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Ted B Usdin - One of the best experts on this subject based on the ideXlab platform.
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A Thalamo-Hypothalamic Pathway That Activates Oxytocin Neurons in Social Contexts in Female Rats.
Endocrinology, 2016Co-Authors: Melinda Cservenák, Ted B Usdin, Éva Renner, András H. Lékó, Dávid Keller, Viktor Kis, Emese A. Fazekas, Hanna Öllös, Éva Rebeka Szabó, Miklós PalkovitsAbstract:Oxytocin is released from neurons in the paraventricular hypothalamic nucleus (PVN) in mothers upon suckling and during adult social interactions. However, neuronal pathways that activate oxytocin neurons in social contexts are not established yet. Neurons in the posterior intralaminar complex of the thalamus (PIL), which contain tuberoinfundibular peptide 39 (TIP39) and are activated by pup exposure in lactating mothers provide a candidate projection. Innervation of oxytocin neurons by TIP39 neurons was examined by double labeling in combination with electron microscopy and retrograde tract-tracing. Potential classical neurotransmitters in TIP39 neurons were investigated by in situ hybridization histochemistry. Neurons activated after encounter with a familiar conspecific female in familiar environment were mapped with the c-fos technique. PVN and the supraoptic nucleus oxytocin neurons were closely apposed by an average of 2.0 and 0.4 TIP39 terminals, respectively. Asymmetric (presumed excitatory) synap...
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the parathyroid hormone second receptor pth2r and its ligand tuberoinfundibular peptide of 39 residues TIP39 regulate intracellular calcium and influence keratinocyte differentiation
Journal of Investigative Dermatology, 2016Co-Authors: Emi Sato, Ted B Usdin, Lingjuan Zhang, Christopher A Adase, Jun Muto, James A Sanford, Toshiya Takahashi, Teruaki Nakatsuji, Richard L GalloAbstract:Genes related to the parathyroid hormone (PTH) influence cutaneous immune defense and development, but the full functions of the PTH family in cutaneous biology remain incompletely understood. In this study, we examined the expression and potential functions of the PTH second receptor (PTH2R) and its ligand, the tuberoinfundibular peptide of 39 residues (TIP39), in the skin. TIP39 and PTH2R mRNA and protein were detectable in both human and mouse skin, and in cultured keratinocytes and adipocytes. TIP39 was observed in the basal layer of human skin, whereas PTH2R was detected in the spinous to granular layer. The subcellular localization of TIP39 in keratinocytes changed during calcium-induced differentiation and shifted to colocalize with PTH2R at the membrane. The addition of recombinant TIP39 to normal human keratinocytes in culture induced an increase in intercellular calcium and triggered aspects of terminal differentiation including decreased keratin-14 and increased involucrin expression. Consistent with these observations, PTH2R −/− mice were observed to have increased epidermal thickness. In summary, identification of TIP39 and its receptor in the epidermis reveals an additional PTH family member that is expressed in the skin and may influence keratinocyte function.
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Thalamic neuropeptide mediating the effects of nursing on lactation and maternal motivation.
Psychoneuroendocrinology, 2013Co-Authors: Melinda Cservenák, Miklós Palkovits, Ted B Usdin, Ibolya Bodnár, Éva R. Szabó, András H. Lékó, György Nagy, Arpád DobolyiAbstract:Nursing has important physiological and psychological consequences on mothers during the postpartum period. Tuberoinfundibular peptide of 39 residues (TIP39) may contribute to its effects on prolactin release and maternal motivation. Since TIP39-containing fibers and the receptor for TIP39, the parathyroid hormone 2 receptor (PTH2 receptor) are abundant in the arcuate nucleus and the medial preoptic area, we antagonized TIP39 action locally to reveal its actions. Mediobasal hypothalamic injection of a virus encoding an antagonist of the PTH2 receptor markedly decreased basal serum prolactin levels and the suckling-induced prolactin release. In contrast, injecting this virus into the preoptic area had no effect on prolactin levels, but did dampen maternal motivation, judged by reduced time in a pup-associated cage during a place preference test. In support of an effect of TIP39 on maternal motivation, we observed that TIP39 containing fibers and terminals had the same distribution within the preoptic area as neurons expressing Fos in response to suckling. Furthermore, TIP39 terminals closely apposed the plasma membrane of 82% of Fos-ir neurons. Retrograde tracer injected into the arcuate nucleus and the medial preoptic area labeled TIP39 neurons in the posterior intralaminar complex of the thalamus (PIL), indicating that these cells but not other groups of TIP39 neurons project to these hypothalamic regions. We also found that TIP39 mRNA levels in the PIL markedly increased around parturition and remained elevated throughout the lactation period, demonstrating the availability of the peptide in postpartum mothers. Furthermore, suckling, but not pup exposure without physical contact, increased Fos expression by PIL TIP39 neurons. These results indicate that suckling activates TIP39 neurons in the PIL that affect prolactin release and maternal motivation via projections to the arcuate nucleus and the preoptic area, respectively.
