Elise C. Cope

Role of zinc in the development and treatment of mood disorders.

Purpose of reviewThe present review is a critical examination of the most recent published work on the role of zinc in the development and treatment of mood disorders. Recent findingsClinical studies and experimental work using animal models have both revealed a link between zinc status and neuropsychological disorders such as depression and anxiety. Not only has zinc deficiency been shown to induce depression-like and anxiety-like behaviors, supplementation has been used as a treatment for major depression. Zinc administration improves the efficacy of antidepressant drugs in depressed patients and may have a particular role to play in treatment-resistant patients. Recent investigations into the molecular mechanisms responsible for these observations suggest a role for zinc in the regulation of neurotransmitter systems, antioxidant mechanisms, neurotrophic factors, and neuronal precursor cells. SummaryThe data reviewed here not only indicate a role for zinc deficiency in the development of mood disorders, but also show that zinc may also be important in their treatment. Given the prevalence of zinc deficiency in human populations, this work has the potential to influence strategies to prevent and treat these disorders.

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.

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.

Immature neurons and radial glia, but not astrocytes or microglia, are altered in adult Cntnap2 and Shank3 mice, models of autism

Abstract Autism spectrum disorder (ASD) is often associated with cognitive deficits and excessive anxiety. Neuroimaging studies have shown atypical structure and neural connectivity in the hippocampus, medial prefrontal cortex (mPFC), and striatum, regions associated with cognitive function and anxiety regulation. Adult hippocampal neurogenesis is involved in many behaviors that are disrupted in ASD, including cognition, anxiety, and social behaviors. Additionally, glial cells, such as astrocytes and microglia, are important for modulating neural connectivity during development, and glial dysfunction has been hypothesized to be a key contributor to the development of ASD. Cells with astroglial characteristics are known to serve as progenitor cells in the developing and adult brain. Here, we examined adult neurogenesis in the hippocampus, as well as astroglia and microglia in the hippocampus, mPFC, and striatum of two models that display autism-like phenotypes, Cntnap2−/− and Shank3+/ΔC transgenic mice. We found a substantial decrease in the number of immature neurons and radial glial progenitor cells in the ventral hippocampus of both transgenic models compared with wild-type controls. No consistent differences were detected in the number or size of astrocytes or microglia in any other brain region examined. Future work is needed to explore the functional contribution of adult neurogenesis to autism-related behaviors as well as to temporally characterize glial plasticity as it is associated with ASD.

New Evidence Linking Obesity and Food Addiction

Obesity rates have skyrocketed over the past few decades. In the United States, approximately 35% of adults are now considered obese, with more than 60% categorized as overweight (1). The health consequences of obesity are substantial. Obesity increases the risk of developing several debilitating conditions, such as diabetes, heart disease, stroke, and mental illness. Because the global obesity epidemic is generally believed to be caused by excessive caloric intake, there has been increasing interest in understanding the neurobiological mechanisms contributing to overeating, defined as continued eating in the absence of metabolic necessity leading to weight gain. The decision to eat involves many body and brain systems. Homeostatic mechanisms in the hypothalamus coordinate food intake with energy expenditure to keep the individual supplied with the necessary nutrients while maintaining a healthy body weight. Hypothalamic nuclei sense and respond to macronutrient and hormonal signals from the gut and adipose tissue to assess satiety and hunger. Evidence is accumulating that brain reward circuits also regulate food consumption. Highly palatable foods, such as processed foods that are rich in sugar and fat, are associated with increased eating. Presumably because of their strong hedonic qualities, these foods can override internal homeostatic mechanisms and lead to overeating and fat deposition. Weight-loss efforts can lead to alterations in metabolism, which also uncouple hunger signals from metabolic need, and lead to further weight gain once a typical diet is resumed. The extreme difficulty that so many obese individuals face in losing weight, and then maintaining a healthy weight, has reinforced the common belief that obese individuals are addicted to food. The notion that excessive food intake might be a form of addiction has a long history in both science and the world at large. The phrase “food addiction” was first used in a scientific publication in the 1950s (2). Since then, human studies have provided some evidence for shared neurobiological features between obesity and drug addiction. Neuroimaging studies have demonstrated that obese individuals have similar overactivation in brain reward circuits as those observed in people with drug addiction (3). Rodent studies have contributed behavioral evidence to suggest that food addiction occurs (4). For example, rats given intermittent access to sugary substances exhibit increased bingelike behaviors, symptoms of withdrawal, and signs of cravings, and have sensitization to drugs of abuse, such as alcohol. Sugar also results in neurochemical brain changes similar to those of drug addiction, such as alterations in dopaminergic and opioid signaling. Perhaps in parallel with the scientific evidence, the possibility

