Deborah R. Morris

Zinc and Neurogenesis: Making New Neurons from Development to Adulthood

Stem cell proliferation, neuronal differentiation, cell survival, and migration in the central nervous system are all important steps in the normal process of neurogenesis. These mechanisms are highly active during gestational and early neonatal brain development. Additionally, in select regions of the brain, stem cells give rise to new neurons throughout the human lifespan. Recent work has revealed key roles for the essential trace element zinc in the control of both developmental and adult neurogenesis. Given the prevalence of zinc deficiency, these findings have implications for brain development, cognition, and the regulation of mood.

Zinc supplementation provides behavioral resiliency in a rat model of traumatic brain injury.

Depression, anxiety, and impairments in learning and memory are all associated with traumatic brain injury (TBI). Because of the strong link between zinc deficiency, depression, and anxiety, in both humans and rodent models, we hypothesized that dietary zinc supplementation prior to injury could provide behavioral resiliency to lessen the severity of these outcomes after TBI. Rats were fed a marginal zinc deficient (5 ppm), zinc adequate (30 ppm), or zinc supplemented (180 ppm) diet for 4 weeks followed by a moderately-severe TBI using the well-established model of controlled cortical impact (CCI). Following CCI, rats displayed depression-like behaviors as measured by the 2-bottle saccharin preference test for anhedonia. Injury also resulted in evidence of stress and impairments in Morris water maze (MWM) performance compared to sham-injured controls. While moderate zinc deficiency did not worsen outcomes following TBI, rats that were fed the zinc supplemented diet for 4 weeks showed significantly attenuated increases in adrenal weight (p<0.05) as well as reduced depression-like behaviors (p<0.001). Supplementation prior to injury improved resilience such that there was not only significant improvements in cognitive behavior compared to injured rats fed an adequate diet (p<0.01), there were no significant differences between supplemented and sham-operated rats in MWM performance at any point in the 10-day trial. These data suggest a role for supplemental zinc in preventing cognitive and behavioral deficits associated with TBI.

Use of Zinc as a Treatment for Traumatic Brain Injury in the Rat: Effects on Cognitive and Behavioral Outcomes

Background. While treatments for the behavioral deficits associated with traumatic brain injury (TBI) are currently limited, animal models suggest that zinc supplementation may increase resilience to TBI. Objective. This work tests the hypothesis that zinc supplementation after TBI can be used as treatment to improve behavioral outcomes such as anxiety, depression, and learning and memory. Methods. TBI was induced by controlled cortical impact to the medial frontal cortex. After TBI, rats were fed either a zinc adequate (ZA, 30 ppm) or zinc supplemented (ZS, 180 ppm) diet. Additional rats in each dietary group (ZA or ZS) were given a single intraperitoneal (ip) injection of zinc (30 mg/kg) 1 hour following injury. Results. Brain injury resulted in significant increases in anxiety-like and depression-like behaviors as well as impairments in learning and memory. None of the zinc treatments (dietary or ip zinc) improved TBI-induced anxiety. The 2-bottle saccharin preference test for anhedonia revealed that dietary ZS also did not improve depression-like behaviors. However, dietary ZS combined with an early ip zinc injection significantly reduced anhedonia (P < .001). Dietary supplementation after injury, but not zinc injection, significantly improved (P < .05) cognitive behavior as measured by the time spent finding the hidden platform in the Morris water maze test compared with injured rats fed a ZA diet. Conclusions. These data suggest that zinc supplementation may be an effective treatment option for improving behavioral deficits such as cognitive impairment and depression following TBI.

Ion channels and zinc: mechanisms of neurotoxicity and neurodegeneration.

Ionotropic glutamate receptors, such as NMDA, AMPA and kainate receptors, are ligand-gated ion channels that mediate much of the excitatory neurotransmission in the brain. Not only do these receptors bind glutamate, but they are also regulated by and facilitate the postsynaptic uptake of the trace metal zinc. This paper discusses the role of the excitotoxic influx and accumulation of zinc, the mechanisms responsible for its cytotoxicity, and a number of disorders of the central nervous system that have been linked to these neuronal ion channels and zinc toxicity including ischemic brain injury, traumatic brain injury, and epilepsy.

Improving treatments and outcomes: an emerging role for zinc in traumatic brain injury.

