Study of brain metabolic dysfunctions in animal models of mood disorder using magnetic resonance spectroscopy

Mood disorders, in particular depression, are a major burden of our society. Due to the poor knowledge of the biological basis of these diseases, classification remains based on arbitrary symptomatic parameters. As a result, the existing pharmacological treatments have difficulties targeting relevant pathophysiological processes leading to high level of non-responding patients. Magnetic resonance spectroscopy (MRS) provides an outstanding means of measuring biochemical processes in vivo and can help identifying metabolic pathways that are associated with a given pathological condition. In this thesis, we have taken advantage of state-of-the-art MRS technologies at high field for studying metabolic dysfunctions associated with behavioral impairments in animal models of mood disorder. The overall goal consisted in finding potential biomarkers and endophenotypes (i.e. heritable biomarkers) with MRS, associate them with a molecular/physiological mechanism and evaluate the effect of a treatment targeting the observed dysfunction. We have successfully identified neuroenergetic abnormalities in different limbic regions of the brain in two mouse models of mood disorders; with a genetic or an environmental origin. Genetic deletion of an important metabolic regulator in mouse brain led to hippocampal neuroenergetic impairment and susceptibility to environmental stressors. Treating the animals with ebselen, an energy boosting mood stabilizer, allowed us to reduce the animalâs sensitivity to stress. With the same approach, we observed energy-related biomarkers associated with susceptibility to stress in the nucleus accumbens of genetically identical mice. We found that social hierarchy can predict the response to a chronic stressor and that behavioral impairments could be prevented by administering an energy stimulating compound, acetyl-L-carnitine. Finally, in an additional project, we have used MRS in an embryonic model in ovo to investigate for markers related to metabolic remodeling during neurogenesis. Our results support the idea that mood disorders arise from energy metabolism fragility in different regions of the limbic system with both environmental and genetic origin. Due to the high translational potential of MRS into clinics, our findings provide new biological targets or routes to study for a better understanding of mood disorders

Utilizing Exercise and Nutrition in the Treatment of Chronic Disease: Community Based Models

The prevalence of chronic diseases in America has increased substantially within the last few decades, increasing the cost of healthcare by billions of dollars. In addition, these diseases have a higher incidence rate for low income populations who may have greater difficulty accessing adequate resources or appropriate treatments. There has been a growing body of literature supporting the use of community-based exercise and nutrition interventions. Community-based interventions emphasize social supports and personal empowerment for behavioral change. Given the chronic and growing nature of these diseases, this paper will examine community-based exercises and the surrounding elements which facilitate and hinder behavioral change

In Vivo Metabolism of [1,6-C-13(2)]Glucose Reveals Distinct Neuroenergetic Functionality between Mouse Hippocampus and Hypothalamus

Glucose is a major energy fuel for the brain, however, less is known about specificities of its metabolism in distinct cerebral areas. Here we examined the regional differences in glucose utilization between the hypothalamus and hippocampus using in vivo indirect C-13 magnetic resonance spectroscopy (H-1-[C-13]-MRS) upon infusion of [1,6-C-13(2)]glucose. Using a metabolic flux analysis with a 1-compartment mathematical model of brain metabolism, we report that compared to hippocampus, hypothalamus shows higher levels of aerobic glycolysis associated with a marked gamma-aminobutyric acid-ergic (GABAergic) and astrocytic metabolic dependence. In addition, our analysis suggests a higher rate of ATP production in hypothalamus that is accompanied by an excess of cytosolic nicotinamide adenine dinucleotide (NADH) production that does not fuel mitochondria via the malate-aspartate shuttle (MAS). In conclusion, our results reveal significant metabolic differences, which might be attributable to respective cell populations or functional features of both structures

New Insights Into the Pivotal Role of CREB-Regulated Transcription Coactivator 1 in Depression and Comorbid Obesity

