Thyroid hormone activation of retinoic acid synthesis in hypothalamic tanycytes.

Thyroid hormone (TH) is essential for adult brain function and its actions include several key roles in the hypothalamus. Although TH controls gene expression via specific TH receptors of the nuclear receptor class, surprisingly few genes have been demonstrated to be directly regulated by TH in the hypothalamus, or the adult brain as a whole. This study explored the rapid induction by TH of retinaldehyde dehydrogenase 1 (Raldh1), encoding a retinoic acid (RA)-synthesizing enzyme, as a gene specifically expressed in hypothalamic tanycytes, cells that mediate a number of actions of TH in the hypothalamus. The resulting increase in RA may then regulate gene expression via the RA receptors, also of the nuclear receptor class. In vivo exposure of the rat to TH led to a significant and rapid increase in hypothalamic Raldh1 within 4 hours. That this may lead to an in vivo increase in RA is suggested by the later induction by TH of the RA-responsive gene Cyp26b1. To explore the actions of RA in the hypothalamus as a potential mediator of TH control of gene regulation, an ex vivo hypothalamic rat slice culture method was developed in which the Raldh1-expressing tanycytes were maintained. These slice cultures confirmed that TH did not act on genes regulating energy balance but could induce Raldh1. RA has the potential to upregulate expression of genes involved in growth and appetite, Ghrh and Agrp. This regulation is acutely sensitive to epigenetic changes, as has been shown for TH action in vivo. These results indicate that sequential triggering of two nuclear receptor signalling systems has the capability to mediate some of the functions of TH in the hypothalamus.

The rhythm of retinoids in the brain.

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.

Resident gut microbiota community determines the efficacy of soluble fiber in reducing adiposity.

Consumption of dietary fiber has been linked to several health benefits. Among these, dietary fiber breakdown through the process of anaerobic fermentation by the colonic microbiota leads to the production of beneficial metabolites, mainly short-chain fatty acids (acetate, propionate, and butyrate), which have been implicated in reduced calorie intake. Nevertheless, the link between gut microbiota and obesity remains unclear. We investigated the effects of dietary fibers on food intake and body weight gain in two independent but similarly designed studies in rats. In the first study, the inclusion of 10% w/w pectin, fructooligosaccharides or beta-glucan (n = 10/group) in the diets each significantly reduced body weight gain ('responders') compared to the cellulose control whereas, in a closely matched, but not fully identical study (n = 8/group), no effect of dietary fiber on body weight ('non-responders') was observed. The aim of this work was to explore the basis of this differential response between the two similarly designed and comparable studies, with a focus on the potential role of the gut microbiota in the control of food intake and body weight.

Financial literacy, behavioral traits, and ePayment adoption and usage in Japan.

This study investigates how financial literacy and behavioral traits affect the adoption of electronic payment (ePayment) services in Japan. We construct a financial literacy index using a representative sample of 25,000 individuals from the Bank of Japan's 2019 Financial Literacy Survey. We then analyze the relationship between this index and the extensive and intensive usage of two types of payment services: electronic money (e-money) and mobile payment apps. Using an instrumental variable approach, we find that higher financial literacy is positively associated with a higher likelihood of adopting ePayment services. The empirical results suggest that individuals with higher financial literacy use payment services more frequently. We also find that risk-averse people are less likely to adopt and use ePayment services, whereas people with herd behavior tend to adopt and use ePayment services more. Our empirical results also suggest that the effects of financial literacy on the adoption and use of ePayment differ among people with different behavioral traits. Supplementary Information: The online version contains supplementary material available at 10.1186/s40854-023-00504-3.

Control by the brain of vitamin A homeostasis.

Vitamin A is a micronutrient essential for vertebrate animals maintained in homeostatic balance in the body; however, little is known about the control of this balance. This study investigated whether the hypothalamus, a key integrative brain region, regulates vitamin A levels in the liver and circulation. Vitamin A in the form of retinol or retinoic acid was stereotactically injected into the 3rd ventricle of the rat brain. Alternatively, retinoids in the mouse hypothalamus were altered through retinol-binding protein 4 (Rbp4) gene knockdown. This led to rapid change in the liver proteins controlling vitamin A homeostasis as well as vitamin A itself in liver and the circulation. Prolonged disruption of Rbp4 in the region of the arcuate nucleus of the mouse hypothalamus altered retinol levels in the liver. This supports the concept that the brain may sense retinoids and influence whole-body vitamin A homeostasis with a possible "vitaminostatic" role.

