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

Effect of vesicoureteral reflux on renal function in children with recurrent urinary tract infections

Effect of vesicoureteral reflux on renal function in children with recurrent urinary tract infections. The functional damage caused by vesicoureteral reflux (VUR) has been examined by unilateral clearance studies in 22 children with recurrent urinary tract infection (UTI) and representing 23 kidneys with large VUR, 7 kidneys with small to moderate VUR and 14 kidneys without VUR. Inulin clearance, Na+ excretion and glucose reabsorption were determined. In kidneys without or with small and moderate VUR, UTI had no effect on renal function if treated. In kidneys with large VUR extending into the pelvis and dilating the ureter, there was a gradual deterioration of glomerular filtration rate (GFR) that was accelerated after the age of 6yr. Before puberty more than 50% of renal function was lost despite strict medical care of the UTI. If this functional loss was unilateral, hyperfunction of the contralateral kidney was generally observed. Maximal glucose reabsorption was depressed in proportion to GFR. In kidneys with unilaterally low GFR, the fractional Na+ excretion was consistently increased as compared to the contralateral kidney with normal GFR. This adaptive increase in Na+ excretion must therefore be of intrarenal origin.Effet du reflux vésico-urétéral sur la fonction chez l'enfant atteint d'infection urinaire récidivante. L'altération de la fonction rénale déterminée par le reflux vésico-urétéral (VUR) a été étudiée par clearance unilatérale chez 22 enfants atteints d'infection urinaire récidivante (UTI). L'étude a porté sur 23 reins avec reflux importants, 7 reins avec reflux minime ou moyen et 14 reins sans reflux. La clearance de l'inuline, l'excrétion de Na et la réabsorption de glucose ont été déterminés. L'infection urinaire récidivante n'a pas d'effets sur la fonction des reins sans reflux ou avec reflux minime ou moyen. Dans les reins avec reflux important atteignant le bassinet et dilatant l'uretère on observe une détérioration progressive de la filtration glomérulaire, détérioration qui est plus rapide après l'âge de 6 ans. Avant la puberté, plus de 50% de la fonction rénale sont perdus malgré un traitement strict de l'infection urinaire récidivante. Quand cette diminution de la fonction est unilatérale, une augmentation de la fonction controlatérale est habituellement observée. La réabsorption maximale de gluclose est diminuée en proportion du débit de filtration glomérulaire. L'excrétion fractionnelle de sodium par les reins dont la filtration glomérulaire est diminuée est nettement plus grande que celle du rein controlatéral dont la filtration glomérulaire est normale. Il semble donc que cette adaptation dans l'excrétion du sodium doive être d'origine intrarénale

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

5-ht inhibition of rat insulin 2 promoter cre recombinase transgene and proopiomelanocortin neuron excitability in the mouse arcuate nucleus

A number of anti-obesity agents have been developed that enhance hypothalamic 5-HT transmission. Various studies have demonstrated that arcuate neurons, which express proopiomelanocortin peptides (POMC neurons), and neuropeptide Y with agouti-related protein (NPY/AgRP) neurons, are components of the hypothalamic circuits responsible for energy homeostasis. An additional arcuate neuron population, rat insulin 2 promoter Cre recombinase transgene (RIPCre) neurons, has recently been implicated in hypothalamic melanocortin circuits involved in energy balance. It is currently unclear how 5-HT modifies neuron excitability in these local arcuate neuronal circuits. We show that 5-HT alters the excitability of the majority of mouse arcuate RIPCre neurons, by either hyperpolarization and inhibition or depolarization and excitation. RIPCre neurons sensitive to 5-HT, predominantly exhibit hyperpolarization and pharmacological studies indicate that inhibition of neuronal firing is likely to be through 5-HT1F receptors increasing current through a voltage-dependent potassium conductance. Indeed, 5-HT1F receptor immunoreactivity co-localizes with RIPCre green fluorescent protein expression. A minority population of POMC neurons also respond to 5-HT by hyperpolarization, and this appears to be mediated by the same receptor-channel mechanism. As neither POMC nor RIPCre neuronal populations display a common electrical response to 5-HT, this may indicate that sub-divisions of POMC and RIPCre neurons exist, perhaps serving different outputs