Abstract
Dim light at night (dLAN) disrupts circadian organization and influences adult behavior. We examined early dLAN exposure on adult affective responses. Beginning 3 (juvenile) or 5 weeks (adolescent) of age, mice were maintained in standard light-dark cycles or exposed to nightly dLAN (5 lux) for 5 weeks, then anxiety-like and fear responses were assessed. Hypothalami were collected around the clock to assess core clock genes. Exposure to dLAN at either age increased anxiety-like responses in adults. Clock and Rev-ERB expression were altered by exposure to dLAN. In contrast to adults, dLAN exposure during early life increases anxiety and fear behavior.
Keywords: light at night, anxiety, fear conditioning, circadian disruption, early life
Introduction
For the vast majority of the earth’s history, life has evolved under brightly illuminated days and dark nights. Consistent with the solar day, most organisms display endogenous ~24-hour, or circadian, rhythms entrained to this external light-dark cycle. Within the past century, however, the widespread adoption of electrical lighting has eliminated clear distinctions between day and night. The technology to provide bright light at night was adopted without a clear understanding of its implications on biology and health. Laboratory, ecological, and epidemiological studies suggest that exposure to light at night (LAN) negatively affects adult circadian (de Jong et al., 2016; Dominoni et al., 2014), metabolic (Fonken et al., 2010; McFadden et al., 2014), immune (Stevens, 2009), as well as affect (Bedrosian et al., 2013). Specifically, chronic exposure to light at night dampens amplitudes of central and peripheral molecular circadian rhythms (Fonken et al., 2013; Shuboni & Yan, 2010), decreases anxiety-like behaviors (Hogan et al., 2015), and increases depressive-like responses (Bedrosian et al., 2013; LeGates et al., 2012) in adult rodents.
In contrast to adults, little is known about the effects of light at night during development when the circadian and other physiological systems are still developing. Children are also exposed to dim light at night; watching television is a common component of many children’s bedtime routines (Owens et al., 1999) and >30% of American children have televisions in their bedrooms (Cespedes et al., 2014). Thus, the potential exists for common nighttime use of electronics by children and adolescents to affect development of the circadian system.
The suprachiasmatic nucleus (SCN) stands at the top of the circadian clock hierarchy, in that it sets the phase of peripheral clocks located throughout the body. In mice the SCN is the first tissue to stabilize the adult phase of rhythmic clock gene expression, typically by 2 weeks of age (Christ et al., 2012). Setting of adult phase in clock gene expression does not stabilize in some peripheral tissues until 8 weeks of age in most rodents (Sládek et al., 2007; Sumová et al., 2006). These rhythms are first driven mainly by maternal signals of the external lighting environment and continue to develop after weaning. Therefore, disruptions of circadian rhythms prior to weaning may have indirect maternal effects. Indeed, mice raised by Clock mutant mothers (Koizumi et al., 2013) or under non-standard lighting conditions, LAN (Borniger et al., 2014) or in short day lengths (Toki et al., 2007), develop anxiety-like behaviors in adulthood, suggesting an important role for the early life lighting environment on affective development.
The early life environment can affect various aspects of behavior and physiology well into adulthood (Gluckman et al., 2008). Maternal and early postnatal exposure to physical (Eiland et al., 2012), immune (Lin et al., 2012), and dietary (Bilbo & Tsang, 2010; Sullivan et al., 2010) stressors increase anxiety- and depressive-like responses in adulthood. These behavioral changes are accompanied by persisting changes in neuronal morphology and hypothalamic-pituitary-adrenal (HPA) reactivity (Bilbo & Tsang, 2010; Eiland et al., 2012; Koehl et al., 1999; Lin et al., 2012; Sullivan et al., 2010). Studies thus far have focused on early developmental time points despite the continued development of the brain into late adolescence (Cunningham et al., 2002; Juraska & Markham, 2004; Spear, 2000). The brains of juvenile (3–4 wks) and adolescent (5 wks) mice are responsive to stressors that subsequently increases anxiety-like behavior in adulthood suggesting a wider window of vulnerability (Boitard et al., 2015; Isgor et al., 2004; Tsoory & Richter-Levin, 2006). We predicted that circadian disruption through exposure to dLAN, beginning at a juvenile (3 wk) and adolescent (5 wk) developmental epoch would also adult anxiety and fear-like behavior in adulthood.
