Optogenetic silencing of locus coeruleus activity in mice impairs cognitive flexibility in an attentional set-shifting task
Key findings
Unilateral optogenetic silencing of locus coeruleus using AAV2-Ef1a-DIO-eNpHR3.0-EYFP in TH-Cre mice selectively impaired cognitive flexibility without affecting locomotion or anxiety. LC-silenced mice required significantly more trials in tasks demanding flexibility: simple discrimination, reversal learning, and extra-dimensional set-shifting showed 50% increased trials to criterion (18.3±1.4 vs 12.2±1.0, p=0.01) compared to controls receiving non-activating red light.
Extra-dimensional set-shifting performance was most severely impaired by LC silencing, requiring 51% more trials to criterion (15.6±2.2 vs 10.3±1.0, p<0.05) while maintaining comparable response latencies (median 32s both groups). Both silenced and control groups successfully formed attentional sets with EDS/IDS VII ratios exceeding unity (1.94 vs 1.44, p<0.01), demonstrating that LC activity is specifically required during acquisition of flexible cognitive strategies rather than for general learning or attentional set formation.