The importance of the nuclear receptor nurr1 for the appropriate development of mesencephalic dopaminesynthesizing neurons has been clearly demonstrated through the targeted disruption of the nurr1 gene. The persistence of nurr1 expression in adult tissue suggests a possible role for this transcription factor in the maintenance, as well as development, of the dopaminergic phenotype. To address this issue, we analyzed the effects of nurr1 on the transcriptional expression of the human dopamine transporter gene (hDAT), one of the most speci®c phenotypic markers for dopaminergic neurons. Nurr1 enhanced the transcriptional activity of hDAT gene constructs transiently transfected into a newly described cell line (SN4741) that expresses a dopaminergic phenotype, whereas other members of the NGFI-B subfamily of nuclear receptors had lesser or no effects. Nurr1 activation of hDAT was not dependent upon heterodimerization with the retinoid X receptor. Unexpectedly, functional analysis of a series of gene constructs revealed that a region of the hDAT 5 H -¯anking sequence devoid of NGFI-B response element (NBRE)-like sites mediated nurr1 activation. Additional experiments using a nurr1 mutant construct suggest that nurr1 activates hDAT transcription via a novel NBRE-independent mechanism.

Risk-taking behaviors involve increased motor activity and reduced anxiety in humans. Total sleep deprivation (SD) in animals produces a similar change in motor and fear behaviors. Investigators studied region-specific brain levels of glutamate in rats after TSD, an animal model of risk-taking behavior. We investigated the effects of sleep deprivation on these behaviors and associated levels of brain glutamate. Compared to the controls, the sleep-deprived rats spent a significantly greater percentage of time in the open arms of the elevated plus maze (EPM), demonstrating reduced fear-like and increased risk-taking behaviors. Additionally, sleep deprivation was associated with a significant increase in glutamate levels in the hippocampus and thalamus. An inverse relationship between glutamate in the medial prefrontal cortex and risk taking in the EPM and a positive association between the ratio of glutamate in the hippocampus to medial prefrontal cortex and risk taking was revealed. The role of sleep deprivation-induced changes in brain glutamate and its relationship to anxiety, fear, and posttraumatic stress disorder (PTSD) is discussed.

Iron is a critical component of the CNS that must be tightly regulated; too little iron can result in energy insufficiency and too much iron can result in oxidative stress. The intracellular iron storage protein ferritin is central to the regulation of iron. In this study, we determined the neurochemical profile of brains of animals deficient in heavy-chain ferritin (H-ferritin) using high-resolution magic angle spin proton magnetic resonance spectroscopy (HR-MAS (1)H MRS). Spectra of 2 mm-thick coronal tissue punches ( approximately 4 mg) were obtained using a CPMG pulse sequence on Bruker Avance 500 and quantified (nmol/mg tissue) using customized LCModel software (16 metabolites). In H-ferritin deficient mice, we found significant increases in striatal glutamate, hippocampal choline, and N-acetyl-aspartyl-glutamate in both the cortex and the hippocampus (t-test, p < 0.05). Neurochemical profiling with principal component analysis (PCA) revealed increased glutamate in the hippocampus, striatum, and ventral tegmental area (VTA) in H-ferritin deficient animals as compared to wild-type. While lactate was increased in the VTA of deficient animals, it was decreased in the striatum. Also, GABA was increased in both cortical and striatal regions of deficient mice. These changes reveal the importance of proper iron management for maintaining neurochemical balance and provide new evidence for region specific differences in neurochemical profiles as a result of compromised ability of neurons to store iron while overall iron status is normal. Because H-ferritin is predominantly expressed in neurons, the neurochemical profile is suggestive of neuronal iron deficiency and may have relevance to the functional consequences associated with brain iron deficiency.