Traumatic brain injury is associated with a wide variety of behavioral deficits, including memory loss, depression, and anxiety. While treatments for these outcomes are currently limited, human clinical data suggest that supplemental zinc can be used during recovery to improve cognitive and behavioral deficits associated with brain injury. Additionally, pre-clinical models suggest that zinc may increase resilience to traumatic brain injury, making it potentially useful in populations at risk for injury.

Effect of zinc supplementation on neuronal precursor proliferation in the rat hippocampus after traumatic brain injury

There is great deal of debate about the possible role of adult-born hippocampal cells in the prevention of depression and related mood disorders. We first showed that zinc supplementation prevents the development of the depression-like behavior anhedonia associated with an animal model of traumatic brain injury (TBI). This work then examined the effect of zinc supplementation on the proliferation of new cells in the hippocampus that have the potential to participate in neurogenesis. Rats were fed a zinc adequate (ZA, 30ppm) or zinc supplemented (ZS, 180ppm) diet for 4wk followed by TBI using controlled cortical impact. Stereological counts of EdU-positive cells showed that TBI doubled the density of proliferating cells 24h post-injury (p<0.05), and supplemental zinc significantly increased this by an additional 2-fold (p<0.0001). While the survival of these proliferating cells decreased at the same rate in ZA and in ZS rats after injury, the total density of newly born cells was approximately 60% higher in supplemented rats 1wk after TBI. Furthermore, chronic zinc supplementation resulted in significant increases in the density of new doublecortin-positive neurons one week post-TBI that were maintained for 4wk after injury (p<0.01). While the effect of zinc supplementation on neuronal precursor cells in the hippocampus was robust, use of targeted irradiation to eliminate these cells after zinc supplementation and TBI revealed that these cells are not the sole mechanism through which zinc acts to prevent depression associated with brain injury, and suggest that other zinc dependent mechanisms are needed for the anti-depressant effect of zinc in this model of TBI.

Zinc in traumatic brain injury: from neuroprotection to neurotoxicity.

Purpose of reviewIn light of the recent recognition that even mild forms of traumatic brain injury (TBI) can lead to long-term cognitive and behavioral deficits, this review examines recent data on the neuroprotective and neurotoxic roles of zinc after brain injury. Recent findingsData show that treatment using dietary and parenteral zinc supplementation can reduce TBI-associated depression and improve cognitive function, specifically spatial learning and memory. However, excessive release of free zinc, particularly in the hippocampus associated with acute injury, can lead to increases in protein ubiquitination and neuronal death. SummaryThis work shows the need for future research to clarify the potentially contradictory roles of zinc in the hippocampus and define the clinical use of zinc as a treatment following brain injury in humans. This is particularly important given the finding that zinc may reduce TBI-associated depression, a common and difficult outcome to treat in all forms of TBI.

Zinc regulation of transcriptional activity during retinoic acid-induced neuronal differentiation ☆

Zinc deficiency impairs the proliferation and differentiation of stem cells in the central nervous system that participate in neurogenesis. To examine the molecular mechanisms responsible for the role of this essential nutrient in neuronal precursor cells and neuronal differentiation, we identified zinc-dependent changes in the DNA-binding activity of zinc finger proteins and other transcription factors in proliferating human Ntera-2 neuronal precursor cells undergoing retinoic acid-stimulated differentiation into a neuronal phenotype. We found that zinc deficiency altered binding activity of 28 transcription factors including retinoid X receptor (RXR) known to participate in neuronal differentiation. Alterations in zinc finger transcription factor activity were not simply the result of removal of zinc from these proteins during zinc deficiency, as the activity of other zinc-binding transcription factors such as the glucocorticoid receptor was increased by as much as twofold over zinc-adequate conditions, and nonzinc-binding transcription factors such as nuclear factor-1 and heat shock transcription factor-1 were increased by as much as fourfold over control. Western analysis did not detect significant decreases in total RXR protein abundance in neuronal precursors, suggesting that the decrease in DNA-binding activity was not simply the result of a reduction in RXR levels in neuronal precursor cells. Rather, use of a reporter gene construct containing retinoic acid response elements upstream from a luciferase coding sequence revealed that zinc deficiency results in decreased transcriptional activity of RXR and reductions in retinoic acid-mediated gene transcription during neuronal differentiation. These results show that zinc deficiency has implications for both developmental and adult neurogenesis.