High‐throughput analysis of vocalizations reveals sex‐specific changes in <i>Fmr1</i> mutant pups

Nolan, Suzanne O.; Hodges, Samantha L.; Lugo, Joaquín N.

doi:10.1111/gbb.12611

Cited by 21 publications

(19 citation statements)

References 39 publications

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“…3a). We note that while this FXS mouse model has been studied extensively as a complete knock-out in male hemizygous Fmr-1 KO/Y mice, only three studies reported modest phenotypes (synaptic and social) in female heterozygous Fmr1 KO/+ mice with the KO allele always transmitted maternally [52][53][54] . Hence, our study is the first to directly compare the phenotypic effect of maternal versus paternal Fmr1 KO allele transmission in heterozygous female mice, while also quantifying the whole-brain distribution of the Fmr1-KO allele-expressing cells in each animal.…”

Section: Paternal XCI Bias Gates Fxs Disease Penetrancementioning

confidence: 96%

Brain X chromosome inactivation is not random and can protect from paternally inherited neurodevelopmental disease

Szelenyi

Fisenne

Knox

et al. 2018

Preprint

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X-chromosome inactivation (XCI) in females is vital for normal brain function and cognition, as many X-linked genetic mutations lead to mental retardation and autism spectrum disorders, such as the fragile X syndrome (FXS). However, the degree by which XCI regulates disease presentation has been poorly investigated. To study this regulation in the mouse, here we quantified the brainwide composition of active-XC cells at single cell resolution using an X-linked MECP2-EGFP allele with known parent-of-origin. We present evidence that whole-brains, including all regions, on average favor maternal XCactive cells by 20%, or 8 million cells. This bias was conserved in heterozygous FXS mutant mice, which also corresponded to disease penetrance in maternal but not paternal FMR1 null mice. To localize the physical source of behavioral penetrance, brain-wide correlational screens successfully mapped mouse performance to cell densities in putative sensorimotor (e.g. sensory hindbrain, thalamus, globus pallidus) and sociability (e.g. visual/entorhinal cortices, bed nucleus stria terminalis, medial preoptic area) behavioral circuits of the open field sensorimotor and 3-chamber sociability assays, respectively. Overall, 50%/50% healthy/mutant cell density ratios in these sub-networks were required for disease presentation in each behavior. These results suggest female X-linked behavioral penetrance of disease is regulated at the distributed level of mutant cell density in behavioral circuits, which is set by XCI that is subject to parent-of-origin effects. This work provides a novel finding behind the broad and varied behavioral phenotypes commonly featured in female patients debilitated by X-linked mental disorders and may offer new entry points for behavioral therapeutics. screens. A) Pearson's correlational analysis conducted amongst behavioral scores and brain-wide healthy ROI cell density. Data is displayed in a 2-dimensional (ROI -y-axis; genotype/behavioral test -x-axis) heat map of significant p-values represented on a double color gradient from 0.05 (black), 0.025 (red), to 0 (yellow). Scale legend is listed at the bottom. Results from FMR1 WT, maternal and paternal FMR1 KO mice (x-axis) are grouped by each behavioral test (left -OFT, center -T-maze, right -3-chamber) and ROIs are listed in order of major hierarchical brain structures. B) Significant ROIs (p=0.01 threshold) from maternal FMR1 KO OFT screening results found in A), heat mapped and overlaid in reference brain space. Individual names of significant ROIs and anterior/posterior location with respect to bregma are listed for each section shown. C) Visualization of structural connectivity weights within the significantly correlated OFT ROI network (Methods). ROI node and edge color assignment is based on major brain structure colors as defined by Allen Brain Atlas (http://atlas.brain-map.org). D) Normalized median connection density of OFT ROI network (red line), and 1000 insilico generated random ROI networks of the same inter-regional distance and ROI amount...

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Section: Paternal XCI Bias Gates Fxs Disease Penetrancementioning

confidence: 96%

Brain X chromosome inactivation is not random and can protect from paternally inherited neurodevelopmental disease

Szelenyi

Fisenne

Knox

et al. 2018

Preprint

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“…The Mouse Song Analyzer is a widely available system used in numerous publications [17][18][19][20][21][22] . It is fully automated and extremely time efficient, as each file takes approximately 2-3 minutes to assess.…”

Section: Introductionmentioning

confidence: 99%

“…One such program is the Mouse Song Analyzer (v.1.3), developed by the Jarvis lab (http://jarvislab.net/research/mouse-vocal-communication/). The Mouse Song Analyzer is a widely available system used in numerous publications 17–22 . It is fully automated and extremely time efficient, as each file takes approximately 2-3 minutes to assess.…”

Section: Introductionmentioning

confidence: 99%

A comparison of the Mouse Song Analyzer and DeepSqueak ultrasonic vocalization analysis systems in C57BL/6J, FVB.129, and FVB mice

