**7.1 VDR in the brain**

Vitamin D receptors are present on the nervous system tissues and cells especially dopaminergic nerves. In the momentary phase of cerebral development, vitamin D may act like a neurosteroid hormone in the areas of neurotransmission, neuroprotection, and neuroimmunomodulation. Vitamin D receptors belong to a hybrid class of nuclear receptor superfamily, which gets activated by vitamin D, a neurosteroid hormone that plays its major role in the nervous system by following mechanisms of differentiating, regulating Ca2+ ions, homeostasis, modulation of neurotrophins, and release and activation of key brain hormones and enzymes for neurotransmitter metabolism. VDR is a large molecular weight protein molecule weighing 50–60 kilodaltons, which consists of several functional binding domains, specifically and typically for all steroid hormones responsible for ligand binding, DNA binding, heterodimerization, nuclear localization, and ligand activation of transcriptional factors [13].

VDR detection in the brain tissue has been studied by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry to understand the localization of nuclear ligand binding sites for the transcription of phenotypic characters [14].

**113**

*Association of Vitamin D Deficiency and Mood Disorders: A Systematic Review*

Two important points of consideration for the production of the active form of vitamin D are 1,25(OH)2 vitamin D3, a vitamin D receptor, and an enzyme 1 α-hydroxylase, which are found in the adult human brain. Identification of both the receptor and the enzyme were done in neuronal and glial cells in a regional and layer-specific pattern. The equivalent distribution of VDR regions and

1α-hydroxylase enzyme regions together with their frequent discrete distribution is

Expression of VDR has been documented in tissues, including the brain, heart, skeletal muscle, breast, prostate, colon, activated macrophages, skin, and the areas prone to tumor expression with any devised mutation. The age factor is known to dominantly decrease the VDR expression. Many in vitro studies with human and animal cells have observed the expression of not only VDRs but also an enzyme, 1α-hydroxylase, which is expressed in most of the body tissues and cells, specifically in the kidneys. Therefore, it appears that these cells locally produce the active form of vitamin D by a regulated mechanism, in a paracrine fashion, to be used in various cellular and physiological functions. This structures the strong biologic basis for the association between serum

VDR gene mutations have been characterized by altered behavior of VDR null mutant mice. A study revealed anxiety-like behavior with decreased exploration when the VDR mutant mice were subjected to anxiety evaluation [16]. Another study focusing on the investigation of anxiety parameters in VDR mutant mice demonstrated unaltered spatial memory, olfaction, gustation, and hedonic responses [17]. VDR gene mutation is considered to influence the working of vitamin D hormone, which is essential for the growth and differentiation of a variety of organs, including the complete central nervous system. Many studies have suggested the crucial role of vitamin D in the brain, inducing many CNS genes. Inhibition of brain neurotransmission can be seen by VDR gene mutation causing modulation of neuroprotection, neurotrophins release, and activity of key neurotransmitter

*7.1.4 Regulation of normal brain neurotransmitters by normal VDR gene*

ing to temperature, touch, pain, osmolarity, taste, and other stimuli [17].

The active form of vitamin D, i.e., calcitriol has a fast and strong ligand binding to their respective receptors located in the bone, brain, and breast tissues, as well as in immune cells [6]. The upregulation of transient receptor potential (TRP) vanilloid calcium-selective cation channels, such as TRPV5 and TRPV6, is done by positive induction of vitamin D. Vitamin D regulated channels may express the role of the hormone by potential modulation of sensory pathways representing several cellular sensors respond-

The immunohistochemical study depicted the distribution of the VDR in multiple brain regions inclusive of neuronal and glial cells and other regions of the substantia nigra in the normal functioning human brain. Further, it also revealed

*DOI: http://dx.doi.org/10.5772/intechopen.90617*

found in layers and subregions of brain tissue [15].

vitamin D concentrations and extra-skeletal physiology [15].

*7.1.1 VDR gene location*

*7.1.2 Expression of VDR*

*7.1.3 VDR gene mutations*

metabolism enzymes [16].

*7.1.5 VDR immunoreactivity*

*Association of Vitamin D Deficiency and Mood Disorders: A Systematic Review DOI: http://dx.doi.org/10.5772/intechopen.90617*

#### *7.1.1 VDR gene location*

*Vitamin D Deficiency*

from 36.7 to 74.0% [3].

**7. Vitamin D receptor**

transcriptional factors [13].

