Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA 94720, USA.
Department of Molecular and Cellular Biology, University of California Berkeley, Berkeley, CA 94720, USA.
Curr Biol. 2022 Sep 12;32(17):3690-3703.e5. doi: 10.1016/j.cub.2022.06.089. Epub 2022 Jul 20.
A major challenge for neuroscience, public health, and evolutionary biology is to understand the effects of scarcity and uncertainty on the developing brain. Currently, a significant fraction of children and adolescents worldwide experience insecure access to food. The goal of our work was to test in mice whether the transient experience of insecure versus secure access to food during the juvenile-adolescent period produced lasting differences in learning, decision-making, and the dopamine system in adulthood. We manipulated feeding schedules in mice from postnatal day (P)21 to P40 as food insecure or ad libitum and found that when tested in adulthood (after P60), males with different developmental feeding history showed significant differences in multiple metrics of cognitive flexibility in learning and decision-making. Adult females with different developmental feeding history showed no differences in cognitive flexibility but did show significant differences in adult weight. We next applied reinforcement learning models to these behavioral data. The best fit models suggested that in males, developmental feeding history altered how mice updated their behavior after negative outcomes. This effect was sensitive to task context and reward contingencies. Consistent with these results, in males, we found that the two feeding history groups showed significant differences in the AMPAR/NMDAR ratio of excitatory synapses on nucleus-accumbens-projecting midbrain dopamine neurons and evoked dopamine release in dorsal striatal targets. Together, these data show in a rodent model that transient differences in feeding history in the juvenile-adolescent period can have significant impacts on adult weight, learning, decision-making, and dopamine neurobiology.
对于神经科学、公共卫生和进化生物学来说，一个主要的挑战是理解匮乏和不确定性对发育中大脑的影响。目前，全世界相当一部分儿童和青少年都无法稳定地获得食物。我们的工作目标是在小鼠中测试，在青少年时期经历不安全的食物获取与安全的食物获取之间的短暂差异是否会在成年后产生学习、决策和多巴胺系统的持久差异。我们在小鼠从出生后第 21 天到第 40 天期间操纵喂养计划，使它们经历不安全的或随意进食的状态，结果发现，当在成年期（P60 后）进行测试时，具有不同发育性喂养史的雄性在学习和决策中的多种认知灵活性指标上表现出显著差异。具有不同发育性喂养史的成年雌性在认知灵活性上没有差异，但在成年体重上存在显著差异。我们接下来将强化学习模型应用于这些行为数据。最佳拟合模型表明，在雄性中，发育性喂养史改变了它们在负面结果后更新行为的方式。这种效应对任务背景和奖励条件敏感。与这些结果一致的是，在雄性中，我们发现两组不同的喂养史在中脑多巴胺神经元投射到伏隔核的兴奋性突触上的 AMPAR/NMDAR 比率以及背侧纹状体靶区的诱发多巴胺释放方面存在显著差异。总之，这些数据表明，在幼年到青春期期间，短暂的喂养史差异会对成年后的体重、学习、决策和多巴胺神经生物学产生重大影响。
