White matter integrity of the frontal brain and its relevance for catatonia and executive function

Catatonia is a CNS derived psychomotor syndrome comprising disturbed volition and aberrant motor and behavioral features. Targeted and effective treatment today is scarce and further impeded by its heterogeneous clinical representation across various CNS disorders. Moreover, respective research on the etiology and underlying cellular pathomechanisms are hampered by sustained conceptual limitations, inadequate clinical rating scales and the lack of reliable animal models. To this end, we had previously reported a catatonia-like phenotype in C57Bl/6 mice heterozygous for the major myelin genes Cnp and Mbp upon progressed age, along with indications of low-grade neuroinflammation. In the first project of my thesis, I thus addressed the question whether neuroinflammation of subcortical white matter is causative to catatonia in both mice and man. Neurological assessment of schizophrenic subjects (n=1095) revealed a high prevalence of catatonic signs (25%), which were more pronounced in carriers of a CNP loss-of-sunction SNP (rs207106-AA). Additionally, elevated signs of white matter hyperintensities were observed in carriers of the SNP in a general population sample by neuroimaging. Cnp-null mutant mice exhibit catatonic signs as early as 8 weeks of age. Importantly, microglia targeted treatment via the CSF1 receptor inhibitor PLX5622, successfully prevented the occurrence of the phenotype upon early treatment and further alleviated catatonic signs even at progressed age. The beneficial impact of PLX5622 on mouse behavior was accompanied by sustained reduction of neuropathology, i.e. microgliosis and neurodegeneration. Collectively these findings indeed suggest key involvement of impaired white matter integriy and neuroinflammation in the etiology of catatonia. Based on a follow-up study, which revealed a strong correlation of catatonia and executive dysfunction in mice and man, the objective of the second project was to determine the relevance of white matter integrity of the frontal brain in the etiology of the psychomotor syndrome. A novel mouseline, lacking the major myelin gene Plp1 in Emx1 expressing ventricular zone stem cells of the forebrain (cKO), was characterized on a behavioral and neuropathological scope. Longitudinal and elaborate behavioral assessment revealed an isolated catatonia-executive dysfunction in cKO mice of both genders, while no other behavioral domain was affected. Neuropathology revealed significant astro- and microgliosis along with neurodegeneration, exclusively in frontal strucutres such as the fimbria and corpus callosum, thereby confirming the crucial importance of white matter integrity of the frontal brain in the observed catatonia-like phenotype in the here reported mouse models

Myelin dysfunction drives amyloid-β deposition in models of Alzheimer's disease

The incidence of Alzheimer's disease (AD), the leading cause of dementia, increases rapidly with age, but why age constitutes the main risk factor is still poorly understood. Brain ageing affects oligodendrocytes and the structural integrity of myelin sheaths(1), the latter of which is associated with secondary neuroinflammation(2,3). As oligodendrocytes support axonal energy metabolism and neuronal health(4-7), we hypothesized that loss of myelin integrity could be an upstream risk factor for neuronal amyloid-beta (A beta) deposition, the central neuropathological hallmark of AD. Here we identify genetic pathways of myelin dysfunction and demyelinating injuries as potent drivers of amyloid deposition in mouse models of AD. Mechanistically, myelin dysfunction causes the accumulation of the A beta-producing machinery within axonal swellings and increases the cleavage of cortical amyloid precursor protein. Suprisingly, AD mice with dysfunctional myelin lack plaque-corralling microglia despite an overall increase in their numbers. Bulk and single-cell transcriptomics of AD mouse models with myelin defects show that there is a concomitant induction of highly similar but distinct disease-associated microglia signatures specific to myelin damage and amyloid plaques, respectively. Despite successful induction, amyloid disease-associated microglia (DAM) that usually clear amyloid plaques are apparently distracted to nearby myelin damage. Our data suggest a working model whereby age-dependent structural defects of myelin promote A beta plaque formation directly and indirectly and are therefore an upstream AD risk factor. Improving oligodendrocyte health and myelin integrity could be a promising target to delay development and slow progression of AD

Myelin dysfunction drives amyloid-β deposition in models of Alzheimer’s disease

Abstract The incidence of Alzheimer’s disease (AD), the leading cause of dementia, increases rapidly with age, but why age constitutes the main risk factor is still poorly understood. Brain ageing affects oligodendrocytes and the structural integrity of myelin sheaths 1 , the latter of which is associated with secondary neuroinflammation 2,3 . As oligodendrocytes support axonal energy metabolism and neuronal health 4–7 , we hypothesized that loss of myelin integrity could be an upstream risk factor for neuronal amyloid-β (Aβ) deposition, the central neuropathological hallmark of AD. Here we identify genetic pathways of myelin dysfunction and demyelinating injuries as potent drivers of amyloid deposition in mouse models of AD. Mechanistically, myelin dysfunction causes the accumulation of the Aβ-producing machinery within axonal swellings and increases the cleavage of cortical amyloid precursor protein. Suprisingly, AD mice with dysfunctional myelin lack plaque-corralling microglia despite an overall increase in their numbers. Bulk and single-cell transcriptomics of AD mouse models with myelin defects show that there is a concomitant induction of highly similar but distinct disease-associated microglia signatures specific to myelin damage and amyloid plaques, respectively. Despite successful induction, amyloid disease-associated microglia (DAM) that usually clear amyloid plaques are apparently distracted to nearby myelin damage. Our data suggest a working model whereby age-dependent structural defects of myelin promote Aβ plaque formation directly and indirectly and are therefore an upstream AD risk factor. Improving oligodendrocyte health and myelin integrity could be a promising target to delay development and slow progression of AD