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The Neuroendocrine Functions of the Parathyroid Hormone 2 Receptor
Frontiers in endocrinology, 2012Co-Authors: Arpád Dobolyi, Eugene Dimitrov, Miklós Palkovits, Ted B UsdinAbstract:The G-protein coupled parathyroid hormone 2 receptor (PTH2R) is concentrated in endocrine and limbic regions in the forebrain. Its endogenous ligand, tuberoinfundibular peptide of 39 residues (TIP39), is synthesized in only two brain regions, within the posterior thalamus and the lateral pons. TIP39-expressing neurons have a widespread projection pattern, which matches the PTH2R distribution in the brain. Neuroendocrine centers including the preoptic area, the periventricular, paraventricular, and arcuate nuclei contain the highest density of PTH2R-positive networks. The administration of TIP39 and an antagonist of the PTH2R as well as the investigation of mice that lack functional TIP39 and PTH2R revealed the involvement of the PTH2R in a variety of neural and neuroendocrine functions. TIP39 acting via the PTH2R modulates several aspects of the stress response. It evokes corticosterone release by activating corticotropin-releasing hormone-containing neurons in the hypothalamic paraventricular nucleus. Block of TIP39 signaling elevates the anxiety state of animals and their fear response, and increases stress-induced analgesia. TIP39 has also been suggested to affect the release of additional pituitary hormones including arginine-vasopressin and growth hormone. A role of the TIP39-PTH2R system in thermoregulation was also identified. TIP39 may play a role in maintaining body temperature in a cold environment via descending excitatory pathways from the preoptic area. Anatomical and functional studies also implicated the TIP39-PTH2R system in nociceptive information processing. Finally, TIP39 induced in postpartum dams may play a role in the release of prolactin during lactation. Potential mechanisms leading to the activation of TIP39 neurons and how they influence the neuroendocrine system are also described. The unique TIP39-PTH2R neuromodulator system provides the possibility for developing drugs with a novel mechanism of action to control neuroendocrine disorders.
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Paralemniscal TIP39 is induced in rat dams and may participate in maternal functions
Brain Structure and Function, 2012Co-Authors: Tamás Varga, Miklós Palkovits, Ted B Usdin, Attila G. Bagó, Katalin Gallatz, Melinda Cservenák, Bence Mogyoródi, Dominika Domokos, Éva Renner, Arpád DobolyiAbstract:The paralemniscal area, situated between the pontine reticular formation and the lateral lemniscus in the pontomesencephalic tegmentum contains some tuberoinfundibular peptide of 39 residues (TIP39)-expressing neurons. In the present study, we measured a 4 times increase in the level of TIP39 mRNA in the paralemniscal area of lactating mothers as opposed to nulliparous females and mothers deprived of pups using real-time RT-PCR. In situ hybridization histochemistry and immunolabeling demonstrated that the induction of TIP39 in mothers takes place within the medial paralemniscal nucleus, a cytoarchitectonically distinct part of the paralemniscal area, and that the increase in TIP39 mRNA levels translates into elevated peptide levels in dams. The paralemniscal area has been implicated in maternal control as well as in pain perception. To establish the function of induced TIP39, we investigated the activation of TIP39 neurons in response to pup exposure as maternal, and formalin injection as noxious stimulus. Both stimuli elicited c - fos expression in the paralemniscal area. Subsequent double labeling demonstrated that 95% of neurons expressing Fos in response to pup exposure also contained TIP39 immunoreactivity and 91% of TIP39 neurons showed c - fos activation by pup exposure. In contrast, formalin-induced Fos does not co-localize with TIP39. Instead, most formalin-activated neurons are situated medial to the TIP39 cell group. Our data indicate that paralemniscal neurons may be involved in the processing of maternal and nociceptive information. However, two different groups of paralemniscal neurons participate in the two functions. In particular, TIP39 neurons may participate in the control of maternal functions.
Arpád Dobolyi - One of the best experts on this subject based on the ideXlab platform.
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Gestational Exposure to the Synthetic Cathinone Methylenedioxypyrovalerone Results in Reduced Maternal Care and Behavioral Alterations in Mouse Pups
Frontiers Media S.A., 2018Co-Authors: László I. Gerecsei, Arpád Dobolyi, András Csillag, Gergely Zachar, Lőrinc Gévai, László Simon, Ágota ÁdámAbstract:The member of synthetic cathinone family, methylenedioxypyrovalerone (MDPV), is a frequently used psychoactive drug of abuse. The objective of our study was to determine the effect of MDPV (administered from the 8th to the 14th day of gestation) on the behavior of neonatal and adolescent mice, as well as its effect on maternal care. We measured maternal care (pup retrieval test, nest building), locomotor activity (open field test), and motor coordination (grip strength test) of dams, whereas on pups we examined locomotor activity at postnatal day 7 and day 21 (open field test) and motor coordination on day 21 (grip strength test). On fresh-frozen brain samples of the dams we examined the expression of two important peptides implicated in the regulation of maternal behavior and lactation: tuberoinfundibular peptide 39 (TIP39) mRNA in the thalamic posterior intralaminar complex, and amylin mRNA in the medial preoptic nucleus. We detected decreased birth rate and survival of offspring, and reduced maternal care in the drug-treated animals, whereas there was no difference between the motility of treated and control mothers. Locomotor activity of the pups was increased in the MDPV treated group both at 7 and 21 days of age, while motor coordination was unaffected by MDPV treatment. TIP39 and amylin were detected in their typical location but failed to show a significant difference of expression between the drug-treated and control groups. The results suggest that chronic systemic administration of the cathinone agent MDPV to pregnant mice can reduce birth rate and maternal care, and it also enhances motility (without impairment of motor coordination) of the offspring
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The parathyroid hormone 2 receptor participates in physiological and behavioral alterations of mother mice.
