Basic mechanisms regulating neuronal excitability and cognitive functions

背景：记忆力下降与 自然衰老归因于大脑中神经元可塑性的缺陷 存储过程所必需的电路。 在内部传递信息 大脑回路通过 化学信号在突触处的传递。这个化学信号就是 转化为电信号(神经元放电)，将传达 信息传递给下一个神经元，这是一个由神经元严密控制的过程 内在的兴奋性。而当 年龄对化学信号传递的影响已被广泛研究 经过研究，我们对时间如何改变神经元的内在兴奋性知之甚少。这 是至关重要的，因为内在兴奋性的调节是 控制神经元经历突触可塑性的能力，从而 记忆的形成。今天，我们知道细胞 调节神经元兴奋性的机制不是静态的，而是 不断地受到不断变化的生理环境的影响，例如 参与记忆过程的关键蛋白质的年龄驱动变化。确定这样的 衰老的分子靶点及其相关的细胞功能，并检查 它们对学习和记忆的贡献是我们理解 时间影响认知功能构建块的机制。这个 Sigma-1受体(1)是 一种神秘的蛋白质参与其中 在内在兴奋性的调节中，即神经元产生电的能力 信号，以及学习和记忆。有趣的是， 1激活内存更多 与年轻人相比，在老年人中表现明显。一个耐人寻味的潜在因素 候选机制是1随着时间的推移调节神经元内在兴奋性的差异能力。 长期目标：识别和检查根本 调节神经元内在兴奋性的细胞机制，突触 可塑性，以及这些机制如何有助于记忆的形成。至 为此，我们结合了从分子、细胞到行为的各种方法 分析。 短期和长期目标：检查促可塑性和 1的促记忆性，目的是 对1的角色有机械性的见解 在这些整个过程中

BACKGROUND: Memory decline associated with natural aging is attributed to deficient neuronal plasticity in brain circuits necessary for memory processes. Transmission of information within brain circuits occurs via transmission of a chemical signal at synapses. This chemical signal is then translated into an electrical signal (neuronal firing) that will convey information to the next neuron, a process that is tightly controlled by neuronal intrinsic excitability. While the effects of age on the transmission of the chemical signal has been extensively studied, we know little on how time alters neuronal intrinsic excitability. This is critical as the modulation of intrinsic excitability is a key mechanism that controls the capability of neurons to undergo synaptic plasticity and thereby memory formation. Today, we know that cellular mechanisms that regulate neuronal excitability are not static, but are continuously subjected to an ever-changing physiological milieu, such as age-driven changes of key proteins involved in memory processes. Identifying such molecular targets of aging, their associated cellular functions, and examining how they contribute to learning and memory is key to our understanding of the mechanisms by which time affects the building blocks of cognitive functions. The sigma-1 receptor (1) is an enigmatic protein involved in both the regulation of intrinsic excitability, i.e., the ability of a neuron to generate the electrical signal, and learning and memory. Interestingly, the beneficial effect of 1 activation on memory is more pronounced in aged individuals compared to young. An intriguing underlying candidate mechanism is the differential ability of 1 to regulate neuronal intrinsic excitability through time. LONG-TERM GOAL: To identify and examine fundamental cellular mechanisms regulating neuronal intrinsic excitability, synaptic plasticity, and how these mechanisms contribute to memory formation. To this end, we combine approaches ranging from molecular, cellular, to behavioral analyses. SHORT- AND LONG-TERM objectives: To examine pro-plasticity and promnesic properties of 1, aiming to gain mechanistic insights into the role of 1 in these processes across the whole