Using flies, a wall-following (WAFO) assay has been developed to quantify response to anxiety-inducing or anxiety-reducing stimuli or pharmaceuticals. In an enclosed area, Drosophila typically stay close to the walls during spontaneous locomotion, crossing the center of the field infrequently. A reduction in the WAFO score (increased travel away from the walls) is interpreted as a reduction in anxiety, and an increase in WAFO as an increase in anxiety. The assay must be performed on multiple individual flies, since there is a significant amount of variation between individuals under the same conditions.
This model has been supported by experiments using known modulators of anxiety: (1) WAFO is reduced when the flies are fed diazepam (Valium), which acts via the inhibitory neurotransmitter GABA; (2) WAFO is increased in animals carrying loss-of-function mutations in 5-HT1B (serotonin class 1 receptor) or SerT (serotonin transporter, ortholog of human SLC6A4, see MIM:607834) and is decreased when either gene is overexpressed; (3) WAFO is increased under environmental stress such as heat shock; (4) WAFO is increased under conditions of prolonged social isolation; (5) supporting observations made in a mouse system, WAFO is reduced by loss-of-function mutations in Dh44-R1 (orthologous to CRHR2 and CRHR1, corticotropin releasing hormone receptors); (6) the large increase in WAFO induced by heat shock is ameliorated by diazepam.
The human Hsap\SLC6A4, Hsap\HTR1B, and Hsap\HTR1D genes have been introduced into flies, but have not been used in the context of this model.
This wall-following assay has been used to assess new gene candidates postulated to affect anxiety-related behaviors; see human disease model reports 'anxiety modulator(s), serotonin class 2 receptor(s)' (FBhh0001006), 'anxiety modulator(s), genes affecting actin filament stability' (FBhh0001007), and 'anxiety modulator(s), CCK-like receptors' (FBhh0001008).
[updated Apr. 2020 by FlyBase; FBrf0222196]
Moderate-scoring ortholog of human HTR1A, HTR1B, HTR1D, and HTR1F; additional related genes in both species). Dmel\5-HT1B shares 28-31% identity and 42-45% similarity with the listed human genes.
High-scoring ortholog of human SLC6A4 (1 Drosophila to 1 human; additional related genes in both species). Dmel\SerT shares 55% identity and 71% similarity with the human gene.
High-scoring ortholog of human CRHR2, moderate-scoring ortholog of CRHR1 (2 Drosophila to 2 human). Dmel\Dh44-R1 shares 35-36% identity and 51-53% similarity with the human genes.
