Mechanisms Underlying Learning Deficits Caused by Paternal Cocaine Taking

 描述(申请人提供)：越来越多的证据表明环境信息是可以遗传的。因此，哺乳动物生殖系中的表观遗传变化可以作为环境扰动的跨代载体。在美国，可卡因成瘾仍然是一个严重的健康问题，长期使用可卡因与神经认知缺陷有关。然而，目前尚不清楚父母滥用可卡因是否会导致子女认知功能下降。这项建议将集中在父亲服用可卡因对后代记忆形成的影响，使用可卡因成瘾的大鼠模型。我们发现，接触可卡因的父亲(SIRS)的后代和孙代存在空间学习缺陷，并损害海马区突触的可塑性。在具体目标1中，我们假设增加海马区NMDA受体信号将改善因父亲服用可卡因而导致的突触可塑性和学习障碍。在具体目标2中，我们将研究暴露于可卡因的雄性后代的基础突触功能和海马区NMDA受体信号转导。综上所述，这项提案将试图阐明父亲服用可卡因导致学习障碍的潜在机制。

 DESCRIPTION (provided by applicant): A growing body of evidence indicates that environmental information can be inherited. Thus, epigenetic changes in the mammalian germline can act as a transgenerational carrier of environmental perturbations. Cocaine addiction remains a significant health problem in the United States and chronic cocaine use is associated with neurocognitive deficits. However, it remains unclear whether cocaine abuse in parents translates to reduced cognitive function in their offspring. This proposal will focus on th effects of paternal cocaine taking on memory formation in offspring using a rat model of cocaine addiction. We found that the offspring and grand-offspring of cocaine-exposed fathers (sires) have spatial learning deficits and impaired hippocampal synaptic plasticity. In Specific Aim 1, we hypothesize that increasing NMDA receptor signaling in the hippocampus will ameliorate synaptic plasticity and learning deficits caused by paternal cocaine taking. In Specific Aim 2, we will investigate basal synaptic function and NMDA receptor signaling in the hippocampus of the descendants of cocaine-exposed sires. Taken together, this proposal will attempt to illuminate the mechanisms underlying learning deficits that are caused by paternal cocaine taking.