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Cognitively driven pupil modulations reflect certain underlying brain functions. What do these reflections tell us? We review findings that have identified key roles for three neural systems: First, cortical modulation of the pretectal olivary nucleus (PON), which controls the pupillary light reflex; second, the superior colliculus (SC), which mediates orienting responses, including pupil changes to salient stimuli; and third, the locus coeruleus (LC)-norepinephrine (NE) neuromodulatory system, which mediates relationships between pupil-linked arousal and cognition. We discuss how these findings can inform the interpretation of pupil measurements in terms of activation of these neural systems. We also highlight caveats, open questions, and key directions for future experiments for improving these interpretations in terms of the underlying neural dynamics throughout the brain.

Ascending neuromodulatory projections from the locus coeruleus (LC) affect cortical neural networks via the release of norepinephrine (NE). However, the exact nature of these modulatory effects on neural activity patterns in vivo is not well understood. Here we show that in awake monkeys, LC activation is associated with changes in coordinated activity patterns in the anterior cingulate cortex (ACC). These effects, which are largely independent of changes in firing rates of individual ACC neurons, depend on the type of LC activation: ACC pairwise correlations are reduced when tonic (baseline) LC activity increases but are enhanced when external events drive phasic LC responses. Both effects also covary with pupil changes that reflect LC activation and arousal. These results suggest that modulations of information processing that reflect changes in coordinated activity patterns in cortical networks can, at least in part, result from ongoing, context-dependent, arousal-related changes in activation of the LC-NE system.

A large body of work spanning 25+ years provides compelling evidence for the involvement of the basal ganglia-superior colliculus pathway in the initiation of rapid, orienting movements of the eyes, called saccades. The role of this pathway in saccade control is similar to the role of the basal ganglia-thalamic pathway in the control of skeletal movement: a transient cessation in tonic inhibition supplied by the basal ganglia to motor structures releases movements via the direct pathway whereas a transient increase in inhibition by the basal ganglia to motor structures prevents movements via the indirect pathway. In parallel with recent advances in the study and treatment of patients with basal ganglia disease and in animal experiments in the skeletal motor system, the results of studies exploring the role of the basal ganglia-superior colliculus pathway in saccades highlight the need for a revisiting of our understanding of the role of this pathway in saccades. The discovery of many different response profiles of neurons in the substantia nigra pars reticulata of the basal ganglia and in the superior colliculus, coupled with advances in experimental and statistical techniques including sophisticated behavioral procedures and multiple neuron recording and analysis, point toward a role for the basal ganglia-superior colliculus pathway in cognitive events intervening between vision and action, such as memory, target selection and saccade choice and valuation.

We describe a method that uses a modified version of juxtacellular labeling [Pinault D. A novel single-cell staining procedure performed in vivo under electrophysiological control: morpho-functional features of juxtacellularly labeled thalamic cells and other central neurons with biocytin or neurobiotin. J Neurosci Meth 1996;65:113-36], which allows us to functionally characterize and subsequently label single neurons in vivo in macaque V1. The method is generally applicable in acute in vivo preparations. Extracellular recording is made with a patch electrode when the electrode is attached to the cell membrane. Initially a 'blind' search method is used as a guide to obtaining a cell attached configuration that we refer to as a loose-patch (LP). The neuron's receptive field properties are functionally characterized, the neuron is labeled and then characterization is confirmed, all in the LP configuration. There are a number of advantages of the method that we describe over other methods. First, we have found that we can obtain stable extracellular recordings for periods of hours that enable us to make a relatively comprehensive visual functional characterization of a neuron's receptive field properties. Second, because the electrode is closely apposed to the cell we obtain excellent isolation of the extracellular spike. Third, the method provides labeling that gives complete dendritic and axonal filling that survives over a number of days, which is an important feature in acute primate experiments. Fourth, the in vivo method of labeling and reconstructing neurons gives complete three-dimensional structure of the neuron including its intra-cortical axonal arbor. These features overcome known limits of the established methods of studying neuronal morphology including the Golgi stain (limited when adult tissue is used) and in vitro whole cell methods (incomplete axonal filling due to limited slice thickness). They also overcome the known limits of the established method of combined function-morphology studies i.e. intracellular recording in vivo. The modified juxtacellular method provides a reliable alternative to the difficult method of characterization by extracellular recording and subsequent intracellular labeling [Anderson JC, Martin KAC, Whitteridge D. Form, function and intracortical projections of neurons in the striate cortex of the monkey Macacus nemestrinus. Cerebral Cortex 1993;3:412-20]. We show the method can be used to record at a range of depths through V1 cortex allowing for sampling of neurons in the different layers and functional subpopulations. Links can then be made with existing knowledge about the anatomical organization of V1, the various morphological classes of neurons found therein, their functional connectivity and visual response properties.