The rhythm of retinoids in the brain

Abstract

The retinoids are a family of compounds that in nature are derived from vitamin A or pro-vitamin A carotenoids. An essential part of the diet for mammals, vitamin A has long been known to be essential for many organ systems in the adult. More recently, however, they have been shown to be necessary for function of the brain and new discoveries point to a central role in processes ranging from neuroplasticity to neurogenesis. Acting in several regions of the central nervous system including the eye, hippocampus and hypothalamus, one common factor in its action is control of biological rhythms. This review summarizes the role of vitamin A in the brain; its action through the metabolite retinoic acid via specific nuclear receptors, and the regulation of its concentration through controlled synthesis and catabolism. The action of retinoic acid to regulate several rhythms in the brain and body, from circadian to seasonal, is then discussed to finish with the importance of retinoic acid in the regular pattern of sleep. We review the role of vitamin A and retinoic acid (RA) as mediators of rhythm in the brain. In the suprachiasmatic nucleus and hippocampus they control expression of circadian clock genes while in the cortex retinoic acid is required for delta oscillations of sleep. Retinoic acid is also central to a second rhythm that keeps pace with the seasons, regulating function in the hypothalamus and pineal gland.

Keywords: circadian; neural plasticity; nuclear receptor; photoperiod; retinoic acid; vitamin A.

Fig 1

Chemical structures of retinoid family members. β-carotene (structure 1) is cleaved by β-carotene 15,15′-monooxygenase to form two molecules of retinaldehyde (structure 4). The double arrow between retinol (structure 2) and retinaldehyde (structure 4) indicates the interconversion between the two retinoids catalyzed by retinol dehydrogenases (RDHs) primarily RDH1 and RDH10 and dehydrogenase/reductase (SDR family) member 9 (DHRS9). The single arrow between retinaldehyde (structure 4) and retinoic acid (structure 5) indicates the irreversible oxidation catalyzed by retinaldhyde dehydrogenase (RALDH) family members. Esterification of retinol is carried out by lecithin:retinol acyltransferase (LRAT) or acyl-CoA:retinol acyltransferase (ARAT). The predominant retinyl ester (structure 3) is retinyl palmitate (r = C₁₅H₃₁).

Fig 2

Retinoic acid in the CNS regulates biological rhythms. Retinoic acid (RA) may contribute to the regulation of circadian rhythms in the suprachiasmatic nucleus (SCN), the central clock of the body (Meng et al. 2011), the pineal gland (Herbert and Reiter 1985; Guillaumond et al. 2005), which signals day/night to the rest of the body, and peripheral clocks such as that of the hippocampus (Golini et al. 2012). There is also considerable evidence suggesting that RA plays a crucial role in the seasonal rhythms of energy balance in the ventromedial hypothalamus (Anzano et al. 1979; Ross et al. 2005; Shearer et al. 2010). Rhythmic EEG oscillations in the cerebral cortex during sleep are altered by RA signalling (Maret et al. 2005).

Fig 3

Rhythmic retinoic acid signalling proteins in the hypothalamus. (a) Immunohistochemistry shows that retinoic acid receptor (RAR)α protein is present in both cell bodies and processes in the adult rat suprachiasmatic nucleus. (b) mRNA expression of the encoding gene, RARA, appears to oscillate through the 24-h day in the rat suprachiasmatic nucleus. (c) Retinaldehyde dehydrogenase (RALDH)1, the retinoic acid (RA)-synthesizing enzyme which shows seasonal changes in rat hypothalamic tanycytes, is also strongly expressed in ventral tanycytes in the mouse hypothalamus.

Fig 4

The influence of retinoic acid (RA) on the circadian oscillator. The core set of proteins that create the cellular circadian pacemaker achieve this by forming a positive and a negative feedback loop (Ko and Takahashi 2006). The positive loop involves a heterodimer of CLOCK:BMAL1. These activate transcription of target genes that contain an enhancer box (E-box) sequence, such as PER and CRY. The opposing half of the circuit is the PER and CRY heterodimer which exerts a repressive action on CLOCK:BMAL transcriptional activity. In addition, not shown in the diagram, are multiple interlocked feedback loops that likely both stabilize and provide robustness to the rhythm. These additional loops include pathways that require retinoic acid receptor-related orphan receptors (RORs). RA is reported to influence the central components of the circadian feedback loop by inhibiting the expression or activity of CLOCK/BMAL (McNamara et al. 2001; Shirai et al. 2006) and inducing expression of PER (Shirai et al. 2006). In turn, the genes that encode retinoic acid receptors (RAR)α, β and retinoid X receptor (RXR)β may be regulated by CLOCK/BMAL via their E-box sites (Navigatore-Fonzo et al. 2013).