Basic mechanisms regulating neuronal excitability and cognitive functions

背景技术背景：与自然衰老相关的记忆力下降归因于记忆过程所必需的大脑回路中神经元可塑性不足。 大脑回路中的信息传输是通过突触上的化学信号传输来实现的。然后，这个化学信号被转化为电信号（神经元放电），将信息传递给下一个神经元，这一过程受到神经元内在兴奋性的严格控制。虽然年龄对化学信号传递的影响已经得到了广泛的研究，但我们对时间如何改变神经元的内在兴奋性知之甚少。这一点至关重要，因为内在兴奋性的调节是控制神经元进行突触可塑性从而形成记忆的关键机制。今天，我们知道调节神经元兴奋性的细胞机制不是静态的，而是不断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。识别这些衰老的分子靶点及其相关的细胞功能，并研究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关键。*sigma-1受体（1）是一种神秘的蛋白质，参与调节内在兴奋性，即，神经元产生电信号的能力，以及学习和记忆。有趣的是，*1激活对记忆的有益影响在老年人中比年轻人更明显。一个有趣的潜在候选机制是1通过时间调节神经元内在兴奋性的差异能力。* 长期目标：识别和研究调节神经元内在兴奋性、突触可塑性的基本细胞机制，以及这些机制如何促进记忆的形成。为此，我们将联合收割机的方法从分子、细胞到行为分析结合起来。短期和长期目标：研究1的前可塑性和 *promnesic属性，旨在 * 获得1* 在整个过程中的作用的机制见解

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