Methods
Mice
Adult male and female Swiss-Webster mice (7 weeks of age) were obtained from Charles River Laboratories to serve as breeding pairs. Mice were housed in heterosexual pairs in polypropylene cages (30 × 15 × 14 cm) at an ambient temperature of 22 ± 1°C, relative humidity of 25± 10%, and 14:10 h light dark cycles with lights on at 2:00 h and lights off at 16:00 h Eastern Time. Regular chow (Harlan Teklad 8640; Madison, WI) and filtered tap water were available ad libitum. Pups obtained from these pairings were housed individually after weaning. All experimental procedures were approved by The Ohio State University Institutional Animal Care and Use Committee, and animals were maintained in accordance with the recommendations of the National Institutes of Health and The Guide for the Care and Use of Laboratory Animals.
Experiment 1. Effect of juvenile and adolescent exposure to light at night on fear behavior
Male and female offspring were reared in standard lighting conditions (LD: 16: 8 h ~130 lux/0 lux) until 3 (n = 64) and 5 (n = 59) weeks of age, at which point they were randomly separated into LD (n = 60) and dim LAN (n = 63; dLAN, 16:8 h ~130 lux/5 lux) conditions. After 5 weeks in their respective lighting conditions mice underwent behavioral testing consisting of open field, elevated plus, and fear conditioning over the course of 5 days. Day 1 consisted of open field testing, day 2 elevated plus, no testing occurred on day 3, day 4–5 fear conditioning. The acquisition and context trials of fear conditioning were conducted during the mid- light phase (0900–1300 h): all other tests were conducted during the early dark phase (1500- 1900 h). Animals were acclimated to the testing room for a minimum of 20 minutes prior to testing. The open field and fear conditioning tests were scored automatically with computerized software as described below. Elevated plus was scored via video by an observer unaware of experimental conditions using the Observer XT 8.0 software (Noldus Information Technology, Leesburg, VA, USA).
Experiment 2. Early life exposure to light at night on clock gene expression
Male and female offspring were reared in standard lighting conditions until 3 and 5 weeks of age and separated into LD and dLAN lighting conditions as described above. After 6 weeks in their respective lighting conditions, mice were killed at 4 time points around the clock, Zeitgeber Time (ZT) 2, 8, 14, and 20. Mice were anesthetized with isoflurane vapors and rapidly decapitated. Brains were collected and placed in RNAlater to facilitate subsequent dissection of the hypothalamus for analysis of clock gene expression using qPCR.
Open Field
The light- and sound- controlled open field chambers contain a 40×40 cm acrylic box surrounded by stacked infrared beam emitter/detectors (San Diego Instruments, Inc., San Diego, CA, USA) to distinguish between horizontal and vertical movement. Mice were placed in the center of acrylic boxes and locomotor activity was recorded for 20 minutes using Photobeam Activity System (PAS) software (San Diego Instruments, San Diego, CA, USA). Activity counts are defined as interruptions in the infrared light sources by the mouse. Total activity, amount of activity in the center of the arena, and number of rears were analyzed.
Elevated Plus Maze
The elevated plus maze apparatus consists of 2 exposed and 2 enclosed (15cm high) arms (67 × 5.5 cm). Mice were placed in the center of the platform facing an open arm and behavior was videotaped for 5 minutes. Recordings were analyzed for latency to enter open arm, number of visits to open arms, and total time spent in open arms.
Fear Conditioning
The fear conditioning apparatus (MedAssociates, Inc., Georgia, VT, USA) consists of a light- and sound- controlled Plexiglas chamber with a metal grid floor, through which a mild electric shock can be administered. A video camera is mounted to the door of the chamber to record animal movement. “Freezing” behavior was analyzed and quantified using VideoFreeze software (Med Associates). Day 1, following 3 minutes of acclimation to the chamber, animals were presented with a series of 7 tones (3500 Hz, 80 dB) for 20 seconds (conditioned stimulus). During the last two seconds of the stimuli, a 0.6 mA foot shock was administered (unconditioned stimulus). After the last tone, animals were left in the chamber for an additional 60 seconds before being returned to their home cage. Day 2, animals were tested for context-dependent fear behavior by recording freezing behavior in response to the testing chamber in the absence of any tone or shock for three minutes. During the dark phase of that same day, animals were tested for amygdala dependent cue conditioning in a novel environment in the absence of a foot shock. The chamber shape was changed into a semi-circle using a white insert and the metal grid flooring was covered by a white panel. Additionally, white lighting was eliminated and a vanilla scent was added to the environment. The tone paradigm is identical to day 1 with the exception of the shock. The entire test is programmed and controlled by VideoFreeze.
qPCR
Collected tissues were homogenized and total RNA extracted using Trizol. RNA was reverse transcribed into cDNA using M-MLV Reverse Transcriptase enzyme (Invitrogen, Carlsbad, CA, USA). Clock gene expression (Clock, Bmal1, Per1, Cry2, and Rev-ERB) were assessed in the whole hypothalamus.
