Plasticity of Hypothalamic Dopamine Neurons during Lactation Results in Dissociation of Electrical Activity and Release

Abstract

Tuberoinfundibular dopamine (TIDA) neurons are the central regulators of prolactin (PRL) secretion. Their extensive functional plasticity allows a change from low PRL secretion in the non-pregnant state to the condition of hyperprolactinemia that characterizes lactation. To allow this rise in PRL, TIDA neurons are thought to become unresponsive to PRL at lactation and functionally silenced. Here we show that, contrary to expectations, the electrical properties of the system were not modified during lactation and that the neurons remained electrically responsive to a PRL stimulus, with PRL inducing an acute increase in their firing rate during lactation that was identical to that seen in non-pregnant mice. Furthermore, we show a long-term organization of TIDA neuron electrical activity with an harmonization of their firing rates, which remains intact during lactation. However, PRL-induced secretion of dopamine (DA) at the median eminence was strongly blunted during lactation, at least in part attributable to lack of phosphorylation of tyrosine hydroxylase, the key enzyme involved in DA synthesis. We therefore conclude that lactation, rather than involving electrical silencing of TIDA neurons, represents a condition of decoupling between electrical activity at the cell body and DA secretion at the median eminence.

Prolactin receptor in regulation of neuronal excitability and channels

“…59 However, loose patch recording from mouse TIDA neurons, identified as dopamine transporter-expressing cells, found oscillation only in 20% neurons. 60 Interestingly, these TIDA neurons displayed irregular spontaneous action potentials, and PRL-induced firing rates were not modified during lactation.…”

Interactions between prolactin and kisspeptin to control reproduction

“…Several biological functions are regulated by prolactin through its action on defined hypothalamic neuronal populations, including the regulation of prolactin secretion through negative feedback, the expression of maternal behaviors and the modulation of energy balance and the reproductive axis (Figure 1). The best known hypothalamic circuitry involving prolactin effects is composed of TIDA neurons that act as a synchronous network to release dopamine and control prolactin secretion (1,(15)(16)(17). TIDA neurons are directly responsive to prolactin as demonstrated by the induction of STAT5 phosphorylation (pSTAT5) after an acute prolactin stimulus and a direct postsynaptic depolarization of cell membranes, which stimulates dopamine secretion (15)(16)(17).…”

“…The best known hypothalamic circuitry involving prolactin effects is composed of TIDA neurons that act as a synchronous network to release dopamine and control prolactin secretion (1,(15)(16)(17). TIDA neurons are directly responsive to prolactin as demonstrated by the induction of STAT5 phosphorylation (pSTAT5) after an acute prolactin stimulus and a direct postsynaptic depolarization of cell membranes, which stimulates dopamine secretion (15)(16)(17). However, during lactation, dopamine secretion is suppressed to allow for physiological hyperprolactinemia.…”

“…However, during lactation, dopamine secretion is suppressed to allow for physiological hyperprolactinemia. Because TIDA neurons remain electrically responsive to prolactin during lactation, the significant decrease in tyrosine hydroxylase phosphorylation is the best-known mechanism so far that is responsible for the suppression of dopamine secretion during this period (17). In addition, prolactin is also known as an important factor that mediates adaptive responses related to maternal behaviors.…”

“…In addition, it has been demonstrated that PRLRs activation is also involved in rapid acute effects that lead to changes in membrane excitability. For example, prolactin acutely induces rapid effects on the membrane excitability of neurons (14)(15)(16)(17)(18). Such effects occur because PRLRs activation can activate fast-acting signaling mechanisms, such as the PI3K pathway, tyrosine kinase-dependent K + channels or the production of intracellular messengers that open voltage-independent Ca 2+ channels, which in turn allows for ionic changes across the cell membrane (1,15).…”