Neuroscience
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Synaptic decay and neurodegeneration are hallmarks of Alzheimer's disease that are thought to precede dementia. Recently, we have reported that the first signs of neuritic dystrophy in a new transgenic mouse model of familial Alzheimer's disease (FAD) called the "5xFAD" are axonal dystrophy followed by loss of spines on basal dendrites. The 5xFAD mouse has profound loss of layer 5 neurons by 12months, and these initial structural insults appear between 4 and 6months of age. ⋯ We found these neurons to be structurally and morphologically sound. In parallel, we used in vitro, whole-cell patch clamp electrophysiology of layer 5 pyramidal neurons, from mice aged 8-12weeks, to reveal significant pre- and postsynaptic defects in these cells. Thus our data suggest that layer 5 neurons in the 5xFAD mouse model have synaptic deficits at an early time point, before any overt structural dystrophy, and that such synaptic failure, with co-temporal biochemical changes, may be an early step in neuronal loss.
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In the first week of postnatal life of all examined mammalian species, there is a wave of apoptosis in the cerebral cortex, accounting for a loss of up to 30% of neuronal content from birth to adulthood. In this review we examine recent advances in the understanding of this curious phenomenon. ⋯ In addition, we discuss pathophysiological situations in which a variety of common drugs used either recreationally or for medical purposes, or pharmacological blockade of N-methyl-d-aspartate receptor (NMDAR) function, can also cause massive levels of apoptosis in this same developmental window. Experimentation linking molecular causes of developmental and pathophysiological apoptosis in postnatal cerebral cortex is discussed.
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Chemical communication is widely used among various organisms to obtain essential information from their environment required for life. Although a large variety of molecules have been shown to act as chemical cues, the molecular and neural basis underlying the behaviors elicited by these molecules has been revealed for only a limited number of molecules. ⋯ Discussing the molecules utilized by mice, insects, and the worm, we focus on how each organism has optimized its reception system to suit its living style. We also highlight how the production of these signaling molecules is regulated, an area in which considerable progress has been recently made.
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Müller cells are not only the main glial cell type in the retina but also latent progenitor/stem cells, which in pathological conditions can transdifferentiate to a neuronal phenotype and regenerate the neurons lost in a mature retina. Several signal transduction pathways can induce the dedifferentiation of mature Müller cells to a progenitor-like state, including that stimulated by glutamate. However, the precise molecular mechanisms by which terminally differentiated cells are initially primed to acquire multipotency remain unclear. ⋯ Importantly, the expression of Müller glia identity genes (i.e., glutamine synthetase; cellular retinaldehyde binding protein, CRALBP) is retained through the process. Dedifferentiated Müller cells held an early neuronal differentiation potential similar to that observed in retinal progenitor-enriched cultures but, contrary to the latter, dedifferentiated Müller cells failed to further differentiate into mature photoreceptor lineages. We speculate that, in spite of the initial triggering of the dedifferentiation pathways, these cells may exhibit a certain degree of epigenetic memory that precludes them from further differentiation.
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Nitric oxide (NO) has been implicated in the regulation of sleep. The perifornical-lateral hypothalamic area (PF-LHA) is a key wake-promoting region and contains neurons that are active during behavioral or cortical activation. Recently, we found higher levels of NO metabolites (NOx), an indirect measure of NO levels, in the PF-LHA during prolonged waking (SD). ⋯ NO levels increased during 3h of SD as compared to undisturbed control (0.58±0.04μM vs. 0.47±0.01μM; p<0.05). The findings indicate that in the PF-LHA, NO is produced during behavioral or cortical activation. Since elevated levels of NO inhibits most of the PF-LHA neurons that are active during cortical activation, these findings support a hypothesis that NO produced in conjunction with the activation of PF-LHA neurons during waking/SD, inhibits the same neuronal population to promote sleep.