Statistical Analyses
Comparisons of central tendency, time spent in open arms between groups were conducted using a two-way ANOVA with diet, lighting condition, and sex as between subject factors. Freezing behavior was analyzed using Student’s t-tests. Unevenly distributed data were assessed for main effects using Mann-Whitney U tests and interactions using Kruskal-Wallis tests. Post hoc tests of statistically significant interactions were performed using Tukey’s HSD test for two-way ANOVA. Data regarding clock gene expression in the hypothalamus were analyzed using a mixed model with random plate effect to account for the within-plate correlation. Analyses were completed with SPSS software (version 21.0.0) and SAS (version 9.3, Cary, NC). A two-sided significance level of α ≤ 0.05 was used for all tests.
Results
Experiment 1
Open Field
Mice exposed to dLAN during development spent less time in the center of the open field (F1,115 = 27.15, p<0.001; Fig 1A, 1D). Females showed less central tendency than males (F1,115 = 31.68, p<0.001). There was no effect of timing; i.e., juvenile and adolescent exposure to dLAN elicited the same anxiety-like response (p>0.05).
Elevated Plus
Exposure to dLAN did not affect behavior on the elevated plus maze at either time point (p>0.05).
Fear Conditioning
Acquisition
Adolescent exposure to dLAN increased freezing response during acquisition at tones 1–4 (Tone 1 t(39) = −2.71, p<0.05; Tone 2 t(41) = −2.04, p<0.05; Tone 3 t(43) = −2.49, p<0.05; Tone 4 t(47) = −2.57, p<0.05; Fig 1E). Juvenile exposure to dLAN had no effect on freezing behavior during acquisition (p>0.05; Fig 1B).
Context
dLAN exposure during development had no effect on freezing behavior during contextual fear testing (p>0.05).
Retention
Exposure to dLAN starting at 3 weeks and 5 weeks of age impaired extinction of fear memories at tone 3 (t(53) = −1.99, p = 0.05; Fig 1C) and tone 2 (t(54) = −2.05, p < 0.05; Fig 1F), respectively.
Experiment 2
Exposure to dLAN altered Clock expression in the hypothalamus in a sex dependent manner (F1,150= 4.44, p<0.05). Both male and female mice exposed to dLAN during development had increased amplitude of Clock gene expression relative to their dark-night exposed counterparts (F2,150 = 4.3, p<0.05 and F2,150 = 7.5, p<0.001, respectively). Conversely, exposure to dLAN decreased amplitude of Rev-ERB gene expression in the hypothalamus (F2,152 = 8.38, p<0.001).
Discussion
Chronic exposure to dim light at night during pre-adolescent development induces anxiety and fear-like behavior in adulthood. Five weeks of dLAN decreased central tendency in the open field, but did not alter behavior in the elevated plus maze. Adolescent dLAN animals also increased freezing response to a fearful stimulus (foot shock). Mice exposed to dLAN during early life required longer to decrease freezing behavior in response to a tone than mice housed in dark nights. Clock gene expression in the whole hypothalamus increased amplitude in young dLAN exposed mice whereas amplitude of Rev-ERB gene expression decreased. This alteration in clock genes along with behavioral alterations demonstrates that dLAN has developmentally-staged effects on the circadian system.
In common with other early life disruption models, juvenile and adolescent exposure to dLAN increased anxiety-like behaviors. These data confirm and extend the window of behavioral vulnerability to dLAN proposed by previous studies (Borniger et al., 2014). In contrast to previous data in adults, the present results suggest that exposure to dLAN starting as late as 5 weeks of age induces anxiety-like behaviors, whereas after 8 weeks of age anxiety-like behaviors are reduced. This may reflect the opposing effects of dLAN on Clock gene expression in the hypothalamus. In adult mice, Clock expression is unaffected by exposure to dLAN, but increases amplitude in pre-adolescent animals exposed to dLAN. Clock amplitude increases in the nucleus accumbens in response to chronic stress, along with increased anxiety- and depressive-like behaviors (Logan et al., 2015). These observations suggest that magnitude and direction of clock disruption may be region specific in anxiety.
