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

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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.