Sensory-evoked responses in visual cortex vary with spontaneous variations in the levels of network activity, with responses enhanced during the cortical up state of slow oscillations (Haider et al., 2007). This “gain modulation” may be related to the activation of LC neurons just before the fully depolarized cortical state, described above. Released in time with the maximum firing of the cortical neurons, NA would modulate, gate, and tune sensory responses (Berridge and Waterhouse, 2003; Sara, 2009). Active reconfiguration

selleck kinase inhibitor of the functional state of networks may underlie attention, sensory-motor coupling, and other cognitive processes. This is in line with data suggesting that LC firing during the transition from down to up states facilitates the achievement of the maximum depolarized state in the cortex (Eschenko et al., 2012). This mechanism of facilitation of transition to the maximum depolarized state by LC may not be limited this website to spontaneous oscillations. It may occur each time LC phasic activity is elicited as part of the orienting response or as part of a CR to behaviorally significant stimuli, the equivalent of the cortical TCR. In the following sections, we will see the extent to which this relation between LC activation, cortical arousal, and the conditioned

orienting response to simple environmental challenges extends to cognitive flexibility. There is some evidence that pupil dilation varies with spontaneous activity in

LC neurons (Aston-Jones and Cohen, 2005), in line with several reports relating the firing of LC neurons with autonomic arousal (Jacobs, 1986; Abercrombie and Jacobs, 1987). Several recent studies have used this noninvasive Farnesyltransferase technique of measuring changes in pupil size in human subjects in an attempt to investigate the role of the LC in cognitive flexibility. A recent example is an experiment aimed at understanding the intrinsic brain mechanisms of bistable perception, a phenomenon in which perception fluctuates between two distinct states when the subject fixates on an ambiguous figure. A typical example is the Necker cube. The state transitions are abrupt and occur spontaneously. The experimental protocol required the subjects to report a state change by pressing a lever. Results showed that pupil dilation occurred just before the change and the amount of dilation predicted the duration of the subsequent perceptual stability (Einhäuser et al., 2008). This experiment does not tell us that LC activation actually caused the abrupt switch in perception, but the loose correlation of the size of the dilation with the duration of the subsequent state suggests a role in maintaining perceptual stability.