Neurotensin, TIDA neurons, and the pregnancy-induced plasticity of a neuroendocrine circuit

我们的目标是了解大脑如何使哺乳动物的身体为怀孕、哺乳和父母行为的巨大挑战做好准备。由于许多这些适应是由生殖荷尔蒙催乳素(PRL)驱动的，本提案侧重于妊娠诱导的结节漏斗多巴胺能神经元(TIDA)的可塑性--这种高度专门化的脑细胞控制着垂体腺PRL的释放。如果TIDA神经元要通过调节催乳素的释放来有效地调节生理和行为，以确保我们满足当前和未来的生殖需求，那么它们必须能够实现两件事。首先，为了积极促进有利于繁殖的条件，它们必须能够对相关信息做出实时反应。其次，考虑到为调动怀孕和父母行为所需的巨大资源所需的努力，他们必须能够“提前计划”并预测未来需要什么。该项目旨在研究脑肽神经降压素(NT)在驱动显著的细胞和电路可塑性中的作用，使TIDA网络能够完成这些计算任务。如果留给自己的设备，产生PRL的垂体细胞将参与持续的激素释放。因此，TIDA神经元通过抑制来控制催乳素水平，持续传递抑制的‘NO’信号--多巴胺(DA)。因此，当需要增加PRL时，PRL调节因子的变化--如NT--会导致TIDA神经元减少其DA输出。在基础的非妊娠条件下，PRL的这种增加在大小和持续时间上都受到负反馈过程的有力限制-负反馈过程是一个抑制环，通过刺激TIDA神经元和增加‘NO’信号来抑制自身的释放。然而，在怀孕期间，孕妇需要极端和持久的高催乳素血症。相应地，TIDA回路和垂体之间的通信必须从负反馈变为正反馈。然而，这场对话是如何从“不”切换到“去”的，目前仍不清楚。目前的数据表明，在怀孕期间，TIDA系统仍然对PRL有反应，但停止释放DA，用GO因子取代这个NO信号。这种GO信号的一个重要候选者是NT，它的TIDA产量在怀孕期间极大地增加。为了研究NT在TIDA控制的反应性和预测性机制中的动态作用，我将检验以下三个步骤的假设：1)TIDA神经元可以直接对NT作出反应。2)NT神经元--控制进食行为、新陈代谢和压力的细胞--与TIDA神经元对话，传递重要的生殖相关信息。3)在怀孕期间，TIDA系统经历了一个“信号开关”，用“GO”信号NT取代了“NO”因子DA--这是一个可预测的步骤，使乳腺轴能够驱动持久的催乳素释放，这是身体为严酷的妊娠、分娩和哺育做准备所必需的。为了测试这些预测，我将使用经过验证的小鼠模型，使我能够选择性地可视化、监测和操纵TIDA和NT神经元。当结合解剖学和生理学方法时，我将不仅能够确定哪些NT神经元与TIDA回路‘交谈’，而且能够确定NT如何影响TIDA网络的细胞和回路特性。最后，我将使用基于CRISPR的尖端技术来防止TIDA回路产生NT，然后观察这种状态依赖的“go”因子的去除如何影响生育、哺乳和父母行为。这项研究将揭示关于调节催乳素释放和生殖行为的神经内分泌网络的适应动态的新的多层次理解，并将揭示新的信号可塑性机制，神经网络通过这些机制使电路性能适应当前环境和未来的要求。

Our goal is to understand how the brain prepares the mammalian body for the enormous challenges of pregnancy, nursing, and parental behaviour. As many of these adaptations are driven by the reproductive hormone prolactin (Prl), this proposal focuses upon the pregnancy induced plasticity of tuberoinfundibular dopaminergic (TIDA) neurons - the highly specialised brain cells that control the release of Prl from the pituitary. If, via their regulation of Prl release, TIDA neurons are to effectively tune physiology and behaviour to ensure we meet both immediate and future reproductive demands, then they must be able to achieve two things. First, in order to actively promote conditions conducive to reproduction, they must be able to REACT to relevant information, in real time. Second, given the effort required to marshal the enormous resources demanded by pregnancy and parental behaviours, it is essential that they be able to 'plan ahead' and PREDICT what is needed in the future. This project is designed to investigate the role of the brain peptide neurotensin (NT) in driving the remarkable cellular and circuit plasticity that enables the TIDA network to fulfil these computational tasks.If left to their own devices, the pituitary cells that produce Prl, will engage in continuous hormone release. Accordingly, TIDA neurons control Prl levels by via inhibition, continuously delivering the inhibitory 'NO' signal, dopamine (DA). As such, when an increase in Prl is required, changes in Prl regulating factors - such as NT - cause TIDA neurons to reduce their DA output. Under basal, non-pregnant conditions, such increases in Prl are powerfully restricted in size and duration by a process of negative feedback - an inhibitory loop where Prl supresses its own release by exciting TIDA neurons and increasing the 'NO' signal. During pregnancy, however, the expectant mother requires extreme and enduring hyperprolactinaemia. Correspondingly, communication between the TIDA circuit and the pituitary must change from negative to positive feedback. Yet, how this conversation switches from "NO" to "GO" remains obscure. Current data suggests that during pregnancy the TIDA system remains responsive to Prl, but ceases to release DA, replacing this NO signal with a GO factor. A prominent candidate for this GO signal is NT, the TIDA production of which increases enormously during pregnancy. To investigate the dynamic role of NT in both reactive and predictive mechanisms of TIDA control, I will test the following three step hypothesis: 1) TIDA neurons can REACT directly to NT. 2) NT neurons - cells that control ingestive behaviour, metabolism and stress - talk to TIDA neurons, relaying vital reproduction relevant information. 3) During pregnancy the TIDA system undergoes a 'signal switch', replacing the 'NO' factor DA with the 'GO' signal NT - a PREDICTIVE step that enables the lactotrophic axis to drive the enduring prolactin release needed to prepare the body for the rigors of gestation, parturition and nursing.To test these predictions, I will use validated mouse models that will enable me to selectively visualise, monitor, and manipulate, both TIDA and NT neurons. When coupled with anatomical and physiological approaches, I will be able to determine not only which NT neurons 'talk' to the TIDA circuit, but how NT affects the cellular and circuit properties of the TIDA network. Finally, I will use cutting-edge CRISPR-based techniques to prevent the TIDA circuit from producing NT and then observe how the removal of this state-dependent 'GO' factor impacts fertility, nursing and parental behaviour.This research will reveal novel multi-level understanding regarding the adaptive dynamism of the neuroendocrine networks governing prolactin release and reproductive behaviour, and will uncover new mechanisms of signal plasticity by which neuronal networks adapt circuit performance to both prevailing circumstance and future requirement.