The cellular mechanisms underlying stress induced behaviors and the development and treatment of stress related psychiatric disorders most likely involve both the 5-HT cell body containing nuclei of the raphe as well as their projection areas in the limbic forebrain. The median (MR) and dorsal raphe (DR) are the principal sites where 5-HT cell bodies are located and they provide the majority of the 5-HT innervation of the forebrain. Approximately 50% of the neurons in the MR and DR are non-5-HT containing. The MR and DR projections terminate in many of the same limbic brain areas, but also have exclusive projections to other brain areas. The anatomy of the different subfields of the DR and within the MR is not the same. These distinctions have important implications in terms of regional selectivity of the subfields of the DR and the MR in controlling different emotional behaviors. The long term goal is to delineate both the common and disparate features of MR and DR cell neural activity. This information will provide a foundation for understanding the factors that differentially regulate 5-HT and non-5-HT physiology and may underlie some of the functional differences. The overall hypothesis is that there are discrete regional cellular differences in the 5-HT and non-5-HT containing neurons of the different subfields of the DR and MR. The excitatory neurotransmitter glutamate, the inhibitory neurotransmitter GABA and the stress hormone CRF are all posed to have selective and regionally distinct modulatory roles on DR and/or MR activity. In this application, the goal is to regionally map the differences in basic cellular characteristics (Specific Aim 1), excitatory glutamatergic (Specific Aim 2) and inhibitory GABAergic neural activity (Specific Aim 3) and their modulation by 5-HT1A, 5-HT1B, and CRF receptor activation. Selective alteration of these responses will be measured in 2 animal models, i.e., swim stressed rats and the 5-HT1B knockout mouse (Specific Aim 4). Whole cell recording techniques, immunohistochemistry, aRNA amplification and histological procedures will be used in the different subfields of the DR and MR in 5-HT and non-5-HT containing neurons. The clinical relevance of these studies is in supplying important information that will be crucial for understanding how the 5-HT neurotransmitter system regulates stress and emotions and how it may be involved in the etiology and treatment of mood disorders such as anxiety and depression.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IFCN-A (02))
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Nadler, Laurie S
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Children's Hospital of Philadelphia
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