Heterogeneous stock rats: a model to study the genetics of despair-like behavior in adolescence.

Major depressive disorder (MDD) is a complex illness caused by both genetic and environmental factors. Antidepressant resistance also has a genetic component. To date, however, very few genes have been identified for major depression or antidepressant resistance. In this study, we investigated whether outbred heterogeneous stock (HS) rats would be a suitable model to uncover the genetics of depression and its connection to antidepressant resistance. The Wistar Kyoto (WKY) rat, one of the eight founders of the HS, is a recognized animal model of juvenile depression and is resistant to fluoxetine antidepressant treatment. We therefore hypothesized that adolescent HS rats would exhibit variation in both despair-like behavior and response to fluoxetine treatment. We assessed heritability of despair-like behavior and response to sub-acute fluoxetine using a modified forced swim test (FST) in 4-week-old HS rats. We also tested whether blood transcript levels previously identified as depression biomarkers in adolescent human subjects are differentially expressed in HS rats with high vs. low FST immobility. We demonstrate heritability of despair-like behavior in 4-week-old HS rats and show that many HS rats are resistant to fluoxetine treatment. In addition, blood transcript levels of Amfr, Cdr2 and Kiaa1539, genes previously identified in human adolescents with MDD, are differentially expressed between HS rats with high vs. low immobility. These data demonstrate that FST despair-like behavior will be amenable to genetic fine-mapping in adolescent HS rats. The overlap between human and HS blood biomarkers suggest that these studies may translate to depression in humans

Using Heterogeneous Stocks for Fine-Mapping Genetically Complex Traits.

In this chapter we will review both the rationale and experimental design for using Heterogeneous Stock (HS) populations for fine-mapping of complex traits in mice and rats. We define an HS as an outbred population derived from an intercross between two or more inbred strains. HS have been used to perform genome-wide association studies (GWAS) for multiple behavioral, physiological, and gene expression traits. GWAS using HS require four key steps, which we review: selection of an appropriate HS population, phenotyping, genotyping, and statistical analysis. We provide advice on the selection of an HS, comment on key issues related to phenotyping, discuss genotyping methods relevant to these populations, and describe statistical genetic analyses that are applicable to genetic analyses that use HS

Premature responding is associated with approach to a food cue in male and female heterogeneous stock rats

RATIONALE: Disorders of behavioral regulation, including attention deficit hyperactivity disorder (ADHD) and drug addiction, are in part due to poor inhibitory control, attentional deficits, and hyper-responsivity to reward-associated cues. OBJECTIVES: To determine whether these traits are related, we tested genetically variable male and female heterogeneous stock rats in the choice reaction time (CRT) task and Pavlovian conditioned approach (PavCA). Sex differences in the response to methylphenidate during the CRT were also assessed. METHODS: In the CRT task, rats were required to withhold responding until one of two lights indicated whether responses into a left or right port would be reinforced with water. Reaction time on correct trials and premature responses were the operational definitions of attention and response inhibition, respectively. Rats were also pre-treated with oral methylphenidate (0, 2, 4 mg/kg) during the CRT task to determine whether this drug would improve performance. Subsequently, during PavCA, presentation of an illuminated lever predicted the delivery of a food pellet into a food-cup. Lever-directed approach (sign-tracking) and food-cup approach (goal-tracking) were the primary measures, and rats were categorized as “sign-trackers” and “goal-trackers” using an index based on these measures. RESULTS: Sign-trackers made more premature responses than goal-trackers, but showed no differences in reaction time. There were sex differences in both tasks, with females having higher sign-tracking, completing more CRT trials, and making more premature responses after methylphenidate administration. CONCLUSIONS: These results indicate that response inhibition is related to reward-cue responsivity, suggesting that these traits are influenced by common genetic factors