Dysfunction of the serotonin (5-HT) and gamma-aminobutyric acid (GABA) systems have been implicated in anxiety since most clinically useful anxiolytic compounds act by stimulating either 5-HT-1a or benzodiazepine receptors that modulate GABA neurotransmission. The specific brain regions involved and the particular interactions between 5-HT and GABA neurotransmitter systems during anxiety and its therapeutic treatment are not well understood. The long-term goal of this proposal is to understand the cellular and molecular substrates of anxiety as well as the specific neural circuits that may be affected in this disorder in order to identify novel targets for anxiolytic treatment. The objective of this application is to examine the particular fear and anxiety states resulting from alterations in the 5-HT and GABA systems in different brain regions using behavioral, electrophysiological and molecular techniques in an animal model of anxiety: the 5-HT-1a knockout (1AKO) mouse.
In AIM 1 I will compare the behavior of 1aKOs and wild-type controls (WTs) to dorsal raphe nucleus (DRN) system-dependent vs. median raphe nucleus (MRN) system-dependent models of fear and anxiety. These studies will indicate the particular fear/anxiety states demonstrated by 1aKO mice as well as the particular circuits disrupted by the genetic deletion. I will then use electrophysiological and molecular techniques in AIMS 2 and 3 to test the specific alterations of 5-HT and GABA neurotransmission in different neural circuits in 1aKOs.
In AIM 2 I will measure membrane characteristics, 5-HT-1a and GABAA receptor-mediated responses in DRN and MRN of 1aKOs and WTs using brain slice electrophysiological recording techniques.
In AIM 3 I will measure 5-HT-1a and GABAA receptor-mediated responses in amygdala or hippocampal slices from 1aKOs and WTs. I will compare the measured electrophysiological response of the cell with its GABAA receptor subunit expression. My hypothesis is that deletion of the 5-HT-1a receptor disrupts 5-HT neurotransmission in specific cell bodies and their projections, altering GABA neurotransmission and ultimately producing the anxious phenotype. The experiments described in this proposal will elucidate neural circuits and altered neurotransmission that may underlie the particular anxiety states expressed by this animal model of anxiety. These experiments will lead to a better understanding of the interactions between the 5-HT and GABA systems during the expression of chronic anxiety and may identify potential targets for novel pharmacological treatments of anxiety disorders.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Scientist Development Award - Research & Training (K01)
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Special Emphasis Panel (ZRG1-IFCN-2 (01))
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Desmond, Nancy L
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Temple University
Anatomy/Cell Biology
Schools of Medicine
United States
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Freeman-Daniels, Emily; Beck, Sheryl G; Kirby, Lynn G (2011) Cellular correlates of anxiety in CA1 hippocampal pyramidal cells of 5-HT1A receptor knockout mice. Psychopharmacology (Berl) 213:453-63
Lemos, Julia C; Zhang, Guojun; Walsh, Teresa et al. (2011) Stress-hyperresponsive WKY rats demonstrate depressed dorsal raphe neuronal excitability and dysregulated CRF-mediated responses. Neuropsychopharmacology 36:721-34
Huang, Peng; Liu-Chen, Lee-Yuan; Kirby, Lynn G (2010) Anxiety-like effects of SR141716-precipitated delta9-tetrahydrocannabinol withdrawal in mice in the elevated plus-maze. Neurosci Lett 475:165-8
Kirby, Lynn G; Freeman-Daniels, Emily; Lemos, Julia C et al. (2008) Corticotropin-releasing factor increases GABA synaptic activity and induces inward current in 5-hydroxytryptamine dorsal raphe neurons. J Neurosci 28:12927-37
Kirby, Lynn G; Pan, Yu-Zhen; Freeman-Daniels, Emily et al. (2007) Cellular effects of swim stress in the dorsal raphe nucleus. Psychoneuroendocrinology 32:712-23
Beck, Sheryl G; Pan, Yu-Zhen; Akanwa, Adaure C et al. (2004) Median and dorsal raphe neurons are not electrophysiologically identical. J Neurophysiol 91:994-1005