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Abstract

Cortical connectivity is organized by cortical layer. Cognitive control over perception relies on connectivity between the prefrontal cortex (PFC) and sensory cortex, yet little is known about their laminar interactions. Moreover, cognition and sensory-evoked activity are modulated by norepinephrine (NE), which has a layer-specific distribution of receptors. We recorded extracellular laminar activity in rat PFC and primary somatosensory cortex (S1) under urethane anesthesia. Tonic NE release (minutes to hours) was increased by chronic administration (28 days) of the NE reuptake inhibitor Atomoxetine (0.03, 0.3, 1.0 mg/Kg or vehicle). Phasic NE release (sec) was increased by brief electrical stimulation (30 μA, 0.4 ms biphasic pulse at 50 Hz) of the locus coeruleus (LC), which releases NE in the PFC and S1. Increasing tonic NE had opposing effects on superficial and deep PFC laminar activity. Atomoxetine (ATX) reduced spiking (20 min recording) in PFC layer 2/3 (vehicle: 2.55 0.77 Hz, N = 12 single units; 1.0 mg/Kg ATX: 1.22 0.22 Hz, N = 30 units), while it increased spiking in layer 5 (vehicle: 0.88 0.22 Hz, N = 17 units; 1.0 mg/Kg ATX: 3.26 0.49 Hz, N = 48 units). Increasing phasic NE predominately evoked sustained (about 1 sec) excitation in a similar proportion of units in all PFC layers. The excitatory effect of phasic NE differed in the context of high tonic NE in that, 83 of units exhibited sustained excitation in the vehicle condition (N = 18 units combined across layers), whereas only 34 (N = 65 units) exhibited this pattern in the 1.0 mg/Kg ATX condition. Furthermore, the magnitude of firing rate change evoked by phasic NE release was significantly reduced under high tonic NE (0.3 and 1.0 mg/Kg ATX versus vehicle). Therefore, although tonic NE has a layer-specific modulatory effect on PFC neurons, phasic NE evokes excitation in a layer non-specific manner. Moreover, at high tonic levels of NE, further brief NE increases have a reduced excitatory effect. Given that NE affects population activity oscillations, ongoing analyses focus on spike timing (Fano factor and noise correlations), excitatory population response (current source density), and laminar spike-LFP relations. Additionally, we will report how NE modulates the long-range communication between local PFC and S1 circuits by measuring Granger causality between the LFP signals in individual layers of PFC and S1. We expect NE to modulate communication from PFC output layers to circuits in individual S1 layers. Indeed, this may be one mechanism by which ATX improves cognition in individuals with mental illness.