Nocturnal Light and Nocturnal Rodents: Similar Regulation of Disparate Functions?

  • Published on

  • View

  • Download

Embed Size (px)


<ul><li><p> of Biological Rhythms</p><p> online version of this article can be found at:</p><p> DOI: 10.1177/0748730413481921</p><p> 2013 28: 95J Biol RhythmsLawrence P. Morin</p><p>Nocturnal Light and Nocturnal Rodents: Similar Regulation of Disparate Functions? </p><p>Published by:</p><p></p><p>On behalf of: </p><p> Society for Research on Biological Rhythms</p><p> can be found at:Journal of Biological RhythmsAdditional services and information for </p><p> Alerts: </p><p> </p><p> </p><p> </p><p> What is This? </p><p>- Apr 19, 2013Version of Record &gt;&gt; </p><p> at CARLETON UNIV on July 6, 2014jbr.sagepub.comDownloaded from at CARLETON UNIV on July 6, 2014jbr.sagepub.comDownloaded from </p><p></p></li><li><p>95</p><p>JOURNAL OF BIOLOGICAL RHYTHMS, Vol. 28 No. 2, April 2013 95-106DOI: 10.1177/0748730413481921 2013 The Author(s)</p><p>1 To whom all correspondence should be addressed: Lawrence P. Morin, Department of Psychiatry, Stony Brook Medical Center, Stony Brook University, Stony Brook, NY 11794-8101; email:</p><p>CONJECTURE</p><p>Nocturnal Light and Nocturnal Rodents: Similar Regulation of Disparate Functions?</p><p>Lawrence P. Morin*,1</p><p>*Department of Psychiatry, Stony Brook Medical Center, Stony Brook University, Stony Brook, NY</p><p>Abstract Investigators typically study one function of the circadian visual system at a time, be it photoreception, transmission of photic information to the suprachiasmatic nucleus (SCN), light control of rhythm phase, locomotor activ-ity, or gene expression. There are good reasons for such a focused approach, but sometimes it is advantageous to look at the broader picture, asking how all the parts and functions complete the whole. Here, several seemingly disparate functions of the circadian visual system are examined. They share common characteristics with respect to regulation by light and, to the extent known, share a common input neuroanatomy. The argument presented is that the 3 hypothalamically mediated effects of light for which there are the most data, circadian clock phase shifts, suppression of nocturnal locomotion (negative masking), and suppression of nocturnal pineal function, are regulated by a common photic input pathway terminating in the SCN. For each, light triggers a relatively fixed interval response that is irradiance-dependent, the effective stimulus can be very brief light exposure, and the response continues to com-pletion in the absence of additional light. The presence of a triggered, fixed-length response interval is of particular importance to the understanding of the circuitry and mechanisms regulating circadian rhythm phase shifts because it implies that the SCN clock response to light is not instantaneous. It also may explain why certain stimuli (neuropeptide Y or novel wheel running) adminis-tered many minutes after light exposure are able to block light-induced phase shifts. The understanding of negative masking is complicated by the fact that it can be represented as a positive change, that is, light-induced sleep, not just as a reduction in locomotion. Acute nocturnal light exposure also induces adrenal hormone secretion and a rapid drop in body temperature, physiological responses that appear to be regulated similarly to the other light effects. The likelihood of a common regulatory basis for the several responses suggests that additional light-induced responses will be forthcoming and raises questions about the relationships between light, SCN cellular anatomy, the molecular clockworks of SCN neurons, and SCN throughput mechanisms for regulating disparate downstream activities.</p><p>Keywords circadian, sleep, masking, melatonin, locomotion, pineal, suprachiasmatic</p><p> at CARLETON UNIV on July 6, 2014jbr.sagepub.comDownloaded from </p><p></p></li><li><p>96 JOURNAL OF BIOLOGICAL RHYTHMS / April 2013</p><p>Circadian rhythm investigators know what masking is despite the absence of a rigorous defini-tion. In his review of the topic, Mrosovsky (1999) defined negative masking in nocturnal animals as a decrease in activity and positive masking as an increase in activity. Other varieties of masking have also been defined (Mrosovsky, 1999). Most investiga-tors are familiar with negative masking as an index of lights suppressive effects on wheel-running behavior. Masking has also been used much more generally in reference to the extent to which virtually any intrinsic or extrinsic stimulus impairs expression of an action of the circadian clock. For example, Redlin (2001) considers light-induced suppression of wheel-running and melatonin to be negative mask-ing responses (also see Mrosovsky, 1999, for discus-sion and references). Rensing prefers to consider the stimulus effects as direct effects rather than as masking effects (Rensing, 1989). Redlin has com-bined terms, referring to masking as resulting from direct effects of light (Redlin, 2001).