Effects of tonic and phasic norepinephrine release on layer-specific activity in the prefrontal cortex in anesthetized and awake rat

Cognitive control relies on functional connectivity between the prefrontal cortex (PFC) and other brain regions. Cortical connections follow a laminar organization, yet little is known about PFC laminar activity. Moreover, cognition is modulated by PFC norepinephrine (NE), which is released in tonic and phasic patterns, but the layer-specific effects of NE on PFC activity are relatively unexplored. We recorded extracellular laminar activity in rat PFC under urethane anesthesia. Tonic and phasic NE were independently manipulated. Tonic NE was increased using the reuptake inhibitor Atomoxetine, ATX, (0.3, 1.0mg/kg), administered acutely (i.p.) or chronically (28 days i.p. diffusion via osmotic pump). Phasic NE release was induced by a brief train (50Hz, 200ms) of mild electric pulses (0.4ms, 30uA) delivered to locus coeruleus (LC). Phasic NE evoked a sustained increase in PFC single unit spiking and population activity (LFP gamma power). The degree of modulation did not differ across different layers. Current source density analysis revealed a current sink in layers 2/3 and 5, suggesting that the cortical activation evoked by phasic NE was mediated via thalamo-cortical afferents. Chronic ATX dampened the PFC response to LC stimulation equally in each layer. Specifically, a smaller proportion of PFC units increased firing rate after LC stimulation (vehicle, 83%; 1.0mg/kg, 34%). In addition, increased NE level resulted in weaker gamma power modulation and lower current sink amplitude in response to NE phasic release. On the other hand, spontaneous activity was increased by ATX. The spontaneous activity enhancement was specific to layers 5,6 (vehicle, 0.9±0.2Hz; 1.0mg/kg, 3.3±0.5Hz). Comparison with acute ATX is ongoing. Given that NE release occurs in response to salient stimuli and decisions, which involve a change in coordinated activity across neurons, we tested the hypothesis that NE altered coordinated activity (spike-gamma LFP phase-locking). Tonic NE increased phase locking after LC stimulation in layers 2/3 and 5 (L2/3: vehicle vs 0.3mg/kg, 1.3±0.5 vs 4.7±0.9; L5: 1.4±0.3 vs 2.8±0.8). Therefore, NE may modulate coordinated activity in thalamocortical recipient layers. Additional analyses of coordinated activity (spike cross-correlations and LFP-LFP synchrony) are underway. Studies in behaving rats will monitor LC and PFC/sensory cortex laminar activity to identify the functional significance of interaction between the NE system and cortex. NE modulation of PFC thalamic input and layer 6 spontaneous activity could effect the output of these layers to sensory cortex and modulate PFC top-down selection of stimuli in sensory cortex