Pharmacological challenges examining the underlying mechanism of altered response inhibition and attention due to circadian disruption in adult Long-Evans rats

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Highlights

  • Circadian disruption impacts cognition by altering the circadian clock at a molecular level.

  • We evaluated two models of circadian disruption in rats.

  • Changes in the diurnal expression pattern occurred in the clock gene Per2 in light phase-tested rats.

  • Rats in both models demonstrated increased sensitivity to nicotine.

Abstract

Endogenous circadian rhythms govern behavior and physiology, while circadian disruption is an environmental factor that impacts cognition by altering the circadian clock at a molecular level. We modeled the effects of 2 sources of circadian disruption – activity occurring during typical rest periods and untimely light exposure – to evaluate the effects of circadian disruption on behavior and underlying neurochemistry. Firstly, adult Long-Evans rats of both sexes were maintained on a 12 h:12 h light:dark cycle and tested using a 5-choice serial reaction time task (5-CSRTT) under 3 conditions: 4 h into the dark phase with no exposure to ambient light during testing (control), 4 h into the dark phase with exposure to ambient light during testing, and 4 h into the light phase. Both models resulted in impulsive behavior and reduced attention compared to control. We established that changes in the diurnal expression pattern occur in the clock gene Period 2 (Per2) in the light phase-tested model. Choline acetyltransferase (Chat) and Dopamine receptor 1 (Drd1) showed rhythmic expression with peak expression during the dark phase regardless of light-testing condition. Next, we performed drug challenges in a new rat cohort to examine the interaction between the cholinergic and dopaminergic neurotransmitter systems in regulating the behavioral changes caused by circadian disruption. We administered the cholinergic agonist nicotine and either the dopamine-1 receptor (DR1) antagonist SCH23390 or the DR2 antagonist eticlopride under the 3 circadian conditions to identify differential drug responses between treatment groups. Rats in both models demonstrated increased sensitivity to nicotine as compared to control, while SCH23390 and eticlopride ameliorated the effect of nicotine on 5-CSRTT performance in both models. Our study is the first to identify detrimental effects of both models of circadian disruption on impulsive behavior, and that the effects of circadian disruption are mediated by an interaction between cholinergic and dopaminergic systems.

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.

References (68)

  • M. Iijima et al.

    Altered food-anticipatory activity rhythm in Cryptochrome-deficient mice

    Neurosci. Res.

    (2005)
  • M.E. Jiménez-Capdeville et al.

    Daily changes in the release of acetylcholine from rat primary somatosensory cortex

    Brain Res.

    (1993)
  • H. Kametani et al.

    Circadian rhythm of cortical acetylcholine release as measured by in vivo microdialysis in freely moving rats

    Neurosci. Lett.

    (1991)
  • P.D. Livingstone et al.

    Nicotinic acetylcholine receptors and the ascending dopamine pathways

    Biochem. Pharmacol.

    (2009)
  • R.E. Mistlberger

    Circadian food-anticipatory activity: formal models and physiological mechanisms

    Neurosci. Biobehav. Rev.

    (1994)
  • N. Murakami et al.

    Effect of light on the acetylcholine concentrations of the suprachiasmatic nucleus in the rat

    Brain Res.

    (1984)
  • P.K. Parekh et al.

    Circadian clock genes: effects on dopamine, reward and addiction

    Alcohol

    (2015)
  • T. Pattij et al.

    The neuropharmacology of impulsive behaviour

    Trends Pharmacol. Sci.

    (2008)
  • A.L. Robertson et al.

    Circadian disruption affects initial learning but not cognitive flexibility in an automated set-shifting task in adult long-Evans rats

    Physiol. Behav.

    (2017)
  • K. Singh et al.

    Sleep in autism spectrum disorder and attention deficit hyperactivity disorder

    Semin. Pediatr. Neurol.

    (2015)
  • E.P. Sleipness et al.

    Diurnal differences in dopamine transporter and tyrosine hydroxylase levels in rat brain: dependence on the suprachiasmatic nucleus

    Brain Res.

    (2007)
  • F.K. Stephan

    Phase shifts of circadian rhythms in activity entrained to food access

    Physiol. Behav.

    (1984)
  • I. Tsutsui-Kimura et al.

    Neuronal codes for the inhibitory control of impulsive actions in the rat infralimbic cortex

    Behav. Brain Res.

    (2016)
  • I.C. Webb et al.

    Diurnal and circadian regulation of reward-related neurophysiology and behavior

    Physiol. Behav.

    (2015)
  • K.P. Wright et al.

    Shift work and the assessment and management of shift work disorder (SWD)

    Sleep Med. Rev.

    (2013)
  • H. Abe et al.

    Anticipatory activity and entrainment of circadian rhythms in Syrian hamsters exposed to restricted palatable diets

    Am. J. Phys. Regul. Integr. Comp. Phys.

    (1992)
  • J. Aschoff et al.

    Zeitgebers, entrainment, and masking: some unsettled questions

  • L. Bizarro et al.

    Attentional effects of nicotine and amphetamine in rats at different levels of motivation

    Psychopharmacology

    (2003)
  • M. Brownstein et al.

    Choline acetyltransferase levels in diencephalic nuclei of the rat

    J. Neurochem.

    (1975)
  • E.D. Buhr et al.

    Molecular components of the mammalian circadian clock

    Handb. Exp. Pharmacol.

    (2013)
  • T.R. Castañeda et al.

    Circadian rhythms of dopamine, glutamate and GABA in the striatum and nucleus accumbens of the awake rat: modulation by light

    J. Pineal Res.

    (2004)
  • A. Christakou

    Prefrontal cortical-ventral striatal interactions involved in affective modulation of Attentional performance: implications for Corticostriatal circuit function

    J. Neurosci.

    (2004)
  • C.A. Córdova et al.

    Sleep deprivation in rats produces attentional impairments on a 5-choice serial reaction time task

    Sleep.

    (2006)
  • F. Damiola

    Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus

    Genes Dev.

    (2000)
  • Cited by (0)

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    Present address: Veterinary Medicine - Physiology and Pharmacology, University of Georgia. 501 D.W. Brooks Drive, Room 2215, Athens, GA, 30602, USA.

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