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Network Principles of Neuroendocrine Control:
Tuberoinfundibular Dopamine (TIDA) Oscillations and the Regulation of Lactation

Final Report Summary - ENDOSWITCH (Network Principles of Neuroendocrine Control: <br/>Tuberoinfundibular Dopamine (TIDA) Oscillations and the Regulation of Lactation)

In this project, we have studied a group of neurons in the brain that control the release of hormones from the master endocrine gland of the body, the pituitary. As the brain and hormonal system constitute the two major long-range communication systems of the body, it is important that their activity is coordinated, a process that happens through the types of “neuroendocrine” neurons that we study. Specifically, we are interested in so-called “TIDA” (for “tuberoinfundibular dopamine”) neurons that use dopamine as a transmitter. The dopamine released from these cells acts on the pituitary where it inhibits the release of the hormone, prolactin. Prolactin is secreted in the mother after delivery and drives several physiological functions typical of early motherhood, including the production of breast milk, maternal behaviour, decreased fertility and increased food intake. Under most other circumstances, however, blood prolactin levels are low due to the suppressing influence of dopamine. When this “brake” is released, by e.g. certain forms of antipsychotic drugs that block the dopamine receptor or in prolactin-producing tumours, blood prolactin increases and can cause a range of adverse effects including impotence, decreased libido, menstrual disturbances, osteoporosis and even breast enlargement and lactation in men.

While the TIDA neurons were first described half a century ago, and much insight has been gleaned on their regulation, it was not until recently that their electrical activity was described. This is an important feature of neurons as it is the charge of their membrane and the dynamic regulation of this feature that allows neurons to respond to impulses form other neurons and communicate through the release of transmitters elicited by the discharge of action potentials. At the onset of this project, we had just described the electrical behaviour of rat TIDA neurons in in vitro preparations, showing that they exhibit a remarkably robust and synchronized oscillation. During the funding period we have used this preparation to investigate several aspects of the system and of neuronal networks in general. Thus, we have identified several of the properties of the membranes of TIDA neurons that allow them to produce rhythmic oscillations. We have shown how these properties can be regulated by several transmitters and hormones implicated in the control of lactation to allow for switches in dopamine output. We have described novel mechanisms for how commonly prescribed antidepressants cause increases in blood prolactin and sexual side effects. Our work identifies several levels of feedback control that normally protect the body from large fluctuations in hormone concentrations. Through an unexpected finding of a core difference in the connectivity between rat and mouse TIDA neurons we have provided new insight on how so-called electrical synapses contribute to determining the features of a network of neurons with variable individual characteristics. We have in recent work expanded our studies to other neuronal populations in the hypothalamus, the evolutionary old part of the brain that controls basic survival behaviours, to determine how their activity is synchronized to enable successful maternal care.

This work sheds new light on the normal regulation of maternal functions as well as how the prolactin-related side effects of several commonly used medications are caused. It also contributes new understanding of the mechanisms whereby the brain controls the endocrine system. Finally, new insights have been harvested on how populations of neurons can coordinate their activity to allow brain circuits to adapt to different challenges and opportunities offered by the environment.