The proliferation of mouse lines bearing mutations of neural genes presents new opportunities for inroads into the neural bases of complex behaviors, such as the regulation of anxiety. Our ability to optimally utilize mouse genetic resources for this purpose is critically dependent on the reliability and sensitivity of behavioral assays. Although standard approaches for assessing anxiety-related behavior in mice have been of substantial benefit, widely recognized limitations in the accuracy, sensitivity and reproducibility of such assays warrant initiatives for the development of novel complementary approaches. We propose to adapt a unique quantitative approach to the analysis of mouse home cage behavior to this problem. We will test the hypothesis that environmental and pharmacological manipulations that modulate anxiety will impact the coordinated expression of spontaneous behaviors exhibited by mice in their home cages. We propose that quantitative analysis of high-resolution home cage behavioral datasets can be adapted to provide a highly sensitive assessment of novel anxiety- related behavioral measures. The proposal consists of 3 Aims.
In Aim 1 we will examine the sensitivity of home cage behavioral patterns to stressors, with the goal of identifying potential candidate anxiety measures. Two inbred mouse strains believed to differ in their expression of anxiety-related behaviors will be used.
In Aim 2, a pharmacological validation approach will be taken to assess the extent to which these measures are appropriately modified by known anxiolytic and anxiogenic drugs. The specificity of these measures will be explored by examining their sensitivity to behaviorally active drugs not known to modulate anxiety.
In Aim 3, we will determine the extent to which quantitative home cage behavioral monitoring approaches may be used to detect slow-onset anxiolytic effects produced by chronic treatment with the serotonin reuptake blocker fluoxetine and the tricyclic antidepressant desipramine. Strains of mice known to respond differently to chronic fluoxetine treatment, C57BL/6J and BALB/cJ, will be used for these studies. Limitations in behavioral assessment methods for determining anxiety levels in the mouse are hindering the development of novel therapeutic agents for anxiety disorders. Here we propose to adapt a novel quantitative behavioral monitoring method we have developed to derive and validate new markers of anxiety state. ? ? ? ?
| Urban, Daniel J; Zhu, Hu; Marcinkiewcz, Catherine A et al. (2016) Elucidation of The Behavioral Program and Neuronal Network Encoded by Dorsal Raphe Serotonergic Neurons. Neuropsychopharmacology 41:1404-15 |
| Goulding, Evan H; Schenk, A Katrin; Juneja, Punita et al. (2008) A robust automated system elucidates mouse home cage behavioral structure. Proc Natl Acad Sci U S A 105:20575-82 |