</p><p>Redlins suggestion that light-induced activity suppression and inhibition of melatonin production are both masking phenomena illustrates some of the semantic confusion surrounding the concept. This arises because the two variables are fundamentally different. Melatonin level is a physiological measure that varies on a continuum from low to high, accord-ing to the prevailing conditions, and it is not known to covary with other measures. In contrast, measures of negative masking have been used as indices of behavioral change, without considering the fact that by definition, all behaviors must always sum to 100%. In other words, when light reduces activity to 0% of ongoing behavior (meaning that negative masking reaches 100%), at least 1 alternate behavior must have correspondingly increased. If we could identify and measure that elevated behavior, would it be an index of positive masking or negative masking? Clarification of this semantic difficulty is necessary in order to uncover organizing principles governing the effects of light on physiology and behavior.</p><p>A second problem regarding the historical use of negative masking is the implication that the behav-ioral change to which it refers is contingent upon the presence of light. A second assumption is explicit: masking effects of light occur by a route that does not involve a pacemaker (Mrosovsky, 1999). Despite wide acceptance of both characteristics (Aschoff, 1960, 1981; Minors and Waterhouse,1989; Mrosovsky, 1999; Redfern et al., 1994; Redlin, 2001), neither </p><p>expectation has been proven. More important for the purposes of the present discussion is the recent dem-onstration that sustained suppression of locomotion does not require the continued presence of light (Morin and Studholme, 2009; Vidal and Morin, 2007). Moreover, research questioning the relationship between light and negative masking has revealed several unexpected results. One is the occurrence of light-induced sleep, hereafter referred to as photo-somnolence. The fact that nocturnal light induces sleep in mice and hamsters (Morin and Studholme, 2009, 2011; Studholme et al., 2013) is a clear example of the above point that if one behavior becomes less likely (e.g., active wakefulness), at least one other behavior must become more likely (e.g., sleep).</p><p>The revelation of photosomnolence requires reconsideration of what negative masking actually represents in order to understand how light modifies physiology and behavior. Here, it is proposed that light induces circadian rhythm phase shifts and suppresses pineal function in ways that are remark-ably similar to the effects of light on negative mask-ing. Indeed, it is plausible that all 3 responses, mediated through the circadian visual system, share a single, light-activated, time-limited mechanism necessary for their expression which, once initiated, continues to completion without additional light being necessary.</p><p>The present discussion focuses on the above high-lighted issues, emphasizing the need for better understanding of the nature of light-induced changes in physiology and behavior while addressing some of the ramifications that the issues may present to circadian rhythm research and the understanding of global SCN function. For the remainder of this pre-sentation, masking refers to negative masking unless otherwise specified and, to avoid semantic confu-sion, will be generally replaced by the term locomotor suppression.</p><p>LOCOmOTOR SUppRESSiON aNd phaSE ShifTiNg aRE SimULTaNEOUSLy iNdUCEd </p><p>by LighT</p><p>Mrosovsky used several novel ways of assessing light-induced locomotor suppression, but the basic procedure has been to provide nocturnal rodents with a running wheel under a standard light-dark (LD) photoperiod and expose them to a 30- or 60-min light pulse during the early activity phase (Mrosovsky, </p><p> at CARLETON UNIV on July 6, 2014jbr.sagepub.comDownloaded from </p><p></p></li><li><p>Morin / EFFECTS OF NOCTURNAL LIGHT 97 </p><p>1999; Mrosovsky et al., 1999 2000, 2001; Redlin and Mrosovsky, 1999b). In a typical study with saturating light, running declines to zero within a few minutes, where it remains during continued expo-sure to the stimulus (Redlin and Mrosovsky, 1999b).