Bidirectional Behavioral Selection in Mice: A Novel Pre-clinical Approach to Examining Compulsivity

Mitra, Swarup; Bult‐Ito, Abel

doi:10.3389/fpsyt.2021.716619

Cited by 5 publications

(2 citation statements)

References 342 publications

(483 reference statements)

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“…While these studies report regression in parasympathetic and motor function, our work here is the first to report a regressive hyposensitivity phenotype in tactile perception between adolescence and adulthood in a female mouse model for RTT. An alternative explanation for increases in tactile interactions from adolescence to adulthood in Het is the emergence of repetitive obsessive-compulsive disorder-like phenotypes over time, as observed in mouse models of this disorder (Ahmari, 2016; Alonso et al, 2015; Mitra and Bult-Ito, 2021). Adult Het perform repetitive jumping during early days of pup retrieval which could be indicative of novelty- or stress-induced stereotypies in a subpopulation of adult Het (Stevenson et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Wild-type MECP2 expression coincides with age-dependent sensory phenotypes in a female mouse model for Rett syndrome

Mykins

Layo

Dunn

et al. 2022

Preprint

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Rett syndrome is characterized by an early period of typical development and then, regression of learned motor and speech skills in girls. The underlying mechanisms from normalcy to regression are unclear. Due to random X-chromosome inactivation, female patients of Rett syndrome, and female mouse models of Rett syndrome (Mecp2Heterozygous, Het) express a functional copy of wild-type MECP2 protein in half of all mature cells in brain and body. By analyzing wild-type MECP2 expression in the context of whisker tactile sensory perception, here we report compensatory increase in MECP2 protein expression in 6-week-old adolescent Het mice, which display normal levels of perineuronal net expression, mild tactile sensory perception deficit and efficient pup retrieval behavior. Comparatively, 12-week-old adult Het mice display decreased MECP2 expression and significant tactile sensory perception deficits. Thus, we have identified a period of normalcy and regression in this female mouse model, which coincide with variable wild-type expression of MECP2. We speculate that compensatory increases in MECP2 expression in Het brains allows for normal functioning, while the inability to maintain these expression level changes leads to behavioral deficits.

show abstract

Section: Discussionmentioning

confidence: 99%

Wild-type MECP2 expression coincides with age-dependent sensory phenotypes in a female mouse model for Rett syndrome

Mykins

Layo

Dunn

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…While these studies report regression in parasympathetic and motor function, our work here is the first to report a regressive hyposensitivity phenotype in tactile perception between adolescence and adulthood in a female mouse model for RTT. An alternative explanation for increases in tactile interactions from adolescence to adulthood in Het is the emergence of repetitive obsessive‐compulsive disorder‐like phenotypes over time, as observed in mouse models of this disorder (Ahmari, 2016; Alonso et al, 2015; Mitra & Bult‐Ito, 2021). Adult Het perform repetitive jumping during early days of pup retrieval which could be indicative of novelty‐ or stress‐induced stereotypies in a subpopulation of adult Het (Stevenson et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Wild‐type MECP2 expression coincides with age‐dependent sensory phenotypes in a female mouse model for Rett syndrome

Mykins

Layo

Dunn

et al. 2023

J of Neuroscience Research

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Rett syndrome is characterized by an early period of typical development and then, regression of learned motor and speech skills in girls. Loss of MECP2 protein is thought to cause Rett syndrome phenotypes. The specific underlying mechanisms from typical developmental trajectory to regression features throughout life are unclear. Lack of established timelines to study the molecular, cellular, and behavioral features of regression in female mouse models is a major contributing factor. Due to random X-chromosome inactivation, female patients with Rett syndrome and female mouse models for Rett syndrome (Mecp2 Heterozygous , Het) express a functional copy of wild-type MECP2 protein in approximately half of all cells. As MECP2 expression is regulated during early postnatal development and experience, we characterized the expression of wild-type MECP2 in the primary somatosensory cortex of female Het mice. Here, we report increased MECP2 levels in non-parvalbumin-positive neurons of 6-week-old adolescent Het relative to age-matched wild-type controls, while also displaying typical levels of perineuronal net expression in the barrel field subregion of the primary somatosensory cortex, mild tactile sensory perception deficits, and efficient pup retrieval behavior. In contrast, 12-week-old adult Het express MECP2 at levels similar to age-matched wild-type mice, show increased perineuronal net expression in the cortex, and display significant tactile sensory perception deficits. Thus, we have identified a set of behavioral metrics and the cellular substrates to study regression during a specific time in the female Het mouse model, which coincides with changes in wild-type MECP2 expression. We speculate that the precocious increase in MECP2 expression within specific cell types of adolescent Het may provide compensatory benefits at the behavioral level, while the inability to further increase MECP2 levels leads to regressive behavioral phenotypes over time.

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Adult Offspring of Deer Mouse Breeding Pairs Selected for Normal and Compulsive‐Like Large Nesting Expression Invariably Show the Same Behavior Without Prior In‐Breeding

Stoppel,

Harvey,

Wolmarans

2024

Developmental Psychobiology

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Obsessive‐compulsive disorder is a neuropsychiatric condition with notable genetic involvement. Against this background, laboratory‐housed deer mice of both sexes varyingly present with excessive and persistent large nesting behavior (LNB), which has been validated for its resemblance of clinical compulsivity. Although LNB differs from normal nesting behavior (NNB) on both a biological and cognitive level, it is unknown to what extent the expression of LNB and NNB is related to familial background. Here, we randomly selected 14 NNB‐ and 14 LNB‐expressing mice (equally distributed between sexes) to constitute 7 breeding pairs of each phenotype. Pairs were allowed to breed two successive generations of offspring, which were raised until adulthood (12 weeks) and assessed for nesting expression. Remarkably, our findings show that offspring from LNB‐expressing pairs build significantly larger nests compared to offspring from NNB‐expressing pairs and the nesting expression of the offspring of each breeding pair, irrespective of parental phenotype or litter, is family specific. Collectively, the results of this investigation indicate that LNB can be explored for its potential to shed light on heritable neurocognitive mechanisms that may underlie the expression of specific persistent behavioral phenotypes.

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Bidirectional Behavioral Selection in Mice: A Novel Pre-clinical Approach to Examining Compulsivity

Cited by 5 publications

References 342 publications

Wild-type MECP2 expression coincides with age-dependent sensory phenotypes in a female mouse model for Rett syndrome

Wild-type MECP2 expression coincides with age-dependent sensory phenotypes in a female mouse model for Rett syndrome

Wild‐type MECP2 expression coincides with age‐dependent sensory phenotypes in a female mouse model for Rett syndrome

Adult Offspring of Deer Mouse Breeding Pairs Selected for Normal and Compulsive‐Like Large Nesting Expression Invariably Show the Same Behavior Without Prior In‐Breeding

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