Abstract
Fear and anxiety are evolutionarily conserved emotions. They act as a signal of danger and threat to trigger the appropriate adaptive responses ensuring species survival. However, aberrant expression of these emotions, and an inability to cope can lead to anxiety disorders such as post-traumatic stress disorder (PTSD), which manifest after exposure to a traumatic event or persistent chronic life stress. PTSD is characterized by re-experiencing symptoms of the trauma that include flashbacks, intrusive thoughts, avoidance of trauma cues, hyperarousal (exaggerated startle) and negative alterations in cognition and mood (anhedonia). Not all individuals exposed to trauma develop PTSD, while some individuals are susceptible, some are remarkably resilient. Genetic risk factors account for up to ~30-40% of heritability seen in PTSD. There is excessive release of the neurotransmitter noradrenaline in response to stress, thus, noradrenergic dysregulation is often seen in PTSD patients. The behavioral responses and neural mechanisms associated with a fearful, anxious state are phylogenetically so conserved that there are important parallels to be drawn between humans and rodents. The amygdala, medial pre-frontal cortex and hippocampus are crucial brain regions involved in orchestrating the fear response. Our lab has utilized rodent breeding schemes and quantitative genetic mapping approaches to generate a novel fearful DBA/2JHd x C3H/HeJHd recombinant inbred mouse strain that was selectively bred for a high fear-sensitized acoustic startle response. The C3H-like recombinant inbred (C3HLRI) mouse strain, compared to its background strain DBA/2J mice, exhibit an exaggerated startle reflex, an inability to extinguish fear and depressive behavior as measured in rodent behavioral paradigms. In the present studies, the noradrenergic-acting, anxiety-inducing drug yohimbine and anxiety-relieving drug clonidine was used to determine if high fear mice show similar noradrenergic responses consistent with those seen in PTSD patients and PTSD animal models. The already fearful C3HLRI mice show increased fear and a fear extinction deficit when given yohimbine, while they show reduced anxiety-like behavior when given clonidine. Differential gene expression analysis in the amygdala, medial pre-frontal cortex and hippocampus between C3HLRI mice and DBA/2J mice revealed the inter-α-trypsin inhibitor heavy chain 3 as a critical candidate gene. Studies support the hypothesis that C3HLRI mice are a model for studying PTSD. Thus, the C3HLRI mouse strain is a valuable addition to the PTSD rodent model tool box, and serve as a model to test better pharmacological treatment options and come up with genetic biomarkers for PTSD.