Systematic analysis of goal-related movement sequences during maternal behavior in a female mouse model for Rett syndrome

Parenting is an ethologically relevant social behavior consisting of stereotypic components involving the care and nourishment of young. First-time rodent dams seek and gather wandering/scattered pups back to the nest (pup retrieval), an essential aspect of maternal care. Over the decades, qualitative observations of the behaving animal have been presented in quantitative discrete units. However, systematic analysis of the dynamic sequences of goal-related movements that comprise the entire behavioral sequence, which would be ultimately essential for understanding the underlying neurobiology, is usually not analyzed. Here, we present systematic analysis of pup retrieval behavior across three days in alloparental female mice (Surrogates or Sur) of two genotypes; Mecp2Heterozygotes (Het), a female mouse model for a neuropsychiatric disorder called Rett syndrome and their wild type (WT) siblings. Additionally, we analyzed CBA/CaJ and C57BL/6J WT surrogates for within-strain comparisons. Frame-by-frame analysis over different phases was performed manually using DataVyu software.We previously showed that Het are inefficient, by measuring latency and errors, at pup retrieval. Here, we show that the sequence of searching, pup-approach and good retrieval crystallizes over time for WT; this sequence does not crystallize in Het. We found that goal-related movements of Het in different phases were similar to WT, suggesting context-driven atypical dynamic patterns in Het. We also identified pup approach and pup grooming as atypical tactile interactions between pups and Het, which contribute to inefficient pup retrieval. Day-by-day analysis showed dynamic changes in goal-related movements in individual animals across genotypes and strains in response to the growing pups. Overall, our approach 1) embraces natural variation in individual mice on different days of pup retrieval behavior, 2) establishes a “gold-standard” manually curated dataset to next build behavioral repertoires using machine learning approaches, and 3) identifies distinct atypical tactile sensory processing in a female mouse model for Rett syndrome.

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Systematic analysis of goal‐related movement sequences during maternal behavior in a female mouse model for Rett syndrome

European Journal of Neuroscience ◽

10.1111/ejn.15327 ◽

2021 ◽

Author(s):

Parker Stevenson ◽

Devin M. Casenhiser ◽

Billy Y.B. Lau ◽

Keerthi Krishnan

Keyword(s):

Mouse Model ◽

Rett Syndrome ◽

Maternal Behavior ◽

Female Mouse ◽

Systematic Analysis ◽

Movement Sequences

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Breathing abnormalities in a female mouse model of Rett syndrome

The Journal of Physiological Sciences ◽

10.1007/s12576-015-0384-5 ◽

2015 ◽

Vol 65 (5) ◽

pp. 451-459 ◽

Cited By ~ 16

Author(s):

Christopher M. Johnson ◽

Ningren Cui ◽

Weiwei Zhong ◽

Max F. Oginsky ◽

Chun Jiang

Keyword(s):

Mouse Model ◽

Rett Syndrome ◽

Female Mouse

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Persistent Unresolved Inflammation in the Mecp2-308 Female Mutated Mouse Model of Rett Syndrome

Mediators of Inflammation ◽

10.1155/2017/9467819 ◽

2017 ◽

Vol 2017 ◽

pp. 1-9 ◽

Cited By ~ 11

Author(s):

Alessio Cortelazzo ◽

Claudio De Felice ◽

Bianca De Filippis ◽

Laura Ricceri ◽

Giovanni Laviola ◽

...

Keyword(s):

Mouse Model ◽

Rett Syndrome ◽

Binding Protein ◽

Neurodevelopmental Disorder ◽

Unknown Origin ◽

Apolipoprotein A1 ◽

Inflammatory Status ◽

Truncating Mutation ◽

Alpha 1 Antitrypsin ◽

First Time

Rett syndrome (RTT) is a rare neurodevelopmental disorder usually caused by mutations in the X-linked gene methyl-CpG-binding protein 2 (MECP2). Several Mecp2 mutant mouse lines have been developed recapitulating part of the clinical features. In particular, Mecp2-308 female heterozygous mice, bearing a truncating mutation, are a validated model of the disease. While recent data suggest a role for inflammation in RTT, little information on the inflammatory status in murine models of the disease is available. Here, we investigated the inflammatory status by proteomic 2-DE/MALDI-ToF/ToF analyses in symptomatic Mecp2-308 female mice. Ten differentially expressed proteins were evidenced in the Mecp2-308 mutated plasma proteome. In particular, 5 positive acute-phase response (APR) proteins increased (i.e., kininogen-1, alpha-fetoprotein, mannose-binding protein C, alpha-1-antitrypsin, and alpha-2-macroglobulin), and 3 negative APR reactants were decreased (i.e., serotransferrin, albumin, and apolipoprotein A1). CD5 antigen-like and vitamin D-binding protein, two proteins strictly related to inflammation, were also changed. These results indicate for the first time a persistent unresolved inflammation of unknown origin in the Mecp2-308 mouse model.

