Dopamine Autoreceptor Regulation of a Hypothalamic Dopaminergic Network

Acknowledgments The authors thank Drs. Gilberto Fisone, Jessica Ausborn, Abdel El Manira, Gilad Silberberg, and members of the C.B. laboratory for advice, as well as Paul Williams for expert help with the graphical abstract. This study was supported by a Starting Investigator Grant from the ERC (ENDOSWITCH 261286), the Swedish Research Council (2010-3250), Novo Nordisk Fonden, and the Strategic Research Programme in Diabetes at Karolinska Institutet.Peer reviewedPublisher PD

Dopamine release dynamics in the tuberoinfundibular dopamine system

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

Dopamine release dynamics in the tuberoinfundibular dopamine system

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

Polysynaptic inhibition between striatal cholinergic interneurons shapes their network activity patterns in a dopamine-dependent manner

Striatal activity is dynamically modulated by acetylcholine and dopamine, both of which are essential for basal ganglia function. Synchronized pauses in the activity of striatal cholinergic interneurons (ChINs) are correlated with elevated activity of midbrain dopaminergic neurons, whereas synchronous firing of ChINs induces local release of dopamine. The mechanisms underlying ChIN synchronization and its interplay with dopamine release are not fully understood. Here we show that polysynaptic inhibition between ChINs is a robust network motif and instrumental in shaping the network activity of ChINs. Action potentials in ChINs evoke large inhibitory responses in multiple neighboring ChINs, strong enough to suppress their tonic activity. Using a combination of optogenetics and chemogenetics we show the involvement of striatal tyrosine hydroxylase-expressing interneurons in mediating this inhibition. Inhibition between ChINs is attenuated by dopaminergic midbrain afferents acting presynaptically on D2 receptors. Our results present a novel form of interaction between striatal dopamine and acetylcholine dynamics

A Neuro-hormonal Circuit for Paternal Behavior Controlled by a Hypothalamic Network Oscillation

Parental behavior is pervasive throughout the animal kingdom and essential for species survival. However, the relative contribution of the father to offspring care differs markedly across animals, even between related species. The mechanisms that organize and control paternal behavior remain poorly understood. Using Sprague-Dawley rats and C57BL/6 mice, two species at opposite ends of the paternal spectrum, we identified that distinct electrical oscillation patterns in neuroendocrine dopamine neurons link to a chain of low dopamine release, high circulating prolactin, prolactin receptor-dependent activation of medial preoptic area galanin neurons, and paternal care behavior in male mice. In rats, the same parameters exhibit inverse profiles. Optogenetic manipulation of these rhythms in mice dramatically shifted serum prolactin and paternal behavior, whereas injecting prolactin into non-paternal rat sires triggered expression of parental care. These findings identify a frequency-tuned brain-endocrine-brain circuit that can act as a gain control system determining a species’ parental strategy

A Neuro-hormonal Circuit for Paternal Behavior Controlled by a Hypothalamic Network Oscillation

Parental behavior is pervasive throughout the animal kingdom and essential for species survival. However, the relative contribution of the father to offspring care differs markedly across animals, even between related species. The mechanisms that organize and control paternal behavior remain poorly understood. Using Sprague-Dawley rats and C57BL/6 mice, two species at opposite ends of the paternal spectrum, we identified that distinct electrical oscillation patterns in neuroendocrine dopamine neurons link to a chain of low dopamine release, high circulating prolactin, prolactin receptor-dependent activation of medial preoptic area galanin neurons, and paternal care behavior in male mice. In rats, the same parameters exhibit inverse profiles. Optogenetic manipulation of these rhythms in mice dramatically shifted serum prolactin and paternal behavior, whereas injecting prolactin into non-paternal rat sires triggered expression of parental care. These findings identify a frequency-tuned brain-endocrine-brain circuit that can act as a gain control system determining a species’ parental strategy

Neuropeptide circuitries regulating food and water intake

An adequate supply of nutrients through food intake is critical for survival, as evidenced by disorders such as obesity and anorexia, which in the long run may be life-threatening. Feeding behaviour is ultimately controlled by interacting neuronal populations in the brain. The aim of this thesis was to investigate, mainly by histochemical methods, the neuronal pathways involved in this regulation. Firstly, we investigated the down-stream targets of neuropeptide Y (NPY)-expressing neurones in the hypothalamic arcuate nucleus, which appears to function as a critical center for receiving hormonal information of the metabolic state of the body and initiating food intake. By using as a marker agouti-gene-related protein (AGRP), which is solely expressed in the NPY neurones, the projections of this cell group were shown to innervate several nuclei extending from the olfactory nuclei to the nucleus tractus solitarii. Some of the hypothalamic target neurones of this projection were defined histochemically, and found to include neurones expressing cocaine- and amphetamine-regulate transcript (CART) in several nuclei, neurones expressing melaninconcentrating hormone or orexin/hypocretin in the lateral hypothalamic area, neurones expressing thyrotropin-releasing hormone in the paraventricular nucleus and neurones expressing pro-opiomelanocortin (POMC) in the arcuate nucleus. In the latter two populations, we also detected the expression of the NPY Y1 receptor, suggesting that NPY acts partly by inhibiting the activity of anorexigenic peptides. Secondly, in the mutant anorexia (anx/anx) mouse, which is characterized by decreased food intake, emaciation and premature death, we observed histochemical alterations in both the NPY and POMC arcuate cell populations. In the former, the levels of AGRP- and NPY-like immunoreactivites (-Lls) was increased in the cell bodies and decreased in terminals, whereas no change was observed in the respective mRNA levels; a pattern suggestive of accumulation. In contrast, markers of POMC neurones were decreased in both their peptide and mRNA forms, and stained in a pattern resembling degeneration/ atrophy. These results indicate that a disturbed NPY-POMC circuitry may underlie part of the anx/anx phenotype. Thirdly, the histochemistry of the nodose ganglion was explored. This ganglion houses the cell bodies of the afferent neurones of the vagus nerve that transmit sensory information from the gastrointestinal tract to the brain, where it may influence food intake on a meal-to-meal basis. Half of the nerve cell bodies in this ganglion expressed CART, and CART peptide-LI could also be detected in the vagus nerve itself and in its central innervation region. In many of the CART neurones, mRNA for the cholecystokinin (CCK)A receptor, which has been implicated as a mediator of satiety, could be detected. These data indicate the existence of a CCK-CART signalling satiety pathway from the gut to the brain. In normal nodose ganglia, expression of CCK and the CCKB receptor was absent/low, but both mRNAs increased dramatically after vagus nerve lesion, suggesting that CCKB receptor signalling may be involved in the neuronal post-traumatic response. Finally, a subpopulation of CCKA receptor-expressing neurones in dorsal root ganglia was also found. These data contribute to defining the central appetite-regulating circuitries on the basis of neuropeptide content. In particular, the two main input stations in the hypothalamus and the brain stem have been investigated, suggesting a possible convergence of these signals. An understanding of these pathways is likely to be of importance in the development of therapies for eating disorders