Neurotrophins and the neuroendocrine brain: different neurotrophins sustain anatomically and functionally segregated subsets of hypothalamic dopaminergic neurons.
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Hypothalamic neurons control a variety of important hormonal and behavioral functions. Little is known, however, about the neurotrophic factors that these neurons may require for survival and/or maintenance of their differentiated functions. We conducted experiments to examine this issue, utilizing a combination of immunohistochemical, in situ hybridization and cell culture approaches. We found that the low affinity receptor for nerve growth factor (p75 NGFR) is present in small subsets of hypothalamic peptidergic neurons identified as such by their content of galanin, luteinizing hormone-releasing hormone (LHRH) and vasointestinal peptide (VIP). More prominently, however, examination of hypothalamic dopaminergic (DA) neurons for the presence of p75 NGFR-like immunoreactivity revealed that the receptor was present on tyrosine hydroxylase (TH)-positive neurons of the zona incerta and periventricular region, but not on neuroendocrine DA neurons of the tuberoinfundibular region. In situ hybridization experiments using a p75 NGFR cRNA confirmed this distribution. Regardless of the presence or absence of p75 NGFR, neither DA group expresses trkA mRNA, indicating that these two major hypothalamic subsets of DNA neurons are NGF-insensitive. A substantial fraction of TH mRNA-positive cells in the zona incerta expresses trkB mRNA, which encodes the receptor for brain derived neurotrophic factor (BDNF); in turn BDNF supports the in vitro survival of hypothalamic TH neurons bearing p75-NGFR, suggesting that BDNF is trophic for DNA neurons of the zona incerta. In contrast, tuberoinfundibular DA neurons do not express trkB mRNA, but some have trkC mRNA, which encodes the receptor for neurotrophin-3 (NT-3). The in vitro survival of TH neurons devoid of p75-NGFR is supported by NT-3, implying that NT-3 may be trophic for a subset of tuberoinfundibular DA neurons. These results suggest that, in spite of expressing an identical neurotransmitter phenotype, anatomically and functionally segregated DA neurons of the neurodendocrine brain are sustained by different neurotrophic factors.