Behavioral insensitivity to restraint stress, absent fear suppression of behavior and impaired spatial learning in transgenic rats with hippocampal neuropeptide Y overexpression

Exogenous neuropeptide Y (NPY) reduces experimental anxiety in a wide range of animal models. The generation of an NPY-transgenic rat has provided a u nique model to examine the role of endogenous NPY in control of stress and anxiety-related behaviors using paradigms previously used by pharmacologica l studies. Locomotor activity and baseline behavior on the elevated plus ma ze were normal in transgenic subjects. Two robust phenotypic traits were ob served. (i) Transgenic subjects showed a markedly attenuated sensitivity to behavioral consequences of stress, in that they were insensitive to the no rmal anxiogenic-like effect of restraint stress on the elevated plus maze a nd displayed absent fear suppression of behavior in a punished drinking tes t. (ii) A selective impairment of spatial memory acquisition was found in t he Morris water maze. Control experiments suggest these traits to be indepe ndent. These phenotypic traits were accompanied by an over-expression of pr epro-NPY mRNA and NPY peptide and decreased NPY-Y1 binding within the hippo campus, a brain structure implicated both in memory processing and stress r esponses. Data obtained using this unique model support and extend a previo usly postulated anti-stress action of NPY and provide novel evidence for a role of NPY in learning and memory.