Mechanisms of experience-dependent hippocampal neurogenesis

我的NSERC资助的研究项目解决了生活经历如何塑造大脑结构和功能的问题。可塑性，或通过生活经验动态改变的能力，是大脑的定义特征之一。海马区神经干细胞产生新神经元就是这种可塑性的一种形式。海马区是一种涉及学习、记忆和情绪的结构。通过关注海马神经发生的这一过程，我们的长期目标是开发一个从行为到基因的综合模型，研究生活经验如何调节大脑功能。 老鼠是研究这个问题的一个简单但强大的哺乳动物模型，因为它们的生活环境可以被严格控制，它们可以被用来进行基因操作来测试特定的假设，它们的大脑功能可以通过学习、记忆和情绪测试来测量。被安置在丰富环境(EE)中的小鼠有更好的学习和记忆以及更多的海马神经发生，但长期以来一直不清楚EE元素是什么起作用(体育锻炼？认知挑战？社会等级制度？压力？感觉刺激？)。在这个研究计划的前一阶段，我的受训人员克服了这一主要障碍，开发了一种新的EE策略，成功地分离了这些因素的影响(我们的第一个主要目标)。我们现在正在测试这些因素中的每一个是否都有助于学习、记忆和/或情绪的变化。 我们的第二个主要目标是确定在海马体本身水平上发生的基因变化，以响应每个EE因子。我的博士后和博士后学生正在合作，使用尖端的遗传和质谱学方法来揭示海马体功能变化的局部中介。我们的第三个主要目标是识别循环信号，丰富的环境通过这些信号与海马体“对话”，从而触发这些基因变化。我的第一个博士后学生正在测试一个特定的假设，即EE诱导的荷尔蒙波动是神经发生变化的系统性中介。 我们的研究计划将产生对环境-大脑相互作用的基本见解。这些研究将提供一个综合的、多层次的分析，将生活经历与大脑基因表达和干细胞活动的变化联系起来。HQP将接受从行为到基因层面的多样化培训，代表着学术界、干细胞行业和政府监管职位的宝贵、专门和多才多艺的专业知识。

My NSERC-funded research program tackles the question of how life experience shapes brain structure and function. Plasticity, or the ability to be dynamically changed by life experience, is one of the brain's defining features. The production of new neurons by neural stem cells in the hippocampus, a structure involved in learning, memory and emotion, is one such form of plasticity. By focusing on this process of hippocampal neurogenesis, our long-term goal is to develop an integrated model, from behaviour to genes, of how life experience regulates brain function. Mice are a simple but powerful mammalian model for studying this question, as their living environments can be tightly controlled, they can be used for genetic manipulations to test specific hypotheses, and their brain function can be measured using tests of learning, memory and emotion. Mice housed in an enriched environment (EE) have better learning and memory and more hippocampal neurogenesis, but it has long been unclear what EE elements are responsible (Physical exercise? Cognitive challenges? Social hierarchies? Stress? Sensory stimulation?). In the preceding stage of this research program, my trainees overcame this major hurdle, developing a novel EE strategy that successfully separates the impact of such factors (our first major goal). We are now testing whether each of these factors contributes to changes in learning, memory and/or emotions. Our second major goal is to identify genetic changes occurring at the level of the hippocampus itself in response to each EE factor. My PhD and postdoc students are collaborating using cutting-edge genetic and mass spectrometry approaches to uncover the local mediators of change in hippocampal function. Our third major goal is to then identify the circulating signals by which an enriched environment “talks” to the hippocampus to trigger these genetic changes. My first postdoc student is testing the specific hypothesis that EE-induced hormonal fluctuations are systemic mediators of neurogenesis changes. Our research program will generate fundamental insights into environment-brain interactions. These studies will provide an integrated, multi-level analysis that links life experiences to changes in brain gene expression and stem cell activity. HQP will receive training that is diverse, from the behavioural to the genetic levels, representing valuable, specialized and versatile expertise for positions in academia, stem cell industry, and government regulation.