autism is a lack of ability to understand other people's thoughts and intentions, which leads to impairments in adjusting behaviors in response to ever-changing social situations in daily life. We compared the ability of BTBR T+tf/J (BTBR), a strain with low sociability, and C57BL/6J (B6), a strain with high sociability, for their abilities to modulate responses to social cues from different partners in the reciprocal social interaction test. Results indicate that BTBR exhibited low sociability toward different partners and displayed minimal ability to modify behaviors toward different partners. In contrast, B6 showed high sociability toward different partners and was able to modify social behaviors toward different partners. Consistent results were found in two independent cohorts of different ages, and in both sexes. In the three-chambered test, high sociability in B6 and low sociability in BTBR were independent of strain of the novel mouse. Since social deficits in BTBR could potentially be caused by physical disabilities in detecting social olfactory cues, or in cognitive abilities, we tested BTBR and B6 mice on measures of olfaction and cognition. BTBR mice displayed more sniffing of social odors emitted by soiled bedding than of an odorless novel object, but failed to show a preference for a live novel mouse over a novel object. On olfactory habituation/dishabituation to a sequence of odors, BTBR displayed discrimination abilities across three non-social and two social odors. However, as compared to B6, BTBR displayed less sniff time for both non-social and social odors, and no significant dishabituation between cage odors from two different novel mouse strains, findings that will be important to investigate further. BTBR was generally normal in spatial acquisition on the Morris water maze test, but showed deficits in reversal learning. Time spent freezing on contextual and cued fear conditioning was lower in BTBR than in B6. Our findings suggest that BTBR has poor abilities to modulate its responses to different social partners, which may be analogous to social cognition deficits in autism, adding to the value of this strain as a mouse model of autism.Physiology & Behavior 01/2012; · 2.87 Impact Factor -
Article: Mainstreaming mice.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 01/2012; 37(1):300-1. · 6.99 Impact Factor -
Article: Automated three-chambered social approach task for mice.
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ABSTRACT: Autism is diagnosed by three major symptom categories: unusual reciprocal social interactions, impaired communication, and repetitive behaviors with restricted interests. Direct social approach in mice has strong face validity to simple social approach behaviors in humans, which are frequently impaired in autism. This unit presents a basic protocol for a standardized, high-throughput social approach test for assaying mouse sociability. Our automated three-chambered social approach task quantifies direct social approach behaviors when a subject mouse is presented with the choice of spending time with either a novel mouse or a novel object. Sociability is defined as the subject mouse spending more time in the chamber containing the novel target mouse than in the chamber containing the inanimate novel object. The Basic Protocol describes procedures for testing one subject at a time in a single apparatus. A Support Protocol addresses data collection.Current protocols in neuroscience / editorial board, Jacqueline N. Crawley ... [et al.] 07/2011; Chapter 8:Unit 8.26. -
Article: Social peers rescue autism-relevant sociability deficits in adolescent mice.
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ABSTRACT: Behavioral therapies are currently the most effective interventions for treating the diagnostic symptoms of autism. We employed a mouse model of autism to evaluate components of behavioral interventions that improve sociability in mice. BTBR T+tf/J (BTBR) is an inbred mouse strain that exhibits prominent behavioral phenotypes with face validity to all three diagnostic symptom categories of autism, including robust and well-replicated deficits in social approach and reciprocal social interactions. To investigate the role of peer interactions in the development of sociability, BTBR juvenile mice were reared in the same home cage with juvenile mice of a highly social inbred strain, C57BL/6J (B6). Subject mice were tested as young adults for sociability and repetitive behaviors. B6 controls reared with B6 showed their strain-typical high sociability. BTBR controls reared with BTBR showed their strain-typical lack of sociability. In contrast, BTBR reared with B6 as juveniles showed significant sociability as young adults. A 20-day intervention was as effective as a 40-day intervention for improving social approach behavior. High levels of repetitive self-grooming in BTBR were not rescued by peer-rearing with B6, indicating specificity of the intervention to the social domain. These results from a robust mouse model of autism support the interpretation that social enrichment with juvenile peers is a beneficial intervention for improving adult outcome in the social domain. This novel paradigm may prove useful for discovering factors that are essential for effective behavioral treatments, and biological mechanisms underlying effective behavioral interventions.Autism Research 10/2010; 4(1):17-27. · 3.69 Impact Factor -
Article: Low stress reactivity and neuroendocrine factors in the BTBR T+tf/J mouse model of autism.
