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

ABSTRACT: Exogenous neuropeptide Y (NPY) reduces experimental anxiety in a wide range of animal models. The generation of an NPY-transgenic rat has provided a unique model to examine the role of endogenous NPY in control of stress and anxiety-related behaviors using paradigms previously used by pharmacological studies. Locomotor activity and baseline behavior on the elevated plus maze were normal in transgenic subjects. Two robust phenotypic traits were observed. (i) Transgenic subjects showed a markedly attenuated sensitivity to behavioral consequences of stress, in that they were insensitive to the normal anxiogenic-like effect of restraint stress on the elevated plus maze and displayed absent fear suppression of behavior in a punished drinking test. (ii) A selective impairment of spatial memory acquisition was found in the Morris water maze. Control experiments suggest these traits to be independent. These phenotypic traits were accompanied by an overexpression of prepro-NPY mRNA and NPY peptide and decreased NPY-Y1 binding within the hippocampus, a brain structure implicated both in memory processing and stress responses. Data obtained using this unique model support and extend a previously postulated anti-stress action of NPY and provide novel evidence for a role of NPY in learning and memory.

SUBMITTER: Thorsell A

PROVIDER: S-EPMC18853 | biostudies-literature | 2000 Nov

REPOSITORIES: biostudies-literature

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

Thorsell A A Michalkiewicz M M Dumont Y Y Quirion R R Caberlotto L L Rimondini R R Mathé A A AA Heilig M M

Proceedings of the National Academy of Sciences of the United States of America 20001101 23

Exogenous neuropeptide Y (NPY) reduces experimental anxiety in a wide range of animal models. The generation of an NPY-transgenic rat has provided a unique model to examine the role of endogenous NPY in control of stress and anxiety-related behaviors using paradigms previously used by pharmacological studies. Locomotor activity and baseline behavior on the elevated plus maze were normal in transgenic subjects. Two robust phenotypic traits were observed. (i) Transgenic subjects showed a markedly ...[more]

PMID: 11058155

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Project description:Neuropeptide Y (NPY) is an endogenous neuropeptide that is abundantly expressed in the central nervous system. NPY is involved in various neurological processes and neuropsychiatric disorders, including fear learning and anxiety disorders. Reduced levels of NPY are reported in Post-Traumatic Stress Disorder (PTSD) patients, and NPY has been proposed as a potential therapeutic target for PTSD. It is therefore important to understand the effects of chronic enhancement of NPY on anxiety and fear learning. Previous studies have shown that acute elevation of NPY reduces anxiety, fear learning and locomotor activity. Models of chronic NPY overexpression have produced mixed results, possibly caused by ectopic NPY expression. NPY is expressed primarily by a subset of GABAergic interneurons, providing specific spatiotemporal release patterns. Administration of exogenous NPY throughout the brain, or overexpression in cells that do not normally release NPY, can have detrimental side effects, including memory impairment. In order to determine the effects of boosting NPY only in the cells that normally release it, we utilized a transgenic mouse line that overexpresses NPY only in NPY+ cells. We tested for effects on anxiety related behaviors in adolescent mice, an age with high incidence of anxiety disorders in humans. Surprisingly, we did not observe the expected reduction in anxiety-like behavior in NPY overexpression mice. There was no change in fear learning behavior, although there was a deficit in nest building. The effect of exogenous NPY on synaptic transmission in acute hippocampal slices was also diminished, indicating that the function of NPY receptors is impaired. Reduced NPY receptor function could contribute to the unexpected behavioral outcomes. We conclude that overexpression of NPY, even in cells that normally express it, can lead to reduced responsiveness of NPY receptors, potentially affecting the ability of NPY to function as a long-term therapeutic.

Project description:KEY MESSAGE:HbMBF1a was isolated and characterized in H. brevisubulatum, and overexpressed HbMBF1a could enhance the salt tolerance and ABA insensitivity in Arabidopsis thaliana. The transcript levels of stress-responsive genes were significantly increased in the transgenic lines under salt and ABA conditions. Salinity is an abiotic stress that considerably affects plant growth, yield, and distribution. Hordeum brevisubulatum is a halophyte that evolved to become highly tolerant to salinity. Multiprotein bridging factor 1 (MBF1) is a transcriptional coactivator and an important regulator of stress tolerance. In this study, we isolated and characterized HbMBF1a based on the transcriptome data of H. brevisubulatum grown under saline conditions. We overexpressed HbMBF1a in Arabidopsis thaliana and compared the phenotypes of the transgenic lines and the wild-type in response to stresses. The results indicated that HbMBF1a expression was induced by salt and ABA treatments during the middle and late stages. The overexpression of HbMBF1a in A. thaliana resulted in enhanced salt tolerance and ABA insensitivity. More specifically, the enhanced salt tolerance manifested as the increased seed germination and seedling growth and development. Similarly, under ABA treatments, the cotyledon greening rate and seedling root length were higher in the HbMBF1a-overexpressing lines, suggesting the transgenic plants were better adapted to high exogenous ABA levels. Furthermore, the transcript levels of stress-responsive genes were significantly increased in the transgenic lines under salt and ABA conditions. Thus, HbMBF1a is a positive regulator of salt and ABA responses, and the corresponding gene may be useful for producing transgenic plants that are salt tolerant and/or ABA insensitive, with few adverse effects. This study involved a comprehensive analysis of HbMBF1a. The results may provide the basis and insight for the application of MBF1 family genes for developing stress-tolerant crops.

Dataset Information

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

Publications

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

Similar Datasets

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