Pranske

Lugo

2021

Preprint

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Vocal communication is an essential behavior in mammals and is relevant to human neurodevelopmental conditions. Mice produce communicative vocalizations, known as ultrasonic vocalizations (USVs), that can be recorded with various programs. The Mouse Song Analyzer is an automated analysis system, while DeepSqueak is a semi-automated system. We used data from C57BL/6J, FVB.129, and FVB mice to compare whether the DeepSqueak and Mouse Song Analyzer systems measure a similar total number, duration, and fundamental frequency of USVs. We found that the two systems detected a similar quantity of USVs for FVB.129 mice (r= .90, p< .001), but displayed lower correlations for C57BL/6J (r= .76, p< .001) and FVB mice (r= .60, p< .001). We also found that DeepSqueak detected significantly more USVs for C57BL/6J mice than the Mouse Song Analyzer. The two systems detected a similar duration of USVs for C57BL/6J (r= .82, p< .001), but lower correlations for FVB.129 (r= .13, p< .001) and FVB mice (r= .51, p< .01) were found, with DeepSqueak detecting significantly more USVs per each strain. We found lower than acceptable correlations for fundamental frequency in C57BL/6J (r= .54, p< .01), FVB.129 (r= .76, p< .001), and FVB mice (r= .07, p= .76), with the Mouse Song Analyzer detecting a significantly higher fundamental frequency for FVB.129 mice. These findings demonstrate that the strain of mouse used significantly affects the number, duration, and fundamental frequency of USVs that are detected between programs. Overall, we found that DeepSqueak is more accurate than the Mouse Song Analyzer.

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“…Because CACNA1C is implicated with several mental illnesses that differentially affect men and women (eg, major depressive disorder and schizophrenia), these data may shed light onto a potential mechanism of sex‐dependent pathophysiologies. USVs also play a key role in pup‐mother communication, and Nolan et al find that male and female Fmr1 (a gene linked to fragile X syndrome) knockout or heterozygous mice exhibit discrete patterns of altered vocalizations compared with their wildtype, same‐sex littermates. Finally, in a mutant mouse model of amyotrophic lateral sclerosis (ALS), Kreilaus et al report that prior to the onset of expected motor deficits, mutant males, but not females exhibited reduced sociability, pointing to a potential sex‐specific early marker of the disease.…”

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confidence: 99%

Sex differences in 3D: Differentiation, dimorphism, or dependence?

Shansky

2020

Genes Brain and Behavior

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Across neuroscience research, the expression "sex differences" has become a catchall term for any phenomenon that we might observe in one sex but not the other-or even a phenomenon observed in both sexes subgroups of males that exhibit distinct patterns of gene expression in the ventral tegmental area (VTA). Intriguingly, these divisions were most tightly predictive of the behavior of the male's female partner, even more so than the behavior of the male himself.Of course, not all social behavior is related to mating, and as three of this issue's research articles demonstrate, genetic modifications can produce sex-dependent effects in a wide range of social outcomes.First, haploinsufficiency of the CACNA1C gene resulted in increased rough-and-tumble play in adolescent female rats, but not males. 6 In contrast, heterozygous males, but not females exhibited altered prosocial ultrasonic vocalizations (USVs). Because CACNA1C is implicated with several mental illnesses that differentially affect men and women (eg, major depressive disorder and schizophrenia), these data may shed light onto a potential mechanism of sex-dependent pathophysiologies. USVs also play a key role in pup-mother communication, and Nolan et al 7 find that male and female Fmr1 (a gene linked to fragile X syndrome) knockout or heterozygous mice exhibit discrete patterns of altered vocalizations compared with their wildtype, same-sex littermates. Finally, in a mutant mouse model of amyotrophic lateral sclerosis (ALS), Kreilaus et al 8 report that prior to the onset of expected motor deficits, mutant males, but not females exhibited reduced sociability, pointing to a potential sex-specific early marker of the disease.Rounding out the issue is a comprehensive review by Brenman-Suttner et al, 9 who explore the complex interactions between genetics, physiology, and time that orchestrate age-related changes in social behaviors. Using D. melanogaster as a model system, the authors discuss a broad range of sex-dependent behaviors, such as courtship, aggression, or egg-laying conditioning, as well as those expressed by both males and females, like social spacing and circadian rhythm entrainment.Together with those in the upcoming companion Special Issue, the articles here comprise a rich sampling of the many ways in which biological sex can contribute to behavioral outcomes in a host of species ranging from fruit flies to humans. The diverse perspectives offered in both issues should serve as food for thought to GB2's readers as they attempt to consider sex as a biological variable in their own research.

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High‐throughput analysis of vocalizations reveals sex‐specific changes in Fmr1 mutant pups

Cited by 21 publications

References 39 publications

Brain X chromosome inactivation is not random and can protect from paternally inherited neurodevelopmental disease

Brain X chromosome inactivation is not random and can protect from paternally inherited neurodevelopmental disease

A comparison of the Mouse Song Analyzer and DeepSqueak ultrasonic vocalization analysis systems in C57BL/6J, FVB.129, and FVB mice

Sex differences in 3D: Differentiation, dimorphism, or dependence?

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