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ABSTRACT: Autism is a neurodevelopmental disorder characterized by abnormal reciprocal social interactions, communication deficits, and repetitive behaviors with restricted interests. BTBR T+tf/J (BTBR) is an inbred mouse strain that displays robust behavioral phenotypes with analogies to all three of the diagnostic symptoms of autism, including low social interactions, reduced vocalizations in social settings, and high levels of repetitive self-grooming. Autism-relevant phenotypes in BTBR offer translational tools to discover neurochemical mechanisms underlying unusual mouse behaviors relevant to symptoms of autism. Because repetitive self-grooming in mice may be a displacement behavior elevated by stressors, we investigated neuroendocrine markers of stress and behavioral reactivity to stressors in BTBR mice, as compared to C57BL/6J (B6), a standard inbred strain with high sociability. Radioimmunoassays replicated previous findings that circulating corticosterone is higher in BTBR than in B6. Higher basal glucocorticoid receptor mRNA and higher oxytocin peptide levels were detected in the brains of BTBR as compared to B6. No significant differences were detected in corticotrophin releasing factor (CRF) peptide or CRF mRNA. In response to behavioral stressors, BTBR and B6 were generally similar on behavioral tasks including stress-induced hyperthermia, elevated plus-maze, light ↔ dark exploration, tail flick, acoustic startle and prepulse inhibition. BTBR displayed less reactivity than B6 to a noxious thermal stimulus in the hot plate, and less immobility than B6 in both the forced swim and tail suspension depression-related tasks. BTBR, therefore, exhibited lower depression-like scores than B6 on two standard tests sensitive to antidepressants, did not differ from B6 on two well-validated anxiety-like behaviors, and did not exhibit unusual stress reactivity to sensory stimuli. Our findings support the interpretation that autism-relevant social deficits, vocalizations, and repetitive behaviors are not the result of abnormal stress reactivity in the BTBR mouse model of autism.Neuroscience 09/2010; 171(4):1197-208. · 3.38 Impact Factor -
Article: Behavioural phenotyping assays for mouse models of autism.
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ABSTRACT: Autism is a heterogeneous neurodevelopmental disorder of unknown aetiology that affects 1 in 100-150 individuals. Diagnosis is based on three categories of behavioural criteria: abnormal social interactions, communication deficits and repetitive behaviours. Strong evidence for a genetic basis has prompted the development of mouse models with targeted mutations in candidate genes for autism. As the diagnostic criteria for autism are behavioural, phenotyping these mouse models requires behavioural assays with high relevance to each category of the diagnostic symptoms. Behavioural neuroscientists are generating a comprehensive set of assays for social interaction, communication and repetitive behaviours to test hypotheses about the causes of autism. Robust phenotypes in mouse models hold great promise as translational tools for discovering effective treatments for components of autism spectrum disorders.Nature Reviews Neuroscience 07/2010; 11(7):490-502. · 26.48 Impact Factor -
Article: Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication.
