Changes in maternal motivation across reproductive states in mice: A role for prolactin receptor activation on GABA neurons

2021 ◽  
Vol 135 ◽  
pp. 105041
Author(s):  
Judith M. Swart ◽  
David R. Grattan ◽  
Sharon R. Ladyman ◽  
Rosemary S.E. Brown
Keyword(s):  
Prolactin Receptor ◽  
Receptor Activation ◽  
Gaba Neurons ◽  
Maternal Motivation

scholarly journals Ventral Tegmental Area GABA, glutamate, and glutamate-GABA neurons are heterogenous in their electrophysiological and pharmacological properties

2020 ◽  
Author(s):  
Jorge Miranda-Barrientos ◽  
Ian Chambers ◽  
Smriti Mongia ◽  
Bing Liu ◽  
Hui-Ling Wang ◽  
...  
Keyword(s):  
Ventral Tegmental Area ◽  
Viral Vectors ◽  
Ex Vivo ◽  
Glutamate Transporter ◽  
Receptor Activation ◽  
Firing Frequency ◽  
Dopamine Neurons ◽  
Gaba Neurons ◽  
Double Transgenic Mouse ◽  
Ventral Tegmental

AbstractThe ventral tegmental area (VTA) contains dopamine neurons intermixed with GABA-releasing (expressing vesicular GABA transporter, VGaT), glutamate-releasing (expressing vesicular glutamate transporter, VGluT2), and co-releasing (co-expressing VGaT and VGluT2) neurons. By delivering INTRSECT viral vectors into VTA of double vglut2-Cre/vgat-Flp transgenic mice, we targeted specific VTA cell populations for ex vivo recordings. We found that VGluT2+ VGaT− and VGluT2+ VGaT+ neurons on average had relatively hyperpolarized resting membrane voltage, greater rheobase, and lower spontaneous firing frequency compared to VGluT2− VGaT+ neurons, suggesting that VTA glutamate-releasing and glutamate-GABA co-releasing neurons require stronger excitatory drive to fire than GABA-releasing neurons. In addition, we detected expression of Oprm1mRNA (encoding μ opioid receptors, MOR) in VGluT2+ VGaT− and VGluT2− VGaT+ neurons, and their hyperpolarization by the MOR agonist DAMGO. Collectively, we demonstrate the utility of the double transgenic mouse to access VTA glutamate, glutamate-GABA and GABA neurons, and show some electrophysiological heterogeneity among them.Impact StatementSome physiological properties of VTA glutamate-releasing and glutamate-GABA co-releasing neurons are distinct from those of VTA GABA-releasing neurons. μ-opioid receptor activation hyperpolarizes some VTA glutamate-releasing and some GABA-releasing neurons.

scholarly journals Novel Association of Vav2 and Nek3 Modulates Signaling through the Human Prolactin Receptor

2005 ◽  
Vol 19 (4) ◽  
pp. 939-949 ◽  
Author(s):  
Sommer L. Miller ◽  
Jamie E. DeMaria ◽  
David O. Freier ◽  
Angela M. Riegel ◽  
Charles V. Clevenger
Keyword(s):  
Breast Cancer ◽  
Signaling Pathways ◽  
Prolactin Receptor ◽  
Chinese Hamster ◽  
Receptor Activation ◽  
Signal Transducer ◽  
Nucleotide Exchange ◽  
T47d Cells ◽  
Related Family ◽  
Guanosine Triphosphatase

