REPRODUCTIVE SIGNALLING IN BRAINSTEM

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Inadequate activities in select brain neurons can cause many diseases, including infertility. For example, reproductive incompetence is a frequent symptom in patients with over-eating and drug problems, both of which can be addictive. The anatomical and physiological associations between obesity, drug addiction and infertility are unknown, although three neurochemicals, i.e., neuropeptide Y (NPY), norepinephrine transporter (NET) and norepinephrine (NE), are likely involved. Each of the three brain substances can influence the secretion of gonadotropin-releasing hormone (GnRH, a deca-peptide that is a key regulator of reproduction). NPY and NE alter eating behavior and NET and NE are involved in addiction. We hypothesize that integration of the three neurochemicals occurs in the brainstem and we utilized the rabbit as an initial model (before primate studies) to identify the distribution of brainstem cells containing NPY, NET and tyrosine hydroxylase (TH, the rate-limiting enzyme for NE synthesis) mRNAs by in situ hybridization. Specific rabbit NET and TH cDNA fragments were cloned by reverse transcription-polymerase chain reaction and their nucleotide sequences were determined. These two cDNA (as well as a human NPY cDNA) fragments were used as probes for hybridization with respective mRNAs through the entire length of rabbit brainstems that were sectioned at 20 fm thickness. Serial sections were also stained for the presence of dopamine- -hydroxylase (D H, a protein enzyme specific for NE synthesis) by immunocytochemistry to mark brainstem NE cells. The data suggest that while NET and TH mRNAs were located in all D H-positive areas including the locus coeruleus (LC, an area that consists of predominantly NE cells), NPY mRNA was not observed in LC cells. However, the lateral tegmentum and the nucleus of the solitary tract contained cells that expressed all three genes. These results provide an anatomical basis for potential NPY, NET and NE integration of peripheral and central signals that may modulate eating behavior, drug addiction and reproductive performance.