Physiology & behavior, 2017Co-Authors: Barbara Gellén, Ted B Usdin, Dóra Zelena, Arpád DobolyiAbstract:Abstract Parathyroid hormone 2 receptor (PTH2R) and its ligand, tuberoinfundibular peptide of 39 residues (TIP39) have been implicated in the maintenance of homeostasis including body temperature in males. The system was recently shown to be activated in mothers. Therefore, we addressed some of its functions during pregnancy and lactation, comparing PTH2R-knockout (PTH2R-KO) mice with their wild type (WT) littermates. Core body temperature (Tc) was recorded via a telemetric device, anxiety was assessed in an open field, depression-like behavior in the forced-swim test while spontaneous and pup retrieval-induced maternal behavior was also observed. Nulliparous virgin KO and WT mice showed a circadian pattern of Tc and locomotion with no differences between groups. WT mothers had an increased Tc during pregnancy and lactation as compared to virgins. This peripartum elevation of Tc was present but reduced in KO mice, even though their locomotor activity was increased. The greater locomotor activity of the KO mice was confirmed in the open field test but no other behavior differences were detected in the test. The maternal behavior was similar in the 2 genotypes except that the KO mice spent more time in the nest. In turn, a marked difference was found in the forced-swim test as the KO mice spent significantly less time struggling and more time floating compared to the WT littermates. The data suggest that the PTH2R contributes to the elevated Tc and reduced depression-like behavior of mother mice. These findings are consistent with specific maternal functions of the activated TIP39-PTH2R neuromodulator system in mothers.
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Thalamic neuropeptide mediating the effects of nursing on lactation and maternal motivation.
Psychoneuroendocrinology, 2013Co-Authors: Melinda Cservenák, Miklós Palkovits, Ted B Usdin, Ibolya Bodnár, Éva R. Szabó, András H. Lékó, György Nagy, Arpád DobolyiAbstract:Nursing has important physiological and psychological consequences on mothers during the postpartum period. Tuberoinfundibular peptide of 39 residues (TIP39) may contribute to its effects on prolactin release and maternal motivation. Since TIP39-containing fibers and the receptor for TIP39, the parathyroid hormone 2 receptor (PTH2 receptor) are abundant in the arcuate nucleus and the medial preoptic area, we antagonized TIP39 action locally to reveal its actions. Mediobasal hypothalamic injection of a virus encoding an antagonist of the PTH2 receptor markedly decreased basal serum prolactin levels and the suckling-induced prolactin release. In contrast, injecting this virus into the preoptic area had no effect on prolactin levels, but did dampen maternal motivation, judged by reduced time in a pup-associated cage during a place preference test. In support of an effect of TIP39 on maternal motivation, we observed that TIP39 containing fibers and terminals had the same distribution within the preoptic area as neurons expressing Fos in response to suckling. Furthermore, TIP39 terminals closely apposed the plasma membrane of 82% of Fos-ir neurons. Retrograde tracer injected into the arcuate nucleus and the medial preoptic area labeled TIP39 neurons in the posterior intralaminar complex of the thalamus (PIL), indicating that these cells but not other groups of TIP39 neurons project to these hypothalamic regions. We also found that TIP39 mRNA levels in the PIL markedly increased around parturition and remained elevated throughout the lactation period, demonstrating the availability of the peptide in postpartum mothers. Furthermore, suckling, but not pup exposure without physical contact, increased Fos expression by PIL TIP39 neurons. These results indicate that suckling activates TIP39 neurons in the PIL that affect prolactin release and maternal motivation via projections to the arcuate nucleus and the preoptic area, respectively.
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The Neuroendocrine Functions of the Parathyroid Hormone 2 Receptor
Frontiers in endocrinology, 2012Co-Authors: Arpád Dobolyi, Eugene Dimitrov, Miklós Palkovits, Ted B UsdinAbstract:The G-protein coupled parathyroid hormone 2 receptor (PTH2R) is concentrated in endocrine and limbic regions in the forebrain. Its endogenous ligand, tuberoinfundibular peptide of 39 residues (TIP39), is synthesized in only two brain regions, within the posterior thalamus and the lateral pons. TIP39-expressing neurons have a widespread projection pattern, which matches the PTH2R distribution in the brain. Neuroendocrine centers including the preoptic area, the periventricular, paraventricular, and arcuate nuclei contain the highest density of PTH2R-positive networks. The administration of TIP39 and an antagonist of the PTH2R as well as the investigation of mice that lack functional TIP39 and PTH2R revealed the involvement of the PTH2R in a variety of neural and neuroendocrine functions. TIP39 acting via the PTH2R modulates several aspects of the stress response. It evokes corticosterone release by activating corticotropin-releasing hormone-containing neurons in the hypothalamic paraventricular nucleus. Block of TIP39 signaling elevates the anxiety state of animals and their fear response, and increases stress-induced analgesia. TIP39 has also been suggested to affect the release of additional pituitary hormones including arginine-vasopressin and growth hormone. A role of the TIP39-PTH2R system in thermoregulation was also identified. TIP39 may play a role in maintaining body temperature in a cold environment via descending excitatory pathways from the preoptic area. Anatomical and functional studies also implicated the TIP39-PTH2R system in nociceptive information processing. Finally, TIP39 induced in postpartum dams may play a role in the release of prolactin during lactation. Potential mechanisms leading to the activation of TIP39 neurons and how they influence the neuroendocrine system are also described. The unique TIP39-PTH2R neuromodulator system provides the possibility for developing drugs with a novel mechanism of action to control neuroendocrine disorders.