The amplitude of the daily rhythm of expression for many clock genes decrease in adult animals exposed to dLAN (Fonken et al., 2013). We observed that young animals exposed to dLAN decreased amplitude of Rev-ERB gene expression in the hypothalamus. Although amplitude of daily Rev-ERB gene expression was reported flattened in the liver and white adipose in adult mice, hypothalamic Rev-ERB gene expression remained unchanged. Unlike adults, young animals increased anxiety-like behavioral responses in response to dLAN. Alterations in Rev-ERB function have been associated with bipolar disorder (Kripke et al., 2009; Severino et al., 2009), which is comorbid with anxiety (Freeman et al., 2002). Elimination of Rev-ERB in the midbrain increases manic behavior, decreased anxiety- and depressive-like behaviors in adult mice, due to a hyperdopaminergic state (Chung et al., 2014). It is possible that alterations to Rev-ERB have differential effects on dopaminergic tone early in life. This is supported by the observation that dopamine negative feedback becomes regulated during the periadolescent period (Spear & Brake, 1983) and may be the underlying difference between the fear responses in the juvenile versus adolescent exposed animals.
Although mice in this study were exposed to dLAN prior to puberty, a sex difference in anxiety-like behavior was observed suggesting activational effects of steroid hormones on the clock-influenced development of affective responses. Young female mice exposed to dLAN increased anxiety-like behavior relative to males. Maternal high fat diet, maternal separation, and neonatal LPS are anxiogenic in male offspring, but have little or even anxiolytic effects in females (Bilbo & Tsang, 2010; Romeo et al., 2003; Tenk et al., 2013; Wigger & Neumann, 1999). The phenotype observed in the present study is reminiscent of nutritional, immune, or affective manipulations during adolescence that preferentially increase anxiety-like behaviors in females (Eiland et al., 2012; C.M. McCormick et al., 2008; Pohl et al., 2007; Weintraub et al., 2010). These anxiety-like behaviors are all associated with disruptions in the development of neurotransmitter balance and the HPA axis (Donner & Lowry, 2013). The circadian system regulates both the HPA axis and a variety of neurotransmitter systems; hypothalamic clock gene disruptions observed in dLAN exposed animals may have downstream effects on integration of a stressful/fearful stimulus.
Adolescence is a time of rapid brain development and stabilization of both endocrine and neurotransmitter systems (Chambers et al., 2003; He & Hodge, 2007; McCormick & Mathews, 2007). There are circadian rhythms in neurotransmitters involved in regulating anxiety state and their receptors, specifically serotonin, GABA, and glutamate (Castañeda et al., 2004; Spanagel et al., 2005; Weiner et al., 1992; Wesemann & Weiner, 1990). Central disruption of these neurotransmitters is associated with anxiety and mood disorders (Donner & Lowry, 2013; McClung, 2007). Although GR abundance reaches adult levels within the first two weeks of age (Meaney et al., 1985), the Clock:Bmal1 heterodimer is able to regulate transcriptional activity of the glucocorticoid receptor (Nader et al., 2009). Sex and dLAN-induced differences in Clock gene expression may be implicated in the functional integration of a stressful stimulus, contributing to the divergent behavioral outcomes in young versus adult animals exposed dLAN. Affective disorders have been associated with disruptions in circadian rhythms (Frank et al., 2014; Sipilä et al., 2010). Children with anxiety-disorders also display altered circadian profiles (Chase & Pincus, 2011; Feder et al., 2004). Exposure to nighttime environmental lighting alters chronotype in adolescents (Vollmer et al., 2012), suggesting some effects of light at night on the adolescent circadian system. This may be cause for concern when exposure to light at night is so prevalent.
Taken together, these data suggest that early life exposure to dLAN alters molecular circadian rhythms and anxiety-like behavior later in life. This response may reflect a developmental vulnerability to dLAN that may be driving the differential effects during early life as opposed to adulthood on behavioral outcomes. Future studies should expand on the downstream effects of these changes in Clock and Rev-ERB gene expression in the hypothalamus and the neuroendocrine balance.
Acknowledgments
The authors thank Anupama Suresh, Tial KaiKai TinKai, Adam Weiss, Evan Thomas, and Elise Lemanski for technical assistance.
Declaration of interest
This work was supported by the National Science Foundation grant IOS 11-18792 (RJN) and National Institutes of Health grant P30NS045758. YMC was supported by NIDCR T32DE014320.
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