Neuroscience
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The A5 area at the ventrolateral pons contains noradrenergic neurons connected with other medullary areas involved in the cardiorespiratory control. Its contribution to the cardiorespiratory regulation was previously evidenced in anesthetized conditions. In the present study, we investigated the involvement of the A5 noradrenergic neurons to the basal and chemoreflex control of the sympathetic and respiratory activities in unanesthetized conditions. ⋯ In adult rats, lesions of A5 noradrenergic neurons did not modify the reflex cardiorespiratory adjustments to hypoxia (7% O2) and hypercapnia (7% CO2). In the in situ preparations, the sympatho-excitation, but not the PN reflex response, elicited by either the stimulation of peripheral chemoreceptors (ΔtSN: 110±12% vs 58±8%, P<0.01) or hypercapnia (ΔtSN: 9.5±1.4% vs 3.9±1.7%, P<0.05) was attenuated in A5-lesioned rats compared to controls. Our data demonstrated that A5 noradrenergic neurons are part of the circuitry recruited for the processing of sympathetic response to hypoxia and hypercapnia in unanesthetized conditions.
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Wntless (Wls) is implicated in the Wnt signaling pathway by regulating the secretion of Wnt molecules. During brain development, Wls is expressed in the isthmic organizer (ISO) and rhombic lip (RL). Wls regulates Wnt1 secretion at the ISO which is required to induce midbrain-hindbrain structures. ⋯ The Wls-cKO cerebellum also exhibits ectopia of several cell types and aberrations in granule cell organization. Finally, there is a loss of 85% of unipolar brush cells. From these findings, Wls-expressing cells in the rhombic lip are implicated in the orchestration of cerebellar development.
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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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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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A challenge in working with preclinical models of neurodegeneration has been how to non-invasively monitor disease progression. Neurofilament proteins are established axonal damage markers and have been found to be elevated in cerebrospinal fluid (CSF) and blood from patients with neurodegenerative disorders like Alzheimer's disease (AD), Parkinson's disease (PD) and tauopathies. We hypothesized that CSF neurofilament light (NF-L) can be used to track progression of neurodegeneration and potentially monitor the efficacy of novel therapeutic agents in preclinical development. ⋯ We found a significant correlation between CSF NF-L and plasma NF-L in Tg4510, suggesting a similar biomarker potential of plasma NF-L. Also, CSF NF-L correlated significantly with tau in Tg4510 brains, suggesting a surrogate biomarker potential of CSF NF-L. Overall, our findings provide further evidence that NF-L correlates with disease severity and our results suggests, that CSF NF-L has utility as a surrogate or adjunct biomarker for neurodegeneration in the Tg4510 model, but independent validation is warranted.