Examining the Reversibility of Long-Term Behavioral Disruptions in Progeny of Maternal SSRI Exposure

Maloney, Susan E.; Akula, Shyam; Rieger, Michael A.; McCullough, Katherine; Chandler, Krystal; Corbett, Adrian M.; McGowin, Audrey E.; Dougherty, Joseph D.

doi:10.1523/eneuro.0120-18.2018

Cited by 30 publications

(67 citation statements)

References 89 publications

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“…Animal housing rooms were kept at 20-22°C with a relative humidity of 50%. All mice were maintained on the FVB/AntJ (65) background from Jackson Labs. All behaviors were done in adulthood between ages P58-P133.…”

Section: Methodsmentioning

confidence: 99%

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Functions of Gtf2i and Gtf2ird1 in the developing brain: transcription, DNA-binding, and long term behavioral consequences

Kopp¹,

Nygaard²,

McCullough³

et al. 2019

Preprint

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AbstractGtf2ird1 and Gtf2i may mediate aspects of the cognitive and behavioral phenotypes of Williams Syndrome (WS) – a microdeletion syndrome encompassing these transcription factors (TFs). Knockout mouse models of each TF show behavioral phenotypes. Here we identify their genomic binding sites in the developing brain, and test for additive effects of their mutation on transcription and behavior. Both TFs target constrained chromatin modifier and synaptic protein genes, including a significant number of ASD genes. They bind promoters, strongly overlap CTCF binding and TAD boundaries, and moderately overlap each other, suggesting epistatic effects. We used single and double mutants to test whether mutating both TFs will modify transcriptional and behavioral phenotypes of single Gtf2ird1 mutants. Despite little difference in DNA-binding and transcriptome-wide expression, Gtf2ird1 mutation caused balance, marble burying, and conditioned fear phenotypes. However, mutating Gtf2i in addition to Gtf2ird1 did not further modify transcriptomic or most behavioral phenotypes, suggesting Gtf2ird1 mutation alone is sufficient.

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Section: Methodsmentioning

confidence: 99%

“…To test balance, we measured how long a mouse could balance on an acrylic ledge with a width of 0.5cm and a height of 38cm as described (65). The time when the mouse fell off the ledge was recorded up to 60 seconds when the trial was stopped.…”

Section: Methodsmentioning

confidence: 99%

Functions of Gtf2i and Gtf2ird1 in the developing brain: transcription, DNA-binding, and long term behavioral consequences

Kopp¹,

Nygaard²,

McCullough³

et al. 2019

Preprint

Self Cite

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“…16 Testing was conducted under dim overhead lighting. 16 Testing was conducted under dim overhead lighting.…”

Section: Spontaneous Alternation T-mazementioning

confidence: 99%

“…Our procedure was previously described. 16 Briefly, mice were placed in a transparent enclosure (47.6 × 25.4 × 20.6 cm) with fresh clean Aspen bedding and 20 clear marbles. After 30 minutes of free exploration, the animal was removed and two independent observers scored buried marbles using the criterion for buried if two-thirds of the marble was covered by bedding, and the average score of buried marbles was analyzed.…”

Section: Marble Burying Taskmentioning

confidence: 99%

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Loss of CELF6 RNA binding protein impairs cocaine conditioned place preference and contextual fear conditioning

Maloney

Rieger

Al‐Hasani

et al. 2019

Genes Brain and Behavior

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In addition to gene expression differences in distinct cell types, there is substantial post‐transcriptional regulation driven in part by RNA binding proteins (RBPs). Loss‐of‐function RBP mutations have been associated with neurodevelopmental disorders, such as Fragile‐X syndrome and syndromic autism. Work performed in animal models to elucidate the influence of neurodevelopmental disorder‐associated RBPs on distinct behaviors has showed a connection between normal post‐transcriptional regulation and conditioned learning. We previously reported cognitive inflexibility in a mouse model null for the RBP CUG‐BP, Elav‐like factor 6 (CELF6), which we also found to be associated with human autism. Specifically, these mice failed to potentiate exploratory hole‐poking behavior in response to familiarization to a rewarding stimuli. Characterization of Celf6 gene expression showed high levels in monoaminergic populations such as the dopaminergic midbrain populations. To better understand the underlying behavioral disruption mediating the resistance to change exploratory behavior in the holeboard task, we tested three hypotheses: Does Celf6 loss lead to global restricted patterns of behavior, failure of immediate response to reward or failure to alter behavior in response to reward (conditioning). We found the acute response to reward was intact, yet Celf6 mutant mice exhibited impaired conditioned learning to both reward and aversive stimuli. Thus, we found that the resistance to change by the Celf6 mutant in the holeboard was most parsimoniously explained as a failure of conditioning, as the mice had blunted responses even to potent rewarding stimuli such as cocaine. These findings further support the role of RBPs in conditioned learning.

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Erroneous inference based on a lack of preference within one group: Autism, mice, and the social approach task

2019

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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 existing assays 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 Withingroup Only Comparisons. Here, we examined the prevalence of EWOCs and used simulations to test whether this approach 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 does not 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 Summary: The 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 these 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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Examining the Reversibility of Long-Term Behavioral Disruptions in Progeny of Maternal SSRI Exposure

Abstract: Visual Abstract

Cited by 30 publications

References 89 publications

Functions of Gtf2i and Gtf2ird1 in the developing brain: transcription, DNA-binding, and long term behavioral consequences

Functions of Gtf2i and Gtf2ird1 in the developing brain: transcription, DNA-binding, and long term behavioral consequences

Loss of CELF6 RNA binding protein impairs cocaine conditioned place preference and contextual fear conditioning

Erroneous inference based on a lack of preference within one group: Autism, mice, and the social approach task

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