5-HT release in nucleus accumbens rescues social deficits in mouse autism model

Walsh, Jessica J.; Christoffel, Daniel J.; Heifets, Boris D.; Ben-Dor, Gabriel A.; Selimbeyoglu, Aslihan; Hung, Lin W.; Deisseroth, Karl; Malenka, Robert C.

doi:10.1038/s41586-018-0416-4

Cited by 203 publications

(160 citation statements)

References 47 publications

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“…Yet, evidence suggests this is not a categorical phenotype and that these data are indeed continuous. Multiple studies have now shown that typical sociability can be heightened or increased following stimulation of different pathways in the brain (Shin et al, 2018; Walsh et al, 2018). For example, optogenetic stimulation of the dorsal raphe neurons or their fibers in the nucleus accumbens increased the social preference index in WT mice (Walsh et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…Unlike reciprocal social interaction assays requiring manual scoring, the Social Approach Task is automated, making it ideal for mechanistic studies that require several experiments with different interventions or genetic models. For example, a recent study showed the role of dorsal raphe serotonergic connections to the nucleus accumbens in social approach behavior, and how stimulation of this pathway can correct social deficits in the 16pll.2 deletion model associated with ASD (Walsh et al, 2018). Another group showed NMDAR activation rescued social approach behavior in Shank -/- and Tbr1 +/- mutants (Lee et al, 2015; Won et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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Erroneous inference based on a lack of preference within one group: autism, mice, and the Social Approach Task

Nygaard¹,

Maloney²,

Dougherty³

2019

Preprint

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The Social Approach Task is commonly used to identify sociability deficits when modeling liability factors for autism spectrum disorder (ASD) in mice. It was developed to expand upon assays available to examine distinct aspects of social behavior in rodents and has become a standard component of mouse ASD-relevant phenotyping pipelines. However, there is variability in the statistical analysis and interpretation of results from this task. A common analytical approach is to conduct within-group comparisons only, and then interpret a difference in significance levels as if it were a group difference, without any direct comparison. As an efficient shorthand, we named this approach EWOCs:Erroneous Within-group Only Comparisons. Here we examined the prevalence of EWOCs and used simulations to test whether it could produce misleading inferences. Our review of Social Approach studies of high-confidence ASD genes revealed 45% of papers sampled used only this analytical approach. Through simulations, we then demonstrate how a lack of significant difference within one group often doesn’t correspond to a significant difference between groups, and show this erroneous interpretation increases the rate of false positives up to 25%. Finally, we define a simple solution: use an index, like a social preference score, with direct statistical comparisons between groups to identify significant differences. We also provide power calculations to guide sample size in future studies. Overall, elimination of EWOCs and adoption of direct comparisons should result in more accurate, reliable, and reproducible data interpretations from the Social Approach Task across ASD liability models.Lay SummaryThe Social Approach Task is widely used to assess social behavior in mice and is frequently used in studies modeling autism. However, reviewing published studies showed nearly half do not use correct comparisons to interpret the data. Using simulated and original data, we argue the correct statistical approach is a direct comparison of scores between groups. This simple solution should reduce false positives and improve consistency of results across studies.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Erroneous inference based on a lack of preference within one group: autism, mice, and the Social Approach Task

Nygaard¹,

Maloney²,

Dougherty³

2019

Preprint

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“…However, when mice were subjected to the various mouse models, the effects of tamoxifen were apparent. Therefore, these effects should be considered when designing or conducting similar experiments …”

