The measurement of pupil diameter in psychology (in short, "pupillometry") has just celebrated 50 years. The method established itself after the appearance of three seminal studies (Hess & Polt, 1960, 1964; Kahneman & Beatty, 1966). Since then, the method has continued to play a significant role within the field, and pupillary responses have been successfully used to provide an estimate of the "intensity" of mental activity and of changes in mental states, particularly changes in the allocation of attention and the consolidation of perception. Remarkably, pupillary responses provide a continuous measure regardless of whether the participant is aware of such changes. More recently, research in neuroscience has revealed a tight correlation between the activity of the locus coeruleus (i.e., the "hub" of the noradrenergic system) and pupillary dilation. As we discuss in this short review, these neurophysiological findings provide new important insights to the meaning of pupillary responses for mental activity. Finally, given that pupillary responses can be easily measured in a noninvasive manner, occur from birth, and can occur in the absence of voluntary, conscious processes, they constitute a very promising tool for the study of preverbal (e.g., infants) or nonverbal participants (e.g., animals, neurological patients).

Pupillometry: A Window to the Preconscious?

Psychosocial stress is associated with altered immune function and development of psychological disorders including anxiety and depression. Here we show that repeated social defeat in mice increased c-Fos staining in brain regions associated with fear and threat appraisal and promoted anxiety-like behavior in a β-adrenergic receptor-dependent manner. Repeated social defeat also significantly increased the number of CD11b+/CD45high/Ly6Chigh macrophages that trafficked to the brain. In addition, several inflammatory markers were increased on the surface of microglia (CD14, CD86, and TLR4) and macrophages (CD14 and CD86) after social defeat. Repeated social defeat also increased the presence of deramified microglia in the medial amygdala, prefrontal cortex, and hippocampus. Moreover, mRNA analysis of microglia indicated that repeated social defeat increased levels of interleukin (IL)-1β and reduced levels of glucocorticoid responsive genes [glucocorticoid-induced leucine zipper (GILZ) and FK506 binding protein-51 (FKBP51)]. The stress-dependent changes in microglia and macrophages were prevented by propranolol, a β-adrenergic receptor antagonist. Microglia isolated from socially defeated mice and cultured ex vivo produced markedly higher levels of IL-6, tumor necrosis factor-α, and monocyte chemoattractant protein-1 after stimulation with lipopolysaccharide compared with microglia from control mice. Last, repeated social defeat increased c-Fos activation in IL-1 receptor type-1-deficient mice, but did not promote anxiety-like behavior or microglia activation in the absence of functional IL-1 receptor type-1. These findings indicate that repeated social defeat-induced anxiety-like behavior and enhanced reactivity of microglia was dependent on activation of β-adrenergic and IL-1 receptors.

https://www.jneurosci.org/content/jneuro/31/17/6277.full.pdf

β-Adrenergic Receptor Antagonism Prevents Anxiety-like Behavior and Microglial Reactivity Induced by Repeated Social Defeat

Emotional arousal enhances perception and memory of high-priority information but impairs processing of other information. Here, we propose that, under arousal, local glutamate levels signal the current strength of a representation and interact with norepinephrine (NE) to enhance high priority representations and out-compete or suppress lower priority representations. In our "glutamate amplifies noradrenergic effects" (GANE) model, high glutamate at the site of prioritized representations increases local NE release from the locus coeruleus (LC) to generate "NE hotspots." At these NE hotspots, local glutamate and NE release are mutually enhancing and amplify activation of prioritized representations. In contrast, arousal-induced LC activity inhibits less active representations via two mechanisms: 1) Where there are hotspots, lateral inhibition is amplified; 2) Where no hotspots emerge, NE levels are only high enough to activate low-threshold inhibitory adrenoreceptors. Thus, LC activation promotes a few hotspots of excitation in the context of widespread suppression, enhancing high priority representations while suppressing the rest. Hotspots also help synchronize oscillations across neural ensembles transmitting high-priority information. Furthermore, brain structures that detect stimulus priority interact with phasic NE release to preferentially route such information through large-scale functional brain networks. A surge of NE before, during, or after encoding enhances synaptic plasticity at NE hotspots, triggering local protein synthesis processes that enhance selective memory consolidation. Together, these noradrenergic mechanisms promote selective attention and memory under arousal. GANE not only reconciles apparently contradictory findings in the emotion-cognition literature but also extends previous influential theories of LC neuromodulation by proposing specific mechanisms for how LC-NE activity increases neural gain.

