Multidimensional Analysis of a Social Behavior Identifies Regression and Phenotypic Heterogeneity in a Female Mouse Model for Rett Syndrome.

Regression is a key feature of neurodevelopmental disorders such as autism spectrum disorder, Fragile X syndrome, and Rett syndrome (RTT). RTT is caused by mutations in the X-linked gene methyl-CpG-binding protein 2 (MECP2). It is characterized by an early period of typical development with subsequent regression of previously acquired motor and speech skills in girls. The syndromic phenotypes are individualistic and dynamic over time. Thus far, it has been difficult to capture these dynamics and syndromic heterogeneity in the preclinical Mecp2-heterozygous female mouse model (Het). The emergence of computational neuroethology tools allows for robust analysis of complex and dynamic behaviors to model endophenotypes in preclinical models. Toward this first step, we utilized DeepLabCut, a marker-less pose estimation software to quantify trajectory kinematics and multidimensional analysis to characterize behavioral heterogeneity in Het in the previously benchmarked, ethologically relevant social cognition task of pup retrieval. We report the identification of two distinct phenotypes of adult Het: Het that display a delay in efficiency in early days and then improve over days like wild-type mice and Het that regress and perform worse in later days. Furthermore, regression is dependent on age and behavioral context and can be detected in the initial days of retrieval. Together, the novel identification of two populations of Het suggests differential effects on neural circuitry, opens new avenues to investigate the underlying molecular and cellular mechanisms of heterogeneity, and designs better studies for stratifying therapeutics.

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

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 (Mecp2Heterozygous , 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.

Barrels XXXV: barrels in-person.

PURPOSE OF THE STUDY: After two years of virtual meetings, the Barrels Meeting resumed to an in-person format on 10 and 11 November 2022 in La Jolla California. MATERIALS AND METHODS: The meeting focused on the rodent sensorimotor system, with a focus on integrated information from the cellular to the systems level. A series of invited and selected oral presentations were delivered in addition to a poster session. RESULTS: The latest results in the whisker-to-barrel pathway were discussed. Presentations included how the system encodes peripheral information, motor planning, and is disrupted in neurodevelopmental disorders. CONCLUSION: The 36th Annual Barrels Meeting brought together the research community to effectively discuss the latest advances in the field.

Barrels XXXIV meeting report: Barrels goes virtual.

Objective: To summarize the state of research in the whisker-to-barrel sensorimotor system based on presentations at the Barrels meeting.Methods: Host the 34th annual Barrels meeting was hosted virtually due to the ongoing Covid-19 pandemic.Results: The Barrels meeting annually focuses on the latest advances in the rodent sensorimotor research. The keynotes featured talks on advanced imaging techniques and the role microglia play in shaping neural circuits. The thematic presentations focused on the role of neocortical layer I, neural control of navigation and locomotion and finally on the utility of psychedelic drugs to study perception. The invited speakers were complemented by submitted short talks and poster presentations from the attendees.Conclusions: The 34th Annual Barrels meeting provided a critical review of the state of the field.

Effect of Osteopathic Cranial Manipulative Medicine on an Aged Rat Model of Alzheimer Disease.

CONTEXT: In the aging brain, reduction in the pulsation of cerebral vasculature and fluid circulation causes impairment in the fluid exchange between different compartments and lays a foundation for the neuroinflammation that results in Alzheimer disease (AD). The knowledge that lymphatic vessels in the central nervous system play a role in the clearance of brain-derived metabolic waste products opens an unprecedented capability to increase the clearance of macromolecules such as amyloid ß proteins. However, currently there is no pharmacologic mechanism available to increase fluid circulation in the aging brain. OBJECTIVE: To demonstrate the influence of an osteopathic cranial manipulative medicine (OCMM) technique, specifically, compression of the fourth ventricle, on spatial memory and changes in substrates associated with mechanisms of metabolic waste clearance in the central nervous system using the naturally aged rat model of AD. RESULTS: Significant improvement was found in spatial memory in 6 rats after 7 days of OCMM sessions. Live animal positron emission tomographic imaging and immunoassays revealed that OCMM reduced amyloid ß levels, activated astrocytes, and improved neurotransmission in the aged rat brains. CONCLUSION: These findings demonstrate the molecular mechanism of OCMM in aged rats. This study and further investigations will help physicians promote OCMM as an evidence-based adjunctive treatment for patients with AD.