Neuroscience
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Activation of the M1 muscarinic acetylcholine receptor (M1R) may be an effective therapeutic approach for Alzheimer's disease (AD), dementia with Lewy bodies, and schizophrenia. Previously, the M1R/M4R agonist xanomeline was shown to improve cognitive function and exert antipsychotic effects in patients with AD and schizophrenia. However, its clinical development was discontinued because of its cholinomimetic side effects. ⋯ Other than in the orbital cortex and claustrum, TAK-071 induced similar c-Fos expression patterns. When donepezil was co-administered to increase the levels of acetylcholine, the number of TAK-071-induced c-Fos-positive cells in these brain regions was increased. TAK-071, through induction of similar neural activation as that seen with xanomeline, may produce procognitive and antipsychotic effects with improved cholinergic side effects.
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Small-for-gestational age (SGA) human newborns have an increased risk of hyperphagia and obesity, as well as a spectrum of neurologic and neurobehavioral abnormalities. We have shown that the SGA hypothalamic (appetite regulatory site) neuroprogenitor cells (NPCs) exhibit reduced proliferation and neuronal differentiation. DNA methylation (DNA methyltransferase; DNMT1) regulates neurogenesis by maintaining NPC proliferation and suppressing premature differentiation. ⋯ In vivo data replicated these findings. In SGA offspring, impaired neurogenesis is epigenetically mediated, in part, via reduction in DNMT1 expression and suppression of Hes1 resulting in NPC differentiation. It is likely that the maturation of regions beyond the hypothalamus (e.g., cerebral cortex, hippocampus) may be impacted, contributing to poor cognitive and neurobehavioral competency in SGA offspring.
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Embryonic light exposure affects similarly functional lateralization in fish and birds. While the light acts on an asymmetric habenular system during the first post fertilization hours in zebrafish, in the domestic chicks it shapes the thalamofugal visual pathway affecting the right retinal photoreceptors in the last stages before hatching. However, recent evidence has shown that also in chicks a precocial embryonic time window seems open to light action. ⋯ The perseveration of pecks directed to irrelevant elements revealed that in all chicks the right hemisphere was heavily attracted by the novel elements when tested with the left eye. When using the right eye, instead, only DK chicks attended repeatedly to distractors whereas LL and EL chicks showed a left hemisphere advantage for fine discrimination and sustained attention; conversely, when tested binocularly, LL chicks perseverated significantly more than both DK and EL chicks, likely compensating the distraction with the analysis carried out by both hemispheres. For the first time, we unveiled a fine graded difference between the light modulation exerted during the two time windows, adding evidence to the idea that genes and environmental factors interplay in several separate routes to the modulation of the neurodevelopment of cerebral lateralization in vertebrates.
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Neurodegenerative diseases such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and Alzheimer's disease (AD) involve loss of cholinergic neurons in the basal forebrain. Here, we investigate how cholinergic dysfunction impacts the frontal cortex during interval timing, a process that can be impaired in PD and AD patients. Interval timing requires participants to estimate an interval of several seconds by making a motor response, and depends on the medial frontal cortex (MFC), which is richly innervated by basal forebrain cholinergic projections. ⋯ Principal component analyses revealed no consistent changes in time-related ramping components, but did reveal changes in higher components. Taken together, these data indicate that scopolamine changes stimulus processing rather than temporal processing in the MFC. These data could help understand how cholinergic dysfunction affects cortical circuits in diseases such as PD, DLB, and AD.
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Tay-Sachs disease (TSD) is a GM2 gangliosidosis lysosomal storage disease caused by a loss of lysosomal hexosaminidase-A (HEXA) activity and characterized by progressive neurodegeneration due to the massive accumulation of GM2 ganglioside in the brain. Here, we generated iPSCs derived from patients with TSD, and found similar potential for neural differentiation between TSD-iPSCs and normal iPSCs, although neural progenitor cells (NPCs) derived from the TSD-iPSCs exhibited enlarged lysosomes and upregulation of the lysosomal marker, LAMP1, caused by the accumulation of GM2 ganglioside. ⋯ TSD-iPSC-derived neurons showed a decrease in exocytotic activity with the accumulation of GM2 ganglioside, suggesting deficient neurotransmission in TSD. Our findings demonstrated that NPCs and mature neurons derived from TSD-iPSCs are potentially useful cellular models of TSD and are useful for investigating the efficacy of drug candidates in the future.