Can platelets mediate adult hippocampal neurogenesis and cognitive function in the aged brain?

成人大脑的海马体对学习和记忆至关重要。在包括人类在内的哺乳动物中，它也代表了一个独特的位置，在那里成年神经发生。在这个过程中，神经干细胞在整个生命过程中产生新的神经元。成年出生的神经元参与认知能力的维持和改善，突出了这一过程在认知障碍条件下的重要性，包括生理性衰老和神经退行性疾病。神经发生的速度可能受到生活方式因素的影响，运动可以显著增加海马中增殖的神经前体细胞的数量。然而，这一现象背后的分子机制尚不清楚。我们最近发现血小板介导运动诱导的成年海马神经发生的增加，在小鼠跑步后血小板被特异性激活。此外，在血液中血小板数量减少的小鼠中，跑步引起的神经前体细胞增殖增加被消除。目前尚不清楚血小板如何通过血脑屏障与神经前体细胞进行物理分离，以及血小板介导的海马神经发生增加是否可以改善认知功能。在本项目中，我们将首先研究血小板-神经前体细胞相互作用的机制。我们将确定血小板是否在运动后积聚在靠近神经前体细胞的海马体中，以及这些脑细胞是否吞噬血小板颗粒。此外，我们将确定这些相互作用是否通过候选蛋白14-3-3 γ介导，该蛋白具有促神经发生作用，并且在运动后血小板中显着增加。其次，我们将研究血小板治疗是否可以增加老年小鼠模型的神经发生和恢复认知功能，表现出与老年人相似的海马相关学习和记忆障碍。最后，在主办机构，我们还获得了一项临床试验参与者的血浆样本，该试验正在研究锻炼对老年人认知能力的益处。我们将确定血小板释放激活标志物血小板因子4在运动后是否发生变化。然后，我们将把这些测量结果与认知分析的结果联系起来，以确定血小板活性是否与老年人学习和记忆的改善有关。这些实验将共同确定血小板是否包含一个内源性储存库，可以用于开发治疗干预措施，以促进衰老和疾病中的认知功能。

The hippocampus of the adult brain is crucial for learning and memory. In mammals, including humans, it also represents a unique location, where adult neurogenesis occurs. During this process new neurons are generated from neural stem cells throughout life. The adult-born neurons are involved in the maintenance and improvement of cognitive abilities, highlighting the importance of this process in conditions with cognitive impairments, including physiological ageing and neurodegenerative diseases. The rate of neurogenesis can be influenced by lifestyle factors, with exercise producing a significant increase in the number of proliferating neural precursor cells in the hippocampus. However, the molecular mechanisms underlying this phenomenon are still unknown. We recently showed that platelets mediate the exercise-induced increase in adult hippocampal neurogenesis, with platelets becoming specifically activated in mice following running. Moreover, the running-induced increase in neural precursor cell proliferation was abolished in mice with a reduced number of platelets in their blood. It is still unclear how platelets communicate with the neural precursor cells due to their physical separation by the blood brain barrier, and whether the platelet-mediated increase in hippocampal neurogenesis can improve cognitive function. In this project, we will first investigate the mechanisms of platelet–neural precursor cell–interactions. We will determine whether platelets accumulate in the hippocampus close to neural precursor cells following exercise and if these brain cells engulf platelet particles. Moreover, we will determine if these interactions are mediated via the candidate protein 14-3-3 gamma, which has pro-neurogenic effects and is significantly increased in platelets following exercise. Secondly, we will investigate whether platelet treatment can increase neurogenesis and restore cognitive function in the aged mouse model, exhibiting similar hippocampus-related learning and memory impairments to those observed in elderly humans. Finally, at the host institute, we also have access to plasma samples from the participants of a clinical trial, in which the benefits of exercise on the cognitive abilities of aged humans are currently being investigated. We will determine whether the platelet-released activation marker platelet factor 4 changes following exercise. We will then correlate these measures with the results of the cognitive analyses to determine if platelet activity is associated with improvements in learning and memory in aged humans. Together these experiments will determine whether platelets comprise an endogenous reservoir that could be harnessed for the development of therapeutic interventions to promote cognitive function in ageing and disease.