Depression and obesity are major public health concerns, and there is mounting evidence that they share etiopathophysiological mechanisms. The neurobiological pathways involved in both mood and energy balance regulation are complex, multifactorial and still incompletely understood. As a coactivator of the pleiotropic transcription factor cAMP response element-binding protein (CREB), CREB-regulated transcription coactivator 1 (CRTC1) has recently emerged as a novel regulator of neuronal plasticity and brain functions, while CRTC1 dysfunction has been associated with neurodegenerative and psychiatric diseases. This review focuses on recent evidence emphasizing the critical role of CRTC1 in the neurobiology of depression and comorbid obesity. We discuss the role of CRTC1 downregulation in mediating chronic stress-induced depressive-like behaviors, and antidepressant response in the light of the previously characterized Crtc1 knockout mouse model of depression. The putative role of CRTC1 in the alteration of brain energy homeostasis observed in depression is also discussed. Finally, we highlight rodent and human studies supporting the critical involvement of CRTC1 in depression-associated obesity.LIFME

The Appearance of the Warburg Effect in the Developing Avian Eye Characterized In Ovo: How Neurogenesis Can Remodel Neuroenergetics

PURPOSE. The avian eye is an established model for exploring mechanisms that coordinate morphogenesis and metabolism during embryonic development. Less is known, however, about trafficking of bioenergetic and metabolic signaling molecules that are involved in retinal neurogenesis. METHODS. Here we tested whether the known 3-day delayed neurogenesis occurring in the pigeon compared with the chick was associated with a deferred reshaping of eye metabolism in vivo. Developmental metabolic remodeling was explored using H-1-magnetic resonance spectroscopy of the whole eye and vitreous body, in ovo, in parallel with biochemical and molecular analyses of retinal, vitreous, and lens extracts from bird embryos. RESULTS. Cross-species comparisons enabled us to show that a major glycolytic switch in the retina is related to neurogenesis rather than to eye growth. We further show that the temporal emergence of an interlocking regulatory cascade controlling retinal oxidative phosphorylation and glycolysis results in the exchange of lactate and citrate between the retina and vitreous. CONCLUSIONS. Our results point to the vitreous as a reservoir and buffer of energy metabolites that provides trophic support to oxidative neurons, such as retinal ganglion cells, in early development. Through its control of key glycolytic regulatory enzymes, citrate, exchanged between extracellular and intracellular compartments between the retina and vitreous, is a key metabolite in the initiation of a glycolytic switch

Excitatory/inhibitory neuronal metabolic balance in mouse hippocampus upon infusion of [U-C-13(6)]glucose

Hippocampus plays a critical role in linking brain energetics and behavior typically associated to stress exposure. In this study, we aimed to simultaneously assess excitatory and inhibitory neuronal metabolism in mouse hippocampus in vivo by applying (18)FDG-PET and indirect C-13 magnetic resonance spectroscopy (H-1-[C-13]-MRS) at 14.1 T upon infusion of uniformly C-13-labeled glucose ([U-C-13(6)]Glc). Improving the spectral fitting by taking into account variable decoupling efficiencies of [U-C-13(6)]Glc and refining the compartmentalized model by including two gamma-aminobutyric acid (GABA) pools permit us to evaluate the relative contributions of glutamatergic and GABAergic metabolism to total hippocampal neuroenergetics. We report that GABAergic activity accounts for similar to 13% of total neurotransmission (V-NT) and similar to 27% of total neuronal TCA cycle (V-TCA) in mouse hippocampus suggesting a higher V-TCA/V-NT ratio for inhibitory neurons compared to excitatory neurons. Finally, our results provide new strategies and tools for bringing forward the developments and applications of C-13-MRS in specific brain regions of small animals

Hierarchical status predicts behavioral vulnerability and nucleus accumbens metabolic profile following chronic social defeat stress.

