Photoperiod Brain and Behavior

描述(申请人提供)：神经科学的一个主要目标是了解调节大脑可塑性的机制。在人类中，情绪、免疫功能和对脑损伤的反应的季节性变化是有据可查的。我们最近建立了一个光周期诱导大脑结构和功能可塑性的实验模型。雄性Permyscus小鼠在短日内减少了海马区的大小和空间记忆能力；短日照减少了顶端CA1棘密度，增加了基底CA3棘密度，这表明由褪黑素编码的光周期改变了大脑结构和认知功能。我们将使用这个系统来了解推动这些变化的因素。目标1：大脑形态和认知功能的哪些方面对光周期或褪黑素有反应？我们将研究以下方面的变化：(1)海马体积/树突状细胞形态，(2)海马神经发生，(3)长时程增强(LTP)，(4)学习和记忆。目的2：性腺类固醇激素在光周期诱导的脑可塑性中的作用是什么？我们将检测长日照和短日照小鼠的芳香酶活性、雄激素(AR)和雌激素受体(ER)亚型(ER1和ER2)的表达，并确定性腺切除或AR和/或ER受体拮抗剂治疗是否消除了大脑可塑性的光周期差异。目的3：光周期和雄激素如何影响脑源性神经营养因子和脑的可塑性？使用qRT-PCR，光周期和雄激素对BDNF的影响将被评估。目的4：光周期影响大脑和行为可塑性的时间进程是什么？我们将在光周期转换的不同时间点对小鼠进行检查。此外，由于出生季节影响许多人类神经疾病，我们将检查光周期对出生在长日或短日，然后在相同或相反的光周期中饲养的小鼠的大脑和行为的持久影响。我们的组合方法将为季节性认知和情感障碍、发育障碍的治疗提供洞察力，并有助于建立大脑可塑性的一般机制。公共卫生相关性光周期对大脑和行为可塑性的作用尚未得到充分研究。传统上，对季节性大脑可塑性感兴趣的神经科学家一直专注于鸣禽。这一建议为季节性研究以及大脑和行为可塑性的研究增加了一个新的维度。我们所有提出的研究背后的工作假设是，短白天与个人转换资源以获得能量储蓄有关。换句话说，我们将大脑和海马体大小、树突棘、神经发生以及空间学习和记忆能力的短期变化视作是由于依赖于光周期、生物钟和褪黑素的能量条件的变化而产生的适应。尤其重要的是，假设某些人类疾病的季节性变化可能至少部分归因于大脑结构和功能的光周期效应的变化。人类的进化史表明，几乎所有的智人祖先都曾生活在这样或那样的情况下，生理上的季节性调整可能被证明是有利的。尽管现有数据表明，现代人的生殖不容易受到光周期调节的影响，但大脑的可塑性和行为功能可能会很好地受到光周期调节的影响。这种可能性值得认真考虑。重要的是，神经内分泌功能、下丘脑加压素、血管活性肠肽(VIP)和5-羟色胺功能的季节性变化也已在人类中被报道。人类行为病理的季节性变化也可以在焦虑和抑郁、偏头痛以及中风的发生率、严重性和死亡率中观察到。因此，尽管生殖功能相对缺乏季节性组织，但很明显，人类保持对光周期的反应，光周期介导的啮齿动物大脑和行为的调节可能对于了解人类大脑和行为的季节性变化可能是重要的。

DESCRIPTION (provided by applicant): A major goal of neuroscience is to understand the mechanisms mediating brain plasticity. Among humans, seasonal alterations in mood, immune function, and response to brain damage are well-documented. We recently established an experimental model of photoperiod-induced plasticity in brain structure and function. Male Peromyscus mice reduce hippocampal size and spatial memory performance in short days; short days decrease apical CA1 spine density and increase basilar CA3 spine density suggesting that photoperiod, encoded by melatonin, alters brain structure and cognitive function. We will use this system to understand the factors driving such changes. Aim 1: What aspects of brain morphology and cognitive function respond to photoperiod or melatonin? We will study changes in: (1) hippocampal volume/dendritic morphology, (2) hippocampal neurogenesis, (3) long-term potentiation (LTP), and (4) learning and memory. Aim 2: What is the role of gonadal steroid hormones in mediating photoperiod-induced brain plasticity? We will examine aromatase activity, androgen (AR), and estrogen receptor (ER) subtype (ER1 and ER2) expression in long- vs. short-day mice, and determine whether gonadectomy or treatment with AR and/or ER receptor antagonists eliminates photoperiodic differences in brain plasticity. Aim 3: How does photoperiod and androgen affect brain-derived neurotrophic factor (BDNF), and brain plasticity? Using qRT-PCR, photoperiod and androgen effects on BDNF will be assessed. Aim 4: What is the time course by which photoperiod affects brain and behavioral plasticity? We will examine mice at different time points during the switch between photoperiods. Also, because season of birth influences many human neurological disorders, we will examine the enduring effects of photoperiod on brain and behavior of mice born in long or short days, then reared in the same or opposite photoperiod. Our combinatorial approach will provide insight into the treatment of seasonal cognitive and affective disorders, developmental disabilities, and help establish general mechanisms underlying brain plasticity. PUBLIC HEALTH RELEVANCE The role of photoperiod on brain and behavioral plasticity is understudied. Traditionally, neuroscientists interested in seasonal brain plasticity have focused on songbirds. This proposal adds a novel dimension to the study of seasonality, as well as the study of brain and behavioral plasticity. The working hypothesis underlying all of our proposed studies is that short days are associated with individuals switching resources to gain energetic savings. In other words, we visualize short-day changes in brain and hippocampal size, dendritic spines, neurogenesis, and spatial learning and memory performance as adaptations due to changing energetic conditions that are dependent on photoperiod, biological clocks, and melatonin. Of particular importance is the postulate that seasonal variation in certain human disorders may be due at least in part to variation in photoperiodic effects of brain structure and function. The evolutionary history of humans suggests that almost all ancestral stocks of Homo sapiens have lived at one time or another in situations where seasonal adjustments in physiology might have proven advantageous. Although the available data suggest that modern human reproduction is not susceptible to photoperiodic regulation, brain plasticity and behavioral function very well might be. This possibility deserves serious consideration. Importantly, seasonal changes in neuroendocrine function, hypothalamic expression of vasopressin, vasoactive intestinal polypeptide (VIP), and serotonin function have also been reported in humans. Seasonal changes in human behavioral pathology are also observed in anxiety and depression, migraine headaches, as well as incidence, severity, and mortality of strokes. Thus, despite the relative lack of seasonal organization of reproductive function, it is apparent that humans retain responsiveness to photoperiod, and that photoperiod-mediated adjustments in rodent brain and behavior may be important to understand seasonal changes in human brain and behavior.