Enlightened: addressing circadian and seasonal changes in photoperiod in animal models of bipolar disorder

Abstract

Bipolar disorders (BDs) exhibit high heritability and symptoms typically first occur during late adolescence or early adulthood. Affected individuals may experience alternating bouts of mania/hypomania and depression, with euthymic periods of varying lengths interspersed between these extremes of mood. Clinical research studies have consistently demonstrated that BD patients have disturbances in circadian and seasonal rhythms, even when they are free of symptoms. In addition, some BD patients display seasonal patterns in the occurrence of manic/hypomanic and depressive episodes as well as the time of year when symptoms initially occur. Finally, the age of onset of BD symptoms is strongly influenced by the distance one lives from the equator. With few exceptions, animal models useful in the study of BD have not capitalized on these clinical findings regarding seasonal patterns in BD to explore molecular mechanisms associated with the expression of mania- and depression-like behaviors in laboratory animals. In particular, animal models would be especially useful in studying how rates of change in photoperiod that occur during early spring and fall interact with risk genes to increase the occurrence of mania- and depression-like phenotypes, respectively. Another unanswered question relates to the ways in which seasonally relevant changes in photoperiod affect responses to acute and chronic stressors in animal models. Going forward, we suggest ways in which translational research with animal models of BD could be strengthened through carefully controlled manipulations of photoperiod to enhance our understanding of mechanisms underlying seasonal patterns of BD symptoms in humans. In addition, we emphasize the value of incorporating diurnal rodent species as more appropriate animal models to study the effects of seasonal changes in light on symptoms of depression and mania that are characteristic of BD in humans.

Fig. 1. A 3-hit model of BD involving an interaction of risk genes (Hit 1) and life stressors (Hit 2) that is filtered through seasonal changes in photoperiod (Hit 3), represented as rates of change in solar insolation.

An idealized pattern of rates of seasonal changes in photoperiod for a location north of the equator is presented, and details relating to this measure may be found in Rosenthal et al. [42]. This model is a modification of the 3-hit model of vulnerability and resilience as originally proposed by Daskalakis and colleagues [62] and is based in part on the social zeitgeber theory of affective disorders [,,].

Fig. 2. Overview of the possible role of the pars tuberalis (PT) in seasonal variations in mood and energy levels that are characteristic of BD.

A A mid-sagittal section of the human brain, with an expanded diagram of the basal portion of the hypothalamus and third ventricle (V3) and the infundibular stalk that connects the pituitary gland to the hypothalamus. B Circulating levels of melatonin at night are reduced during the long days (LD) of summer and increase with the short days (SD) of winter. This diagram depicts a coronal section through the V3, PT, and the anterior pituitary. The PT wraps around the infundibular stalk and contains a high density of melatonin (MT1) receptors on PT-specific thyrotrophs. A retrograde pathway from the PT involves the release of thyroid stimulating hormone (TSHβ) that stimulates receptors on β2 tanycytes that line the base of V3. Under long-day conditions of summer, type 2 deiodinase is upregulated to facilitate the conversion of the prohormone thyroxine (T4) to the bioactive triiodothyronine (T3). T3 is taken up into brain areas to increase reproductive functions, energy levels and mood. PT-specific thyrotrophs also communicate through an anterograde pathway to the pars distalis (anterior pituitary) by releasing the endocannabinoids, N-arachidonoylethanolamine (anandamide, AEA) and 2-arachidonoylglycerol (2-AG), which stimulate folliculo-stellate (FS) cells in the anterior pituitary, leading to the release of ACTH from corticotrophs and prolactin from lactrotrophs [–74].