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P.219 The antidiabetic drug metformin improves cognitive flexibility deficits in a female mouse model of Rett syndrome

European Neuropsychopharmacology ◽

10.1016/j.euroneuro.2021.01.048 ◽

2021 ◽

Vol 44 ◽

pp. S28-S29

Author(s):

C. Urbinati ◽

L. Cosentino ◽

M. Evoli ◽

B. De Filippis

Keyword(s):

Mouse Model ◽

Rett Syndrome ◽

Cognitive Flexibility ◽

Female Mouse ◽

Antidiabetic Drug

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Tsix–Mecp2 female mouse model for Rett syndrome reveals that low-level MECP2 expression extends life and improves neuromotor function

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1800931115 ◽

2018 ◽

Vol 115 (32) ◽

pp. 8185-8190 ◽

Cited By ~ 12

Author(s):

Lieselot L. G. Carrette ◽

Roy Blum ◽

Weiyuan Ma ◽

Raymond J. Kelleher ◽

Jeannie T. Lee

Keyword(s):

Mouse Model ◽

Rett Syndrome ◽

Female Mouse ◽

Neurodevelopmental Disorder ◽

Specific Treatment ◽

Therapeutic Benefit ◽

Repetitive Behaviors ◽

Allelic Series ◽

Neuromotor Function ◽

Excessive Grooming

Rett syndrome (RTT) is a severe neurodevelopmental disorder caused by a mutation in the X-linked methyl-CpG-binding protein 2 (MECP2). There is currently no disease-specific treatment, but MECP2 restoration through reactivation of the inactive X (Xi) has been of considerable interest. Progress toward an Xi-reactivation therapy has been hampered by a lack of suitable female mouse models. Because of cellular mosaicism due to random X-chromosome inactivation (XCI), Mecp2+/− heterozygous females develop only mild RTT. Here, we create an improved female mouse model by introducing a mutation in Tsix, the antisense regulator of XCI allelic choice. Tsix–Mecp2 mice show reduced MECP2 mosaicism and closely phenocopy the severely affected Mecp2-null males. Tsix–Mecp2 females demonstrate shortened lifespan, motor weakness, tremors, and gait disturbance. Intriguingly, they also exhibit repetitive behaviors, as is often seen in human RTT, including excessive grooming and biting that result in self-injury. With a Tsix allelic series, we vary MECP2 levels in brain and demonstrate a direct, but nonlinear correlation between MECP2 levels and phenotypic improvement. As little as 5–10% MECP2 restoration improves neuromotor function and extends lifespan five- to eightfold. Our study thus guides future pharmacological strategies and suggests that partial MECP2 restoration could have disproportionate therapeutic benefit.

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Silicone Oil-Induced Ocular Hypertension in Mouse Models Glaucomatous Neurodegeneration and Neuroprotection

10.1101/547661 ◽

2019 ◽

Author(s):

Jie Zhang ◽

Liang Li ◽

Haoliang Huang ◽

Hannah C. Webber ◽

Pei Zhuang ◽

...

Keyword(s):

Mouse Model ◽

Silicone Oil ◽

Vitreoretinal Surgery ◽

Axon Degeneration ◽

Dynamic Changes ◽

Intracameral Injection ◽

Iop Elevation ◽

First Time ◽

Neuroprotective Therapies

AbstractUnderstanding the molecular mechanism of glaucoma and development of neuroprotectants are significantly hindered by the lack of a reliable animal model that accurately recapitulates human glaucoma. Here we sought to develop a mouse model for the secondary glaucoma that is often observed in humans after silicone oil (SO) blocks the pupil or migrates into the anterior chamber following vitreoretinal surgery. We observed similar intraocular pressure (IOP) elevation after intracameral injection into mouse eyes of SO, and removing the SO allows the IOP level to quickly return to normal. This simple, inducible and reversible mouse model showed dynamic changes of visual function that correlate with progressive RGC loss and axon degeneration. We also used a single AAV vector for the first time to co-express miRNA-based shRNA and a neuroprotective transgene and further validated this model as an effective in vivo means to test neuroprotective therapies by targeting neuronal endoplasmic reticulum stress.

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