Accumulating data highlight the contribution of brain mitochondria and bioenergetics to psychiatric disorders and stress-related pathologies. Although anxiety has not received much attention in this ...booming literature, a bidirectional interplay between anxiety and brain mitochondria and metabolism has recently started to emerge. Substantial observations indicate alterations in mitochondria and metabolism in highly anxious individuals and, conversely, anxiety symptoms in humans suffering from mitochondrial disorders. Genetic and pharmacological efforts have made substantial progress at advancing the causal involvement of specific mitochondrial and metabolic factors in anxiety. In this review, we discuss this converging evidence and highlight the relevance of developing a research focused on targeting mitochondria as an approach to alleviate anxiety.
Despite the established link between mitochondrial dysfunction and various psychiatric disorders, the contribution of mitochondria in anxiety disorders has not been extensively addressed.Mitochondria are emerging as modulators of anxiety-related behavior, as evidenced both by animal and human studies.There is a bidirectional link between mitochondria and anxiety. Mitochondrial, energy metabolism, and oxidative stress alterations are observed in high anxiety; conversely, changes in mitochondrial function can lead to heightened anxiety.Pharmacological manipulation of mitochondria may be a potential therapeutic approach to relieve high anxiety symptoms.
Cannabinol (CBN) is a degradation product of the cannabis metabolite Δ9-tetrahydrocannabinol. The CBN concentration in cannabis leaves ranges between 0.1 and 1.6% (w/w of dry weight); it increases as ...the plant ages and its formation is affected by the storage conditions. As CBN has not been extensively studied so far, the need to examine its impact in vivo is imperative due to the increasing use of cannabis globally. In the study herein, the CBN toxicity, effects on heart physiology, morphological malformations, behavioral changes and alterations in metabolic pathways of zebrafish larvae upon CBN exposure to sublethal concentrations were examined. The LD50 value was estimated at 1.12 mg/l. At the same time, malformations in zebrafish larvae increased significantly in a dose-dependent manner and exposure to CBN concentrations greater than 0.75 mg/l provoked abnormalities like pericardial edema, yolk sac anomalies and tail bending. Concentrations above this threshold resulted in elongated and shorter in width hearts and in separation of ventricle from atrium. The total movement distance and velocity were increased in dark and decreased in light conditions, in a concentration-dependent manner. Our results showed that CBN acts both as a stimulant and a sedative, with larvae to exhibit altered velocity and bradycardia, respectively. The metabolomic analysis revealed alterations mainly to amino acids, which are related to acute toxicity and hint towards systemic metabolic and neuropathophysiological changes. Taken together, our data indicate increased toxic effects as CBN exposure concentration increases, which should be taken into consideration when studying the impact of cannabis on organisms.
•Cannabinol (CBN), an unknown cannabis metabolite under thorough toxicometabolomic study.•Effects of CΒΝ in the zebrafish embryos life cycle.•LD50 determination.•Morphological, heart and metabolic alterations provoked from CBN.•Important results for future use of CBN and cannabinoids in general.
Early handling (EH), the brief separation of pups from their mother during early life, has been shown to exert beneficial effects. However, the impact of EH in a high anxiety background as well as ...the role of brain mitochondria in shaping EH-driven responses remain elusive.Here, we used a high (HAB) vs. normal (NAB) anxiety-related behavior mouse model to study how EH affects pup and dam behavior in divergent anxiety backgrounds. We also investigated EH-induced effects at the protein and mRNA levels in adult male HAB mice in the hypothalamus, the prefrontal cortex, and the hippocampus by examining the same mitochondrial/energy pathways and mitochondrial dynamics mechanisms (fission, fusion, biogenesis, and mitophagy) in all three brain regions.EH exerts anxiolytic effects in adult HAB but not NAB male mice and does not affect HAB or NAB maternal behavior, although basal HAB vs. NAB maternal behaviors differ. In adult HAB male mice, EH does not impact oxidative phosphorylation (OXPHOS) and oxidative stress in any of the brain regions studied but leads to increased protein expression of glycolysis enzymes and a correlation of anxiety-related behavior with Krebs cycle enzymes in HAB mice in the hypothalamus. Intriguingly, EH alters mitochondrial dynamics by increasing hypothalamic DRP1, OPA1, and PGC1a protein levels. At the mRNA level, we observe altered, EH-driven mitochondrial dynamics mRNA signatures which predominantly affect the prefrontal cortex.Taken together, our results show that EH exerts anxiolytic effects in adulthood in high anxiety and modulates mitochondrial dynamics pathways in a brain region-specific manner.
