Seasonal Plasticity in Steroid-Sensitive Neural Circuits

描述（由申请人提供）：20世纪后期，与现代神经科学发展相关的最重要的范式转变之一是认识到大脑功能的动态变化在一定程度上是常态，而不是例外。这些变化被统称为“神经可塑性”的例子，指的是各种各样的经历可以导致成人神经系统结构和功能的持久变化。了解这种大脑变化是如何被调节的，以及究竟是什么变化，对于全面阐明神经功能至关重要。这些数据对于为临床大脑干预提供科学依据也很重要。在许多物种中，大脑会对环境刺激做出有规律的反应，比如那些调节季节性繁殖时间的刺激。这些变化调节着温带物种在不同季节成功生存和繁殖所需的行为和生理适应。鸣禽（如金丝雀）大脑的季节性变化已成为研究自然发生的激素调节的大脑可塑性的最佳模型系统之一。雄性鸣禽与发声控制有关的脑核体积随季节变化。睾丸素(T)在春天促进神经过程的生长。成年神经发生在鸣禽的大脑中，T促进脑容量增加的一种方式是通过这些大脑区域的神经元募集和存活。社会刺激，如女性的存在，以及单个男性的歌唱活动也可以诱导大脑形态的变化，而不受睾丸激素的影响。我们提出了10个实验，分为5个目的来研究T和其他独立于T的事件如何促进这种成人神经可塑性。在目的1研究提出表征大脑可塑性变化的时间与内分泌条件的变化相关的变化与季节状态的变化，并调查是否有大脑对T作用的反应性的变化作为季节性生殖状态的功能。在Aim II中，我们将系统地研究环境线索和行为事件，以促进独立于T的成人神经可塑性，并研究与歌核体积变化相关的细胞事件。特别是社会线索以及雄性鸣叫产生的变化将被操纵，并且将评估鸣叫核中表达儿茶酚胺合成相关酶的细胞数量和纤维的测量。在目的III中，提出了一项实验来研究T对成人神经可塑性的作用在男性/女性方面可能存在的差异。在Aim IV中，将研究通过特定神经毒素进行的去甲肾上腺素能去神经支配对脑可塑性的T依赖和独立调节的影响。我们将比较这种去神经对T，社会线索和歌唱活动能力的影响，以促进成人季节性神经可塑性。目的五关注双皮质素蛋白在成人神经可塑性中参与细胞迁移的调控及其作用。公共卫生相关性：阐明成人大脑的形态和生理变化如何受到类固醇激素作用和环境刺激的调节，可以为旨在减轻与脑病变或退行性疾病相关的行为缺陷的临床干预提供科学基础。本文提出的研究涉及类固醇激素以及社会、活动依赖和环境刺激对成人大脑变化相关基因的调节。这些基因的调控将被研究，它们可以通过作用于细胞迁移和细胞募集到神经回路的过程来影响成人神经发生。

DESCRIPTION (provided by applicant): One of the most important paradigm shifts associated with the growth of modern neuroscience in late 20th century is the realization of the extent to which dynamic changes in brain function are the norm rather than the exception. These changes are collectively referred to as examples of "neuroplasticity" and refer to the fact that experiences of various sorts can lead to enduring changes in the structure and functioning of the adult nervous system. Understanding how such brain changes are regulated and what exactly changes is essential for a full elucidation of neural functioning. Such data are also important to provide a scientific underpinning for clinical brain interventions. In many species, the brain changes regularly in response to environmental stimuli such as those that regulate the timing of seasonal reproduction. These changes regulate behavioral and physiological adaptations required for temperate zone species to survive and reproduce successfully in different seasons. Seasonal variation in the brain of songbirds (e.g., canaries Serinus canaria) has emerged as one of the best model systems for the study of naturally occurring hormone-regulated brain plasticity. The volume of brain nuclei associated with the control of vocalizations changes with season in male songbirds. Testosterone (T) promotes the growth of neuronal processes in the spring. Adult neurogenesis occurs in the songbird brain and one way that T promotes increases in brain volume is via neuronal recruitment and survival in these brain areas. Social stimuli, such as the presence of a female, as well as song activity of an individual male can also induce changes in brain morphology independently of testosterone. Ten experiments organized into 5 aims are proposed to study how T and other events that act independently of T can promote this adult neuroplasticity. In aim I studies are proposed to characterize the timing of changes in brain plasticity in relation to changes in endocrine condition associated with changes in seasonal state and to investigate whether there are changes in the brain responsiveness to T action as a function of seasonal reproductive state. In Aim II studies of environmental cues and behavioral events known to facilitate adult neuroplasticity independently of T will be systematically investigated in relation to cellular events associated with variation in song nucleus volume. In particular social cues as well as variation in song production by a male will be manipulated and measures of cell numbers and fibers expressing enzymes related to catecholamine synthesis in the song nuclei will be assessed. In aim III an experiment is proposed to investigate possible male/female differences in the action of T on adult neuroplasticity. In Aim IV the effects of noradrenergic denervation via a specific neurotoxin on T- dependent and independent regulation of brain plasticity will be investigated. We will compare the effects of such a denervation on the ability of T, social cues and singing activity to promote adult seasonal neuroplasticity. Aim V focuses on the regulation of and role played by doublecortin a protein involved in cell migration in adult neuroplasticity. PUBLIC HEALTH RELEVANCE: The elucidation of how morphological and physiological changes in the adult brain are regulated by steroid hormone action and environmental stimuli can provide a scientific underpinning for clinical interventions aimed at relieving behavioral deficits related to brain lesions or degenerative disorders. The studies proposed here concern the regulation of genes related to adult brain change by steroid hormones as well as by social, activity-dependent and environmental stimuli. The genes whose regulation will be studied can influence adult neurogenesis via actions on the processes of cell migration and cell recruitment into neural circuits.