Neuroscience
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The classic hypothesis presents the cerebrospinal fluid (CSF) as the "third circulation," which flows from the brain ventricles through the entire CSF system to the cortical subarachnoid space to eventually be passively absorbed into the superior sagittal sinus through arachnoid granulations. The choroid plexus (CP) represents a key organ in the classic CSF physiology and a powerful biological pump, which exclusively secretes CSF. ⋯ The classic hypothesis cannot provide an explanation for these controversies but the recently formulated Bulat-Klarica-Orešković hypothesis can. According to this hypothesis, CSF production and absorption (CSF exchange) are constant and present everywhere in the CSF system, and although the CSF is partially produced by the CP, it is mainly formed as a consequence of water filtration between the capillaries and interstitial fluid.
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As the predominant mediator of the delayed rectifier current, KV2.1 is an important regulator of neuronal excitability. KV2.1, however, also plays a well-established role in apoptotic cell death. Apoptogenic stimuli induce syntaxin-dependent trafficking of KV2.1, resulting in an augmented delayed rectifier current that acts as a conduit for K+ efflux required for pro-apoptotic protease/nuclease activation. ⋯ By overexpression of a protein derived from the C-terminus of the cognate channel KV2.2 (KV2.2CT), we induced calcineurin-independent disruption of KV2.1 somato-dendritic clusters in rat cortical neurons, without altering the electrophysiological properties of the channel. We observed that KV2.2CT-expressing neurons are less susceptible to oxidative stress-induced cell death. Critically, expression of KV2.2CT effectively blocked the increased current density of the delayed rectifier current associated with oxidative injury, supporting a vital role of KV2.1-somato-dendritic clusters in apoptogenic increases in KV2.1-mediated currents.
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Alzheimer's disease (AD), a debilitating neurodegenerative illness, is characterized by neuronal cell loss, mental deficits, and abnormalities in several neurotransmitter and protein systems. AD is also associated with visual disturbances, but their causes remain unidentified. We hypothesize that the visual disturbances stem from retinal changes, particularly changes in the retinal cholinergic system, and that the etiology in the retina parallels the etiology in the rest of the brain. ⋯ We observed that Tg-SwDI mice showed an initial upregulation of AChR gene expression early on (young adults and middle-aged adults), but a downregulation later on (old adults). Furthermore, transgenic animals displayed significant cell loss in the photoreceptor layer and inner retina of the young adult animals, as well as specific cholinergic cell loss, and increased astrocytic gliosis in the middle-aged adult and old adult groups. Our results suggest that the changes observed in AD cerebrum are also present in the retina and may be, at least in part, responsible for the visual deficits associated with the disease.
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Exercise has been proven to promote learning and memory, and is closely related to increased adult neurogenesis in the hippocampus. In our study, the β subunit of Glycogen synthase kinase-3 (GSK3β) can be significantly regulated by exercise, and the modulation of GSK3β activity can enhance adult neurogenesis and memory. To explore the mechanism by which exercise can improve cognitive function and adult neurogenesis, and the role GSK3β plays in this process, we established a mouse model of voluntary exercise to examine the expression and activity of GSK3β, and its associated signaling pathways, in the hippocampus dentate gyrus. ⋯ The activity of the insulin pathway, which negatively regulates GSK3β, was also increased. Moreover, our results showed that the dopamine D1 receptor (DARP D1) pathway and adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) were also activated, which indicates a relationship between GSK3β and neurogenesis. Overall, our findings demonstrated that voluntary exercise promotes cognition and neurogenesis in the adult mouse dentate gyrus by the regulation of GSK3β expression and activity, which may be implemented through the DARP D1 receptor-signaling pathway.
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Major depression is a common cause of chronic disability. Despite decades of efforts, no equivocally accepted animal model is available for studying depression. We tested the validity of a new model based on the three-hit concept of vulnerability and resilience. ⋯ Urocortin1 neurons became over-active in CMVS-exposed PACAP knock out (KO) mice with MD180 history, suggesting the contribution of centrally projecting Edinger-Westphal nucleus to the reduced depression and anxiety level of stressed KO mice. Serotoninergic neurons of the dorsal raphe nucleus lost their adaptation ability to CVMS in MD180 mice. In conclusion, the construct and face validity criteria suggest that MD180 PACAP HZ mice on CD1 background upon CVMS may be used as a reliable model for the three-hit theory.