Vitamin D and Health

Vitamin D and Health

~ October 2003 No.173 ~

Vitamin D is called the sunshine vitamin because the human skin synthesizes vitamin D when it is exposed to sunlight. When humans wore fewer clothes and were out of doors more, this was not a problem. However, in modern western society our time in the sun is often restricted to the occasional visit to the beach. Even then, sun screens cut down on our exposure to the sun, which is good to prevent skin cancer, but could be lowering the production of Vitamin D. It has been estimated that 10-15 minutes of sunshine 3 times a week is sufficient exposure to produce most people's requirement for vitamin D. Those living in northern regions are often at greater risk as are those who are housebound.

Vitamin D is called the sunshine vitamin because the human skin synthesizes vitamin D when it is exposed to sunlight.

Vitamin D is a fat soluble vitamin. This means that it must be dissolved in oil to be absorbed into the body. It is most commonly found it foods that are also sources of oil (fat) such as certain fish, egg yolk, some vegetable oils, and fatty fish such as salmon and tuna. This presents a problem when people are trying to cut down on the fat content in their diet. They may simultaneously be reducing their vitamin D intake. Disease conditions that reduce fat absorption such as pancreatic enzyme deficiency, Crohn's disease, cystic fibrosis, sprue, and some forms of liver disease can also lead to vitamin D deficiency.

Vitamin D helps the body absorb calcium and plays a role in the development of bones and teeth. A deficiency of vitamin D can lead to soft bones or rickets. It now appears that low vitamin D status is involved in the onset of osteoporosis. Vitamin D also is involved in the regulation of the levels of calcium and phosphorus in the blood.

Recently vitamin D has been implicated in other health / disease states that may go beyond its relationship with calcium and bones. Intervention studies have shown that vitamin D or some of the compounds derived from vitamin D can 1) reduce blood pressure in hypertensives 2) improve blood glucose levels in diabetics 3) improve symptoms of rheumatoid arthritis and multiple sclerosis. There are preliminary studies ttat indicate that low vitamin D intake may lead to increased risk of prostrate, breast, colon and other cancers.

Breast fed babies are particularly sensitive population to Vitamin D deficiency.. Human breast milk is low in vitamin D and this, together with the trend to breast feed longer, has raised concerns. If the vitamin D status of the mother is low, this only magnifies the poor nutrition of the breast feeding baby.

Milk with added vitamin D still appears to be the most common source of this important vitamin. Therefore adolescents and young women of reproductive age should ensure that they are getting enough vitamin D. For many people a daily supplement that contains vitamin D may be the best way to ensure good vitamin D status.

1. Reference
2. Zittermann, A. Vitamin D in preventive medicine: are we ignoring the evidence? British Journal of Nutrition, volume 89, 552-572

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O estresse degenera neurônios. A depressão está associada a uma progressão mais virulenta e rápida das doenças.

O estresse degenera neurônios. A depressão está associada a uma progressão mais virulenta e rápida das doenças..- Activin in the Brain Modulates Anxiety-Related Behavior and Adult Neurogenesis

 Estresse, neurônios, doenças, adulto, Brain, Neurogenesis

Activin in the Brain Modulates Anxiety-Related Behavior and Adult Neurogenesis

Hiroshi Ageta,^1,2 Akiko Murayama,^1,2 Rika Migishima,¹ Satoshi Kida,^2,4 Kunihiro Tsuchida,⁵ Minesuke Yokoyama,^1,6 and Kaoru Inokuchi^1,2,3*

¹Mitsubishi Kagaku Institute of Life Sciences (MITILS), Machida, Tokyo, Japan

²Japan Science and Technology Corporation (JST), CREST, Kawaguchi, Japan

³Graduate School of Environment and Information Sciences, Yokohama National University, Yokohama, Japan

⁴Department of Bioscience, Tokyo University of Agriculture, Setagaya-ku, Tokyo, Japan

⁵Division for Therapies Against Intractable Diseases, Institute for Comprehensive Medical Science, Fujita Health University, Aichi, Japan

⁶Brain Research Institute, Niigata University, Niigata, Japan

Seth G. N. Grant, Editor

Wellcome Trust Sanger Institute, United Kingdom

* E-mail: kaoru@mitils.jp

Conceived and designed the experiments: KI HA. Performed the experiments: HA AM RM MY. Analyzed the data: HA. Contributed reagents/materials/analysis tools: SK KT. Wrote the paper: KI HA. Other: Supervised the entire project: KI.

Received August 24, 2007; Accepted February 22, 2008.

This article has been cited by other articles in PMC.

