The impact of age and Alzheimer’s disease on locus coeruleus mediated neuromodulation of neural circuits and goal-directed behavior

Abstract

Neuromodulators affect cognition and behavior via their actions on brain wide neural networks. The locus coeruleus norepinephrine (LC-NE) system is one of the brain’s major neuromodulatory systems. Aging and neurological diseases lead to changes in brain structure that impact the normal functioning of brain networks. Although the precise nature of this impact and how to diagnose it remain a challenge, recent studies have started to reveal details about neuromodulation of neural networks and behavior. I will review what we know about networks that perform computations driving perception and action and how these networks are affected by the LC-NE system. I will examine aging and Alzheimer’s disease related changes in these networks and in the LC-NE system and the resulting effects on perception and action. I will discuss how relationships between activation of this system and changes in pupil size, recently explored with precision in humans and in animal models, provide a basis for the use of pupillometry as a non-invasive assay of age- and disease-related decline in neuromodulatory function.

Eye movements reveal age differences in how arousal modulates saliency priority but not attention processing speed

“…Last, we investigated the relationship between measures of oculomotor function and evoked pupil responses, as both measures are characterized as functional indicators of the locus coeruleus-noradrenaline system (Joshi, 2023). We focused on fixation time as an overall measure of behavioral performance underlying eye movements and mean saccadic latencies as the primary locus coeruleus-related measures of oculomotor function (Joshi, 2023; Yamagishi & Furukawa, 2020). Interestingly, we observed that both measures of oculomotor function exhibited a marginally positive relationship with pupil dilation responses in young adults (see Figure 9D-E), that is phasic noradrenergic activity as seen in evoked pupil dilation responses exhibited a trending relationship with oculomotor function.…”

“…Our data show that young adults have greater pupil dilation responses to the distractor during feature search as expected, but not in older adults. Furthermore, we identified that two proposed measures of locus coeruleus function (oculomotor function and evoked pupil responses; Joshi, 2023) are marginally related in young adults but not in older adults. It is pertinent to evaluate the appropriateness of utilizing evoked pupil responses in older adults as a measure of phasic noradrenergic function in older adults, given what we know about dysregulated locus coeruleus function and decreased functional connectivity of the locus coeruleus in older adults.…”

Linking tonic and phasic pupil responses to P300 amplitude in an emotional face‐word Stroop task

“…The LC‐NE system plays a significant role in cognitive control (Aston‐Jones & Cohen, 2005; Mather & Harley, 2016). Moreover, the connections between the LC‐NE system and various clinical conditions have been consistently observed, including depression/anxiety, attention deficit hyperactivity disorder, post‐traumatic stress disorder, substance use disorders, Alzheimer's disease, sleep disorders, pain perception, and cardiovascular disorders (Betts et al., 2019; Dahl et al., 2022; Downs & McElligott, 2022; Gong et al., 2021; Howells et al., 2012; Joshi, 2023; Mather et al., 2020; Morris et al., 2020; Naegeli et al., 2018; Suárez‐Pereira et al., 2022; Van Someren, 2021; Waterhouse & Navarra, 2019; Wood & Valentino, 2017). Understanding the dysfunction of the LC‐NE system can provide valuable insights into clinical investigations, highlighting the necessity of developing an easy‐to‐use and non‐invasive method for assessing the LC‐NE system.…”

“…Specifically, the midbrain superior colliculus (SC), which coordinates the orienting circuit, has been shown to play a causal role in orienting and attention (Corneil & Munoz, 2014;Krauzlis et al, 2013;White & Munoz, 2011). Studies have also demonstrated that microstimulation of the SC leads to pupil dilation (Joshi et al, 2016;Wang et al, 2012;Wang & Munoz, 2021), suggesting that the SC-mediated circuit can modulate spatial attention and influence pupil size (Wang & Munoz, 2015, 2023. When the parasympathetic and sympathetic systems are unquestionably interconnected and interact, it is suggested that the SC-centered circuit is primarily associated with the parasympathetic system, whereas the LC-centered circuit is predominantly linked to the sympathetic system (Joshi & Gold, 2020;Strauch et al, 2022).…”

“…Evidence has demonstrated that the locus coeruleus (LC), which modulates the arousal system by releasing norepinephrine (NE) throughout most of the brain (referred to hereafter as LC‐NE), plays a significant role in cognitive control (Aston‐Jones & Cohen, 2005; Breton‐Provencher & Sur, 2019; Carter et al., 2010; Grueschow et al., 2022; Mather & Harley, 2016; Poe et al., 2020). Furthermore, the dysfunction of the LC‐NE system is often associated with various clinical symptoms (Betts et al., 2019; Dahl et al., 2022; Gong et al., 2021; Joshi, 2023; Mather et al., 2020; Morris et al., 2020). Consequently, there is a clinical imperative to develop a non‐invasive means for assessing LC‐NE function.…”