Microglia play an active role in obesity-associated cognitive decline

Obesity affects >600 million people worldwide, a staggering number that appears to be on the rise. One of the lesser known consequences of obesity is its deleterious effects on cognition, which have been well documented across many cognitive domains and age groups. To investigate the cellular mechanisms that underlie obesity-associated cognitive decline, we used diet-induced obesity in male mice and found memory impairments along with reductions in dendritic spines, sites of excitatory synapses, increases in the activation of microglia, the brains resident immune cells, and increases in synaptic profiles within microglia, in the hippocampus, a brain region linked to cognition. We found that partial knockdown of the receptor for fractalkine, a chemokine that can serve as a “find me” cue for microglia, prevented microglial activation and cognitive decline induced by obesity. Furthermore, we found that pharmacological inhibition of microglial activation in obese mice was associated with prevention of both dendritic spine loss and cognitive degradation. Finally, we observed that pharmacological blockade of microglial phagocytosis lessened obesity-associated cognitive decline. These findings suggest that microglia play an active role in obesity-associated cognitive decline by phagocytosis of synapses that are important for optimal function. SIGNIFICANCE STATEMENT Obesity in humans correlates with reduced cognitive function. To investigate the cellular mechanisms underlying this, we used diet-induced obesity in mice and found impaired performance on cognitive tests of hippocampal function. These deficits were accompanied by reduced numbers of dendritic spines, increased microglial activation, and increased synaptic profiles within microglia. Inhibition of microglial activation by transgenic and pharmacological methods prevented cognitive decline and dendritic spine loss in obese mice. Moreover, pharmacological inhibition of the phagocytic activity of microglia was also sufficient to prevent cognitive degradation. This work suggests that microglia may be responsible for obesity-associated cognitive decline and dendritic spine loss.

Cytokines Make an Indelible Impression on Neural Stem Cells

Infections during pregnancy have been associated with increased risks of neuropsychiatric disorders in offspring, although the underlying mechanisms have not been determined. Gallagher et al. (2013) show that maternal exposure to the infection-induced inflammatory cytokine IL-6 produces lasting effects on forebrain stem cell pools of offspring during embryogenesis and throughout life.

The effects of living in an outdoor enclosure on hippocampal plasticity and anxiety-like behavior in response to nematode infection

The hippocampus of rodents undergoes structural remodeling throughout adulthood, including the addition of new neurons. Adult neurogenesis is sensitive to environmental enrichment and stress. Microglia, the brains resident immune cells, are involved in adult neurogenesis by engulfing dying new neurons. While previous studies using laboratory environmental enrichment have investigated alterations in brain structure and function, they do not provide an adequate reflection of living in the wild, in which stress and environmental instability are common. Here, we compared mice living in standard laboratory settings to mice living in outdoor enclosures to assess the complex interactions among environment, gut infection, and hippocampal plasticity. We infected mice with parasitic worms and studied their effects on adult neurogenesis, microglia, and functions associated with the hippocampus, including cognition and anxiety regulation. We found an increase in immature neuron numbers of mice living in outdoor enclosures regardless of infection. While outdoor living prevented increases in microglial reactivity induced by infection in both the dorsal and ventral hippocampus, outdoor mice with infection had fewer microglia and microglial processes in the ventral hippocampus. We observed no differences in cognitive performance on the hippocampus‐dependent object location task between infected and uninfected mice living in either setting. However, we found that infection caused an increase in anxiety‐like behavior in the open field test but only in outdoor mice. These findings suggest that living conditions, as well as gut infection, interact to produce complex effects on brain structure and function.