Stress sensitization during the juvenile period in rodents: Impact of neurotrophins and behavioral flexibility

啮齿类动物幼年期的应激敏化：神经营养素和行为灵活性的影响

• 批准号: RGPIN-2016-06139
• 负责人: Anisman, Hymie
• 金额: $ 2.99万
• 依托单位: Carleton University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=616122
• 关键词: Stress; sensitization; during; juvenile; period

Stressors may engender the ‘sensitization’ of neurobiological processes (e.g., neurotransmitter, hormone and growth factors) so that later responses to stressors are markedly exaggerated. As well, ‘cross-sensitization’ effects may occur wherein a stressor augments the later response to a different challenge (e.g., cocaine or immune acting agents). Sensitization effects in rodents can occur at any age, but are especially pronounced if the stressor was initially encountered in early life (first few postnatal days) or during the adolescent (juvenile) period. These sensitization effects have variously been attributed to altered sensitivity of particular receptors in brain, or altered growth factor functioning, some of which may stem from epigenetic changes.It is commonly thought that stressors at critical times necessarily have adverse effects. This may be true of strong stressors owing to reduced BDNF functioning. However, mild, tolerable stressors during early life, by increasing BDNF functioning, may enhance an animal’s capacity to deal with later stressors, possibly through sensitized BDNF functioning might similarly be engendered upon later stress re-exposure, which may favor greater neurobiological and behavioral flexibility. There is yet another important element that needs to be considered in this context. Although endogenously diminished BDNF functioning, may have negative behavioral consequences, in some instances this may actually have positive effects. Adequate BDNF functioning augments synaptic plasticity, and thus an organism may gain from positive early life experiences, and be negatively affected by stressful encounters. In the absence of adequate BDNF functioning, the organism will be less likely to gain from early life positive experiences, but on the flip side, they will also be less likely to be damaged by stressful experiences.The proposed studies will assess the hypothesis that mild social stressors or fairly strong challenges encountered during the juvenile period (PND 28-30) will, respectively, enhance or disrupt later (during adulthood) cognitive flexibility in problem solving tests as well as behavior in social situations. These changes will be paralleled by neurotrophin and receptor variations. Moreover, by using genetically engineered strains of mice (conditional knockouts) we will determine whether the absence of genes for BDNF (knocked out at the juvenile period) influence later behavioral changes, as well as neurochemical variations otherwise engendered by stressors (e.g., changes of monoamines, metabolites, and receptor mRNA expression) within stress-sensitive brain regions. It is further hypothesized that the negative effects of strong juvenile stressor experiences can be reversed by subsequent positive events (essentially, the bell can be unrung), and these outcomes will be linked to neurotrophins.

应激源可以引起神经生物学过程的“敏感化”（例如，神经递质、激素和生长因子），因此后来对压力源的反应被明显夸大。同样，“交叉致敏”效应可能发生，其中应激源增强了对不同挑战的后期反应（例如，可卡因或免疫作用剂）。啮齿动物的致敏效应可以发生在任何年龄，但如果最初在生命早期（出生后的头几天）或青春期（少年）期间遇到压力，则特别明显。这些致敏效应被不同地归因于大脑中特定受体的敏感性改变，或生长因子功能的改变，其中一些可能源于表观遗传变化。这可能是真实的强大的压力，由于减少BDNF功能。然而，在早期生活中，轻度的，可忍受的压力，通过增加BDNF功能，可能会提高动物的能力，以处理后来的压力，可能通过敏化BDNF功能可能同样会产生后，压力再暴露，这可能有利于更大的神经生物学和行为的灵活性。在这方面，还有另一个重要因素需要考虑。虽然内源性减少BDNF功能，可能有负面的行为后果，在某些情况下，这实际上可能有积极的影响。充足的BDNF功能增强了突触可塑性，因此有机体可能从积极的早期生活经历中获益，并受到压力遭遇的负面影响。在缺乏足够的BDNF功能的情况下，有机体将不太可能从早期生活的积极经验中获益，但另一方面，它们也不太可能被压力经历所损害。拟议的研究将评估这一假设，即在青少年时期遇到的轻微社会压力或相当强烈的挑战（PND 28-30）将分别增强或破坏以后（成年期）在解决问题测试中的认知灵活性以及社交场合中的行为。这些变化将被神经营养因子和受体变异所掩盖。此外，通过使用基因工程小鼠品系（条件性敲除），我们将确定BDNF基因的缺失（在幼年期敲除）是否会影响后来的行为变化，以及由应激源引起的神经化学变化（例如，应激敏感脑区内单胺、代谢物和受体mRNA表达的变化）。进一步假设，强烈的青少年压力经历的负面影响可以被随后的积极事件逆转（基本上，钟声可以被取消），这些结果将与神经营养因子有关。