Abstract Prolactin (PRL) receptor activation contributes to the progression and motility of human breast cancer. This event activates multimeric signaling pathways, including the activation of the Vav family of guanine nucleotide exchange factors. To detect novel proteins interacting with Vav, yeast two-hybrid analysis was performed and demonstrated an interaction between the serine/threonine NIMA (never in mitosis A)-related family kinase p56Nek3 and Vav1. The PRL-dependent interaction of Nek3 with Vav1 and Vav2 was confirmed by coimmunoprecipitation analysis. PRL stimulation of T47D cells induced Nek3 kinase activity and the interaction of Vav2/Nek3 with the PRL receptor. Increased Nek3 levels up-regulated Vav2 serine and tyrosine phosphorylation, whereas knockdown of Nek3 resulted in a reduction of Vav2 phosphorylation. Activation of guanosine triphosphatase Rac-1 in Chinese hamster ovary transfectants required both Nek3 and Vav2 and was inhibited by the overexpression of a kinase inactivating Nek3 mutant. However, overexpression of either Nek3 or kinase-inactive Nek3 had no effect on Vav2-potentiated signal transducer and activator of transcription 5-mediated gene expression. Overexpression of kinase inactive Nek3 in T47D cells led to a 50% increase in apoptosis vs. controls. These data suggest that the PRL-mediated activation of Nek3 contributes differentially to Vav2 signaling pathways involving Rac1 and signal transducer and activator of transcription 5 and implicates Nek3 during PRL-mediated actions in breast cancer.

scholarly journals SUN-LB45 Identifying a Role for Lactogenic Hormones in Maternal Motivation

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Judith M Swart ◽  
Sharon Rachel Ladyman ◽  
David Ross Grattan ◽  
Rosemary Shanon Eileen Brown
Keyword(s):  
Knockout Mice ◽  
Preoptic Area ◽  
Medial Preoptic Area ◽  
Maternal Behaviour ◽  
Reward Circuitry ◽  
Gaba Neurons ◽  
Pup Retrieval ◽  
Pregnant Mice ◽  
Maternal Motivation ◽  
Lactogenic Hormones

Abstract The onset of appropriate maternal behaviour is essential for the survival of dependent offspring in mammals. Lactogenic hormones, including prolactin and placental lactogen, play an important role in the regulation of this behaviour, mediated through prolactin receptor expression in the medial preoptic area (MPOA) of the hypothalamus1. However, it is unclear how lactogenic action in this region induces the display of maternal behaviour. It has been shown that activation of neuronal projections from the MPOA to the ventral tegmental area (VTA) is necessary for maternal behaviour2, with reward circuitry activated in order to motivate a mother to invest in time- and resource-costly care for her young. We aimed to investigate whether lactogenic hormones play a role in the activation of reward circuitry for maternal behaviour. First, we characterised specific aspects of motivation and reward behaviour in wildtype female C57BL/6 mice of different reproductive states, using three behavioural testing paradigms. We showed that virgin and pregnant mice develop a preference for contexts associated with the presence of foster pups in a conditioned place preference test (p<0.01, n=9 per group), an aspect of reward behaviour that was not observed in lactating females (p=0.14, n=8). However, in a novel T maze and when a climbable barrier was placed in the home cage, virgin and pregnant mice showed low motivation for pup retrieval compared to lactating mice (p<0.05, n≤6 per group). These data demonstrate that reproductive state differentially affects passive reward learning and active motivation for maternal care in wildtype mice. Moreover, we can differentiate between maternal and non-maternal states of pup-related reward behaviour with the use of the T maze and barrier climbing paradigms. Next, we tested mice with a conditional deletion of prolactin receptors in Gamma-Aminobutyric Acid (GABA) neurons (Prlr flox/VGat Cre) in the T maze during lactation. Knockout mice showed incomplete retrieval behaviour, and latencies for pup retrieval were significantly longer than in controls (p<0.01, n≤6 per group). The behavioural impairments observed in Prlr flox/VGat Cre knockout mice in the T maze imply that the action of lactogenic hormones on GABA neurons is required for full maternal motivation. 1.Brown RSE, et al. Prolactin action in the medial preoptic area is necessary for postpartum maternal nursing behavior. Proc Natl Acad Sci U S A114, 10779-10784 (2017). 2.Fang YY, Yamaguchi T, Song SC, Tritsch NX, Lin D. A Hypothalamic Midbrain Pathway Essential for Driving Maternal Behaviors. Neuron98, 192-207 e110 (2018).

scholarly journals Induction of Relaxin Messenger RNA Expression in Response to Prolactin Receptor Activation Requires Protein Kinase C δ Signaling

