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

应激源可能会导致神经生物学过程(如神经递质、激素和生长因子)的“敏感化”，从而使后来对应激源的反应明显夸大。此外，还可能发生“交叉敏化”效应，即应激源增强对不同挑战(例如可卡因或免疫作用剂)的后期反应。啮齿动物的致敏效应可发生在任何年龄，但如果应激源最初出现在生命早期(出生后最初几天)或青春期(少年)，则尤其明显。这些敏化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。 人们普遍认为，紧要关头的压力源必然会产生负面影响。这可能是由于脑源性神经营养因子功能降低而导致的强烈应激源的情况。然而，早期生命中温和的、可耐受的应激源，通过增加BDNF的功能，可能会增强动物应对后期应激源的能力，可能是通过敏化的BDNF功能，也可能类似地在以后的应激再暴露中产生，这可能有利于更大的神经生物学和行为灵活性。在这方面还有另一个需要考虑的重要因素。尽管BDNF功能的内源性减弱可能会产生负面的行为后果，但在某些情况下，这实际上可能会产生积极的影响。足够的BDNF功能增强了突触的可塑性，因此有机体可能从积极的早期生活经验中获益，而受到应激接触的负面影响。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中获得积极的经历，但另一方面，它们也不太可能受到压力经历的损害。 建议的研究将评估一种假设，即在青少年时期(PND 28-30)遇到的轻微的社会压力或相当强烈的挑战分别会增强或破坏以后(成年)在问题解决测试中的认知灵活性以及在社交场合中的行为。这些变化将与神经营养素和受体的变化平行。此外，通过使用基因工程小鼠品系(条件性基因敲除)，我们将确定BDNF(在幼年期被敲除)基因的缺失是否会影响后来的行为变化，以及原本由应激源引起的神经化学变化(例如，应激敏感脑区内单胺类物质、代谢物和受体mRNA表达的变化)。进一步假设，强烈的青少年应激源经历的负面影响可以被随后的积极事件逆转(本质上，钟声可以解除)，这些结果将与神经营养因子有关。

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.