Abstract
Attention-deficit/hyperactivity disorder (ADHD) is a syndrome characterized by impaired attention, impulsivity and hyperactivity in children. These symptoms are often maintained in adults. During adolescence, prefrontal cortex develops connectivity with other brain regions to engage executive functions such as, latent inhibition, attention and inhibitory control. In our previous work, we demonstrated the validity of the neonatal 6-Hydroxydopamine (6-OHDA) mouse model, a classical neurodevelopmental model mimicking major symptoms of the human ADHD pathology. In order to evaluate pathological forms of executive functions and impulsive behavior in 6-OHDA mice during young age, we first tested latent inhibition (LI) after weaning, and then we evaluated the impulsive behavior using a cliff avoidance reaction test. Our results demonstrated that 6-OHDA mice showed disruption in latent inhibition, suggesting a deficit in selective attention, and displayed repetitive peering-down behavior, indicating a maladaptive impulsive behavior. Subsequently, to assess impulsivity and attention in young mice, we performed a modified 5-choice serial reaction time task test (5-CSRTT), optimizing the degree of food restriction for young animals and shortening the training duration. This test allowed us to demonstrate a deficit in inhibitory control and a loss of accuracy of 6-OHDA mice in the 5-CSRTT. In conclusion, we demonstrated that the 6-OHDA mouse model reproduces human symptoms of ADHD in childhood and early adulthood periods, as seen in human. Taken together, the 6-OHDA mouse model will be useful alongside other animal models to understand the neurobiological mechanisms underlying complex, heterogeneous neurological disorders.
Highlights
Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder identified by hyperactivity, impulsivity and inattention (American Psychiatric Association, 2013) in children
To confirm that 6-OHDA mice display neurochemical features of ADHD and especially dopamine depletion, we examined THimmunoreactivity (IR) in the striatum of sham and 6-OHDA adolescent mice
Statistical analysis revealed that the 6-OHDA groups showed a significant decrease in the intensity of TH immunolabelling in comparison to sham (p < 0.001; Supplementary Figure S1B)
Summary
Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder identified by hyperactivity, impulsivity and inattention (American Psychiatric Association, 2013) in children. (ii) Coloboma mice which have a mutation in the Snap sequence are hyperactive (Hess et al, 1996), exhibit an impairment of latent inhibition, indicating inattention (Lubow and Josman, 1993; Bruno et al, 2007) This animal model displays impulsive behavior as demonstrated by delayed reward paradigms which require subjects to choose between an immediately available small reward or a delayed greater reward (Bruno et al, 2007). At 2–3 weeks following the lesion, these rats exhibit hyperactivity comparable to that observed in childhood ADHD (Erinoff et al, 1979; Miller et al, 1981; Archer et al, 1988), but there are not impulsive (Arime et al, 2011) Hyperactivity in this model has sometimes been associated with inattention (Oke and Adams, 1978; Archer et al, 1988). The executive functions such as latent inhibition, attention and impulsivity have not been systematically investigated during young age in this 6-OHDA model
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