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Paralemniscal TIP39 is induced in rat dams and may participate in maternal functions
Brain Structure and Function, 2012Co-Authors: Tamás Varga, Miklós Palkovits, Ted B Usdin, Attila G. Bagó, Katalin Gallatz, Melinda Cservenák, Bence Mogyoródi, Dominika Domokos, Éva Renner, Arpád DobolyiAbstract:The paralemniscal area, situated between the pontine reticular formation and the lateral lemniscus in the pontomesencephalic tegmentum contains some tuberoinfundibular peptide of 39 residues (TIP39)-expressing neurons. In the present study, we measured a 4 times increase in the level of TIP39 mRNA in the paralemniscal area of lactating mothers as opposed to nulliparous females and mothers deprived of pups using real-time RT-PCR. In situ hybridization histochemistry and immunolabeling demonstrated that the induction of TIP39 in mothers takes place within the medial paralemniscal nucleus, a cytoarchitectonically distinct part of the paralemniscal area, and that the increase in TIP39 mRNA levels translates into elevated peptide levels in dams. The paralemniscal area has been implicated in maternal control as well as in pain perception. To establish the function of induced TIP39, we investigated the activation of TIP39 neurons in response to pup exposure as maternal, and formalin injection as noxious stimulus. Both stimuli elicited c - fos expression in the paralemniscal area. Subsequent double labeling demonstrated that 95% of neurons expressing Fos in response to pup exposure also contained TIP39 immunoreactivity and 91% of TIP39 neurons showed c - fos activation by pup exposure. In contrast, formalin-induced Fos does not co-localize with TIP39. Instead, most formalin-activated neurons are situated medial to the TIP39 cell group. Our data indicate that paralemniscal neurons may be involved in the processing of maternal and nociceptive information. However, two different groups of paralemniscal neurons participate in the two functions. In particular, TIP39 neurons may participate in the control of maternal functions.
Miklós Palkovits - One of the best experts on this subject based on the ideXlab platform.
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A Thalamo-Hypothalamic Pathway That Activates Oxytocin Neurons in Social Contexts in Female Rats.
Endocrinology, 2016Co-Authors: Melinda Cservenák, Ted B Usdin, Éva Renner, András H. Lékó, Dávid Keller, Viktor Kis, Emese A. Fazekas, Hanna Öllös, Éva Rebeka Szabó, Miklós PalkovitsAbstract:Oxytocin is released from neurons in the paraventricular hypothalamic nucleus (PVN) in mothers upon suckling and during adult social interactions. However, neuronal pathways that activate oxytocin neurons in social contexts are not established yet. Neurons in the posterior intralaminar complex of the thalamus (PIL), which contain tuberoinfundibular peptide 39 (TIP39) and are activated by pup exposure in lactating mothers provide a candidate projection. Innervation of oxytocin neurons by TIP39 neurons was examined by double labeling in combination with electron microscopy and retrograde tract-tracing. Potential classical neurotransmitters in TIP39 neurons were investigated by in situ hybridization histochemistry. Neurons activated after encounter with a familiar conspecific female in familiar environment were mapped with the c-fos technique. PVN and the supraoptic nucleus oxytocin neurons were closely apposed by an average of 2.0 and 0.4 TIP39 terminals, respectively. Asymmetric (presumed excitatory) synap...
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Thalamic neuropeptide mediating the effects of nursing on lactation and maternal motivation.
Psychoneuroendocrinology, 2013Co-Authors: Melinda Cservenák, Miklós Palkovits, Ted B Usdin, Ibolya Bodnár, Éva R. Szabó, András H. Lékó, György Nagy, Arpád DobolyiAbstract:Nursing has important physiological and psychological consequences on mothers during the postpartum period. Tuberoinfundibular peptide of 39 residues (TIP39) may contribute to its effects on prolactin release and maternal motivation. Since TIP39-containing fibers and the receptor for TIP39, the parathyroid hormone 2 receptor (PTH2 receptor) are abundant in the arcuate nucleus and the medial preoptic area, we antagonized TIP39 action locally to reveal its actions. Mediobasal hypothalamic injection of a virus encoding an antagonist of the PTH2 receptor markedly decreased basal serum prolactin levels and the suckling-induced prolactin release. In contrast, injecting this virus into the preoptic area had no effect on prolactin levels, but did dampen maternal motivation, judged by reduced time in a pup-associated cage during a place preference test. In support of an effect of TIP39 on maternal motivation, we observed that TIP39 containing fibers and terminals had the same distribution within the preoptic area as neurons expressing Fos in response to suckling. Furthermore, TIP39 terminals closely apposed the plasma membrane of 82% of Fos-ir neurons. Retrograde tracer injected into the arcuate nucleus and the medial preoptic area labeled TIP39 neurons in the posterior intralaminar complex of the thalamus (PIL), indicating that these cells but not other groups of TIP39 neurons project to these hypothalamic regions. We also found that TIP39 mRNA levels in the PIL markedly increased around parturition and remained elevated throughout the lactation period, demonstrating the availability of the peptide in postpartum mothers. Furthermore, suckling, but not pup exposure without physical contact, increased Fos expression by PIL TIP39 neurons. These results indicate that suckling activates TIP39 neurons in the PIL that affect prolactin release and maternal motivation via projections to the arcuate nucleus and the preoptic area, respectively.