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Abstract

Activin, a member of the transforming growth factor-β superfamily, is an endocrine hormone that regulates differentiation and proliferation of a wide variety of cells. In the brain, activin protects neurons from ischemic damage. In this study, we demonstrate that activin modulates anxiety-related behavior by analyzing ACM4 and FSM transgenic mice in which activin and follistatin (which antagonizes the activin signal), respectively, were overexpressed in a forebrain-specific manner under the control of the αCaMKII promoter. Behavioral analyses revealed that FSM mice exhibited enhanced anxiety compared to wild-type littermates, while ACM4 mice showed reduced anxiety. Importantly, survival of newly formed neurons in the subgranular zone of adult hippocampus was significantly decreased in FSM mice, which was partially rescued in ACM4/FSM double transgenic mice. Our findings demonstrate that the level of activin in the adult brain bi-directionally influences anxiety-related behavior. These results further suggest that decreases in postnatal neurogenesis caused by activin inhibition affect an anxiety-related behavior in adulthood. Activin and its signaling pathway may represent novel therapeutic targets for anxiety disorder as well as ischemic brain injury.

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Introduction

Anxiety disorder represents one of the most common mental illnesses [1]–[3]. Recently, disturbance in adult hippocampal neurogenesis was proposed to underlie anxiety-like behavior in rodents [4], [5]; however, molecular mechanisms that link hippocampal neurogenesis to anxiety disorder remains poorly understood.

Activin, a member of the transforming growth factor-β superfamily, is an endocrine hormone that regulates differentiation and proliferation of a wide variety of cells [6]. In the brain, activin receptor ActRII is highly expressed in forebrain region [7], [8], and its scaffold protein ARIP/S-SCAM is also localized in synaptic region [9], [10]. Furthermore, activin protects neurons from ischemic damage [11], and its expression is upregulated by neuronal activity [12], [13]. Recently, we showed that activin modulates dendritic spin morphology that is important for synaptic plasticity in the hippocampus [14], [15].

In this study, we generated and analyzed transgenic mice in which activin function in the forebrain is either suppressed or enhanced. We found that the activin activity in the adult forebrain influences locomotor activity, anxiety-related behavior, and hippocampal neurogenesis.

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Results

We explored the role activin plays in anxiety-related behavior using a transgenic mouse model that overexpresses activin or follistatin, an activin-inhibitory protein, in a forebrain-specific manner. Disturbance of activin signal during the developmental stage causes a lethal phenotype in mammals [16], [17]. To achieve postnatal, forebrain-specific expression, the αCaMKII promoter was used to drive expression of a transgene (Fig. 1A) [18], [19]. We microinjected activin and follistatin transgenes into 549 and 1183 fertilized eggs, and obtained 42 and 55 weaned mice, respectively. From these, two lines of activin transgene-integrated mice (designated ACM3 and ACM4) and one line of follistatin transgene-integrated mice (designated FSM) were obtained. Transgene-integrated mice were generated in 1% of microinjected fertilized eggs [20]. This low efficacy may have been caused by unexpected transgene expression in various tissues during the embryonic stage, because the activin signal is important for normal development. In contrast to previously generated activin- or follistatin-transgenic mice [21]–[23], these heterozygous transgenic mice were fertile and bred healthily, and their body weight (data not shown) and muscular strength were normal when compared to their wild-type littermates (Figure S1). Since ACM3 mice showed phenotypes similar to ACM4 mice in behavioral experiments, we hereafter describe the phenotypes of ACM4 and FSM mice.

Figure 1 Generation of transgenic mice and expression analysis of the transgene.

In situ hybridization analyses of brain sections revealed that transgene expression was restricted to the forebrain such as the hippocampus and neocortex in the adult brain (Fig. 1B). ELISA analyses also showed forebrain-specific expression of activin and follistatin in ACM4 and FSM adult mice, respectively (Fig. 1C). Low level of endogenous activin was detected in the hippocampus and neocortex in wild-type mice. Follistatin level in FSM was enough to antagonize this level of activin activity [24]. Follistatin was not detected in the infant hippocampus of FSM mice (Fig. 1C). RT-PCR revealed that follistatin- and activin-transgene were not expressed in peripheral tissues including, heart, lung, spleen, liver and kidney (Figure S2). Nissel staining showed no apparent structural abnormality in the hippocampus of each transgenic mice (Figure S3).

Open field tests were performed on transgenic mice to investigate locomotor activity (Fig. 2). FSM mice showed a decrease in time spent in locomotion and rearing when compared with wild-type littermates. In contrast, ACM4 mice showed a significant increase in rearing time. There was no genotype effect in the walking speed (Fig. 2B) and the total pathlength (Fig. 2C), indicating that walking ability of FSM and ACM4 mice was normal. These results indicate that the level of functional activin in the brain is related to general locomotor activity in a novel environment.