Extensive data highlight the existence of major differences in individuals’ susceptibility to stress [1; 2; 3 ; 4]. While genetic factors [5 ; 6] and exposure to early life stress [7 ; 8] are key components for such neurobehavioral diversity, intriguing observations revealed individual differences in response to stress in inbred mice [9; 10; 11 ; 12]. This raised the possibility that other factors might be critical in stress vulnerability. A key challenge in the field is to identify non-invasively risk factors for vulnerability to stress. Here, we investigated whether behavioral factors, emerging from preexisting dominance hierarchies, could predict vulnerability to chronic stress [9; 13; 14; 15 ; 16]. We applied a chronic social defeat stress (CSDS) model of depression in C57BL/6J mice to investigate the predictive power of hierarchical status to pinpoint which individuals will exhibit susceptibility to CSDS. Given that the high social status of dominant mice would be the one particularly challenged by CSDS, we predicted and found that dominant individuals were the ones showing a strong susceptibility profile as indicated by strong social avoidance following CSDS, while subordinate mice were not affected. Data from 1H-NMR spectroscopy revealed that the metabolic profile in the nucleus accumbens (NAc) relates to social status and vulnerability to stress. Under basal conditions, subordinates show lower levels of energy-related metabolites compared to dominants. In subordinates, but not dominants, levels of these metabolites were increased after exposure to CSDS. To the best of our knowledge, this is the first study that identifies non-invasively the origin of behavioral risk factors predictive of stress-induced depression-like behaviors associated with metabolic changes

Metabolic signature in nucleus accumbens for anti-depressant-like effects of acetyl-L-carnitine

Emerging evidence suggests that hierarchical status provide vulnerability to develop stress-induced depression. Energy metabolic changes in the nucleus accumbens (NAc) were recently related to hierarchical status and vulnerability to develop depression-like behavior. Acetyl-L-carnitine (LAC), a mitochondria-boosting supplement, has shown promising antidepressant-like effects opening therapeutic opportunities for restoring energy balance in depressed patients. We investigated the metabolic impact in the NAc of antidepressant LAC treatment in chronically-stressed mice using (1)H-magnetic resonance spectroscopy ((1)H-MRS). High rank, but not low rank, mice, as assessed with the tube test, showed behavioral vulnerability to stress, supporting a higher susceptibility of high social rank mice to develop depressive-like behaviors. High rank mice also showed reduced levels of several energy-related metabolites in the NAc that were counteracted by LAC treatment. Therefore, we reveal a metabolic signature in the NAc for antidepressant-like effects of LAC in vulnerable mice characterized by restoration of stress-induced neuroenergetics alterations and lipid function

Mitochondrial gene signature in the prefrontal cortex for differential susceptibility to chronic stress

Mitochondrial dysfunction was highlighted as a crucial vulnerability factor for the development of depression. However, systemic studies assessing stress-induced changes in mitochondria-associated genes in brain regions relevant to depression symptomatology remain scarce. Here, we performed a genome-wide transcriptomic study to examine mitochondrial gene expression in the prefrontal cortex (PFC) and nucleus accumbens (NAc) of mice exposed to multimodal chronic restraint stress. We identified mitochondria-associated gene pathways as most prominently affected in the PFC and with lesser significance in the NAc. A more detailed mitochondrial gene expression analysis revealed that in particular mitochondrial DNA-encoded subunits of the oxidative phosphorylation complexes were altered in the PFC. The comparison of our data with a reanalyzed transcriptome data set of chronic variable stress mice and major depression disorder subjects showed that the changes in mitochondrial DNA-encoded genes are a feature generalizing to other chronic stress-protocols as well and might have translational relevance. Finally, we provide evidence for changes in mitochondrial outputs in the PFC following chronic stress that are indicative of mitochondrial dysfunction. Collectively, our work reinforces the idea that changes in mitochondrial gene expression are key players in the prefrontal adaptations observed in individuals with high behavioral susceptibility and resilience to chronic stress

Hypothetical scenario in which a habitat variable influences both absolute population size <i>N</i> and also individual detection probability <i>p</i>.

<p>In this case, changes in the habitat variable (e.g., over time or when comparing different sites) will translate into a divergence of <i>N</i> and <i>C</i>, the beginning of which is denoted by the vertical bars.</p