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

压力源可能导致神经生物学过程的“敏感化”（例如，神经递质、激素和生长因子），因此对压力源的后期反应显着夸大。此外，“交叉致敏”效应也可能发生，其中压力源增强了对不同挑战（例如，可卡因或免疫作用剂）的后期反应。啮齿类动物的致敏效应可以发生在任何年龄，但如果压力源最初是在生命早期（出生后的头几天）或在青春期（少年期）遇到的，则特别明显。这些致敏效应不同地归因于大脑中特定受体敏感性的改变，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，在关键时刻，压力源必然会产生不利影响。这可能是由于BDNF功能减少而导致的强烈压力源。然而，在生命早期，轻度的、可耐受的压力源，通过增加BDNF的功能，可能会增强动物处理后期压力源的能力，可能通过敏感的BDNF功能，可能类似地在以后的压力再次暴露中产生，这可能有利于更大的神经生物学和行为灵活性。在这方面还需要考虑另一个重要因素。虽然内源性BDNF功能的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。充分的BDNF功能增强了突触的可塑性，因此生物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BDNF功能的情况下，生物体将不太可能从早期生活的积极经历中获益，但另一方面，它们也不太可能受到压力经历的损害。拟议的研究将评估一个假设，即在青少年时期（PND 28-30）遇到的轻度社会压力或相当强烈的挑战，分别会增强或破坏后来（成年期）在解决问题测试中的认知灵活性以及在社会情境中的行为。这些变化将与神经营养因子和受体的变化并行。此外，通过使用小鼠的基因工程菌株（条件敲除），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，以及应激源（如单胺、代谢物和受体mRNA表达的变化）在应激敏感脑区域内引起的神经化学变化。进一步假设，强烈的青少年压力源经历的负面影响可以被随后的积极事件逆转（本质上，铃声可以被取消），这些结果将与神经营养素有关。

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.