Photoperiodic expression of two RALDH enzymes and the regulation of cell proliferation by retinoic acid in the rat hypothalamus.

Retinoic acid (RA) has been found to regulate hypothalamic function, but precisely where it acts is unknown. This study shows expression of retinaldehyde dehydrogenase (RALDH) enzymes in tanycytes that line the third ventricle in an area overlapping with the site of hypothalamic neural stem cells. The influence of RA was examined on the proliferation of progenitors lining the third ventricle using organotypic slice cultures. As has been shown in other regions of neurogenesis, RA was found to inhibit proliferation. Investigations of the dynamics of RALDH1 expression in the rat hypothalamus have shown that this enzyme is in tanycytes under photoperiodic control with highest levels during long versus short days. In parallel to this shift in RA synthesis, cell proliferation in the third ventricle was found to be lowest during long days when RA was highest, implying that RALDH1 synthesized RA may regulate neural stem cell proliferation. A second RA synthesizing enzyme, RALDH2 was also present in tanycytes lining the third ventricle. In contrast to RALDH1, RALDH2 showed little change with photoperiodicity, but surprisingly the protein was present in the apparent absence of mRNA transcript and it is hypothesized that the endocytic tanycytes may take this enzyme up from the cerebrospinal fluid (CSF).

Circadian Rhythms in Resting Metabolic Rate Account for Apparent Daily Rhythms in the Thermic Effect of Food.

CONTEXT: Daily variation in the thermic effect of food (TEF) is commonly reported and proposed as a contributing factor to weight gain with late eating. However, underlying circadian variability in resting metabolic rate (RMR) is an overlooked factor when calculating TEF associated with eating at different times of the day. OBJECTIVE: This work aimed to determine whether methodological approaches to calculating TEF contribute to the reported phenomena of daily variation in TEF. METHODS: Fourteen overweight to obese but otherwise healthy individuals had their resting and postprandial energy expenditure (EE) measured over 15.5 hours at a clinical research unit. TEF was calculated for breakfast, lunch, and dinner using standard methods (above a baseline and premeal RMR measure) and compared to a method incorporating a circadian RMR by which RMR was derived from a sinusoid curve model and TEF was calculated over and above the continuously changing RMR. Main outcome measures were TEF at breakfast, lunch, and dinner calculated by different methods. RESULTS: Standard methods of calculating TEF above a premeal measured RMR showed that morning TEF (60.8 kcal ±â€…5.6) (mean ±â€…SEM) was 1.6 times greater than TEF at lunch (36.3 kcal ±â€…8.4) and 2.4 times greater than dinner TEF (25.2 kcal ±â€…9.6) (P = .022). However, adjusting for modeled circadian RMR nullified any differences between breakfast (54.1 kcal ±â€…30.8), lunch (49.5 kcal ±â€…29.4), and dinner (49.1 kcal ±â€…25.7) (P = .680). CONCLUSION: Differences in TEF between morning and evening can be explained by the underlying circadian resting EE, which is independent of an acute effect of eating.

Timing of daily calorie loading affects appetite and hunger responses without changes in energy metabolism in healthy subjects with obesity.

Morning loaded calorie intake in humans has been advocated as a dietary strategy to improve weight loss. This is also supported by animal studies suggesting time of eating can prevent weight gain. However, the underlying mechanisms through which timing of eating could promote weight loss in humans are unclear. In a randomized crossover trial (NCT03305237), 30 subjects with obesity/overweight underwent two 4-week calorie-restricted but isoenergetic weight loss diets, with morning loaded or evening loaded calories (45%:35%:20% versus 20%:35%:45% calories at breakfast, lunch, and dinner, respectively). We demonstrate no differences in total daily energy expenditure or resting metabolic rate related to the timing of calorie distribution, and no difference in weight loss. Participants consuming the morning loaded diet reported significantly lower hunger. Thus, morning loaded intake (big breakfast) may assist with compliance to weight loss regime through a greater suppression of appetite.

