Prepulse inhibition deficits in inbred and outbred rats and between-strain differences in startle habituation do not depend on startle reactivity levels.

The acoustic startle response and prepulse inhibition (PPI) of startle are measures related to information processing, which is impaired in schizophrenia. Some studies have provided inconclusive patterns of association between both measures in rodents. We assessed the influence of baseline startle response on PPI in large samples of Roman high-(RHA) and low-avoidance (RLA) rat strains and in genetically heterogeneous stock (HS) rats. Results show that RHAs exhibit a PPI deficit compared to RLA rats, which is present regardless of the startle response levels. HS rats were stratified in two sub-samples according to their high or low PPI (HS-highPPI or HS-lowPPI, respectively) scores, and then they were grouped by their differential baseline startle amplitude (high reactivity -HR- or low reactivity -LR-) within each sub-sample. Differences between high- and low-PPI-stratified HS rats remained regardless of their high or low startle amplitude scores. Thus, the impairments in %PPI found in both RHA and HS-LowPPI rats are present irrespective of the relatively high or low levels of startle amplitude in pulse-alone trials. Another objective of the present study was to evaluate whether habituation to the startling stimulus (i.e., pulse) depends on the initial baseline startle response. RLA rats habituated to the startling stimulus more effectively than RHAs regardless of their baseline startle responses. Conversely, there were no differences in startle habituation in the HS rats grouped by their extreme scores of baseline startle. Altogether, these findings suggest a deficit in information processing in RHA rats, which along with evidence indicating that this strain displays other attentional/cognitive impairments, strengthens the validity of the RHA strain as a putative model of schizophrenia-relevant features.

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.

Mild daily stressors in adulthood may counteract behavioural effects after constant presence of mother during early life.

This study investigated adult rat behaviour in three early life conditions, and how behaviour was affected after exposure to chronic mild stressors in later life. During postnatal days 2-14, male Wistar rats were exposed daily to either long or brief maternal separation, or were left undisturbed with their mothers (non-handled). As adults, non-handled and long maternally separated offspring demonstrated less object exploration than brief maternally separated offspring. Non-handled offspring also showed lower pre-pulse inhibition compared to both long and brief maternally separated offspring. Sucrose preference and open field behaviour as adults did not differ between the early life conditions. Exposure to four weeks of chronic mild stress in adulthood (mimicking daily hassles in humans) increased object exploration, increased pre-pulse inhibition and induced habituation of acoustic startle in non-handled offspring, similar to brief maternally separated offspring. Long maternally separated offspring exposed to chronic mild stress failed to show an increase in object exploration and enhanced pre-pulse inhibition, and did not show habituation of acoustic startle. In conclusion, different early life conditions have a different long-term impact on behaviour. Offspring from all three conditions differed from each other in terms of adult behaviour. Mild daily stressors in the adulthood counteracted the effects observed in the non-handled condition.

Genetic influences on brain gene expression in rats selected for tameness and aggression.

Interindividual differences in many behaviors are partly due to genetic differences, but the identification of the genes and variants that influence behavior remains challenging. Here, we studied an F2 intercross of two outbred lines of rats selected for tame and aggressive behavior toward humans for >64 generations. By using a mapping approach that is able to identify genetic loci segregating within the lines, we identified four times more loci influencing tameness and aggression than by an approach that assumes fixation of causative alleles, suggesting that many causative loci were not driven to fixation by the selection. We used RNA sequencing in 150 F2 animals to identify hundreds of loci that influence brain gene expression. Several of these loci colocalize with tameness loci and may reflect the same genetic variants. Through analyses of correlations between allele effects on behavior and gene expression, differential expression between the tame and aggressive rat selection lines, and correlations between gene expression and tameness in F2 animals, we identify the genes Gltscr2, Lgi4, Zfp40, and Slc17a7 as candidate contributors to the strikingly different behavior of the tame and aggressive animals.