</p><p>Phase shift studies are conducted similarly. Depending on whether an Aschoff Type I or II procedure is used, animals are either in constant dark (DD) or LD and are exposed to a 5- to 60-min light pulse. In rhythm studies, a great deal of emphasis has been placed on effects of light on the circadian clock and the phase response curves (PRCs) that describe those effects. Masking receives little or no mention. Nevertheless, it should be abundantly clear that procedures for dem-onstrating masking and phase shifting are essentially identical and that every phase shift study is, by default, a masking study. The major difference between the two is the elapsed time before a result can be considered reliable. From a practical perspec-tive, useful results about negative masking can be obtained within a few minutes of stimulus onset, whereas reliable phase shift detection requires many hours or days after the stimulus to collect the data.</p><p>More bluntly, 2 different responses are elicited via the identical stimulus (Fig. 1). One is considered to be a demonstration of the most important function of the circadian visual system, namely, the ability to maintain a stable temporal relationship with the environmental photoperiod through the phase shift-ing action of light on the circadian clock. Masking, in contrast, is usually considered (if it is considered at all) to be a hindrance to circadian rhythm assessment, a mere by-product resulting from a procedure by which light is used to induce a phase shift. Because identical methods are used to test phase shifting and masking, an obligatory conclusion is that in the absence of other qualifying information, experiments designed to evaluate how light alters intrinsic func-tion of the circadian clock (i.e., the SCN) cannot distinguish between effects on clock phase and effects on masking. Mrosovsky (1999) lamented, with good reason, that so little study has been devoted to masking compared to that lavished on entrainment.</p><p>A B</p><p>0 6 12 18 24</p><p>**</p><p>figure 1. a millisecond light stimulus effective for eliciting phase shifts is also effec-tive for eliciting a masking response. here, several days of a running record obtained from a constant dark-housed mouse (Mus musculus) are shown. The stimulus consisted of 10 flashes of 2 msec each, distributed equally across a 5-min interval beginning at CT13. in (a), the circadian periods before and after the stimulus are indicated by the slope of each black line fitted through the daily activity onsets. The effect of the light stimulus yielded a subsequent phase shift indicated by the greek letters DF in the enlargement (b). The exact time of onset for the flash sequence is indicated by the black arrow in (b). The asterisks in (a) and (b) indicate the interval of locomotor sup-pression induced by the flashes. modified after fig. 1 in morin and Studholme (2009).</p><p>ThE phOTiC iNpUT paThwayS fOR maSkiNg aNd phaSE ShifTiNg </p><p>may bE idENTiCaL</p><p>Circadian rhythm phase shifts and masking respond to photic information arriving in the brain via very similar, if not identical, input pathways involving classical rod/cone and ganglion cell photo-reception. As is now well known, about 1% to 2% of mammalian retinal ganglion cells are photoreceptive (pRGCs) (Berson et al., 2002; Hattar et al., 2002) and use melanopsin as a photopigment (Panda et al., 2005; Qiu et al., 2005). Both classical (rod/cone) pho-toreceptors and pRGCs mediate masking and circa-dian rhythm phase and account for all non-image-forming visual responses (Hattar et al., 2003; Mrosovsky and Hattar, 2003; Mrosovsky et al., 2001; Thompson et al., 2008). Moreover, photic infor-mation received by classical photoreceptors appar-ently must pass through pRGCs in order to elicit those non-image-forming visual responses (Goz et al., 2008; Guler et al., 2008; Hatori et al., 2008).</p><p>Retinal ganglion cells project to about 30 retinore-cipient brain regions (Morin and Blanchard, 1999) and the pRGCs project to many of these regions (Ecker et al., 2010; Gooley and Saper, 2003; Hattar et al., 2006; Morin et al., 2003). In particular, pRGCs densely innervate the SCN, intergeniculate leaflet (IGL), and olivary pretectum and less densely innervate the dorsal lateral geniculate and superior colliculus.</p><p> at CARLETON UNIV on July 6, 2014jbr.sagepub.comDownloaded from </p><p></p></li><li><p>98 JOURNAL OF BIOLOGICAL RHYTHMS / April 2013</p><p>It has been known since 1972 that destruction of the SCN eliminates circadian rhythmicity in rodents (Moore and Eichler, 1972; Stephan and Zucker, 1972). Lesions elsewhere in the brain generally have no effect on rhythm expression. Two exceptions are the IGL and pretectal-tectal region, both of which medi-ate rhythm response to light (Harrington and Rusak, 1986; Marchant and Morin, 1999; Morin and Pace, 2002; Pickard et al., 1987). This information is back-ground for a series of studies by Mrosovsky and col-leagues designed to determine which brain region is necessary for masking. Masking has been tested after lesions of the retinorecipient pretectum, tectum, dor-sal lateral geniculate, ventral lateral geniculate, IGL, and visual cortex (Edelstein and Mrosovsky, 2001; Mrosovsky, 1999; Redlin et al., 2003; Redlin et al., 1999). The results are unequivocal: masking persists i...</p></li></ul>