Photoperiodic regulation of glycogen metabolism, glycolysis, and glutamine synthesis in tanycytes of the Siberian hamster suggests novel roles of tanycytes in hypothalamic function.

The objective of this study is to investigate the impact of photoperiod on the temporal and spatial expression of genes involved in glucose metabolism in the brain of the seasonal mammal Phodopus sungorus (Siberian hamster). In situ hybridization was performed on brain sections obtained from male hamsters held in long photoperiod (high body weight and developed testes) or short photoperiod (reduced body weight with testicular regression). This analysis revealed upregulation in expression of genes involved in glycogen and glucose metabolism in short photoperiod and localized to the tanycyte layer of the third ventricle. On the basis of these data and a previously identified photoperiod-dependent increase in activity of neighboring hypothalamic neurons, we hypothesized that the observed expression changes may reflect alteration in either metabolic fuel or precursor neurotransmitter supply to surrounding neurons. Gene expression analysis was performed for genes involved in lactate and glutamate transport. This analysis showed that the gene for the lactate transporter MCT2 and glutamate transporter GLAST was decreased in the tanycyte layer in short photoperiod. Expression of mRNA for glutamine synthetase, the final enzyme in the synthesis of the neuronal neurotransmitter precursor, glutamine, was also decreased in short photoperiod. These data suggest a role for tanycytes in modulating glutamate concentrations and neurotransmitter supply in the hypothalamic environment.

Ancestral TSH mechanism signals summer in a photoperiodic mammal.

In mammals, day-length-sensitive (photoperiodic) seasonal breeding cycles depend on the pineal hormone melatonin, which modulates secretion of reproductive hormones by the anterior pituitary gland [1]. It is thought that melatonin acts in the hypothalamus to control reproduction through the release of neurosecretory signals into the pituitary portal blood supply, where they act on pituitary endocrine cells [2]. Contrastingly, we show here that during the reproductive response of Soay sheep exposed to summer day lengths, the reverse applies: Melatonin acts directly on anterior-pituitary cells, and these then relay the photoperiodic message back into the hypothalamus to control neuroendocrine output. The switch to long days causes melatonin-responsive cells in the pars tuberalis (PT) of the anterior pituitary to increase production of thyrotrophin (TSH). This acts locally on TSH-receptor-expressing cells in the adjacent mediobasal hypothalamus, leading to increased expression of type II thyroid hormone deiodinase (DIO2). DIO2 initiates the summer response by increasing hypothalamic tri-iodothyronine (T3) levels. These data and recent findings in quail [3] indicate that the TSH-expressing cells of the PT play an ancestral role in seasonal reproductive control in vertebrates. In mammals this provides the missing link between the pineal melatonin signal and thyroid-dependent seasonal biology.

Synaptic dysregulation and hyperexcitability induced by intracellular amyloid beta oligomers.

Intracellular amyloid beta oligomer (iAßo) accumulation and neuronal hyperexcitability are two crucial events at early stages of Alzheimer's disease (AD). However, to date, no mechanism linking iAßo with an increase in neuronal excitability has been reported. Here, the effects of human AD brain-derived (h-iAßo) and synthetic (iAßo) peptides on synaptic currents and action potential firing were investigated in hippocampal neurons. Starting from 500 pM, iAßo rapidly increased the frequency of synaptic currents and higher concentrations potentiated the AMPA receptor-mediated current. Both effects were PKC-dependent. Parallel recordings of synaptic currents and nitric oxide (NO)-associated fluorescence showed that the increased frequency, related to pre-synaptic release, was dependent on a NO-mediated retrograde signaling. Moreover, increased synchronization in NO production was also observed in neurons neighboring those dialyzed with iAßo, indicating that iAßo can increase network excitability at a distance. Current-clamp recordings suggested that iAßo increased neuronal excitability via AMPA-driven synaptic activity without altering membrane intrinsic properties. These results strongly indicate that iAßo causes functional spreading of hyperexcitability through a synaptic-driven mechanism and offers an important neuropathological significance to intracellular species in the initial stages of AD, which include brain hyperexcitability and seizures.

Photoperiodic regulation of retinoic acid signaling in the hypothalamus.