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ABSTRACT: SHANK3 is a protein in the core of the postsynaptic density (PSD) and has a critical role in recruiting many key functional elements to the PSD and to the synapse, including components of α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid (AMPA), metabotropic glutamate (mGlu) and N-methyl-D-aspartic acid (NMDA) glutamate receptors, as well as cytoskeletal elements. Loss of a functional copy of the SHANK3 gene leads to the neurobehavioral manifestations of 22q13 deletion syndrome and/or to autism spectrum disorders. The goal of this study was to examine the effects of haploinsufficiency of full-length Shank3 in mice, focusing on synaptic development, transmission and plasticity, as well as on social behaviors, as a model for understanding SHANK3 haploinsufficiency in humans. We used mice with a targeted disruption of Shank3 in which exons coding for the ankyrin repeat domain were deleted and expression of full-length Shank3 was disrupted. We studied synaptic transmission and plasticity by multiple methods, including patch-clamp whole cell recording, two-photon time-lapse imaging and extracellular recordings of field excitatory postsynaptic potentials. We also studied the density of GluR1-immunoreactive puncta in the CA1 stratum radiatum and carried out assessments of social behaviors. In Shank3 heterozygous mice, there was reduced amplitude of miniature excitatory postsynaptic currents from hippocampal CA1 pyramidal neurons and the input-output (I/O) relationship at Schaffer collateral-CA1 synapses in acute hippocampal slices was significantly depressed; both of these findings indicate a reduction in basal neurotransmission. Studies with specific inhibitors demonstrated that the decrease in basal transmission reflected reduced AMPA receptor-mediated transmission. This was further supported by the observation of reduced numbers of GluR1-immunoreactive puncta in the stratum radiatum. Long-term potentiation (LTP), induced either with θ-burst pairing (TBP) or high-frequency stimulation, was impaired in Shank3 heterozygous mice, with no significant change in long-term depression (LTD). In concordance with the LTP results, persistent expansion of spines was observed in control mice after TBP-induced LTP; however, only transient spine expansion was observed in Shank3 heterozygous mice. Male Shank3 heterozygotes displayed less social sniffing and emitted fewer ultrasonic vocalizations during interactions with estrus female mice, as compared to wild-type littermate controls. We documented specific deficits in synaptic function and plasticity, along with reduced reciprocal social interactions in Shank3 heterozygous mice. Our results are consistent with altered synaptic development and function in Shank3 haploinsufficiency, highlighting the importance of Shank3 in synaptic function and supporting a link between deficits in synapse function and neurodevelopmental disorders. The reduced glutamatergic transmission that we observed in the Shank3 heterozygous mice represents an interesting therapeutic target in Shank3-haploinsufficiency syndromes.Molecular autism. 01/2010; 1(1):15. -
Article: Simple behavioral assessment of mouse olfaction.
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ABSTRACT: This unit presents two basic protocols that offer rapid assessments of anosmia (the absence of a sense of smell) in mice. The buried food test is used to check for the ability to smell volatile odors. The olfactory habituation/dishabituation test is used to test whether the animal can detect and differentiate different odors, including both nonsocial and social odors. A non-contact method of odor presentation, along with a general method for collecting urine samples, is given as an alternate protocol. The tests described in this unit only require simple equipment and can be adopted readily by most laboratories.Current protocols in neuroscience / editorial board, Jacqueline N. Crawley ... [et al.] 08/2009; Chapter 8:Unit 8.24. -
Article: Postnatal lesion evidence against a primary role for the corpus callosum in mouse sociability.
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ABSTRACT: The BTBR T+tf/J (BTBR) strain is an inbred strain of mice that displays prominent social deficits and repetitive behaviors analogous to the defining symptoms of autism, along with complete congenital agenesis of the corpus callosum (CC). The BTBR strain is genetically distant from the widely used C57BL/6J (B6) strain, which exhibits high levels of sociability, a low level of repetitive behaviors, and an intact CC. Emerging evidence implicates compromised interhemispherical connectivity in some cases of autism. We investigated the hypothesis that the disconnection of CC fiber tracts contributes to behavioral traits in mice that are relevant to the behavioral symptoms of autism. Surgical lesion of the CC in B6 mice at postnatal day 7 had no effect on juvenile play and adult social approaches, and did not elevate repetitive self-grooming. In addition, LP/J, the strain that is genetically closest to the BTBR strain but has an intact CC, displayed juvenile play deficits and repetitive self-grooming similar to those seen in BTBR mice. These corroborative results offer evidence against the hypothesis that the CC disconnection is a primary cause of low sociability and a high level of repetitive behaviors in inbred mice. Our findings indicate that genes mediating other aspects of neurodevelopment, including those whose mutations underlie more subtle disruptions in white matter pathways and connectivity, are more likely to contribute to the aberrant behavioral phenotypes in the BTBR mouse model of autism.European Journal of Neuroscience 05/2009; 29(8):1663-77. · 3.63 Impact Factor -
Article: Light phase testing of social behaviors: not a problem.
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ABSTRACT: The rich repertoire of mouse social behaviors makes it possible to use mouse models to study neurodevelopmental disorders characterized by social deficits. The fact that mice are naturally nocturnal animals raises a critical question of whether behavioral experiments should be strictly conducted in the dark phase and whether light phase testing is a major methodologically mistake. Although mouse social tasks have been performed in both phases in different laboratories, there seems to be no general consensus on whether testing phase is a critical factor or not. A recent study from our group showed remarkably similar social scores obtained from inbred mice tested in the light and the dark phase, providing evidence that light phase testing could yield reliable results as robust as dark phase testing for the sociability test. Here we offer a comprehensive review on mouse social behaviors measured in light and dark phases and explain why it is reasonable to test laboratory mice in experimental social tasks in the light phase.Frontiers in Neuroscience 01/2009; 2(2):186-91. -
Article: Criteria for validating mouse models of psychiatric diseases.
