title: Conditional Deletion of the Prolactin Receptor Reveals Functional Subpopulations of Dopamine Neurons in the Arcuate Nucleus of the Hypothalamus.
abstract: Tuberoinfundibular dopamine (TIDA) neurons, known as neuroendocrine regulators of prolactin secretion from the pituitary gland, also release GABA within the hypothalamic arcuate nucleus. As these neurons express prolactin receptors (Prlr), prolactin may regulate GABA secretion from TIDA neurons, potentially mediating actions of prolactin on hypothalamic function. To investigate whether GABA is involved in feedback regulation of TIDA neurons, we examined the physiological consequences of conditional deletion of Prlr in GABAergic neurons. For comparison, we also examined mice in which Prlr were deleted from most forebrain neurons. Both neuron-specific and GABA-specific recombination of the Prlr gene occurred throughout the hypothalamus and in some extrahypothalamic regions, consistent with the known distribution of Prlr expression, indicative of knock-out of Prlr. This was confirmed by a significant loss of prolactin-induced phosphorylation of STAT5, a marker of prolactin action. Several populations of GABAergic neurons that were not previously known to be prolactin-sensitive, notably in the medial amygdala, were identified. Approximately 50% of dopamine neurons within the arcuate nucleus were labeled with a GABA-specific reporter, but Prlr deletion from these dopamine/GABA neurons had no effect on feedback regulation of prolactin secretion. In contrast, Prlr deletion from all dopamine neurons resulted in profound hyperprolactinemia. The absence of coexpression of tyrosine hydroxylase, a marker for dopamine production, in GABAergic nerve terminals in the median eminence suggested that rather than a functional redundancy within the TIDA population, the dopamine/GABA neurons in the arcuate nucleus represent a subpopulation with a functional role distinct from the regulation of prolactin secretion.
  
  
  
  Using a novel conditional deletion of the prolactin receptor, we have identified functional subpopulations in hypothalamic dopamine neurons. Although commonly considered a uniform population of neuroendocrine neurons involved in the control of prolactin secretion, we have shown that approximately half of these neurons express GABA as well as dopamine, but these neurons are not necessary for the feedback regulation of prolactin secretion. The absence of tyrosine hydroxylase in GABAergic nerve terminals in the median eminence suggests that only the non-GABAergic dopamine neurons are involved in the control of pituitary prolactin secretion, and the GABAergic subpopulation may function as interneurons within the arcuate nucleus to regulate other aspects of hypothalamic function.
authors: Centre for Neuroendocrinology and Department of Anatomy, Otago School of Medical Sciences, University of Otago, Dunedin 9054, New Zealand.
authors: Rosemary S E
authors: RS
authors: Brown
authors: Centre for Neuroendocrinology and Department of Anatomy, Otago School of Medical Sciences, University of Otago, Dunedin 9054, New Zealand.
authors: Ilona C
authors: IC
authors: Kokay
authors: Centre for Neuroendocrinology and Department of Anatomy, Otago School of Medical Sciences, University of Otago, Dunedin 9054, New Zealand.
authors: Hollian R
authors: HR
authors: Phillipps
authors: Centre for Neuroendocrinology and Department of Anatomy, Otago School of Medical Sciences, University of Otago, Dunedin 9054, New Zealand.
authors: Siew Hoong
authors: 0000-0002-7395-947X
authors: SH
authors: Yip
authors: Centre for Neuroendocrinology and Department of Anatomy, Otago School of Medical Sciences, University of Otago, Dunedin 9054, New Zealand.
authors: Papillon
authors: P
authors: Gustafson
authors: Centre for Neuroendocrinology and Department of Anatomy, Otago School of Medical Sciences, University of Otago, Dunedin 9054, New Zealand.
authors: Amanda
authors: 0000-0003-1107-3857
authors: A
authors: Wyatt
authors: Centre for Neuroendocrinology and Department of Anatomy, Otago School of Medical Sciences, University of Otago, Dunedin 9054, New Zealand.
authors: Caroline M
authors: CM
authors: Larsen
authors: Centre for Neuroendocrinology and Department of Anatomy, Otago School of Medical Sciences, University of Otago, Dunedin 9054, New Zealand.
authors: Penelope
authors: P
authors: Knowles
authors: Centre for Neuroendocrinology and Department of Anatomy, Otago School of Medical Sciences, University of Otago, Dunedin 9054, New Zealand.
authors: Sharon R
authors: SR
authors: Ladyman
authors: Centre for Integrative Physiology, University of Edinburgh, Edinburgh EH8 9YL, United Kingdom, and.
authors: Paul
authors: 0000-0002-7220-5705
authors: P
authors: LeTissier
authors: Centre for Neuroendocrinology and Department of Anatomy, Otago School of Medical Sciences, University of Otago, Dunedin 9054, New Zealand, Maurice Wilkins Centre for Molecular Biodiscovery, New Zealand dave.grattan@otago.ac.nz.
authors: David R
authors: 0000-0001-5606-2559
authors: DR
authors: Grattan
mesh_terms: D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000166:cytology*; D059290:Dopaminergic Neurons / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000378:metabolism; D022661:RNA, Untranslated / Q000235:genetics / Q000378:metabolism; D011863:Radioimmunoassay; D051381:Rats; D011981:Receptors, Prolactin / Q000235:genetics / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D018709:Statistics, Nonparametric; D005680:gamma-Aminobutyric Acid / Q000378:metabolism* / Q000494:pharmacology
chemical_list: C110853:Gt(ROSA)26Sor non-coding RNA, mouse; D012333:RNA, Messenger; D022661:RNA, Untranslated; D011981:Receptors, Prolactin; D050799:STAT5 Transcription Factor; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1
keywords: GABA; arcuate nucleus; conditional knock-out; prolactin receptor; tuberoinfundibular dopamine neurons