Both retinoic acid (RA) and thyroid hormone (TH) regulate transcription via specific nuclear receptors. TH regulates hypothalamic homeostasis and active T3 is generated by deiodinase enzymes in tanycytes surrounding the third ventricle. However, RA has not been previously considered in such a role. Data presented here highlights novel parallels between the TH and RA synthetic pathways in the hypothalamus implying that RA also acts to regulate hypothalamic gene expression and function. Key elements of the RA cellular signaling pathway were shown to be regulated in the rodent hypothalamus. Retinoid synthetic enzymes and the retinol transport protein Stra6 were located in the cells lining the third ventricle allowing synthesis of RA from retinol present in the CNS to act via RA receptors and retinoid X receptors in the hypothalamus. Photoperiod manipulation was shown to alter the expression of synthetic enzymes and receptors with lengthening of photoperiod leading to enhanced RA signaling. In vitro RA can regulate the hypothalamic neuroendocrine peptide adrenocorticotrophic hormone. This work presents the new concept of controlled RA synthesis by hypothalamic tanycytes giving rise to possible involvement of this system in endocrine, and possibly vitamin A, homeostasis.

Mealtime: A circadian disruptor and determinant of energy balance?

Circadian rhythms play a critical role in the physiological processes involved in energy metabolism and energy balance (EB). A large array of metabolic processes, including the expression of many energy-regulating endocrine hormones, display temporal rhythms that are driven by both the circadian clock and food intake. Mealtime has been shown to be a compelling zeitgeber in peripheral tissue rhythms. Inconsistent signalling to the periphery, because of mismatched input from the central clock vs time of eating, results in circadian disruption in which central and/or peripheral rhythms are asynchronously time shifted or their amplitudes reduced. A growing body of evidence supports the negative health effects of circadian disruption, with strong evidence in murine models that mealtime-induced circadian disruption results in various metabolic consequences, including energy imbalance and weight gain. Increased weight gain has been reported to occur even without differences in energy intake, indicating an effect of circadian disruption on energy expenditure. However, the translation of these findings to humans is not well established because the ability to undertake rigorously controlled dietary studies that explore the chronic effects on energy regulation is challenging. Establishing the neuroendocrine changes in response to both acute and chronic variations in mealtime, along with observations in populations with routinely abnormal mealtimes, may provide greater insight into underlying mechanisms that influence long-term weight management under different meal patterns. Human studies should explore mechanisms through relevant biomarkers; for example, cortisol, leptin, ghrelin and other energy-regulating neuroendocrine factors. Mistiming between aggregate hormonal signals, or between hormones with their receptors, may cause reduced signalling intensity and hormonal resistance. Understanding how mealtimes may impact on the coordination of endocrine factors is essential for untangling the complex regulation of EB. Here a review is provided on current evidence of the impacts of mealtime on energy metabolism and the underlying neuroendocrine mechanisms, with a specific focus on human research.

A unifying hypothesis for control of body weight and reproduction in seasonally breeding mammals.

Animals have evolved diverse seasonal variations in physiology and reproduction to accommodate yearly changes in environmental and climatic conditions. These changes in physiology are initiated by changes in photoperiod (daylength) and are mediated through melatonin, which relays photoperiodic information to the pars tuberalis of the pituitary gland. Melatonin drives thyroid-stimulating hormone transcription and synthesis in the pars tuberalis, which, in turn, regulates thyroid hormone and retinoic acid synthesis in the tanycytes lining the third ventricle of the hypothalamus. Seasonal variation in central thyroid hormone signalling is conserved among photoperiodic animals. Despite this, different species adopt divergent phenotypes to cope with the same seasonal changes. A common response amongst different species is increased hypothalamic cell proliferation/neurogenesis in short photoperiod. That cell proliferation/neurogenesis may be important for seasonal timing is based on (i) the neurogenic potential of tanycytes; (ii) the fact that they are the locus of striking seasonal morphological changes; and (iii) the similarities to mechanisms involved in de novo neurogenesis of energy balance neurones. We propose that a decrease in hypothalamic thyroid hormone and retinoic acid signalling initiates localised neurodegeneration and apoptosis, which leads to a reduction in appetite and body weight. Neurodegeneration induces compensatory cell proliferation from the neurogenic niche in tanycytes and new cells are born under short photoperiod. Because these cells have the potential to differentiate into a number of different neuronal phenotypes, this could provide a mechanistic basis to explain the seasonal regulation of energy balance, as well as reproduction. This cycle can be achieved without changes in thyroid hormone/retinoic acid and explains recent data obtained from seasonal animals held in natural conditions. However, thyroid/retinoic acid signalling is required to synchronise the cycles of apoptosis, proliferation and differentiation. Thus, hypothalamic neurogenesis provides a framework to explain diverse photoperiodic responses.