2000 ◽  
Vol 14 (4) ◽  
pp. 576-590
Author(s):  
Carl A. Peters ◽  
Evelyn T. Maizels ◽  
May C. Robertson ◽  
Robert P.C. Shiu ◽  
Melvin S. Soloff ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Messenger Rna ◽  
Prolactin Receptor ◽  
Receptor Activation ◽  
Rna Expression ◽  
Kinase C

scholarly journals The WSXWS Motif in Cytokine Receptors Is a Molecular Switch Involved in Receptor Activation: Insight from Structures of the Prolactin Receptor

Structure ◽  
2012 ◽  
Vol 20 (2) ◽  
pp. 270-282 ◽  
Author(s):  
Robert Dagil ◽  
Maiken J. Knudsen ◽  
Johan G. Olsen ◽  
Charlotte O'Shea ◽  
Magnus Franzmann ◽  
...  
Keyword(s):  
Prolactin Receptor ◽  
Receptor Activation ◽  
Molecular Switch ◽  
Cytokine Receptors

scholarly journals Multiple cis-trans conformers of the prolactin receptor proline-rich motif (PRM) peptide detected by reverse-phase HPLC, CD and NMR spectroscopy

1996 ◽  
Vol 315 (3) ◽  
pp. 833-844 ◽  
Author(s):  
Kevin D. O'NEAL ◽  
Mohan V. CHARI ◽  
Charles H. McDONALD ◽  
Richard G. COOK ◽  
Li-yuan YU-LEE ◽  
...  
Keyword(s):  
Nmr Spectroscopy ◽  
Prolactin Receptor ◽  
Conformational Dynamics ◽  
Receptor Activation ◽  
Reverse Phase Hplc ◽  
Reverse Phase ◽  
Proline Isomerization ◽  
Fk506 Binding Protein ◽  
Rp Hplc ◽  
Slow Kinetics

An eight-amino-acid synthetic peptide (Ile1-Phe2-Pro3-Pro4-Val5-Pro6-Gly7-Pro8) corresponding to the conserved proline-rich motif (PRM) of the intracellular domain of the prolactin receptor (PRL-R) was studied by one- and two-dimensional (1D and 2D) proton NMR spectroscopy in water and DMSO in order to characterize its conformational dynamics. The purified PRL-R PRM peptide eluted as two partially resolved peaks in equilibrium on reverse-phase HPLC (RP-HPLC) at 20 °C with a ratio of 60:40. At 30 °C, the two peaks coalesced into a single peak. The two RP-HPLC peaks correspond to two peptide conformers resulting from the slow cis–trans isomerization of one of the four proline amide bonds. Although the peptide has only three amide (NH) protons, its 1D NMR spectrum in water contains approximately 15 discernible NH region peaks, providing evidence for multiple conformers. The amide resonances were assigned on the basis of 2D-COSY spectra, chemical shift values, resonance splitting patterns and temperature coefficients. The cis:trans ratio for each proline in water, calculated from integrated intensities and/or peak heights of the appropriate resonances, were Phe2-Pro3 (35:65), Pro3-Pro4 (40:60), Val5-Pro6 (70:30), and Gly7-Pro8 (30:70). Temperature studies (25–70 °C) were used to semi-quantitatively estimate the rates of isomerization for the different prolines. In water, Pro8 undergoes rapid isomerization; Pro3 isomerizes at an intermediate rate; while Pro4 and Pro6 both appear to isomerize very slowly since no coalescence of amide resonances was observed. In DMSO, only Pro4 displayed slow isomerization. Slow kinetics combined with a similar 60:40 ratio of conformers determined by RP-HPLC and NMR suggests that isomerization of the Pro3-Pro4 bond generates the two RP-HPLC peaks. Both proximal and distal proline isomerization effects were observed in NMR experiments. All of the 16 theoretical (24 = 16) proline configurations appear to exist in equilibrium in water. The predominant (19%) conformation, trans3-trans4-cis6-trans8, may reflect the configuration of the PRM prolines in the native PRL-R. Isomerization of Pro6 from cis to trans generates an interaction between the peptide N-and C-termini, suggesting an overall pseudo-cyclic conformation. This all-trans proline configuration may play an important biochemical role in the function of cytokine/haematopoietin receptors. A model is proposed which suggests that isomerization of the PRM by an immunophilin such as the FK506-binding protein (FKBP) serves as an on–off switch for cytokine receptor activation.

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