Defining vitamin D receptor expression in the brain using a novel VDR^Cre mouse

Abstract

Vitamin D action has been linked to several diseases regulated by the brain including obesity, diabetes, autism, and Parkinson's. However, the location of the vitamin D receptor (VDR) in the brain is not clear due to conflicting reports. We found that two antibodies previously published as specific in peripheral tissues are not specific in the brain. We thus created a new knockin mouse with cre recombinase expression under the control of the endogenous VDR promoter (VDRCre). We demonstrated that the cre activity in the VDRCre mouse brain (as reported by a cre‐dependent tdTomato expression) is highly overlapping with endogenous VDR mRNAs. These VDR‐expressing cells were enriched in multiple brain regions including the cortex, amygdala, caudate putamen, and hypothalamus among others. In the hypothalamus, VDR partially colocalized with vasopressin, oxytocin, estrogen receptor‐α, and β‐endorphin to various degrees. We further functionally validated our model by demonstrating that the endogenous VDR agonist 1,25‐dihydroxyvitamin D activated all tested tdTomato+ neurons in the paraventricular hypothalamus but had no effect on neurons without tdTomato fluorescence. Thus, we have generated a new mouse tool that allows us to visualize VDR‐expressing cells and to characterize their functions.

Attenuation of morphine conditioned place preference and reinstatement by vitamin D

“…Furthermore, there is interesting co-localization of VDR with the brain regions engaged with morphine reward circuits, such as the hippocampus, amygdala, striatum, bed nucleus of stria terminalis, cortex and hypothalamus (Kim et al , 2016; Liu et al , 2021), indicating the possibility of modulation of morphine reward circuitry by vitamin D.…”

The Synaptic and Circuit Functions of Vitamin D in Neurodevelopment Disorders

“…The presence of vitamin D and its nuclear receptors (VDRs), as well as its metabolism enzymes (CYP27A1, CYP27B1 and CYP24A1) in the brain has been systematically reviewed elsewhere. [14][15][16] All of the VDRs, CYP27B1 and CYP24A1 have been identified in neurons and glia cells throughout life, raising the notion that vitamin D might be involved in the fundamental functions of mammalian brains. 15,17 These functions, such as learning, memory, cognition, and behavioral processes, all rely on the connection of neurons.…”

‘Unpredictable chronic mild stress does not exacerbate memory impairment or altered neuronal and glial plasticity in the hippocampus of middle‐aged vitamin D deficient mice’

“…Underlying mechanisms by which vitamin D deficiency could lead to cognitive decline and/or depression are not yet fully elucidated. The presence of vitamin D receptor (VDR) and metabolizing enzymes in the brain suggests its local autocrine and paracrine properties (Eyles et al, 2005; Landel et al, 2018; Liu et al, 2021). VDR is highly expressed in limbic structures, such as the hippocampus and amygdala, as well as in the cerebellum, cortex, caudate putamen, and hypothalamus (Liu et al, 2021; Prüfer et al, 1999; Stumpf et al, 1982; Taniura et al, 2006; Wang et al, 2012), which participate in cognition, motivational behaviour and regulation of stress.…”

“…The presence of vitamin D receptor (VDR) and metabolizing enzymes in the brain suggests its local autocrine and paracrine properties (Eyles et al, 2005; Landel et al, 2018; Liu et al, 2021). VDR is highly expressed in limbic structures, such as the hippocampus and amygdala, as well as in the cerebellum, cortex, caudate putamen, and hypothalamus (Liu et al, 2021; Prüfer et al, 1999; Stumpf et al, 1982; Taniura et al, 2006; Wang et al, 2012), which participate in cognition, motivational behaviour and regulation of stress. Vitamin D is involved in neuronal differentiation and trophic support (Bayat et al, 2021; Mayne & Burne, 2019; Naveilhan et al, 1996; Neveu et al, 1994; Orme et al, 2013) as well as in calcium homeostasis (Gezen‐Ak & Dursun, 2019) and prevention of oxidative damage (Garcion et al, 1997; Mokhtari‐Zaer et al, 2020).…”