New Animal Model Uncovers the Role of Beta-2 Nicotinic Receptors in the Activity-rest Cycle, Natural Reward, and Anxiety
Researchers at Northwestern University Feinberg School of Medicine have created a new mouse animal model to study a rare form of human epilepsy. The research team, led by Anis Contractor, PhD, published their first findings in the July online issue of the journal Molecular Psychiatry, and demonstrated new roles for Beta-2 (β2) nicotinic receptors, including involvement in the activity-rest cycle, natural reward, and anxiety.
The team created the model to study autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), a rare form of human partial epilepsy characterized by frequently-occurring clusters of nocturnal motor seizures. ADNFLE is a lifelong condition of unknown prevalence that is seen increasingly in families and is sometimes misdiagnosed as night terrors, nightmares, or sleep apnea. The condition is linked to chromosome mutations in humans.
The animal model was created by introducing a human mutation into β2 receptors in the mouse genome to generate a “knock-in” strain.
“This study begins to tell us something more about what the mutation does beyond the expected seizure phenotype — the interesting behavioral disruptions in these mice could also be present in people,” says Contractor, assistant professor in the Department of Physiology at Feinberg. “One of the more compelling results of our study seems to suggest that the affected mice may have deficits in natural reward-seeking behavior.”
Natural reward, says Contractor, is important for survival and dictates when a person or animal is motivated by sex, food, or exercise. Affected mice in this study appeared uninterested in running on wheels, a classic sign of a deficit in natural reward-seeking behavior that may also be related to ADFLNE in humans â and overlooked. The study is the first to show that nicotinic receptors are involved in natural reward.
“Our understanding of the roles of nicotinic receptors in the brain are still emerging, however, it is clear these neurotransmitter receptors which have been extensively studied because of their role in tobacco addiction, are also central to normal function of the brain. They have been implicated in the pathophysiology of epilepsies, Alzheimer’s disease and schizophrenia. We now show that they also have roles in the brain circuits that control natural reward, and therefore may be important targets for behavioral addictions such as food or sex addiction,” says Contractor.
Additional observations of the affected mice included alterations in the activity-rest pattern, altered motor learning, effects on anxiety-like behaviors, and increased sensitivity to nicotine-induced seizure. The effects on activity-rest cycles suggest nicotinic receptors might be involved in regulating daily (circadian) rhythms.
“These mice have provided novel insight into a human disorder and also into the roles of nicotinic receptors in normal brain function. We are particularly excited about the prospect of targeting nicotinic receptors for disorders of natural reward. We are currently using drugs that target nicotinic receptors in these mice to determine whether we can rescue some of these deficits. This would be strong preclinical evidence for proposing the use of these drugs in human clinical trials to treat disorders of human natural reward,” says Contractor.