Section: Discussionmentioning

confidence: 99%

The effects of tamoxifen on mouse behavior

Chen

et al. 2019

Genes Brain and Behavior

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The CreERT2 recombinase system is an advanced method to temporally control site‐specific mutagenesis in adult rodents. In this process, tamoxifen is injected to induce Cre recombinase expression, and then, Cre recombinase can excise LoxP‐flanked DNA. However, tamoxifen is a nonselective estrogen receptor antagonist that may influence behavioral alterations. Therefore, we designed five different protocols (acute effects, chronic effects, chronic effects after social defeat model, chronic effects after learned helplessness model, chronic effects after isolation models) to explore whether tamoxifen affects mouse behavior. Researching the acute/chronic effects of tamoxifen, we found that tamoxifen could influence locomotor activity, anxiety and immobility time in the forced swimming test. Researching the chronic effects of tamoxifen after social defeat/learned helplessness/isolation models, we found that tamoxifen could also influence locomotor activity, social interaction and anxiety. Therefore, the effects of tamoxifen are more complex than previously reported. Our results show, for the first time, that tamoxifen affects behavior in mouse models. Meanwhile, we compare the effects of tamoxifen in different protocols. These results will provide important information when designing similar experiments.

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“…During other effort‐related behaviors (i.e., lever‐pressing tasks), serotonin neurons in the median raphe exhibited transient increases in activity and the transient signal was suggested to regulate the ventral hippocampal activities for the maintenance of effort behavior . In the NAc, optogenetic activation of serotonin axons increased social behavior of adult male mice toward juvenile male mice transiently in the order of 5 min . In the bed nucleus of the stria terminalis, the optogenetic activation of serotonin neuron enhanced freezing behavior and anxiety‐like behaviors .…”

Section: Effects Of Transient Dopamine and Serotonin On Behaviormentioning

confidence: 99%

“…42 In the NAc, optogenetic activation of serotonin axons increased social behavior of adult male mice toward juvenile male mice transiently in the order of 5 min. 43 In the bed nucleus of the stria terminalis, the optogenetic activation of serotonin neuron enhanced freezing behavior and anxiety-like behaviors. 56 Similarly, serotonin neurons projecting to the amygdala increased responses to electrical shock transiently, and their activation caused anxiety-like behavior.…”

Section: Effects Of Transient Dopamine and Serotonin On Behaviormentioning

confidence: 99%

Transient and sustained effects of dopamine and serotonin signaling in motivation‐related behavior

Yagishita

2019

Psychiatry Clin Neurosci

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Pharmacological studies of antidepressants and atypical antipsychotics have suggested a role of dopamine and serotonin signaling in depression. However, depressive symptoms and treatment effects are difficult to explain based simply on brain‐wide decrease or increase in the concentrations of these molecules. Recent animal studies using advanced neuronal manipulation and observation techniques have revealed detailed dopamine and serotonin dynamics that regulate diverse aspects of motivation‐related behavior. Dopamine and serotonin transiently modulate moment‐to‐moment behavior at timescales ranging from sub‐second to minutes and also produce persistent effects, such as reward‐related learning and stress responses that last longer than several days. Transient and sustained effects often exhibit specific roles depending on the projection sites, where distinct synaptic and cellular mechanisms are required to process the neurotransmitters for each transient and sustained timescale. Therefore, it appears that specific aspects of motivation‐related behavior are regulated by distinct synaptic and cellular mechanisms in specific brain regions that underlie the transient and sustained effects of dopamine and serotonin signaling. Recent clinical studies have implied that subjects with depressive symptoms show impaired transient and sustained signaling functions; moreover, they exhibit heterogeneity in depressive symptoms and neuronal dysfunction. Depressive symptoms may be explained by the dysfunction of each transient and sustained signaling mechanism, and distinct patterns of impairment in the relevant mechanisms may explain the heterogeneity of symptoms. Thus, detailed understanding of dopamine and serotonin signaling may provide new insight into depressive symptoms.

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5-HT release in nucleus accumbens rescues social deficits in mouse autism model

Cited by 203 publications

References 47 publications

Erroneous inference based on a lack of preference within one group: autism, mice, and the Social Approach Task

Erroneous inference based on a lack of preference within one group: autism, mice, and the Social Approach Task

The effects of tamoxifen on mouse behavior

Transient and sustained effects of dopamine and serotonin signaling in motivation‐related behavior

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