/pdf/norepinephrine-ignites-local-hotspots-of-neuronal-excitation-38wbaiuurf.pdf

Norepinephrine ignites local hotspots of neuronal excitation: How arousal amplifies selectivity in perception and memory.

Our decisions are guided by the rewards we expect. These expectations are often based on incomplete knowledge and are thus subject to uncertainty. While the neurophysiology of expected rewards is well understood, less is known about the physiology of uncertainty. We hypothesize that uncertainty, or more specifically errors in judging uncertainty, are reflected in pupil dilation, a marker that has frequently been associated with decision-making, but so far has remained largely elusive to quantitative models. To test this hypothesis, we measure pupil dilation while observers perform an auditory gambling task. This task dissociates two key decision variables – uncertainty and reward – and their errors from each other and from the act of the decision itself. We first demonstrate that the pupil does not signal expected reward or uncertainty per se, but instead signals surprise, that is, errors in judging uncertainty. While this general finding is independent of the precise quantification of these decision variables, we then analyze this effect with respect to a specific mathematical model of uncertainty and surprise, namely risk and risk prediction error. Using this quantification, we find that pupil dilation and risk prediction error are indeed highly correlated. Under the assumption of a tight link between noradrenaline (NA) and pupil size under constant illumination, our data may be interpreted as empirical evidence for the hypothesis that NA plays the same role for uncertainty as dopamine does for reward, namely the encoding of error signals.

/pdf/pupil-dilation-signals-surprise-evidence-for-noradrenaline-s-22ijt0e7kr.pdf

Pupil Dilation Signals Surprise: Evidence for Noradrenaline's Role in Decision Making.

https://cyberleninka.org/article/n/1450567.pdf

Beyond eye gaze: What else can eyetracking reveal about cognition and cognitive development?

The locus coeruleus (LC) is the major noradrenergic nucleus of the brain, giving rise to fibres innervating extensive areas throughout the neuraxis. Recent advances in neuroscience have resulted in the unravelling of the neuronal circuits controlling a number of physiological functions in which the LC plays a central role. Two such functions are the regulation of arousal and autonomic activity, which are inseparably linked largely via the involvement of the LC. The LC is a major wakefulness-promoting nucleus, resulting from dense excitatory projections to the majority of the cerebral cortex, cholinergic neurones of the basal forebrain, cortically-projecting neurones of the thalamus, serotoninergic neurones of the dorsal raphe and cholinergic neurones of the pedunculopontine and laterodorsal tegmental nucleus, and substantial inhibitory projections to sleep-promoting GABAergic neurones of the basal forebrain and ventrolateral preoptic area. Activation of the LC thus results in the enhancement of alertness through the innervation of these varied nuclei. The importance of the LC in controlling autonomic function results from both direct projections to the spinal cord and projections to autonomic nuclei including the dorsal motor nucleus of the vagus, the nucleus ambiguus, the rostroventrolateral medulla, the Edinger-Westphal nucleus, the caudal raphe, the salivatory nuclei, the paraventricular nucleus, and the amygdala. LC activation produces an increase in sympathetic activity and a decrease in parasympathetic activity via these projections. Alterations in LC activity therefore result in complex patterns of neuronal activity throughout the brain, observed as changes in measures of arousal and autonomic function.

Functional neuroanatomy of the noradrenergic locus coeruleus: its roles in the regulation of arousal and autonomic function part I: principles of functional organisation.

E Szabadi

Papers

Functional neuroanatomy of the noradrenergic locus coeruleus: its roles in the regulation of arousal and autonomic function part I: principles of functional organisation.