Dopamine Release Dynamics in the Tuberoinfundibular Dopamine System

Abstract

The relationship between neuronal impulse activity and neurotransmitter release remains elusive. This issue is especially poorly understood in the neuroendocrine system, with its particular demands on periodically voluminous release of neurohormones at the interface of axon terminals and vasculature. A shortage of techniques with sufficient temporal resolution has hindered real-time monitoring of the secretion of the peptides that dominate among the neurohormones. The lactotropic axis provides an important exception in neurochemical identity, however, as pituitary prolactin secretion is primarily under monoaminergic control, via tuberoinfundibular dopamine (TIDA) neurons projecting to the median eminence (ME). Here, we combined electrical or optogenetic stimulation and fast-scan cyclic voltammetry to address dopamine release dynamics in the male mouse TIDA system. Imposing different discharge frequencies during brief (3 s) stimulation of TIDA terminals in the ME revealed that dopamine output is maximal at 10 Hz, which was found to parallel the TIDA neuron action potential frequency distribution during phasic discharge. Over more sustained stimulation periods (150 s), maximal output occurred at 5 Hz, similar to the average action potential firing frequency of tonically active TIDA neurons. Application of the dopamine transporter blocker, methylphenidate, significantly increased dopamine levels in the ME, supporting a functional role of the transporter at the neurons' terminals. Lastly, TIDA neuron stimulation at the cell body yielded perisomatic release of dopamine, which may contribute to an ultrafast negative feedback mechanism to constrain TIDA electrical activity. Together, these data shed light on how spiking patterns in the neuroendocrine system translate to vesicular release toward the pituitary and identify how dopamine dynamics are controlled in the TIDA system at different cellular compartments.A central question in neuroscience is the complex relationship between neuronal discharge activity and transmitter release. By combining optogenetic stimulation and voltammetry, we address this issue in dopamine neurons of the neuroendocrine system, which faces particular spatiotemporal demands on exocytotic release; large amounts of neurohormone need to be secreted into the portal capillaries with precise timing to adapt to physiological requirements. Our data show that release is maximal around the neurons' default firing frequency. We further provide support for functional dopamine transport at the neurovascular terminals, shedding light on a long-standing controversy about the existence of neuroendocrine transmitter reuptake. Finally, we show that dopamine release occurs also at the somatodendritic level, providing a substrate for an ultrashort autoregulatory feedback loop.

Trpc5 deficiency causes hypoprolactinemia and altered function of oscillatory dopamine neurons in the arcuate nucleus

“…The observed increase in instantaneous burst frequency after Trpc5 deletion could result in enhanced release of dopamine, thereby leading to prolactin deficiency. A recent report in male mice analyzing dopamine release dynamics at the median eminence using optogenetic stimulation and fast-scan voltammetry showed that dopamine output is maximal at action potential frequencies near 10 Hz within a single 5-s burst (21). However, these experiments did not test the impact of altered burst intervals within the time range of our findings.…”

“…Thus, the firing properties of these neurons are likely to control the release of dopamine (17)(18)(19)(20) and therefore should be critical to determine reproductive success. A recent report investigating dopamine release dynamics confirmed the tight relationship between impulse activity and vesicular release in the tuberoinfundibular dopamine system (21).…”

Morphological plasticity of the tuberoinfundibular dopaminergic neurones in the rat during the oestrous cycle and lactation

“…Confirmation that such close appositions represent true synaptic contacts must await ultrastructural studies or dual‐labelling for synaptic marker proteins. The neurochemical nature of such interactions is unknown although optogenetic studies suggest TIDA may inhibit adjacent neurones via the release of GABA or dopamine 14,35 . It is important to note that, although our investigation identifies TH‐expressing neurones within the arcuate nucleus, it does not confirm that all such neurones project to the median eminence and can thus be considered truly neuroendocrine in nature.…”

“…Although the physiological consequence of axonal projection origin is uncertain, it is interesting to note a dendritic origin has been suggested to promote back‐propagation of action potentials that may support the dendritic release of neurotransmitter 34 . In the current context, such an action could be important because the perisomatic release of dopamine, most probably from surrounding dendrites, has been shown to act via dopamine D2 receptors to inhibit the electrical activity of TIDA neurones, thus providing an ultrafast negative‐feedback mechanism 15,35 . It remains to be determined whether TIDA neurones with dendritic axonal origin play a disproportionate role in this process.…”

“…34 In the current context, such an action could be important because the perisomatic release of dopamine, most probably from surrounding dendrites, has been shown to act via dopamine D2 receptors to inhibit the electrical activity of TIDA neurones, thus providing an ultrafast negative-feedback mechanism. 15,35 It remains to be determined whether TIDA neurones with dendritic axonal origin play a disproportionate role in this process.…”