A current major focus of the laboratory is investigation of the physiological functions of the neuropeptide Tuberoinfundibular Peptide of 39 residues (TIP39) and its receptor, the Parathyroid Hormone 2 (PTH2) receptor. These molecules were discovered in this laboratory several years ago. In previous years of this project we mapped the neuroanatomical distributions of TIP39 and the PTH2 receptor. TIP39 is synthesized by three discrete groups of neurons, two at the caudal border of the thalamus and one in the brainstem. TIP39 synthesizing neurons project to several brain areas that are involved in the regulation of emotional function. These areas contain a matching distribution of the PTH2 receptor, and neurons in these regions project to the areas containing TIP39 neurons. Thus the system is ideally positioned to coordinate and modulate functions relevant to mental disorders. Following this anatomical mapping, laboratory projects turned to investigation of hypotheses derived from the distribution of TIP39 and the PTH2R. We found recently that TIP39 modulates activation of neurons in the paraventricular nucleus of the hypothalamus, which controls several neuroendocrine functions, including release of glucocorticoid stress hormone from the adrenal gland. TIP39 increased the stress hormone corticosterone. TIP39 does this by acting on the terminals of neurons within the paraventricular nucleus that release the classic fast-acting transmitter glutamate, thus it modulates excitatory inputs to neuroendocrine cells. We also found that TIP39 modulates pain sensitivity, acting primarily within the brain to affect the processing of painful sensory information. The brain areas where TIP39 appears to modulate pain are also implicated in affective disorders, so a hypothesis we plan to examine in the future is that TIP39 signaling is involved in the strong relationship between chronic pain and depression. In previous years of the project we found that mice with genetic deletion of the gene encoding TIP39 (TIP39-KO) have increased anxiety-like behavior that depends upon the stress created by the testing conditions. Under conditions of minimal stress loss of TIP39 had little effect, while under increased stress animals without TIP39 exhibited significantly greater anxiety-like behavior than mice with normal TIP39 function. During this reporting period we investigated the role of TIP39 in modulating the effects of stress on cognitive function. We tested TIP39-KO mice and mice with null mutation of its receptor, the parathyroid hormone 2 receptor (PTH2-R), in tasks of short-term declarative and social memory (object recognition and social recognition tests, respectively), and of working memory (Y-maze test) under conditions of novelty-induced arousal or acclimation to the test conditions. Mice lacking TIP39 signaling because of either ligand or receptor loss showed memory impairment, under conditions of novelty-induced arousal but not when acclimated to the testing environment. We also found that acute intracerebral administration of a PTH2R antagonist we developed reproduced the effect of the genetic mutations, indicating that these deficits resulted from loss of TIP39 signaling at the time of the experiment. Thus our data suggest that TIP39 signaling may normally limit the detrimental effects of environmental stress on cognitive performance. Patients with a number of mental health disorders exhibit much greater dysfunction in a novel environment and under stress than under familiar conditions. We previously found that the neuroanatomical distributions of TIP39 and the PTH2-R are almost identical in humans and rodents, so this suggests that TIP39 signaling may be involved in limiting deleterious effects of stress in humans. During this reporting period we also began looking at the effects of TIP39 signaling on long-term emotional memory. We used a mouse model of post-traumatic stress disorder in which the animals are exposed to a single traumatic event (electric foot-shock) after which fear memory is evaluated by re-exposing them to the context of the traumatic event and measuring the time spent motionless (freezing, a rodent fear-like response). The lack of TIP39 signaling did not cause a detectable change in fear memory one week after the shock. However, both mice lacking the peptide gene as well as mice with null mutation in the PTH2-R gene exhibited greater fear-like behavior than wild-type mice two weeks following the shock. This suggests that, similar to its role in short-term cognitive performance, TIP39 normally limits the long-term detrimental effects of fear or stress. Mice without TIP39 signaling also exhibited increased anxiety-like behavior two weeks following the shock, a behavior also consistent with a post-traumatic stress disorder model. Most of our studies have been performed in male animals, although we did find a significant sexual dimorphism in the postnatal expression of TIP39 in rats. There is a significant post-pubertal decline in TIP39 in male rats and a significantly smaller decline in females, suggesting involvement in sex specific functions. In the previous reporting period we found that TIP39 modulates release of the pituitary hormone prolactin in male mice. Prolactin is a major mediator of maternal functions, including milk production. We have now begun examining the role of TIP39 signaling in female-specific functions. In a continuing collaboration with Dr. Arpad Dobolyi of Semmelweis University in Hungary, we found that TIP39 levels are significantly increased in lactating females, that pup suckling activates the neurons that synthesize TIP39, and that acute block of TIP39 signaling inhibits the stimulation of prolactin release normally caused by pup suckling. In a study comparing wild-type and PTH2R-KO mouse dams we found no significant differences in their maternal behaviors, but the pups of PTH2R-KO dams gained weight significantly more slowly than the pups of WT dams in the postnatal period. By mating wild-type males with KO females and KO males with WT females all pups had identical genotypes. Pup weights were the same at birth, indicating that postnatal and not prenatal factors affected the weight gain, which is consistent with TIP39 modulation of the sensitivity of prolactin release to pup suckling. Together with previous data this suggests that TIP39 helps to control which or how effectively hypothalamic excitatory pathways control neuroendocrine function, contributing to an appropriate hormonal response to changing conditions.

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Cservenák, Melinda; Kis, Viktor; Keller, Dávid et al. (2017) Maternally involved galanin neurons in the preoptic area of the rat. Brain Struct Funct 222:781-798
Cservenák, Melinda; Keller, Dávid; Kis, Viktor et al. (2017) A Thalamo-Hypothalamic Pathway That Activates Oxytocin Neurons in Social Contexts in Female Rats. Endocrinology 158:335-348
Usdin, Ted B; Dimitrov, Eugene L (2016) The Effects of Extended Pain on Behavior: Recent Progress. Neuroscientist 22:521-33
Sato, Emi; Muto, Jun; Zhang, Ling-Juan et al. (2016) The Parathyroid Hormone Second Receptor PTH2R and its Ligand Tuberoinfundibular Peptide of 39 Residues TIP39 Regulate Intracellular Calcium and Influence Keratinocyte Differentiation. J Invest Dermatol 136:1449-1459
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Silberman, Yuval; Fetterly, Tracy L; Awad, Elias K et al. (2015) Ethanol produces corticotropin-releasing factor receptor-dependent enhancement of spontaneous glutamatergic transmission in the mouse central amygdala. Alcohol Clin Exp Res 39:2154-62
Dimitrov, Eugene L; Kuo, Jonathan; Kohno, Kenji et al. (2013) Neuropathic and inflammatory pain are modulated by tuberoinfundibular peptide of 39 residues. Proc Natl Acad Sci U S A 110:13156-61
Cservenák, Melinda; Szabó, Éva R; Bodnár, Ibolya et al. (2013) Thalamic neuropeptide mediating the effects of nursing on lactation and maternal motivation. Psychoneuroendocrinology 38:3070-84
Dimitrov, Eugene L; Yanagawa, Yuchio; Usdin, Ted B (2013) Forebrain GABAergic projections to locus coeruleus in mouse. J Comp Neurol 521:2373-97
Dobolyi, Arpad; Dimitrov, Eugene; Palkovits, Miklos et al. (2012) The neuroendocrine functions of the parathyroid hormone 2 receptor. Front Endocrinol (Lausanne) 3:121

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