Question

Numerous studies, mostly in mutant organisms, have demonstrated that the period of a biological rhythm is an inherited trait. Describe some of the studies, or propose studies (include animal studies) that would help determine the inheritance of the period of a biological rhythm.

Answer 1

STUDY 1:

Biological Rhythms of the Mouse

Stephan Steinlechner, in The Laboratory Mouse (Second Edition), 2012

Biological rhythms are a universal feature of all organisms. This chapter gives an overview of rhythmic functions in the mouse with a special emphasis on the circadian (~24 h) rhythms. The physiology and behaviour of the mouse are temporally organized in a programme that allows anticipation of the daily light and dark cycle rather than simply reacting to this recurrent change. The molecular mechanisms underlying the mammalian circadian clock have been defined primarily through studies involving mice with either mutations or deletions that led to aberrant rhythmic phenotypes. It turns out that the mammalian circadian system is organized in a hierarchy of oscillators. The master clock, localized in the suprachiasmatic nuclei of the anterior hypothalamus, coordinates independent peripheral oscillators in all major organs and their coordinated action appears indispensable for a healthy organism. The cell-autonomous, self-sustained rhythms are based on transcriptional–translational feedback loops driving expression patterns of a number of clock genes and clock-controlled genes.

STUDY 2:

Environmental Relations and Behavior

Horst O. Schwassmann, in Fish Physiology, 1971

Biological rhythms of daily, tidal, lunar, and annual periodicity, which are an inherent feature of organismic organization, are recognized as adaptations to our periodically changing environment. Considering the experimental evidence, it is obvious that rhythmic phenomena in many species of fish are in no way different from those known in other organisms regarding the endogenous nature and the control of phase and period by periodic environmental variables. Therefore, certain established generalities resulting from studies on different organisms must also be valid for biological rhythms in fish.

Experimental evidence is available for circadian rhythms in several species of fish; most of it, however, is limited to demonstrating a persistence of overt periodic functions in constant conditions. Concerning annual rhythms, several studies investigated mainly change of day length and temperature for their effect in timing annual reproductive cycles in about 10 teleost species. Rhythms of tidal, semilunar, and lunar periodicity in fish of the intertidal zones are known from a few rather spectacular examples, but with one exception they have not been investigated in the laboratory.

Most progress has been made recently in the field of functional analysis of circadian rhymicity. Circadian organization seems to be the phylogenetically oldest feature and might well be of common origin, whereas the many diverse overt functions could be considered secondary consequences of the circadian system. A major role of circadian organization appears to lie in its involvement in the mechanism of photoperiodic control as an adjustment to the temporal order of annual environmental cycles. In photoperiodism, the circadian oscillation makes possible the sensitivity to the length of the daily light period. The ecologically significant effect of photoperiodic control, especially evident from studies on annual breeding in fish, appears to be in adjusting the temporal sequence of a physiological rhythm of gonadal maturation rather than to actually trigger certain specific physiological events. Photoperiodic control cannot account for the timing of reproduction and preceding migratory movements of species living in the tropics, where a coincidence of spawning activity with the onset of the rainy season appears to be a fairly common phenomenon.

Most experimental studies involved animals of temperate zones which may have led to the current emphasis of photoperiodic control mechanisms. Experimental work concerning possible timing mechanisms of breeding cycles in tropical fish seems to be hampered by the scarcity of information about their natural behavior and the times of reproductive activity in natural habitats of different meteorological conditions. In spite of the great progress achieved by laboratory studies of rhythmic phenomena in diverse organisms, including fish, essentially in terms of functional systems analysis, it is this writer's opinion that further achievements will depend on field studies which not only provide the basis for any experimental analysis in the laboratory but also test present generalizations and theories.

STUDY 3:

Molecular Architecture and Neurobiology of Bipolar Disorder

Carrie E. Bearden, ... Nelson B. Freimer, in Genomics, Circuits, and Pathways in Clinical Neuropsychiatry, 2016

Circadian Disturbances in Bipolar Disorder

Disruptions in biological rhythms are a hallmark of BP. Because the disorder typically displays cyclic, episodic, and often seasonal patterns, a number of investigators have speculated that circadian dysregulation may underlie its pathophysiology (Kripke, Mullaney, Atkinson, & Wolf, 1978; Lewy, Lefler, Emens, & Bauer, 2006; Mansour, Monk, & Nimgaonkar, 2005). Disruptions in the sleep–wake cycle may be the most frequent precipitants of manic and depressive episodes, regardless of whether such disruptions derive from external or endogenous influences (Frank, Swartz, & Kupfer, 2000). Furthermore, sleep disturbance is among the most commonly reported prodromal symptoms preceding the onset of an initial manic episode (Conus et al., 2008, 2010). As such, it has been hypothesized that reduced sleep may act as a “final common pathway” in triggering mania. Investigation of the molecular mechanisms underlying sleep and circadian rhythm alterations associated with BP may therefore be a key to elucidating the pathogenesis of the disorder.

A meta-analytic review compiled studies that employed actigraphy, sleep diary, polysomnography, and questionnaire measures to investigate sleep–wake patterns in individuals with interepisode BP and/or those at high risk, as defined by family history or subthreshold symptoms (Ng et al., 2014). The authors conclude that across studies, sleep onset latency, wake after sleep onset, and variability of sleep–wake measures displayed the most consistent disruption in patients with interepisode BP relative to healthy control subjects. In addition, patients with interepisode BP spend a similar amount of time trying to fall asleep as do individuals with primary insomnia. Compared with control subjects, individuals at high risk for BP demonstrated greater variability in sleep efficiency and lower relative amplitude, as evidenced by weaker and more unstable rest–activity cycles, and (according to one study) greater variability in total sleep time (Meyer & Maier, 2006). These findings are consistent with the instability model of BP originally put forth by Goodwin and Jamison (2007) and suggest that variability in sleep–wake cycle may be a possible endophenotype for BP. However, more prospective research in familial high-risk individuals is warranted to determine whether sleep–wake cycle variability is predictive of outcome.

Most tissues throughout the body incorporate endogenous molecular clocks, which have critical roles in regulating physiological processes, including those influencing mood states. Several studies in animal models have implicated specific circadian genes in regulating mood and reward responsivity. For example, mice with a Clock gene mutation have a behavioral phenotype involving hyperactivity, reduced sleep, lowered “depression-like” and anxiety behavior, and enhanced value for rewarding stimuli (cocaine, sucrose, and medial forebrain bundle stimulation) (Roybal et al., 2007), ie, one that resembles the manic phase of bipolar illness, as well as increased dopamine synthesis and dopaminergic activity (Coque et al., 2011). Administration of lithium to these mice leads to normalization in their behavior (Roybal et al., 2007) and in striatal dopamine activity (Coque et al., 2011). Investigation in mouse models generated with mutations in other circadian rhythm genes, including GSK3beta and sirtuin 1, have also described the development of “manic-like” behaviors in such mice (McClung, 2013). Knockout in mice of the circadian gene Period leads to increased mesolimbic dopamine levels and altered neuronal activity in the striatum, which may be relevant to reduction in the mutant mice in behaviors that have commonly been related to depression (reduced immobility on the forced-swim test) (Hampp et al., 2008). Chung et al. (2014) discovered that the circadian nuclear receptor REV-ERBa affects midbrain dopamine production and mood-related behavior in mice. Deletion of the REV-ERBa gene or pharmacological inhibition of REV-ERBa activity in the ventral midbrain induced mania-like behavior, concomitant with a central hyperdopaminergic state. Collectively, these findings indicate molecular links between the regulation of circadian rhythms, mesolimbic dopaminergic function, and mood.