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Impact of early life SSRI exposure on neural circuit formation and function

生命早期接触 SSRI 对神经回路形成和功能的影响

基本信息

批准号：
MR/T033320/1
负责人：
Simon Butt
金额：
$ 60.82万
依托单位：
University of Oxford
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2021
资助国家：
英国
起止时间：
2021 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FT033320%2F1
关键词：
Impact early life SSRI exposure

项目摘要

Selective serotonin reuptake inhibitors (SSRIs) are the first-line pharmacological treatment for depression and anxiety and as such, one of the most widely used drug therapies in primary care and psychiatry. Their mode of action is to increase the levels of the neurotransmitter serotonin (5-HT) in brain and through a constellation of targets ameliorate the symptoms of these debilitating psychological disorders. However normal development and function of the nervous system is dependent on balance between a variety of neurotransmitter system and elevated levels of 5-HT might have off-targets effects. This is a particular concern in pregnant women who are taking SSRIs to control depression: SSRIs will cross the placenta and lead to elevated levels of 5-HT in the foetus at a critical stage in brain development; a stage very much driven by 5-HT in concert with other neurotransmitter. The fundamental question this gives rise to is whether the elevated 5-HT levels alter development sufficiently to impact on brain development. At present, research is divided on this issue with some groups finding that SSRI use during pregnancy can result in autism and ADHD in the offspring. While other studies suggest that the SSRIs themselves are not the issue, rather that there is more of a link with genetic factors inherited from the mother. If we accept the latter, then SSRI use is probably beneficial during pregnancy while if we accept the former then pregnant women should not take SSRIs even though this might have significant implications for their mental well-being and potentially lead to an equally poor outcome. Our proposal is to address this question directly using a model system. The benefit of this approach is that we can separate genetic (maternal background) from environmental factors (elevated 5-HT levels due to SSRIs) and directly assess the impact of the the latter on circuit formation and emergent perception. Our hypothesis is that elevated 5-HT will result in early circuit abnormalities - current published evidence suggest that this is the case, but that the neonatal brain is sufficient plastic to overcome this early insult. By tracking brain developing and using an array of advanced optical and electrophysiological techniques, we should be able to prise apart the contribution of individual cell types to emergent cognition and understand exactly how and when any dysfunction arises. Ultimately, this programme of research will help us understand how SSRIs influence the developing brain and whether or not the consequences of elevated 5-HT manifest in altered cognition that could underpin conditions as debilitating and distressing as autism and ADHD. More specifically, we hope that the results of this study will better inform our clinical colleagues when making the decision to prescribe or withdraw SSRI medication in this vulnerable population of pregnant women.

选择性5-羟色胺再摄取抑制剂（SSRIs）是抑郁症和焦虑症的一线药物治疗，因此是初级保健和精神病学中最广泛使用的药物治疗之一。其作用模式是增加大脑中神经递质5-羟色胺（5-HT）的水平，并通过一系列靶点改善这些使人衰弱的心理障碍的症状。然而，神经系统的正常发育和功能依赖于多种神经递质系统之间的平衡，5-HT水平升高可能具有脱靶效应。这是一个特别关注的孕妇谁是服用SSRIs控制抑郁症：SSRIs将穿过胎盘，并导致5-HT水平升高的胎儿在大脑发育的关键阶段;一个阶段非常驱动5-HT与其他神经递质。这引起的根本问题是，升高的5-HT水平是否足以改变发育，从而影响大脑发育。目前，关于这个问题的研究存在分歧，一些研究小组发现，怀孕期间使用SSRI会导致后代患上自闭症和多动症。虽然其他研究表明，SSRIs本身不是问题，而是与母亲遗传的遗传因素有更多的联系。如果我们接受后者，那么在怀孕期间使用SSRI可能是有益的，而如果我们接受前者，那么孕妇不应该服用SSRI，即使这可能对他们的心理健康产生重大影响，并可能导致同样糟糕的结果。我们的建议是直接使用模型系统来解决这个问题。这种方法的好处是，我们可以将遗传（母亲背景）与环境因素（由于SSRIs导致的5-HT水平升高）分开，并直接评估后者对回路形成和紧急感知的影响。我们的假设是，升高的5-HT将导致早期电路异常-目前公布的证据表明，情况确实如此，但新生儿大脑有足够的可塑性来克服这种早期损伤。通过跟踪大脑发育并使用一系列先进的光学和电生理技术，我们应该能够区分单个细胞类型对新兴认知的贡献，并确切了解任何功能障碍是如何以及何时出现的。最终，这项研究计划将帮助我们了解SSRIs如何影响发育中的大脑，以及5-HT升高的后果是否表现为认知改变，这可能会导致自闭症和ADHD等令人衰弱和痛苦的疾病。更具体地说，我们希望这项研究的结果将更好地告知我们的临床同事，当决定在这个脆弱的孕妇群体中开药或停药时。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Non-canonical role for Lpar1-EGFP subplate neurons in early postnatal mouse somatosensory cortex.

DOI：
10.7554/elife.60810
发表时间：
2021-07-12
期刊：
eLife
影响因子：
7.7
作者：
Ghezzi F;Marques-Smith A;Anastasiades PG;Lyngholm D;Vagnoni C;Rowett A;Parameswaran G;Hoerder-Suabedissen A;Nakagawa Y;Molnar Z;Butt SJ
通讯作者：
Butt SJ

GABAergic circuits reflect different requirements for emergent perception in postnatal mouse neocortex

GABA能回路反映了出生后小鼠新皮质对紧急感知的不同要求