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The Neuroendocrine Functions of the Parathyroid Hormone 2 Receptor
Frontiers in endocrinology, 2012Co-Authors: Arpád Dobolyi, Eugene Dimitrov, Miklós Palkovits, Ted B UsdinAbstract:The G-protein coupled parathyroid hormone 2 receptor (PTH2R) is concentrated in endocrine and limbic regions in the forebrain. Its endogenous ligand, tuberoinfundibular peptide of 39 residues (TIP39), is synthesized in only two brain regions, within the posterior thalamus and the lateral pons. TIP39-expressing neurons have a widespread projection pattern, which matches the PTH2R distribution in the brain. Neuroendocrine centers including the preoptic area, the periventricular, paraventricular, and arcuate nuclei contain the highest density of PTH2R-positive networks. The administration of TIP39 and an antagonist of the PTH2R as well as the investigation of mice that lack functional TIP39 and PTH2R revealed the involvement of the PTH2R in a variety of neural and neuroendocrine functions. TIP39 acting via the PTH2R modulates several aspects of the stress response. It evokes corticosterone release by activating corticotropin-releasing hormone-containing neurons in the hypothalamic paraventricular nucleus. Block of TIP39 signaling elevates the anxiety state of animals and their fear response, and increases stress-induced analgesia. TIP39 has also been suggested to affect the release of additional pituitary hormones including arginine-vasopressin and growth hormone. A role of the TIP39-PTH2R system in thermoregulation was also identified. TIP39 may play a role in maintaining body temperature in a cold environment via descending excitatory pathways from the preoptic area. Anatomical and functional studies also implicated the TIP39-PTH2R system in nociceptive information processing. Finally, TIP39 induced in postpartum dams may play a role in the release of prolactin during lactation. Potential mechanisms leading to the activation of TIP39 neurons and how they influence the neuroendocrine system are also described. The unique TIP39-PTH2R neuromodulator system provides the possibility for developing drugs with a novel mechanism of action to control neuroendocrine disorders.
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Paralemniscal TIP39 is induced in rat dams and may participate in maternal functions
Brain Structure and Function, 2012Co-Authors: Tamás Varga, Miklós Palkovits, Ted B Usdin, Attila G. Bagó, Katalin Gallatz, Melinda Cservenák, Bence Mogyoródi, Dominika Domokos, Éva Renner, Arpád DobolyiAbstract:The paralemniscal area, situated between the pontine reticular formation and the lateral lemniscus in the pontomesencephalic tegmentum contains some tuberoinfundibular peptide of 39 residues (TIP39)-expressing neurons. In the present study, we measured a 4 times increase in the level of TIP39 mRNA in the paralemniscal area of lactating mothers as opposed to nulliparous females and mothers deprived of pups using real-time RT-PCR. In situ hybridization histochemistry and immunolabeling demonstrated that the induction of TIP39 in mothers takes place within the medial paralemniscal nucleus, a cytoarchitectonically distinct part of the paralemniscal area, and that the increase in TIP39 mRNA levels translates into elevated peptide levels in dams. The paralemniscal area has been implicated in maternal control as well as in pain perception. To establish the function of induced TIP39, we investigated the activation of TIP39 neurons in response to pup exposure as maternal, and formalin injection as noxious stimulus. Both stimuli elicited c - fos expression in the paralemniscal area. Subsequent double labeling demonstrated that 95% of neurons expressing Fos in response to pup exposure also contained TIP39 immunoreactivity and 91% of TIP39 neurons showed c - fos activation by pup exposure. In contrast, formalin-induced Fos does not co-localize with TIP39. Instead, most formalin-activated neurons are situated medial to the TIP39 cell group. Our data indicate that paralemniscal neurons may be involved in the processing of maternal and nociceptive information. However, two different groups of paralemniscal neurons participate in the two functions. In particular, TIP39 neurons may participate in the control of maternal functions.
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Tuberoinfundibular Peptide of 39 Residues Is Activated during Lactation and Participates in the Suckling-Induced Prolactin Release in Rat
Endocrinology, 2010Co-Authors: Melinda Cservenák, Miklós Palkovits, Ted B Usdin, Ibolya Bodnár, György M. Nagy, Arpád DobolyiAbstract:Tuberoinfundibular peptide of 39 residues (TIP39) and the PTH-2 receptor (PTH2R) constitute a peptide-receptor neuromodulator system. Based on the abundance of TIP39 fibers and axonal terminals as well as PTH2R-containing neurons and their processes in the hypothalamic para- and periventricular and arcuate nuclei TIP39 has been suggested to play a role in neuroendocrine regulation. We showed previously that TIP39 expression decreased dramatically by adulthood. In the present study, using in situ hybridization histochemistry, real-time RT-PCR, and immunohistochemistry, we found that TIP39 mRNA and peptide expression levels are markedly elevated in the posterior intralaminar complex of the thalamus (PIL) of lactating dams, one of the three locations of TIP39-containing cell bodies in the brain. In addition, in mother rats, these TIP39 neurons showed Fos expression in response to pup exposure. Transection of TIP39 fibers originating in the PIL resulted in an ipsilateral disappearance of TIP39 immunoreactivit...
Ted B Usdin - One of the best experts on this subject based on the ideXlab platform.
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The parathyroid hormone 2 receptor participates in physiological and behavioral alterations of mother mice.