**7.1 VDR in the brain**

status which measures both vitamin D-binding protein (DBP)-bound and free 25(OH) vitamin D. In the light of widespread variation in measured results and divergent results in response to vitamin D supplementation, there is a need for a distinct method for estimation of vitamin D levels. Further, free 25(OH) vitamin D levels may vary according to genotype and single nucleotide polymorphisms (SNPs)

Vitamin D receptors are traced throughout the brain explaining the role of vitamin D in psychosomatic disorders, and it was found to have an equivocal call

Vitamin D insufficiency/deficiency is a worldwide problem, affecting all ages and races. Optimal 25(OH) vitamin D concentrations for skeletal health are >30 ng/ml. Serum 25(OH) vitamin D concentrations are generally lower in blacks than in whites and people who avoid exposing them to the sun. The increased use of sunscreens is hypothesized to increase the prevalence of vitamin D deficiency. Older adults, as a result of hyperparathyroidism related to renal insufficiency, tend to require more vitamin D to achieve adequate levels of 25(OH) vitamin D. As a result of the change in the definition of adequate concentrations, the prevalence of vitamin D deficiency is higher than previously thought. The prevalence of vitamin D deficiency among older men and women living in the United States and Europe ranges from 40–100%. The National Health and Nutrition Examination Survey from 2000 to 2004 found that ~25% of men >50 years of age and 30–35% of women >50 years of age had 25(OH) vitamin D concentrations <0.001. Two studies performed in Colorado and Georgia found that despite reported consumption of more than the required daily intake of vitamin D (400–600 IU/d), the prevalence of vitamin D insufficiency (defined as <32 ng/mL and < 20 ng/ml, respectively) among community-dwelling older adults (mean age, 77.8 and 77.0 years, respectively) ranged

Vitamin D receptors are present on the nervous system tissues and cells especially dopaminergic nerves. In the momentary phase of cerebral development, vitamin D may act like a neurosteroid hormone in the areas of neurotransmission, neuroprotection, and neuroimmunomodulation. Vitamin D receptors belong to a hybrid class of nuclear receptor superfamily, which gets activated by vitamin D, a neurosteroid hormone that plays its major role in the nervous system by following mechanisms of differentiating, regulating Ca2+ ions, homeostasis, modulation of neurotrophins, and release and activation of key brain hormones and enzymes for neurotransmitter metabolism. VDR is a large molecular weight protein molecule weighing 50–60 kilodaltons, which consists of several functional binding domains, specifically and typically for all steroid hormones responsible for ligand binding, DNA binding, heterodimerization, nuclear localization, and ligand activation of

VDR detection in the brain tissue has been studied by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry to understand the localization of nuclear ligand binding sites for the transcription of phenotypic characters [14].

in the DBP gene for which the assays are still not well established [5].

for vitamin D deficiency and depression going hand in hand [12].

**6. Prevalence of vitamin D deficiency**

**112**

Two important points of consideration for the production of the active form of vitamin D are 1,25(OH)2 vitamin D3, a vitamin D receptor, and an enzyme 1 α-hydroxylase, which are found in the adult human brain. Identification of both the receptor and the enzyme were done in neuronal and glial cells in a regional and layer-specific pattern. The equivalent distribution of VDR regions and 1α-hydroxylase enzyme regions together with their frequent discrete distribution is found in layers and subregions of brain tissue [15].

#### *7.1.2 Expression of VDR*

Expression of VDR has been documented in tissues, including the brain, heart, skeletal muscle, breast, prostate, colon, activated macrophages, skin, and the areas prone to tumor expression with any devised mutation. The age factor is known to dominantly decrease the VDR expression. Many in vitro studies with human and animal cells have observed the expression of not only VDRs but also an enzyme, 1α-hydroxylase, which is expressed in most of the body tissues and cells, specifically in the kidneys. Therefore, it appears that these cells locally produce the active form of vitamin D by a regulated mechanism, in a paracrine fashion, to be used in various cellular and physiological functions. This structures the strong biologic basis for the association between serum vitamin D concentrations and extra-skeletal physiology [15].

#### *7.1.3 VDR gene mutations*

VDR gene mutations have been characterized by altered behavior of VDR null mutant mice. A study revealed anxiety-like behavior with decreased exploration when the VDR mutant mice were subjected to anxiety evaluation [16]. Another study focusing on the investigation of anxiety parameters in VDR mutant mice demonstrated unaltered spatial memory, olfaction, gustation, and hedonic responses [17].

VDR gene mutation is considered to influence the working of vitamin D hormone, which is essential for the growth and differentiation of a variety of organs, including the complete central nervous system. Many studies have suggested the crucial role of vitamin D in the brain, inducing many CNS genes. Inhibition of brain neurotransmission can be seen by VDR gene mutation causing modulation of neuroprotection, neurotrophins release, and activity of key neurotransmitter metabolism enzymes [16].

#### *7.1.4 Regulation of normal brain neurotransmitters by normal VDR gene*

The active form of vitamin D, i.e., calcitriol has a fast and strong ligand binding to their respective receptors located in the bone, brain, and breast tissues, as well as in immune cells [6]. The upregulation of transient receptor potential (TRP) vanilloid calcium-selective cation channels, such as TRPV5 and TRPV6, is done by positive induction of vitamin D. Vitamin D regulated channels may express the role of the hormone by potential modulation of sensory pathways representing several cellular sensors responding to temperature, touch, pain, osmolarity, taste, and other stimuli [17].

#### *7.1.5 VDR immunoreactivity*

The immunohistochemical study depicted the distribution of the VDR in multiple brain regions inclusive of neuronal and glial cells and other regions of the substantia nigra in the normal functioning human brain. Further, it also revealed

the presence of the VDR and 1α- hydroxylase in the human brain and confirmed the cell expression for either the receptor or the activating enzyme in neuronal or glial origin [14, 15].
