下丘脑中的神经元在学习和先天行为期间调节动物的状态,下丘脑发育的改变可能会导致焦虑等病理状况,抑郁症或肥胖症。尽管有许多关于下丘脑发育和功能的研究,胚胎发育和先天行为之间的联系仍未被探索。这里,专注于胚胎表达的含有同源结构域的基因发育中的大脑同源盒1(Dbx1),我们探索了胚胎谱系之间的关系,出生后神经元身份和对先天线索的谱系特异性反应。我们发现Dbx1在多个发育中的下丘脑亚结构域中广泛表达。使用标准和可诱导的命运映射来追踪Dbx1衍生的神经元,我们确定了它们对下丘脑核中特定神经元亚型的贡献,并进一步绘制了它们响应于一系列明确定义的先天行为的激活模式。
Dbx1来源的神经元占据多个出生后下丘脑核,包括外侧下丘脑(LH),弓状核(Arc)和下丘脑腹侧内侧(VMH)。在这些原子核中,Dbx1(+)祖细胞产生很大比例的Pmch-,Nesfatin-,车-,Hcrt-,表达Agrp和ERα的神经元群体,在较小程度上,Pomc-,TH和芳香化酶表达群体。可诱导的命运映射揭示了Dbx1衍生的LH和Arc种群发育的不同时间窗口,Arc中的Agrp(+)和Cart(+)种群早期出现(E7.5-E9.5),而LH中的Pmch()和Hcrt()种群来自后来表达Dbx1的祖细胞(E9.5-E11.5)。此外,正如c-Fos标签所揭示的,男性和女性LH中的Dbx1衍生细胞,Arc和VMH在交配和侵略期间具有响应性。相比之下,Arc和LH中的Dbx1谱系细胞具有更广泛的行为调节,其中包括对禁食和捕食者气味线索的反应。
我们针对下丘脑祖细胞区的Dbx1表达定义了下丘脑的新命运图。我们证明了以时间调节的方式,Dbx1衍生的神经元有助于LH中分子不同的神经元群体,Arc和VMH与各种下丘脑驱动的行为有关。与此一致,LH中Dbx1衍生的神经元,电弧和VMH在压力和其他先天行为反应期间被激活,暗示他们参与了这些不同的行为。
Neurons in the hypothalamus function to regulate the state of the animal during both learned and innate behaviors, and alterations in hypothalamic development may contribute to pathological conditions such as anxiety, depression or obesity. Despite many studies of hypothalamic development and function, the link between embryonic development and innate behaviors remains unexplored. Here, focusing on the embryonically expressed homeodomain-containing gene Developing Brain Homeobox 1 (Dbx1), we explored the relationship between embryonic lineage, post-natal neuronal identity and lineage-specific responses to innate cues. We found that Dbx1 is widely expressed across multiple developing hypothalamic subdomains. Using standard and inducible fate-mapping to trace the Dbx1-derived neurons, we identified their contribution to specific neuronal subtypes across hypothalamic nuclei and further mapped their activation patterns in response to a series of well-defined innate behaviors.
Dbx1-derived neurons occupy multiple postnatal hypothalamic nuclei including the lateral hypothalamus (LH), arcuate nucleus (Arc) and the ventral medial hypothalamus (VMH). Within these nuclei, Dbx1 (+) progenitors generate a large proportion of the Pmch-, Nesfatin-, Cart-, Hcrt-, Agrp- and ERα-expressing neuronal populations, and to a lesser extent the Pomc-, TH- and Aromatase-expressing populations. Inducible fate-mapping reveals distinct temporal windows for development of the Dbx1-derived LH and Arc populations, with Agrp(+) and Cart(+) populations in the Arc arising early (E7.5-E9.5), while Pmch(+) and Hcrt(+) populations in the LH derived from progenitors expressing Dbx1 later (E9.5-E11.5). Moreover, as revealed by c-Fos labeling, Dbx1-derived cells in male and female LH, Arc and VMH are responsive during mating and aggression. In contrast, Dbx1-lineage cells in the Arc and LH have a broader behavioral tuning, which includes responding to fasting and predator odor cues.
We define a novel fate map of the hypothalamus with respect to Dbx1 expression in hypothalamic progenitor zones. We demonstrate that in a temporally regulated manner, Dbx1-derived neurons contribute to molecularly distinct neuronal populations in the LH, Arc and VMH that have been implicated in a variety of hypothalamic-driven behaviors. Consistent with this, Dbx1-derived neurons in the LH, Arc and VMH are activated during stress and other innate behavioral responses, implicating their involvement in these diverse behaviors.