Isolated catatonia-like executive dysfunction in mice with forebrain-specific loss of myelin integrity

A key feature of advanced brain aging includes structural defects of intracortical myelin that are associated with secondary neuroinflammation. A similar pathology is seen in specific myelin mutant mice that model ‘advanced brain aging’ and exhibit a range of behavioral abnormalities. However, the cognitive assessment of these mutants is problematic because myelin-dependent motor-sensory functions are required for quantitative behavioral readouts. To better understand the role of cortical myelin integrity for higher brain functions, we generated mice lacking Plp1 , encoding the major integral myelin membrane protein, selectively in ventricular zone stem cells of the mouse forebrain. In contrast to conventional Plp1 null mutants, subtle myelin defects were restricted to the cortex, hippocampus, and underlying callosal tracts. Moreover, forebrain-specific Plp1 mutants exhibited no defects of basic motor-sensory performance at any age tested. Surprisingly, several behavioral alterations reported for conventional Plp1 null mice (Gould et al., 2018) were absent and even social interactions appeared normal. However, with novel behavioral paradigms, we determined catatonia-like symptoms and isolated executive dysfunction in both genders. This suggests that loss of myelin integrity has an impact on cortical connectivity and underlies specific defects of executive function. These observations are likewise relevant for human neuropsychiatric conditions and other myelin-related diseases.Deutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/501100001659Deutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/501100001659Deutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/501100001659Dr. Miriam and Sheldon G. Adelson Medical Research Foundation http://dx.doi.org/10.13039/100005984European Research Council http://dx.doi.org/10.13039/501100000781European Research Council http://dx.doi.org/10.13039/100010663Boehringer Ingelheim Fonds http://dx.doi.org/10.13039/501100001645Max Planck Institute for Multidisciplinary Science

IntelliR: A comprehensive and standardized pipeline for automated profiling of higher cognition in mice

Gastaldi VD, Hindermann M, Wilke JBH, et al. IntelliR: A comprehensive and standardized pipeline for automated profiling of higher cognition in mice. bioRxiv. 2024.In the rapidly evolving field of rodent behavior research, observer-independent methods facilitate data collection within a social, stress-reduced, and thus more natural environment. A prevalent system in this research area is the IntelliCage, which empowers experimenters to design individual tasks and higher cognitive challenges for mice, driven by their motivation to access reward. The extensive amount and diversity of data provided by the IntelliCage system explains the growing demand for automated analysis among users. Here, we introduce IntelliR, a standardized pipeline for analyzing raw data generated by the IntelliCage software, as well as novel parameters including the cognition index, which enables comparison of performance across various challenges. With IntelliR, we provide the tools to implement and automatically analyze 3 challenges that we designed, encompassing spatial, episodic-like, and working memory with their respective reversal tests. Using results from 3 independent control cohorts of adult female wildtype mice, we demonstrate their ability to comprehend and learn the tasks, thereby improving their proficiency over time. To validate the sensitivity of our approach for detecting cognitive impairment, we used adult female NexCreERT2xRosa26-eGFP-DTA mice after tamoxifen induced diphtheria toxin-mediated ablation of pyramidal neurons in cortex and hippocampus. We observed deterioration in learning capabilities and cognition index across several tests. IntelliR can be readily integrated into and adapted for individual research, thereby improving time management and reproducibility of data analysis. **HIGHLIGHTS**IntelliR is a standardized pipeline for analyzing raw data of IntelliCage software.Domains include spatial, episodic-like, and working memory with reversals.WT mice (3 cohorts) comprehend, learn and improve proficiency over time.Cognition index permits comparison of performance across cognitive domains.Mice with ablation of pyramidal neurons decline mainly in working memory.</p

Hippocampal neurons respond to brain activity with functional hypoxia

Physical activity and cognitive challenge are established non-invasive methods to induce comprehensive brain activation and thereby improve global brain function including mood and emotional well-being in healthy subjects and in patients. However, the mechanisms underlying this experimental and clinical observation and broadly exploited therapeutic tool are still widely obscure. Here we show in the behaving brain that physiological (endogenous) hypoxia is likely a respective lead mechanism, regulating hippocampal plasticity via adaptive gene expression. A refined transgenic approach in mice, utilizing the oxygen-dependent degradation (ODD) domain of HIF-1α fused to CreERT2 recombinase, allows us to demonstrate hypoxic cells in the performing brain under normoxia and motor-cognitive challenge, and spatially map them by light-sheet microscopy, all in comparison to inspiratory hypoxia as strong positive control. We report that a complex motor-cognitive challenge causes hypoxia across essentially all brain areas, with hypoxic neurons particularly abundant in the hippocampus. These data suggest an intriguing model of neuroplasticity, in which a specific task-associated neuronal activity triggers mild hypoxia as a local neuron-specific as well as a brain-wide response, comprising indirectly activated neurons and non-neuronal cells