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ABSTRACT: Animal models of human diseases are in widespread use for biomedical research. Mouse models with a mutation in a single gene or multiple genes are excellent research tools for understanding the role of a specific gene in the etiology of a human genetic disease. Ideally, the mouse phenotypes will recapitulate the human phenotypes exactly. However, exact matches are rare, particularly in mouse models of neuropsychiatric disorders. This article summarizes the current strategies for optimizing the validity of a mouse model of a human brain dysfunction. We address the common question raised by molecular geneticists and clinical researchers in psychiatry, "what is a 'good enough' mouse model"?American Journal of Medical Genetics Part B Neuropsychiatric Genetics 06/2008; 150B(1):1-11. · 3.70 Impact Factor -
Article: Social deficits in BTBR T+tf/J mice are unchanged by cross-fostering with C57BL/6J mothers.
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ABSTRACT: Inbred strains of mice are useful model systems for studying the interactions of genetic and environmental contributions during neurodevelopmental stages. We recently reported an inbred strain, BTBR T+tf/J (BTBR), which, as compared to the commonly used C57BL/6J (B6) strain, displays lower social interactions as juveniles, lower social approach in adult ages, and higher levels of repetitive self-grooming throughout developmental stages. The present study investigated whether the early postnatal maternal environment contributes substantially to the unusually low expression of social behaviors and high self-grooming in BTBR as compared to B6. Within 24h of birth, entire litters of pups were cross-fostered to either a dam of the same strain or a dam of the opposite strain. Control litters were left with their own mothers. Offspring were tested for juvenile play at postnatal day 21+/-1, for sociability at 8 weeks of age in an automated three-chambered social approach test, and for self-grooming at 9-11 weeks of age. Results indicate that deficits in play behaviors in juvenile BTBR pups were not rescued by a B6 maternal environment. Similarly, a BTBR maternal environment did not induce play deficits in B6 pups. Cross-fostering had no effect on sociability scores in adults. The high self-grooming in BTBR and low self-grooming in B6 were not affected by maternal environment. These findings favor a genetic interpretation of the unusual social behaviors and self-grooming traits of BTBR, and support the use of the BTBR inbred strain as a mouse model to study genetic mechanism of autism.International Journal of Developmental Neuroscience 01/2008; 25(8):515-21. · 2.42 Impact Factor -
Article: Social approach behaviors are similar on conventional versus reverse lighting cycles, and in replications across cohorts, in BTBR T+ tf/J, C57BL/6J, and vasopressin receptor 1B mutant mice.
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ABSTRACT: Mice are a nocturnal species, whose social behaviors occur primarily during the dark phase of the circadian cycle. However, laboratory rodents are frequently tested during their light phase, for practical reasons. We investigated the question of whether light phase testing presents a methodological pitfall for investigating mouse social approach behaviors. Three lines of mice were systematically compared. One cohort of each line was raised in a conventional lighting schedule and tested during the light phase, under white light illumination; another cohort was raised in a reverse lighting schedule and tested during their dark phase, under dim red light. Male C57BL/6J (B6) displayed high levels of sociability in our three-chambered automated social approach task when tested in either phase. BTBR T+ tf/J (BTBR) displayed low levels of sociability in either phase. Five cohorts of vasopressin receptor subtype 1b (Avpr1b) null mutants, heterozygotes, and wildtype littermate controls were tested in the same social approach paradigm: three in the dark phase and two in the light phase. All three genotypes displayed normal sociability in four out of the five replications. In the juvenile play test, testing phase had no effect on play soliciting behaviors in Avpr1b mice, but had modest effects on nose sniff and huddling. Taken together, these findings indicate that testing phase is not a crucial factor for studying some forms of social approach in juvenile and adult mice.Frontiers in Behavioral Neuroscience 02/2007; 1:1.
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2007–2013
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National Institute of Mental Health (NIMH)
Bethesda, MD, USA
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