G protein-coupled receptor 101 mRNA expression in supraoptic and paraventricular nuclei in rat hypothalamus is altered by pregnancy and lactation.

In a previous study performed in mouse models of energetic challenge, there was evidence to suggest that the orphan G protein-coupled receptor GPCR101 may have a role in the regulation of energy balance. To further investigate this possibility, we utilised in situ hybridisation to determine the effect of energetic challenges experienced by pregnant and lactating rats on GPCR101 mRNA expression. In the rat hypothalamus, GPCR101 mRNA expression was detected in a number of hypothalamic nuclei. During pregnancy and lactation, GPCR101 mRNA level remained unchanged in most nuclei, but had increased in the supraoptic nucleus by the end of pregnancy and remained elevated during lactation. GPCR101 mRNA expression showed a similar pattern of expression in the rostral ventromedial parvocellular subdivision of the paraventricular nucleus. A common feature of these two nuclei is the production of the peptide oxytocin. Dual in situ hybridisation revealed GPCR101 and oxytocin mRNA co-expression in neurons of these two nuclei. In the supraoptic nucleus, in situ hybridisation revealed that the temporal regulation of oxytocin and GPCR101 mRNA expression were similar. In the paraventricular nucleus, although temporal changes in oxytocin mRNA expression were similar to GPCR101, the spatial expression of the two mRNA species was different; in contrast to GPCR101, oxytocin mRNA expression changed in both parvo- and magnocellular neurons during lactation. In conclusion, increased GPCR101 mRNA expression in supraoptic and paraventricular nuclei from late pregnancy to late lactation may reflect the functional importance of this receptor in the regulation of neurons of these nuclei during this period.

Diet induced obesity is independent of metabolic endotoxemia and TLR4 signalling, but markedly increases hypothalamic expression of the acute phase protein, SerpinA3N.

Hypothalamic inflammation is thought to contribute to obesity. One potential mechanism is via gut microbiota derived bacterial lipopolysaccharide (LPS) entering into the circulation and activation of Toll-like receptor-4. This is called metabolic endotoxemia. Another potential mechanism is systemic inflammation arising from sustained exposure to high-fat diet (HFD) over more than 12 weeks. In this study we show that mice fed HFD over 8 weeks become obese and show elevated plasma LPS binding protein, yet body weight gain and adiposity is not attenuated in mice lacking Tlr4 or its co-receptor Cd14. In addition, caecal microbiota composition remained unchanged by diet. Exposure of mice to HFD over a more prolonged period (20 weeks) to drive systemic inflammation also caused obesity. RNAseq used to assess hypothalamic inflammation in these mice showed increased hypothalamic expression of Serpina3n and Socs3 in response to HFD, with few other genes altered. In situ hybridisation confirmed increased Serpina3n and Socs3 expression in the ARC and DMH at 20-weeks, but also at 8-weeks and increased SerpinA3N protein could be detected as early as 1 week on HFD. Overall these data show lack of hypothalamic inflammation in response to HFD and that metabolic endotoxemia does not link HFD to obesity.

VGF-derived peptide, TLQP-21, regulates food intake and body weight in Siberian hamsters.

The Siberian hamster survives winter by decreasing food intake and catabolizing abdominal fat reserves, resulting in a sustained, profound loss of body weight. VGF gene expression is photoperiodically regulated in the hypothalamus with significantly higher expression in lean Siberian hamsters. The aim of this study was to investigate the role of VGF in regulating these seasonal cycles by determining the effects of a VGF-derived peptide (TLQP-21) on food intake and body weight. Acute intracerebroventricular administration of TLQP-21 decreased food intake, and chronic treatment caused a sustained reduction in food intake and body weight and decreased abdominal fat depots. Behavioral analysis revealed that TLQP-21 reduced meal size but not the frequency of feeding bouts, suggesting a primary action on satiety. Hamsters treated with TLQP-21 lost a similar amount of weight as a pair-fed group in which food intake was matched to that of the TLQP-21-treated group. Central or peripheral treatment with TLQP-21 did not produce a significant effect on resting metabolic rate. We conclude that the primary action of TLQP-21 is to decrease food intake rather than increase energy expenditure. TLQP-21 treatment caused a decrease in UCP-1 mRNA in brown adipose tissue, but hypothalamic expression of orexigenic and anorexigenic neuropeptide genes remained unchanged after TLQP-21 treatment, although compensatory increases in NPY and AgRP mRNA were observed in the pair-fed hamsters. The effects of TLQP-21 administration are similar to those in hamsters in short days, suggesting that increased VGF activity may contribute to the hypophagia that underlies the seasonal catabolic state.