Figure 2 Activin protein levels in the brain influence locomotor activity.

In open field tests, the amount of time spent in the center of the field is strongly correlated with an animal's level of anxiety, a characteristic called risk-taking behavior [25], [26]. FSM mice showed decreased performance in risk-taking behavior (Fig. 2D), while ACM4 mice showed increased performance. To further assess these differences, a light and dark choice test and elevated plus-maze test were conducted. In the light and dark test, ACM4 mice accessed the lighted compartment significantly more often than wild-type littermates (Fig. 3A), however, FSM mice spent significantly more time in the dark compartment as compared to wild-type littermates. In the elevated plus-maze test, ACM4 mice spent significantly more time in the open arms of the testing apparatus than did wild-type and FSM mice (Fig. 3B). FSM mice showed no significant change in phenotype for this test.

Figure 3 Activin protein levels in the brain modulate anxiety-related behavior.

We next designed and performed an original behavioral test to measure anxiety levels (Fig. 3C), based on the observation that mice generally prefer novel objects encountered in a familiar place [27]. In this test, mice were placed in a closed box on the first day to become familiar with the box. On the second day mice were placed in the same box to which a cylinder with two entrances (novel area) had been added. FSM mice spent significantly less time accessing the novel area as compared to wild-type mice, while the total distance they traveled during the test was normal. This suggests that higher anxiety in FSM mice resulted in lower access to the novel area. Taken together, the level of functional activin in the brain modulates anxiety-related behavior. Finally, no depressive behavior was observed in FSM mice in the forced swimming test (Figure S4).

Adult neurogenesis is the production of new neurons in areas of the adult brain including the subventricular zone (SVZ) and subgranular zone (SGZ) of the hippocampus [28]. This formation of new neurons plays a number of physiological roles including damaged neuron replacement[29], [30], memory formation [31], [32] and response to stress [33]. Moreover, some reports have recently shown that neurogenesis is involved in depression [34], [35].

We therefore examined adult neurogenesis in hippocampal SGZ of FSM and ACM4 mice (Fig. 4) using 5-bromodeoxyuridine (BrdU)-labeling experiments. Transgenic mice were injected with BrdU (75 mg/kg body weight) three times per day for three consecutive days. Mice were sacrificed either 24 h or 4 weeks after the final injection day. BrdU is incorporated into genomic DNA by cells at S-phase, therefore, by staining with a neuronal marker (NeuN) and an anti-BrdU antibody, newly generated neurons were easily detected. A significant difference between FSM and ACM4 mice was observed in the number of SGZ BrdU-positive cells after 24 h (Fig. 4A, B). No significant difference, however, was observed between transgenic mice and wild-type littermates, indicating that the number of neuronal progenitor cells and the rate of BrdU incorporation into progenitor cells in transgenic mice were essentially normal. At the 4-week stage, however, the number of BrdU- and NeuN-double positive cells in FSM mice was markedly decreased (Fig. 4C). This reduction was partially rescued by crossing with ACM4 (Fig. 4D). These results indicated that the level of activin in the brain is crucial for the maturation and maintenance of newly generated neurons.

Figure 4 Activin signal is essential for survival of newly generated neurons.

The decrease in BrdU- and NeuN-double positive cells at the 4-week stage may be attributed to a decrease in the survival rate of newly formed neurons or a decrease in the rate for neuronal differentiation of new cells. Therefore, the change in the number of BrdU- and NeuN-double positive cells following BrdU injections (Fig. 4E) was monitored at various developmental stages. The number of BrdU- and NeuN-double positive cells was normal at the 1-week stage in FSM mice, suggesting a normal differentiation rate. However, a marked decrease was observed in the number of BrdU- and NeuN-double positive cells at 2- and 3-week stages compared with wild-type littermates. Therefore, in FSM mice, the survival of newly generated neurons is significantly decreased. This indicates that activin signal is essential for the maintenance of newly generated neurons. Activin overexpression did not enhance the number of BrdU- and NeuN-double positive cells at 4 weeks, suggesting that activin overexpression is not sufficient for enhancement of adult neurogenesis (Fig. 4C).

Taken together, FSM and ACM4 mice showed opposite phenotypes in behavior. Furthermore, decrease in neurogenesis in FSM mice was partially rescued in FSM/ACM4 double transgenic mice. These results strongly suggest that the observed effects of overexpression, either follistatin or activin, are not positional transgene effects such as insertional mutations.

 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2270335/