Background Although anxiety disorders are the most prevalent psychiatric disorders, no molecular biomarkers exist for their premorbid diagnosis, accurate patient subcategorization, or treatment ...efficacy prediction. To unravel the neurobiological underpinnings and identify candidate biomarkers and affected pathways for anxiety disorders, we interrogated the mouse model of high anxiety-related behavior (HAB), normal anxiety-related behavior (NAB), and low anxiety-related behavior (LAB) employing a quantitative proteomics and metabolomics discovery approach. Methods We compared the cingulate cortex synaptosome proteomes of HAB and LAB mice by in vivo15 N metabolic labeling and mass spectrometry and quantified the cingulate cortex metabolomes of HAB/NAB/LAB mice. The combined data sets were used to identify divergent protein and metabolite networks by in silico pathway analysis. Selected differentially expressed proteins and affected pathways were validated with immunochemical and enzymatic assays. Results Altered levels of up to 300 proteins and metabolites were found between HAB and LAB mice. Our data reveal alterations in energy metabolism, mitochondrial import and transport, oxidative stress, and neurotransmission, implicating a previously nonhighlighted role of mitochondria in modulating anxiety-related behavior. Conclusions Our results offer insights toward a molecular network of anxiety pathophysiology with a focus on mitochondrial contribution and provide the basis for pinpointing affected pathways in anxiety-related behavior.
Current treatment strategies for anxiety disorders are predominantly symptom-based. However, a third of anxiety patients remain unresponsive to anxiolytics highlighting the need for more effective, ...mechanism-based therapeutic approaches. We have previously compared high vs low anxiety mice and identified changes in mitochondrial pathways, including oxidative phosphorylation and oxidative stress. In this work, we show that selective pharmacological targeting of these mitochondrial pathways exerts anxiolytic effects in vivo. We treated high anxiety-related behavior (HAB) mice with MitoQ, an antioxidant that selectively targets mitochondria. MitoQ administration resulted in decreased anxiety-related behavior in HAB mice. This anxiolytic effect was specific for high anxiety as MitoQ treatment did not affect the anxiety phenotype of C57BL/6N and DBA/2J mouse strains. We furthermore investigated the molecular underpinnings of the MitoQ-driven anxiolytic effect and found that MitoQ treatment alters the brain metabolome and that the response to MitoQ treatment is characterized by distinct molecular signatures. These results indicate that a mechanism-driven approach based on selective mitochondrial targeting has the potential to attenuate the high anxiety phenotype in vivo, thus paving the way for translational implementation as long-term MitoQ administration is well-tolerated with no reported side effects in mice and humans.
Despite intensive research efforts to understand the molecular underpinnings of psychological stress and stress responses, the underlying molecular mechanisms remain largely elusive. Towards this ...direction, a plethora of stress rodent models have been established to investigate the effects of exposure to different stressors. To decipher affected molecular pathways in a holistic manner in these models, metabolomics approaches addressing altered, small molecule signatures upon stress exposure in a high-throughput, quantitative manner provide insightful information on stress-induced systemic changes in the brain. In this review, we discuss stress models in mice and rats, followed by mass spectrometry (MS) and nuclear magnetic resonance (NMR) metabolomics studies. We particularly focus on acute, chronic and early life stress paradigms, highlight how stress is assessed at the behavioral and molecular levels and focus on metabolomic outcomes in the brain and peripheral material such as plasma and serum. We then comment on common metabolomics patterns across different stress models and underline the need for unbiased -omics methodologies and follow-up studies of metabolomics outcomes to disentangle the complex pathobiology of stress and pertinent psychopathologies.
Delayed therapeutic responses and limited efficacy are the main challenges of existing antidepressant drugs, thereby incentivizing the search for new potential treatments. Cannabidiol (CBD), ...non-psychotomimetic component of cannabis, has shown promising antidepressant effects in different rodent models, but its mechanism of action remains unclear. Herein, we investigated the antidepressant-like effects of repeated CBD treatment on behavior, neuroplasticity markers and lipidomic profile in the prefrontal cortex (PFC) of Flinders Sensitive Line (FSL), a genetic animal model of depression, and their control counterparts Flinders Resistant Line (FRL) rats. Male FSL animals were treated with CBD (10 mg/kg; i.p.) or vehicle (7 days) followed by Open Field Test (OFT) and the Forced Swimming Test (FST). The PFC was analyzed by a) western blotting to assess markers of synaptic plasticity and cannabinoid signaling in synaptosome and cytosolic fractions; b) mass spectrometry-based lipidomics to investigate endocannabinoid levels (eCB). CBD attenuated the increased immobility observed in FSL, compared to FRL in FST, without changing the locomotor behavior in the OFT. In synaptosomes, CBD increased ERK1, mGluR5, and Synaptophysin, but failed to reverse the reduced CB1 and CB2 levels in FSL rats. In the cytosolic fraction, CBD increased ERK2 and decreased mGluR5 expression in FSL rats. Surprisingly, there were no significant changes in eCB levels in response to CBD treatment. These findings suggest that CBD effects in FSL animals are associated with changes in synaptic plasticity markers involving mGluR5, ERK1, ERK2, and synaptophysin signaling in the PFC, without increasing the levels of endocannabinoids in this brain region.
