PubMed · 13696971
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T I ENTIN. 1960. [Synapses in the visual cortex].. https://pubmed.ncbi.nlm.nih.gov/13696971/
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DNA packaging into heterochromatin is a fundamental mechanism of transcriptional silencing, yet its role in regulating neural progenitor behavior during brain development remains poorly understood. Trimethylation of histone H3 lysine 9 (H3K9me3), catalyzed by the methyltransferases SETDB1, SUV39H1, and SUV39H2, is a defining feature of heterochromatin, but functional redundancy among these enzymes has obscured their developmental roles. Here, we generated a cortex-specific triple knockout mouse model lacking Setdb1, Suv39h1, and Suv39h2 to directly interrogate H3K9me3 function during corticogenesis. Combined loss of H3K9 methyltransferases caused genome-wide depletion of H3K9me3, disruption of neural progenitor cell-cycle progression, and impaired cortical neurogenesis, resulting in microcephaly. H3K9 methyltransferases preserve neural progenitor identity and function by silencing clustered protocadherins, meiosis-associated genes, and a cell-cycle restraint program through H3K9me3 deposition. Loss of H3K9me3 promoted local chromatin opening and increased transcription factor occupancy, enabling transposable elements to acquire cryptic enhancer activity and modulate proximal gene expression. Together, these findings establish H3K9me3 heterochromatin as an active regulator of neural progenitor dynamics and lineage fidelity, revealing a central epigenetic mechanism that restricts aberrant transcriptional programs to ensure cortical growth.
To address computational "scale-up" issues in modeling large regions of the cortex, many coarse-graining procedures have been invoked to obtain effective descriptions of neuronal network dynamics. However, because of local averaging in space and time, these methods do not contain detailed spike information and, thus, cannot be used to investigate, e.g., cortical mechanisms that are encoded through detailed spike-timing statistics. To retain high-order statistical information of spikes, we develop a hybrid theoretical framework that embeds a subnetwork of point neurons within, and fully interacting with, a coarse-grained network of dynamical background. We use a newly developed kinetic theory for the description of the coarse-grained background, in combination with a Poisson spike reconstruction procedure to ensure that our method applies to the fluctuation-driven regime as well as to the mean-driven regime. This embedded-network approach is verified to be dynamically accurate and numerically efficient. As an example, we use this embedded representation to construct "reverse-time correlations" as spiked-triggered averages in a ring model of orientation-tuning dynamics.
Parkinson disease is the most common cause of parkinsonism, but other causes should always be excluded because they have a different prognosis, respond differently to medical treatment, and should not be managed by surgical means. However, diagnosis, even by experts, is challenging; one autopsy series showed an error rate of 24%. Distinction between various diagnostic possibilities depends on the history and examination findings. The use of certain medications, the rapid rate of disease progression, early onset of falling, the presence of certain dysautonomic symptoms, cognitive or behavioral changes, or a history of poor response to dopaminergic therapy may suggest an atypical form of parkinsonism. Postural hypotension, dementia, supranuclear ophthalmoparesis, or early postural instability should alert the examiner to consider an atypical cause of parkinsonism. Tests of autonomic function and brain imaging are often helpful in distinguishing these diseases.