The developmental onset of a rudimentary form of play fighting in C57 mice

Pasztor, Tamara J.

doi:10.1002/(sici)1098-2302(199904)34:3<175::aid-dev2>3.0.co;2-#

Cited by 70 publications

(48 citation statements)

References 43 publications

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“…Unlike Mecp2 mice that have only shown a relative reduction in social interest in the three chamber test, female Mecp2 ZFN/+ rats indeed show a phenotype that is consistent with findings from other ASD mouse models with impaired sociability. Furthermore, by refining our social behaviour studies to focus on play behaviour (41), an age- and species-specific complex set of behaviours that is only present at a rudimentary level in the mouse (43) and is genuinely present in rats, we found that female Mecp2 ZFN/+ rats display juvenile play deficits similar to those observed in other ASD rats such as the Fmr1 (62) and Nlgn3 (62) ZFN models. Despite the potential confound of reduced motor/exploratory activity as may potentially be suggested by the open field data (Figure 2B), measures quantified during the direct social interaction test, such as evaluating the number and duration of ‘following’, ‘self-grooming’ and ‘non-social active’ exploratory behaviours, provided an additional layer of control (Figure 3H,I,K).…”

Section: Discussionmentioning

confidence: 85%

“…Normally, rats in direct contact with each other display social interaction patterns that include age-restricted rough-and-tumble play behaviour (41,43,62,63). We found that juvenile female Mecp2 ZFN/+ rats engage their conspecific partners less in both generalized contact and specific juvenile play behaviours compared with female wild-type littermate rats (Figure 3A–C).…”

Section: Resultsmentioning

confidence: 99%

“…Rats provide an alternative rodent model and are currently the translational model system of choice for validation of therapeutic strategies (40). In addition, rats display sophisticated social and cognitive behaviours (41,42), some of which are not present in mice (43). The purpose of our study was to therefore determine the extent to which constitutive loss of MeCP2 in female rats recapitulates behavioural features of RTT.…”

Section: Introductionmentioning

confidence: 99%

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Loss of MeCP2 in the rat models regression, impaired sociability and transcriptional deficits of Rett syndrome

et al. 2016

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Mouse models of the transcriptional modulator Methyl-CpG-Binding Protein 2 (MeCP2) have advanced our understanding of Rett syndrome (RTT). RTT is a ‘prototypical’ neurodevelopmental disorder with many clinical features overlapping with other intellectual and developmental disabilities (IDD). Therapeutic interventions for RTT may therefore have broader applications. However, the reliance on the laboratory mouse to identify viable therapies for the human condition may present challenges in translating findings from the bench to the clinic. In addition, the need to identify outcome measures in well-chosen animal models is critical for preclinical trials. Here, we report that a novel Mecp2 rat model displays high face validity for modelling psychomotor regression of a learned skill, a deficit that has not been shown in Mecp2 mice. Juvenile play, a behavioural feature that is uniquely present in rats and not mice, is also impaired in female Mecp2 rats. Finally, we demonstrate that evaluating the molecular consequences of the loss of MeCP2 in both mouse and rat may result in higher predictive validity with respect to transcriptional changes in the human RTT brain. These data underscore the similarities and differences caused by the loss of MeCP2 among divergent rodent species which may have important implications for the treatment of individuals with disease-causing MECP2 mutations. Taken together, these findings demonstrate that the Mecp2 rat model is a complementary tool with unique features for the study of RTT and highlight the potential benefit of cross-species analyses in identifying potential disease-relevant preclinical outcome measures.

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Section: Discussionmentioning

confidence: 85%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Loss of MeCP2 in the rat models regression, impaired sociability and transcriptional deficits of Rett syndrome

et al. 2016

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“…Importantly, our present data extend the role of opioid-eCB interactions in the modulation of social interaction to social interaction in young mice. In contrast to rats, in which social play behavior is easy to distinguish from non-playful social behavior (Panksepp and Beatty, 1980; Vanderschuren et al, 1997), social play behavior is hard to recognize as such in mice (Pellis and Pasztor, 1999). Therefore, we can not say with confidence whether the nature of the social behavior in mice reported here is strictly playful.…”

Section: Discussionmentioning

confidence: 99%

Interacting Cannabinoid and Opioid Receptors in the Nucleus Accumbens Core Control Adolescent Social Play

Manduca

Lassalle

Sepers

et al. 2016

Front. Behav. Neurosci.