Physiology & behavior, 2017Co-Authors: Barbara Gellén, Ted B Usdin, Dóra Zelena, Arpád DobolyiAbstract:Abstract Parathyroid hormone 2 receptor (PTH2R) and its ligand, tuberoinfundibular peptide of 39 residues (TIP39) have been implicated in the maintenance of homeostasis including body temperature in males. The system was recently shown to be activated in mothers. Therefore, we addressed some of its functions during pregnancy and lactation, comparing PTH2R-knockout (PTH2R-KO) mice with their wild type (WT) littermates. Core body temperature (Tc) was recorded via a telemetric device, anxiety was assessed in an open field, depression-like behavior in the forced-swim test while spontaneous and pup retrieval-induced maternal behavior was also observed. Nulliparous virgin KO and WT mice showed a circadian pattern of Tc and locomotion with no differences between groups. WT mothers had an increased Tc during pregnancy and lactation as compared to virgins. This peripartum elevation of Tc was present but reduced in KO mice, even though their locomotor activity was increased. The greater locomotor activity of the KO mice was confirmed in the open field test but no other behavior differences were detected in the test. The maternal behavior was similar in the 2 genotypes except that the KO mice spent more time in the nest. In turn, a marked difference was found in the forced-swim test as the KO mice spent significantly less time struggling and more time floating compared to the WT littermates. The data suggest that the PTH2R contributes to the elevated Tc and reduced depression-like behavior of mother mice. These findings are consistent with specific maternal functions of the activated TIP39-PTH2R neuromodulator system in mothers.
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Maternally involved galanin neurons in the preoptic area of the rat
Brain Structure and Function, 2017Co-Authors: Melinda Cservenák, Éva Renner, Éva R. Szabó, Dávid Keller, Viktor Kis, Diána Dimén, Lilla Menyhárt, Szilvia Oláh, János Barna, Ted B UsdinAbstract:Recent selective stimulation and ablation of galanin neurons in the preoptic area of the hypothalamus established their critical role in control of maternal behaviors. Here, we identified a group of galanin neurons in the anterior commissural nucleus (ACN), and a distinct group in the medial preoptic area (MPA). Galanin neurons in ACN but not the MPA co-expressed oxytocin. We used immunodetection of phosphorylated STAT5 (pSTAT5), involved in prolactin receptor signal transduction, to evaluate the effects of suckling-induced prolactin release and found that 76 % of galanin cells in ACN, but only 12 % in MPA were prolactin responsive. Nerve terminals containing tuberoinfundibular peptide 39 (TIP39), a neuropeptide that mediates effects of suckling on maternal motivation, were abundant around galanin neurons in both preoptic regions. In the ACN and MPA, 89 and 82 % of galanin neurons received close somatic appositions, with an average of 2.9 and 2.6 per cell, respectively. We observed perisomatic innervation of galanin neurons using correlated light and electron microscopy. The connection was excitatory based on the glutamate content of TIP39 terminals demonstrated by post-embedding immunogold electron microscopy. Injection of the anterograde tracer biotinylated dextran amine into the TIP39-expressing posterior intralaminar complex of the thalamus (PIL) demonstrated that preoptic TIP39 fibers originate in the PIL, which is activated by suckling. Thus, galanin neurons in the preoptic area of mother rats are innervated by an excitatory neuronal pathway that conveys suckling-related information. In turn, they can be topographically and neurochemically divided into two distinct cell groups, of which only one is affected by prolactin.
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Incubation of Fear Is Regulated by TIP39 Peptide Signaling in the Medial Nucleus of the Amygdala.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2015Co-Authors: Mumeko C. Tsuda, Jonathan Kuo, Ho-man Yeung, Ted B UsdinAbstract:Fear-related psychopathologies such as post-traumatic stress disorder are characterized by impaired extinction of fearful memories. Recent behavioral evidence suggests that the neuropeptide tuberoinfundibular peptide of 39 residues (TIP39), via its receptor, the parathyroid hormone 2 receptor (PTH2R), modulates fear memory. Here we examined the anatomical and cellular localization of TIP39 signaling that contributes to the increase in fear memory over time following a traumatic event, called fear memory incubation. Contextual freezing, a behavioral sign of fear memory, was significantly greater in PTH2R knock-out than wild-type male mice 2 and 4 weeks after a 2 s 1.5 mA footshock. PTH2R knock-out mice had significantly reduced c-Fos activation in the medial amygdala (MeA) following both footshock and fear recall, but had normal activation in the hypothalamic paraventricular nucleus and the amygdalar central nucleus compared with wild-type. We therefore investigated the contribution of MeA TIP39 signaling to fear incubation. Similar to the effect of global TIP39 signaling loss, blockade of TIP39 signaling in the MeA by lentivirus-mediated expression of a secreted PTH2R antagonist augmented fear incubation. Ablation of MeA PTH2R-expressing neurons also strengthened the fear incubation effect. Using the designer receptor exclusively activated by designer drug pharmacogenetic approach, transient inhibition of MeA PTH2R-expressing neurons before or immediately after the footshock, but not at the time of fear recall, enhanced fear incubation. Collectively, the findings demonstrate that TIP39 signaling within the MeA at the time of an aversive event regulates the increase over time in fear associated with the event context. SIGNIFICANCE STATEMENT Fear-related psychopathologies such as post-traumatic stress disorder (PTSD) are characterized by excessive responses to trauma-associated cues. Fear responses can increase over time without additional cue exposure or stress. This work shows that modulatory processes within the medial nucleus of the amygdala near the time of a traumatic event influence the strength of fear responses that occur much later. The modulatory processes include signaling by the neuropeptide TIP39 and neurons that express its receptor. These findings will help in the understanding of why traumatic events sometimes have severe psychological consequences. One implication is that targeting neuromodulation in the medial amygdala could potentially help prevent development of PTSD.
