Basic mechanisms regulating neuronal excitability and cognitive functions

背景：记忆力下降与 与自然衰老的关系归因于大脑中神经元可塑性不足 存储过程所需的电路。 内部信息传输 大脑回路通过 突触传递化学信号的过程。这种化学信号 转化为电信号（神经元放电）， 信息传递到下一个神经元，这是一个由神经元严格控制的过程。 内在兴奋性而 年龄对化学信号传递的影响已被广泛研究， 然而，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一种关键机制， 控制神经元经历突触可塑性的能力， 记忆形成今天，我们知道， 调节神经元兴奋性的机制不是静态的，而是 不断受到不断变化的生理环境，如 参与记忆过程的关键蛋白质的年龄驱动变化。识别此类 衰老的分子靶点，它们相关的细胞功能，以及 它们如何促进学习和记忆是我们理解 时间影响认知功能的机制。的 sigma-1受体（1）是 一种神秘的蛋白质 在内在兴奋性的调节中，即，神经元产生电流的能力 信号和学习记忆有趣的是， 1激活内存更多 与年轻人相比，老年人更明显。一个有趣的潜在的 候选机制是1随时间调节神经元内在兴奋性的不同能力。 长期目标：确定和审查 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。到 为此，我们将联合收割机的方法从分子、细胞到行为 分析。 短期和长期目标：研究前可塑性和 1的性能，旨在 获得对1的作用的机械见解 在整个过程中，

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