•Repeated treatment with CBD induces antidepressant-like effects in the Flinders Sensitive Line (FSL) rats.•CBD antidepressant effect is associated with changes in synaptic plasticity markers in the prefrontal cortex.•Lipidomic (endocannabinoid) levels in the prefrontal cortex were not affected by the repeated treatment with CBD.
Dysfunction of metabolic pathways characterises a plethora of common pathologies and has emerged as an underlying hallmark of disease phenotypes. Here, we focus on psychiatric disorders and brain ...tumours and explore changes in the interplay between glycolysis and mitochondrial energy metabolism in the brain. We discuss alterations in glycolysis versus core mitochondrial metabolic pathways, such as the tricarboxylic acid cycle and oxidative phosphorylation, in major psychiatric disorders and brain tumours. We investigate potential common patterns of altered mitochondrial metabolism in different brain regions and sample types and explore how changes in mitochondrial number, shape and morphology affect disease‐related manifestations. We also highlight the potential of pharmacologically targeting mitochondria to achieve therapeutic effects.
Metabolic and mitochondrial alterations are observed both in psychiatric disorders and brain tumors. In this review, we discuss changes in the crosstalk of glycolysis‐oxidative phosphorylation and mitochondrial dynamics in these two distinct disease groups. We also explore common altered molecular patterns and potential shared therapeutic strategies in psychiatric disorders and brain tumors.
Selective Serotonin Reuptake Inhibitors (SSRIs) are commonly used drugs for the treatment of psychiatric diseases including major depressive disorder (MDD). For unknown reasons a substantial number ...of patients do not show any improvement during or after SSRI treatment. We treated DBA/2J mice for 28 days with paroxetine and assessed their behavioral response with the forced swim test (FST). Paroxetine-treated long-time floating (PLF) and paroxetine-treated short-time floating (PSF) groups were stratified as proxies for drug non-responder and responder mice, respectively. Proteomics and metabolomics profiles of PLF and PSF groups were acquired for the hippocampus and plasma to identify molecular pathways and biosignatures that stratify paroxetine-treated mouse sub-groups. The critical role of purine and pyrimidine metabolisms for chronic paroxetine treatment response in the mouse was further corroborated by pathway protein expression differences in both mice and patients that underwent chronic antidepressant treatment. The integrated -omics data indicate purine and pyrimidine metabolism pathway activity differences between PLF and PSF mice. Furthermore, the pathway protein levels in peripheral specimens strongly correlated with the antidepressant treatment response in patients. Our results suggest that chronic SSRI treatment differentially affects purine and pyrimidine metabolisms, which may explain the heterogeneous antidepressant treatment response and represents a potential biosignature.
Depression and anxiety disorders affect a great number of people worldwide. Whereas singular factors have been associated with the pathogenesis of psychiatric disorders, growing evidence emphasizes ...the significance of dysfunctional neural circuits and signaling pathways. Hence, a systems biology approach is required to get a better understanding of psychiatric phenotypes such as depression and anxiety. Furthermore, the availability of biomarkers for these disorders is critical for improved diagnosis and monitoring treatment response. In the present study, a mouse model presenting with robust high versus low anxiety phenotypes was subjected to thorough molecular biomarker and pathway discovery analyses. Reference animals were metabolically labeled with the stable 15N isotope allowing an accurate comparison of protein expression levels between the high anxiety-related behavior versus low anxiety-related behavior mouse lines using quantitative mass spectrometry. Plasma metabolomic analyses identified a number of small molecule biomarkers characteristic for the anxiety phenotype with particular focus on myo-inositol and glutamate as well as the intermediates involved in the tricarboxylic acid cycle. In silico analyses suggested pathways and subnetworks as relevant for the anxiety phenotype. Our data demonstrate that the high anxiety-related behavior and low anxiety-related behavior mouse model is a valuable tool for anxiety disorder drug discovery efforts.
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