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neuropathic and inflammatory pain are modulated by tuberoinfundibular peptide of 39 residues
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Eugene Dimitrov, Jonathan Kuo, Kenji Kohno, Ted B UsdinAbstract:Nociceptive information is modulated by a large number of endogenous signaling agents that change over the course of recovery from injury. This plasticity makes understanding regulatory mechanisms involved in descending inhibition of pain scientifically and clinically important. Neurons that synthesize the neuropeptide TIP39 project to many areas that modulate nociceptive information. These areas are enriched in its receptor, the parathyroid hormone 2 receptor (PTH2R). We previously found that TIP39 affects several acute nociceptive responses, leading us to now investigate its potential role in chronic pain. Following nerve injury, both PTH2R and TIP39 knockout mice developed less tactile and thermal hypersensitivity than controls and returned to baseline sensory thresholds faster. Effects of hindpaw inflammatory injury were similarly decreased in knockout mice. Blockade of α-2 adrenergic receptors increased the tactile and thermal sensitivity of apparently recovered knockout mice, returning it to levels of neuropathic controls. Mice with locus coeruleus (LC) area injection of lentivirus encoding a secreted PTH2R antagonist had a rapid, α-2 reversible, apparent recovery from neuropathic injury similar to the knockout mice. Ablation of LC area glutamatergic neurons led to local PTH2R-ir loss, and barley lectin was transferred from local glutamatergic neurons to GABA interneurons that surround the LC. These results suggest that TIP39 signaling modulates sensory thresholds via effects on glutamatergic transmission to brainstem GABAergic interneurons that innervate noradrenergic neurons. TIP39’s normal role may be to inhibit release of hypoalgesic amounts of norepinephrine during chronic pain. The neuropeptide may help maintain central sensitization, which could serve to enhance guarding behavior.
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Maternal Absence of the Parathyroid Hormone 2 Receptor Affects Postnatal Pup Development
Journal of neuroendocrinology, 2011Co-Authors: Laurence Coutellier, Milan Rusnak, Allison Logemann, Ted B UsdinAbstract:During the lactation period, mothers have a variety of adaptive changes in brain physiology and behaviour that allow them to properly raise their pups. The exact circuitries and mechanisms responsible for these changes are not fully understood. Recent evidence suggests that the neuropeptide tuberoinfundibular peptide of 39 residues (TIP39) and its receptor, the parathyroid hormone 2 receptor (PTH2-R), contribute to these mechanisms. To further investigate this idea, we evaluated the growth rate of pups from dams with a genetically inactivated PTH2-R (PTH2-R-KO), as well as maternal behavioural and neuroendocrine parameters. We observed that PTH2-R-KO-reared pups had a slowed growth rate. This was associated with a reduced volume of milk yielded by PTH2-R-KO dams after 30-min suckling compared to wild-type (WT) dams when pups were returned after 5 h of separation. Our data suggest a reduced sensitivity of PTH2-R-KO dams to pup stimulation. We also observed a significant reduction in suckling-induced c-Fos expression in the paraventricular hypothalamic nucleus and signs of lower prolactin levels in the PTH2-R-KO dams. Our data suggest that the reduced growth rate of PTH2-R-KO-reared pups was likely the result of alterations in the milk-production pathway rather than modifications in behaviour. Although PTH2-R-KO dams showed increased anxiety in the elevated zero-maze test, no differences from WT dams in maternal behaviour were observed. Taken together, our findings suggest the involvement of the TIP39/PTH2-R system in the pathways involved in the successful development of the pups.
Richard L Gallo - One of the best experts on this subject based on the ideXlab platform.
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the parathyroid hormone family member TIP39 interacts with sarco endoplasmic reticulum ca2 atpase activity by influencing calcium homoeostasis
Experimental Dermatology, 2017Co-Authors: Emi Sato, James A Sanford, Michael R. Williams, George L. Sen, Takekuni Nakama, Shinichi Imafuku, Richard L GalloAbstract:Darier disease (DD) is a genetic skin disease that is associated with mutations in the ATP2A2 gene encoding the type 2 sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2). Mutations of this gene result in alterations of calcium homeostasis, abnormal epidermal adhesion and dyskeratosis. Silencing of ATP2A2 in monolayer cell culture of keratinocytes reduces desmoplakin expression at the borders of cells and impacts cell adhesion. Here, we report establishment of a three-dimensional (3D) epidermal model of DD, and use this model to evaluate peptide therapy with tuberoinfundibular peptide of 39 residues (TIP39) to normalize calcium transport. Gene silencing of ATP2A2 in keratinocytes grown in a 3D model resulted in dyskeratosis, partial parakeratosis and suprabasal clefts that resembled the histological changes seen in skin biopsies from patients with DD. TIP39, a peptide recently identified as a regulator of keratinocyte calcium transport, , was then applied to this ATP2A2 silenced 3D epidermal model. In normal keratinocytes, TIP39 increased [Ca2+]i through the inositol trisphosphate (IP3) receptor pathway and stimulated differentiation. In monolayer ATP2A2-silenced keratinocytes, although TIP39 increased cytosolic calcium from the endoplasmic reticulum (ER), the response was incomplete compared with its control. TIP39 was observed to reduce intercellular clefts of the gene silenced epidermal model but did not significantly upregulate keratinocyte differentiation genes such as keratin10 and filaggrin. These findings indicate that TIP39 is a modulator of ER calcium signaling and may be used as a potential strategy for improving aspects of DD.
