Progesterone Receptor Expression in the Developing Mesocortical Dopamine Pathway: Importance for Complex Cognitive Behavior in Adulthood.
Progesterone Receptor Expression in the Developing Mesocortical Dopamine Pathway: Importance for Complex Cognitive Behavior in Adulthood.
复制标题
DOI：
10.1159/000434725
复制
发表时间：
2016
影响因子：
4.1
通讯作者：
Wagner CK
中科院分区：
文献类型：
--
作者：
Willing J;Wagner CK
许多精神和行为障碍，如自闭症，注意力缺陷障碍和精神分裂症可能涉及中皮质多巴胺通路的发育中断，该通路由从中脑腹侧被盖区（VTA）到内侧前额叶皮层（mPFC）的多巴胺能投射组成。核类固醇激素受体是强大的转录因子，可以深刻和永久地改变神经发育的基本过程。核孕激素受体（PR）是瞬时表达的腹侧被盖区和PFC的啮齿动物在围产期的生活，这表明PR可能调节这一重要的行为电路的正常发展。在这里，我们表明，几乎所有的PR免疫反应（PRIR）细胞在腹侧被盖区也表达酪氨酸羟化酶-IR（THIR）。此外，逆行追踪显示，许多PRir细胞在腹侧被盖区项目的mPFC。在新生儿期给予大鼠PR拮抗剂可降低青少年（P25）前边缘mPFC中THir纤维密度，并降低成人VTA中THir水平。新生儿治疗与PR拮抗剂损害成年人的表现，被动抑制回避任务和注意力转移任务，行为抑制/冲动和认知灵活性的措施，分别。VTA中THir水平降低，PR敲除小鼠的认知灵活性也受损。这些研究结果提供了新的见解PR在发展中的行为障碍，涉及复杂的认知行为障碍的病因学的潜在作用，并在关键的神经发育时期在人类中使用合成孕激素的影响。
Numerous psychiatric and behavioral disorders such as Autism, Attention Deficit Disorder and Schizophrenia may involve disruptions in the development of the mesocortical dopamine pathway, consisting of dopaminergic projections from the midbrain ventral tegmental area (VTA) to the medial prefrontal cortex (mPFC). Nuclear steroid hormone receptors are powerful transcription factors and can profoundly and permanently alter fundamental processes of neural development. Nuclear progesterone receptor (PR) is transiently expressed in both the VTA and the PFC of rodents during perinatal life, suggesting that PR may regulate the normal development of this important behavioral circuit. Here, we demonstrate that virtually all PR immunoreactive (PRir) cells in the VTA also express tyrosine hydroxylase-ir (THir). In addition, retrograde tract tracing reveals that many PRir cells in the VTA project to the mPFC. Administration of a PR antagonist to rats during the neonatal period decreased THir fiber density in prelimbic mPFC of juveniles (P25) and decreased levels of THir in the VTA of adults. Neonatal treatment with a PR antagonist impaired adult performance on a passive inhibitory avoidance task and an attentional set shift task, measures of behavioral inhibition/impulsivity and cognitive flexibility, respectively. THir levels in VTA were reduced and cognitive flexibility was impaired in PR knockout mice as well. These findings provide novel insights into a potential role for PR in the developmental etiology of behavioral disorders that involve impairments in complex cognitive behaviors and have implications for the use of synthetic progestins in humans during critical neurodevelopmental periods.