Additionally, a zebrafish model of Huntington’s disease (HD) was generated through a reverse genetics technique, using a morpholino (antisense morpholino-modified oligonucleuotides) to inhibit translation of the protein huntingtin (16,31). The huntingtin (Htt) knockdown zebrafish displayed abnormal physiological phenotypes associated with HD in humans, including reduced expression of brain-derived neurotrophic factor (BDNF), widespread neuronal apoptosis, and other developmental disruptions linked to HD. Unfortunately, no behavioral testing was performed in this experiment; however, a spatial alternation screen using reward stimuli as described by Williams and colleagues (32) could illuminate the learning and memory deficits associated with HD. In addition, assessing anhedonia, motor coordination, and anxiety in Htt knockdown zebrafish may help in fully defining a zebrafish transgenic model of HD.

Expression patterns in genes related to deafness begin to provide a basis for understanding the roles of various cell types within the cochlea and bring to light the causes of both syndromic and non-syndromic forms of deafness (33). Recently, a large scale mutagenesis screen in zebrafish identified 8 genes that are essential for proper balance and hearing (33). Zebrafish have proven to be effective models with respect to studying the molecular basis of development and function of sensory hair cells (33). Importantly, anatomical studies have shown that the structure of the vestibular inner ear is highly conserved between teleost fish and higher animals. Additionally, fish sensory hair cells are morphologically and physiologically similar to hair cells in higher vertebrates (33). As such, zebrafish emerge as a novel translational model for examining the pathogenesis that occurs as a result of mutations in deafness genes (33).

Zebrafish are also proving useful as genetic models to examine the complex processes involved in the development of addiction, which is a principle health issue throughout the world. The use of forward genetic manipulation in conjunction with a selective behavioral screen for the classification of cocaine sensitivity in mutant zebrafish has helped to identify candidate genes responsible for sensitivity to addiction. In the highlighted experiment, a cocaine-induced conditioned place preference developed in a sensitivity-dependent manner. Sensitivity to cocaine, and the resulting behavioral phenotypes observed in the conditioned place preference paradigm, was shown to be dependent on the dominant mutations in single genes (33). Indeed, certain mutagenized zebrafish exhibited abnormally low responses to cocaine. Performance profiles of these zebrafish in additional behavioral screens measuring visual adaptation and learning suggested that their low response to cocaine was the result of mutations in genes that affect dopaminergic signaling in both the retina and the brain (34). This forward genetics approach in which the genome is mutagenized, resulting phenotypes characterized through behavioral screening, and underlying genes classified and cloned using a vertebrate species represents a valuable tool to advance the research. Zebrafish in particular are an idea choice for the forward genetic manipulation due to their ability to reproduce quickly, and their low maintenance cost (34). These benefits along with the fact that zebrafish lend themselves well to behavioral observation paradigms further expands their role as translational models in biomedical research.