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activation of parathyroid hormone 2 receptor induces decorin expression and promotes wound repair
Journal of Investigative Dermatology, 2017Co-Authors: Emi Sato, Lingjuan Zhang, Robert A Dorschner, Christopher A Adase, Biswa Choudhury, Richard L GalloAbstract:In this study, we report that TIP39, a parathyroid hormone ligand family member that was recently identified to be expressed in the skin, can induce decorin expression and enhance wound repair. Topical treatment of mice with TIP39 accelerated wound repair, whereas TIP39-deficient mice had delayed repair that was associated with formation of abnormal collagen bundles. To study the potential mechanism responsible for the action of TIP39 in the dermis, fibroblasts were cultured in three-dimensional collagen gels, a process that results in enhanced decorin expression unless activated to differentiate to adipocytes, whereupon these cells reduce expression of several proteoglycans, including decorin. Small interfering RNA-mediated silencing of parathyroid hormone 2 receptor (PTH2R), the receptor for TIP39, suppressed the expression of extracellular matrix-related genes, including decorin, collagens, fibronectin, and matrix metalloproteases. Skin wounds in TIP39 –/– mice had decreased decorin expression, and addition of TIP39 to cultured fibroblasts induced decorin and increased phosphorylation and nuclear translocation of CREB. Fibroblasts differentiated to adipocytes and treated with TIP39 also showed increased decorin and production of chondroitin sulfate. Furthermore, the skin of PTH2R –/– mice showed abnormal extracellular matrix structure, decreased decorin expression, and skin hardness. Thus, the TIP39-PTH2R system appears to be a previously unrecognized mechanism for regulation of extracellular matrix formation and wound repair.
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The parathyroid hormone family member TIP39 interacts with sarco/endoplasmic reticulum Ca2+ - ATPase activity by influencing calcium homoeostasis.
Experimental dermatology, 2017Co-Authors: Emi Sato, James A Sanford, Michael R. Williams, George L. Sen, Takekuni Nakama, Shinichi Imafuku, Richard L GalloAbstract:Darier disease (DD) is a genetic skin disease that is associated with mutations in the ATP2A2 gene encoding the type 2 sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2). Mutations of this gene result in alterations of calcium homeostasis, abnormal epidermal adhesion and dyskeratosis. Silencing of ATP2A2 in monolayer cell culture of keratinocytes reduces desmoplakin expression at the borders of cells and impacts cell adhesion. Here, we report establishment of a three-dimensional (3D) epidermal model of DD, and use this model to evaluate peptide therapy with tuberoinfundibular peptide of 39 residues (TIP39) to normalize calcium transport. Gene silencing of ATP2A2 in keratinocytes grown in a 3D model resulted in dyskeratosis, partial parakeratosis and suprabasal clefts that resembled the histological changes seen in skin biopsies from patients with DD. TIP39, a peptide recently identified as a regulator of keratinocyte calcium transport, , was then applied to this ATP2A2 silenced 3D epidermal model. In normal keratinocytes, TIP39 increased [Ca2+]i through the inositol trisphosphate (IP3) receptor pathway and stimulated differentiation. In monolayer ATP2A2-silenced keratinocytes, although TIP39 increased cytosolic calcium from the endoplasmic reticulum (ER), the response was incomplete compared with its control. TIP39 was observed to reduce intercellular clefts of the gene silenced epidermal model but did not significantly upregulate keratinocyte differentiation genes such as keratin10 and filaggrin. These findings indicate that TIP39 is a modulator of ER calcium signaling and may be used as a potential strategy for improving aspects of DD.
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the parathyroid hormone second receptor pth2r and its ligand tuberoinfundibular peptide of 39 residues TIP39 regulate intracellular calcium and influence keratinocyte differentiation
Journal of Investigative Dermatology, 2016Co-Authors: Emi Sato, Ted B Usdin, Lingjuan Zhang, Christopher A Adase, Jun Muto, James A Sanford, Toshiya Takahashi, Teruaki Nakatsuji, Richard L GalloAbstract:Genes related to the parathyroid hormone (PTH) influence cutaneous immune defense and development, but the full functions of the PTH family in cutaneous biology remain incompletely understood. In this study, we examined the expression and potential functions of the PTH second receptor (PTH2R) and its ligand, the tuberoinfundibular peptide of 39 residues (TIP39), in the skin. TIP39 and PTH2R mRNA and protein were detectable in both human and mouse skin, and in cultured keratinocytes and adipocytes. TIP39 was observed in the basal layer of human skin, whereas PTH2R was detected in the spinous to granular layer. The subcellular localization of TIP39 in keratinocytes changed during calcium-induced differentiation and shifted to colocalize with PTH2R at the membrane. The addition of recombinant TIP39 to normal human keratinocytes in culture induced an increase in intercellular calcium and triggered aspects of terminal differentiation including decreased keratin-14 and increased involucrin expression. Consistent with these observations, PTH2R −/− mice were observed to have increased epidermal thickness. In summary, identification of TIP39 and its receptor in the epidermis reveals an additional PTH family member that is expressed in the skin and may influence keratinocyte function.