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, which were discovered in this laboratory several years ago. TIP39 is synthesized by two discrete groups of neurons that project to areas involved in 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. Our experimental work is performed in rodents, but to evaluate its relevance to human behavior we have begun comparing the neuroanatomical distribution of TIP39 and PTH2 receptor expression in humans and non-human primates with the distribution in rodents, and obtained data suggesting that they are quite similar. During this reporting period we used mice with null mutation of the gene encoding TIP39 (TIP39-KO) to investigate function of the system. TIP39-KO mice appear normal on initial observation and in screening assays for health and neurological function. We found that TIP39-KO mice are sterile. Detailed anatomical observation revealed a defect in the maturation of spermatogenic cells. By selectively expressing TIP39 within the testes we learned that TIP39 expression within the testes is sufficient for maturation of sperm, and in combination with its normal expression there we infer that TIP39 synthesized within the gonads normally functions as an essential permissive factor in germ cell maturation. We also investigated the behavioral effects of TIP39 loss. We found using established behavioral tests such as the open-field, dark-light emergence, shock-probe burying and the elevated plus maze under varied lighting or following restraint, that TIP39-KO mice have increased anxiety-like behavior when stressed. We also found that they exhibit greater fear-like behavior in a Pavlovian conditioning paradigm. The increased fear-like behavior (freezing behavior in the test) appeared to result from increased learning or increased significance of cues and not to a change in extinction of a learned association. The male gonadal hormone testosterone is produced by Leydig cells which were intact, and its level was normal, so we believe that the behavioral effects observed in TIP39-KO mice result from its absence within the brain. Our interpretation of these data is that TIP39 may normally function to modulate behavioral responses to stress. We speculate that dysregulation of TIP39 or genes like TIP39 could increase the vulnerability to psychiatric disorders and intend to test this idea in rodent models.
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