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Social play behavior is a highly rewarding, developmentally important form of social interaction in young mammals. However, its neurobiological underpinnings remain incompletely understood. Previous work has suggested that opioid and endocannabinoid neurotransmission interact in the modulation of social play. Therefore, we combined behavioral, pharmacological, electrophysiological, and genetic approaches to elucidate the role of the endocannabinoid 2-arachidonoylglycerol (2-AG) in social play, and how cannabinoid and opioid neurotransmission interact to control social behavior in adolescent rodents. Systemic administration of the 2-AG hydrolysis inhibitor JZL184 or the opioid receptor agonist morphine increased social play behavior in adolescent rats. These effects were blocked by systemic pretreatment with either CB1 cannabinoid receptor (CB1R) or mu-opioid receptor (MOR) antagonists. The social play-enhancing effects of systemic morphine or JZL184 treatment were also prevented by direct infusion of the CB1R antagonist SR141716 and the MOR antagonist naloxone into the nucleus accumbens core (NAcC). Searching for synaptic correlates of these effects in adolescent NAcC excitatory synapses, we observed that CB1R antagonism blocked the effect of the MOR agonist DAMGO and, conversely, that naloxone reduced the effect of a cannabinoid agonist. These results were recapitulated in mice, and completely abolished in CB1R and MOR knockout mice, suggesting that the functional interaction between CB1R and MOR in the NAcC in the modulation of social behavior is widespread in rodents. The data shed new light on the mechanism by which endocannabinoid lipids and opioid peptides interact to orchestrate rodent socioemotional behaviors.

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“…Limbic structures including amygdala, prefrontal cortex and hippocampus are maturing during postnatal development and human s allele carriers as well as 5-htt−/− mice exhibit disrupted mPFC-amygdala functional connectivity that likely arises during early circuit maturation 58, 59 . The DA-sensitive, peri-adolescent period coincides with the developmental onset of play fighting in rodents 60, 61 and non-human primates 62 , and human adolescence is characterized by dynamic changes in aggressive behavior 63 .…”

Section: Discussionmentioning

confidence: 99%

Dopamine and serotonin signaling during two sensitive developmental periods differentially impact adult aggressive and affective behaviors in mice

et al. 2014

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Pharmacologic blockade of monoamine oxidase A (MAOA) or serotonin transporter (5-HTT) has antidepressant and anxiolytic efficacy in adulthood. Yet, genetically conferred MAOA or 5-HTT hypo-activity is associated with altered aggression and increased anxiety/depression. Here we test the hypothesis that increased monoamine signaling during development causes these paradoxical aggressive and affective phenotypes. We find that pharmacologic MAOA blockade during early postnatal development (P2-P21) but not during peri-adolescence (P22-41) increases anxiety- and depression-like behavior in adult (> P90) mice, mimicking the effect of P2-21 5-HTT inhibition. Moreover, MAOA blockade during peri-adolescence, but not P2-21 or P182-201, increases adult aggressive behavior, and 5-HTT blockade from P22-P41 reduced adult aggression. Blockade of the dopamine transporter, but not the norepinephrine transporter, during P22-41 also increases adult aggressive behavior. Thus, P2-21 is a sensitive period during which 5-HT modulates adult anxiety/depression-like behavior, and P22-41 is a sensitive period during which DA and 5-HT bi-directionally modulate adult aggression. Permanently altered DAergic function as a consequence of increased P22-P41 monoamine signaling might underlie altered aggression. In support of this hypothesis, we find altered aggression correlating positively with locomotor response to amphetamine challenge in adulthood. Proving that altered DA function and aggression are causally linked, we demonstrate that optogenetic activation of VTA DAergic neurons increases aggression. It therefore appears that genetic and pharmacologic factors impacting dopamine and serotonin signaling during sensitive developmental periods can modulate adult monoaminergic function and thereby alter risk for aggressive and emotional dysfunction.

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The developmental onset of a rudimentary form of play fighting in C57 mice

Cited by 70 publications

References 43 publications

Loss of MeCP2 in the rat models regression, impaired sociability and transcriptional deficits of Rett syndrome

Loss of MeCP2 in the rat models regression, impaired sociability and transcriptional deficits of Rett syndrome

Interacting Cannabinoid and Opioid Receptors in the Nucleus Accumbens Core Control Adolescent Social Play

Dopamine and serotonin signaling during two sensitive developmental periods differentially impact adult aggressive and affective behaviors in mice

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