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    • Our in vitro and in vivo studies

    2018-10-20

    Our in vitro and in vivo studies show an increase in neurogenesis in the presence of CsA. Our findings are consistent with the idea that CsA is enhancing the survival of DG NPCs and these cells proliferate to give rise to newly born neurons. We cannot rule out the possibility that the DG contains a population of latent NPCs which are activated by CsA and promoting their proliferation. Indeed, recent studies have suggested that the neurogenic SVZ of the forebrain contains a population of quiescent neural stem cells (Codega et al,. 2014). A study by Walker et al. (2008) observed a 3-fold increase in the number of neurospheres generated from adult mouse DG following neural excitation using depolarizing levels of potassium chloride. Interestingly, the neural excitation resulted in the increase in the number of neurospheres that gave rise to neurons in vitro. We have previously demonstrated that the mechanism by which CsA promotes the survival of SVZ NPCs is through binding with cyclophilin D and inhibition of mitochondrial pore formation, thereby blocking apoptosis (Sachewsky et al., 2014). We propose a similar mechanism for NPC survival in the DG. However, further investigation is needed to rule out the activation of a latent population of DG NPCs. The observed increase in neurogenesis in vivo has implications for regenerative repair strategies in regard to citco injuries. Injuries in the hippocampus can lead to impaired spatial recognition, learning, and memory. Studies have shown that impairing the process of neurogenesis also impairs spatial recognition and learning (Zhao et al., 2003), highlighting the importance of neurogenesis in these tasks. One study showed that an approximately 3-fold increase in adult mouse neurogenesis through exercise led to approximately 50% improvement in performance in the Morris water maze spatial recognition task over control mice (van Praag et al., 1999). A positive correlation between promoting neurogenesis in the hippocampus and cognitive function recovery has been shown by intraventricular infusion of S100B, a neurotrophic protein secreted by astrocytes, and subsequent cognitive tests using the Morris water maze (Kleindienst et al., 2005). More recently, metformin, a drug used to treat type II diabetes, has also been shown to promote neurogenesis in the hippocampus and improve behavior in the Morris water maze (Wang et al., 2012). Another recent study involving a different factor, prolactin, also showed a correlation between neurogenesis and cognitive function. Mice that were deficient in prolactin exhibited decreased neurosphere formation in vitro and decreased BrdU+ cells in the DG in vivo (Walker et al., 2012). Prolactin-null mice also displayed poorer performance in cognitive tasks such as the Morris water maze and this deficiency was rescued by infusion of prolactin into the hippocampus (Walker et al., 2012). However, it remains unclear as to whether increasing adult hippocampal neurogenesis is sufficient on its own to improve cognitive function as prior studies increased neurogenesis as a consequence of an intervention such as drugs or exercise. One study by Sahay et al. (2011) genetically and cell autonomously increased neurogenesis in the mouse DG and found that while this improved pattern separation tasks, they saw no improvement in spatial learning or memory tasks. Also, hippocampal function can be modified by factors beyond neurogenesis such as dendritic complexity, synaptogenesis, and angiogenesis. Given that existing neurons, glial, and vascular cells far outnumber adult-born neurons, it can be difficult to wholly attribute cognitive functional improvements as a result of an intervention to neurogenesis alone (Ho et al., 2013). Nonetheless, adult neurogenesis plays a role in cognitive functional performance and it remains a key process in age-related cognitive declines, neurodegenerative diseases, and repair after injury (Yau et al., 2014). Our studies show a significant increase in immature neurons after CsA exposure, suggesting that future studies to examine whether CsA leads to improvements in the functional performance of the hippocampus, in normal or diseased conditions, may be warranted.