Stimulus dosing in electroconvulsive therapy and the threshold multiple method.

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.

Cerebral Cortex↗

PubMed2002

Abnormal expression of cdk5 in focal cortical dysplasia in humans.

Focal cortical dysplasia (FCD) is an important cause of refractory epilepsy in humans. The origin of its pathognomonic abnormal cell types and the links between abnormal cell morphology and epileptogenicity remain unknown. The developmentally-regulated kinase cdk5 and its neuronal activator p35 are known to be central to a number of key components in neuronal development, cellular morphology, cytoskeletal function, synaptic plasticity and neurodegeneration. Here we examine eight cases of human FCD for expression of cdk5. We show abnormal cdk5 immunoreactivity and aggregation of protein suggesting alterations in cdk5 may also be involved in this important epileptogenic human pathology.

Cerebral Cortex↗

PubMed2002

Multi-directional shifts of optokinetic responses to binocular-rivalrous motion stimuli.

Previous dichoptic experiments showed that dissimilar stationary pattern stimuli resulted in the perception of binocular rivalry, whereas oppositely-directly moving grating stimuli resulted in alternating optokinetic nystagmus (OKN) and the perception of binocular motion rivalry. The present study extended these dichoptic motion experiments by introducing obliquely-oriented targets with the aim of probing further the cortical mechanisms underlying binocular processing of motion. Two-dimensional eye movements were recorded along with their subjective perceptual responses. The stimuli consisted of two tilted gratings, one moving diagonally upwards and to the right (UR, 45 degrees ) and the other diagonally upwards and to the left (UL, 135 degrees ), which were presented dichoptically to subjects under two stimulus modes. For the non-exchange mode, the OKN slow phases exhibited three types of directional shifts. Two of these directional shifts tracked the stimuli (i.e. UR or UL), whereas the third moved purely upwards (UP). Since physically there was no upward-moving target, the OKN and perceptual responses appeared to be associated with a perceptual interocular grouping of the two dichoptic stimuli in their reassembled vector-sum direction. The OKN shifts were also found to be highly correlated with the psychophysical responses of motion perception. For the rapid-exchange mode, in which the stimuli were rapidly exchanged between the two eyes, the OKN slow phases exhibited primarily two types of directional shifts, UR and UL, but no UP responses for most subjects. It also appeared that these two coherent motion percepts, UL and UR, were interocularly regrouped from the exchanged stimuli. Moreover, the lack of perceptual grouping to create an UP response in the rapid-exchange mode indicated that temporal integration of at least 200 ms was necessary for the development of a reassembled vector-sum-direction motion percept. The findings under both stimulus modes support the stimulus-feature rivalry hypothesis, in which higher cortical centers mediate interocular perceptual grouping and the associated motor response.

Cerebral Cortex↗