Pharmacological challenges examining the underlying mechanism of altered response inhibition and attention due to circadian disruption in adult Long-Evans rats
Introduction
Industrialization has led to the development of modern technology that has been beneficial to prosperity and health of the general population. Yet this progress has been accompanied by novel, unintended effects on human and wildlife health. Circadian rhythms are approximately 24 hour-long endogenous rhythms that modulate behavior and physiology. These rhythms are governed by the suprachiasmatic nucleus (SCN), located in the hypothalamus, Environmental factors such as light have a direct effect on the SCN, in turn affecting the modulation of normal behavior and physiology (Silver and Kriegsfeld, 2014). Untimely exposure to light, which is one form of circadian disruption, can cause a conflict with intrinsically-entrained rhythms and has detrimental effects on both behavior and physiology (Potter et al., 2016; Arble et al., 2010; Karatsoreos, 2012; Robertson et al., 2017). Circadian disruption affects cognitive functioning, attention, working memory, and learning (Robertson et al., 2017; Frank and Ovens, 2002; Gritton et al., 2012; Gritton et al., 2013), making this an issue with extensive societal effects. In this study we modeled two types of circadian disruption: 1) testing during a period when an organism is typically at rest (Wright et al., 2013), and 2) light-at-night (LAN), which is the untimely exposure to light during the dark phase of the circadian cycle (Fonken and Nelson, 2014; Dominoni et al., 2016).
Attention is a multidimensional construct, which is broadly defined as the prioritized processing of one piece of information over others (Stefanatos and Baron, 2007). Response inhibition is the suppression of unwanted actions that could interfere with goal-driven behavior (Mostofsky and Simmonds, 2008). Deficiency in response inhibition gives rise to impulsive behavior, i.e., the inability to prevent detrimental actions that interfere with achieving goals. This kind of behavior includes inappropriately-timed actions, poor decision making, increased risk-taking and the inability to delay gratification (Dalley et al., 2011). Furthermore, lack of attention and impulsive behavior are often seen in conjunction with neurological disorders such as attention deficit hyperactivity disorder (ADHD), autism, schizophrenia, depressive and bipolar disorders, and Alzheimer's disease (Coogan et al., 2013; Landgraf et al., 2014). Attentional deficits and impulsive behavior, as well as disorders like ADHD and autism, are associated with disrupted sleep and circadian patterns (Singh and Zimmerman, 2015; Coogan et al., 2016), indicating an interaction between altered circadian rhythms and behavior.
The SCN regulates circadian rhythms in part via acetylcholine (ACh) signaling (Wright et al., 2012). Studies have shown that there can be a bidirectional relationship between attention and circadian rhythms, and this relationship is modulated in part by ACh (Gritton et al., 2012; Landgraf et al., 2014). Impulsive behavior is regulated by dopamine (DA) via binding to the dopamine-1 or -2 receptors (DR1s or DR2s) (Dalley and Roiser, 2012). In several brain regions including the prefrontal cortex, a brain region critical for both attention and impulsivity, and nucleus accumbens and striatum, cholinergic functioning interacts with dopaminergic signaling. In these regions, ACh release stimulates dopaminergic neurons to release DA via binding of nicotinic ACh receptors (nAChRs) on the dopaminergic neurons (van Gaalen et al., 2006; Livingstone and Wonnacott, 2009).
To better understand the effects of circadian disruption on behavior and cognition, we used the rodent models of two different types of circadian disruption, and tested the rats on the 5-choice serial reaction time task (5-CSRTT) which assesses attention and impulsive behavior (Robbins, 2002). The control group consisted of rats tested during the dark phase of their light cycle that were not exposed to ambient light at the time of testing, which is an appropriate control for rats given that they are nocturnal. We hypothesized that rats tested in both models of circadian disruption would exhibit poor attention and increased impulsive behavior compared to the control group. We also postulated that circadian disruption would affect the underlying neurochemistry, which would manifest as altered behavioral responses. To test the hypothesis that circadian disruption would alter the underlying neurochemistry, we quantified the expression of both cholinergic and dopaminergic-related genes using qPCR in brain regions relevant to attention and impulsive behavior, the dorsomedial striatum, nucleus accumbens core, and infralimbic cortex (Christakou, 2004; Tsutsui-Kimura et al., 2016). Finally, we studied the effects of cholinergic and dopaminergic drugs on impulsive behavior under different conditions of circadian disruption which have been previously unexplored. Our hypothesis was that there would be differential drug responses due to circadian disruption. In order to address this, we examined the effects of combinations of the cholinergic agonist, nicotine, and dopaminergic antagonists for both DR1 (SCH23390) and DR2 (eticlopride) on accuracy and premature responding on 5-CSRTT, where the behavioral measures correspond to attention and impulsive behavior.
Section snippets
Subjects
In the first experiment, 3 cohorts of 40 Long-Evans rats per cohort, 20 of each sex (120 total rats), approximately 70 days of age, were purchased from Envigo (Indianapolis, IN). Rats were single-housed in polycarbonate shoebox cages with wood-chip bedding (Beta Chip, Northeastern Products Corp., Warrensburg, NY) in a temperature- and humidity-controlled room (targeted 22 °C, 40–55% humidity). 2020X Teklad Rodent Diet (Envigo) was fed to the rats. Food restriction was initiated after a one-week
Experiment 1: effects of circadian disruption on attention and response inhibition
The total number of days rats took to meet criteria and progress through the initial training phases was significantly different between light condition groups (F2, 114 = 6.8, p = 0.002). The light-phase group took significantly longer to complete the initial training (17.4 ± 0.4 days) than the control group (15.4 ± 0.4 days) (p = 0.003). The LAN group also took significantly longer (17.1 ± 0.4 days) than controls (p = 0.012). Total initial training days for the light-phase and LAN groups were
Discussion
The purpose of this study was to examine the effects of two models of circadian disruption on attention and impulsive action using % accuracy and % premature in the 5-CSRTT as proxy measures (Robbins, 2002). By analyzing gene expression, we aimed to identify the changes in the underlying neurochemistry brought about by both models of circadian disruption. The overall results of the study indicate that both light-at-night (LAN) and light phase-tested models of circadian disruption were
Acknowledgements
We appreciate the invaluable assistance of Arlene Ow and several undergraduate research assistants.
Funding
This work was supported by the University of Illinois Urbana-Champaign Research Board grant RB16191 and Toxicology Scholar - Interdisciplinary Environmental Toxicology Program.
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