Hypothalamic thyroid hormone catabolism acts as a gatekeeper for the seasonal control of body weight and reproduction.

Seasonal adaptations in physiology exhibited by many animals involve an interface between biological timing and specific neuroendocrine systems, but the molecular basis of this interface is unknown. In this study of Siberian hamsters, we show that the availability of thyroid hormone within the hypothalamus is a key determinant of seasonal transitions. The expression of the gene encoding type III deiodinase (Dio3) and Dio3 activity in vivo (catabolism of T(4) and T(3)) is dynamically and temporally regulated by photoperiod, consistent with the loss of hypothalamic T(3) concentrations under short photoperiods. Chronic replacement of T(3) in the hypothalamus of male hamsters exposed to short photoperiods, thus bypassing synthetic or catabolic deiodinase enzymes located in cells of the ependyma of the third ventricle, prevented the onset of short-day physiology: hamsters maintained a long-day body weight phenotype and failed to undergo testicular and epididymal regression. However, pelage moult to a winter coat was not affected. Type II deiodinase gene expression was not regulated by photoperiod in these hamsters. Collectively, these data point to a pivotal role for hypothalamic DIO3 and T(3) catabolism in seasonal cycles of body weight and reproduction in mammals.

Dietary Uncoupling of Gut Microbiota and Energy Harvesting from Obesity and Glucose Tolerance in Mice.

Evidence suggests that altered gut microbiota composition may be involved in the development of obesity. Studies using mice made obese with refined high-fat diets have supported this; however, these have commonly used chow as a control diet, introducing confounding factors from differences in dietary composition that have a key role in shaping microbiota composition. We compared the effects of feeding a refined high-fat diet with those of feeding either a refined low-fat diet or a chow diet on gut microbiota composition and host physiology. Feeding both refined low- or high-fat diets resulted in large alterations in the gut microbiota composition, intestinal fermentation, and gut morphology, compared to a chow diet. However, body weight, body fat, and glucose intolerance only increased in mice fed the refined high-fat diet. The choice of control diet can dissociate broad changes in microbiota composition from obesity, raising questions about the previously proposed relationship between gut microbiota and obesity.

Photoperiodic regulation of cellular retinol binding protein, CRBP1 [corrected] and nestin in tanycytes of the third ventricle ependymal layer of the Siberian hamster.

Tanycytes in the ependymal layer of the third ventricle act both as a barrier and a communication gateway between the cerebrospinal fluid, brain and portal blood supply to the pituitary gland. However, the range, importance and mechanisms involved in the function of tanycytes remain to be explored. In this study, we have utilized a photoperiodic animal to examine the expression of three unrelated gene sequences in relation to photoperiod-induced changes in seasonal physiology and behaviour. We demonstrate that cellular retinol binding protein [corrected] (CRBP1), a retinoic acid transport protein, GPR50, an orphan G-protein-coupled receptor and nestin, an intermediate filament protein, are down-regulated in short-day photoperiods. The distribution of the three sequences is very similar, with expression located in cells with tanycyte morphology in the region of the ependymal layer where tanycytes are located. Furthermore, CRBP1 expression in the ependymal layer is shown to be independent of a circadian clock and altered testosterone levels associated with testicular regression in short photo-period. Pinealectomy of Siberian hamsters demonstrates CRBP1 expression is likely to be dependent on melatonin output from the pineal gland. This provides evidence that tanycytes are seasonally responsive cells and are likely to be an important part of the mechanism to facilitate seasonal physiology and behaviour in the Siberian hamster.