Long-Lasting Changes in Neural Networks Induced by Early Exposure to Nicotine

 描述（由申请人提供）：大脑发育期间的早期尼古丁暴露会产生持久的行为变化，这些变化在多种方面都是有害的。这些包括更大的尼古丁成瘾倾向，注意力缺陷多动障碍，焦虑， 萧条其机制尚不清楚。我们有初步证据表明，小鼠幼崽在哺乳期（出生后第2-16天）早期暴露于哺乳期母亲的尼古丁，可使突触数量持续增加，并增加兴奋性与抑制性突触输入神经元的比例。初步结果还表明，即使经过长时间的尼古丁戒断，成年小鼠也有 异常大量的神经元，当用尼古丁短暂地重新激发时显示出高水平的活性。这可以在急性切片或活体动物体内成像中看到。细胞水平的这种变化是新的，可能对报告的长期行为变化有重要贡献。为了研究潜在的机制并评估其后果，我们提出以下建议。我们将使用免疫染色和膜片钳记录急性切片神经元，以确定增加的程度后，从母亲通过护理或在子宫内尼古丁暴露后，他们收到的多巴胺能输入。我们将确定这些变化是否会在尼古丁停止后很长时间内延续到成年期，以及这些动物在受到后续尼古丁挑战时是否比未接触过尼古丁的动物更容易受到网络变化的影响。此外，我们将确定在这些条件下的神经元亚群是否可以通过表达的立即早期基因c-fos，高活性的特点，我们还将使用清醒小鼠的体内成像检查的性质超活性细胞。待检查的神经元群体包括海马CA 1区的锥体神经元（因为它们在记忆形成中的作用）和腹侧被盖区的多巴胺能神经元（因为它们参与奖赏通路）。这些研究将确定导致早期尼古丁暴露长期影响的机制和途径。它们将为指导电路形成和大脑发育的重要方面的机制提供新的见解。重要的是，它们也将具有重要的生物医学意义，因为目前的医疗政策建议吸烟的孕妇使用尼古丁替代疗法。这一过程，再加上电子烟的使用越来越多，构成了严重的健康威胁，但人们对这些威胁的认识还不够。本文的研究结果将有助于阐明这些结果，并为勘探指明新的战略。

 DESCRIPTION (provided by applicant): Early nicotine exposure during brain development produces long-lasting behavioral changes that are detrimental in multiple ways. These include greater propensities for nicotine addiction, attention deficit hyperactivity disorder, anxiety, and depression. The mechanisms remain unclear. We have preliminary evidence indicating that early exposure of mouse pups to nicotine from the lactating mother during nursing (postnatal day 2-16) produces long-lasting increases in the number of glutamatergic synapses and increases in the ratio of excitatory-to-inhibitory synaptic input neurons receive. The preliminary results also indicate that even after a long period of nicotine abstention, the mice as adults have abnormally large numbers of neurons that display high levels of activity when re-challenged briefly with nicotine. This can be seen either in acute slices or in alive animals with in vivo imaging. Such changes at the cellular level are new and likely to contribute importantly to the long-lasting behavioral changes reported. To examine the underlying mechanisms and evaluate their consequences, we propose the following. We will use immunostaining and patch-clamp recording from neurons in acute slices to determine the extent of increases in the glutamatergic input they receive after nicotinic exposure from the mother via nursing or in utero. We will determine whether the changes extend into adulthood long after nicotine cessation, and whether such animals are more vulnerable to network changes when challenged with subsequent nicotine than are naïve animals. Further, we will determine whether subpopulations of neurons under these conditions can be identified by expression of the immediate early gene c-fos, characteristic of high activity, and we will also use in vivo imaging of awake mice to examine the properties of hyper-active cells. Neuronal populations to be examined include pyramidal neurons in the hippocampal CA1 because of their roles in memory formation and dopaminergic neurons in the ventral tegmental area because of their participation in reward pathways. These studies will identify mechanisms and pathways contributing to the long-lasting effects of early nicotine exposure. They will provide new insight into mechanisms guiding important aspects of circuit formation and brain development. Importantly, they will also have significant biomedical relevance because of current medical policy recommending nicotine replacement therapy for pregnant women who smoke. That procedure, together with the increasing usage of electronic cigarettes, pose serious health threats that are insufficiently understood. The results obtained here will help clarify the consequences and indicate new strategies for exploration.