Ablation of the Central Noradrenergic Neurons for Unraveling Their Roles in Stress and Anxiety

Abstract

Despite considerable evidence suggesting the relationship between the central noradrenergic (NA) system and fear/anxiety states, previous animal studies have not demonstrated sheer involvement of the locus coeruleus (LC) in mediating fear or anxiety. Following the negative results of 6-hydroexydopamine (6-OHDA)-induced LC ablation in fear-conditioning studies, most researchers dared not approach this problem using the ablation strategy. The results obtained by a limited number of endeavors, conducted later, were not consistent with the idea of LC being related to anxiety, either, with the exception of the study by Lapiz and colleagues. Since methodological problems were recognized in the neurotoxin-induced NA ablation, employed in previous studies, a novel mouse model was developed in which the LC-NA neurons were ablated selectively and thoroughly by the immunotoxin-mediated cellular targeting. The use of this model clearly demonstrated that the LC was part of the anxiety circuitry. The reason for the discrepancy between the latest study and previous ones is not clear, but it may be due either to the difference in the experimental paradigms or to the different methods for LC ablation. In any case, our findings have shed light on the LC as a locus pertaining to anxiety behavior, and may help link the apparently inconsistent results in previous studies. In addition, the novel method for the LC cell targeting, presented here may provide a potential means for studying the physiological roles of the LC including sleep/wakefulness, as well as its possible involvement in the pathogenesis of psychiatric disorders, including depression, anxiety disorders, and attention deficit/hyperactivity disorder.