Activated Tryptophan-Kynurenine metabolic system in the human brain is associated with learned fear

Battaglia, Maria Rita; Fazio, Chiara; Battaglia, Simone

doi:10.3389/fnmol.2023.1217090

Cited by 30 publications

(25 citation statements)

References 118 publications

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“…In this multidisciplinary endeavor, neuropharmacological research plays a pivotal role. The study of how drugs and compounds interact with the intricate neural networks present in preclinical models provides a deeper understanding of potential therapeutic agents [62][63][64][65][66][67][68][69]. These insights guide the future development of pharmacological interventions that can target the specific molecular pathways implicated in neuropsychiatric conditions.…”

Section: Discussionmentioning

confidence: 99%

Emerging Translational Research in Neurological and Psychiatric Diseases: From In Vitro to In Vivo Models

Tanaka,

Szabó,

Vécsei

et al. 2023

IJMS

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Section: Discussionmentioning

confidence: 99%

Emerging Translational Research in Neurological and Psychiatric Diseases: From In Vitro to In Vivo Models

Tanaka,

Szabó,

Vécsei

et al. 2023

IJMS

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“…Over 95% of 5-HT precursor Trp is catabolized in the Trp-KYN metabolic system, producing a variety of bioactive molecules including oxidants, antioxidants, inflammation suppressants, neurotoxins, neuroprotectants, and/or immunomodulators [156]. More and more data revealed the disturbance of KYN metabolism in MDD, bipolar disorder, and SCZ [157][158][159]. Previously, it was proposed that KYN metabolites are categorized into neuroprotective or neurotoxic molecules [160].…”

Section: Discussionmentioning

confidence: 99%

Exploring the Neurobiological Roots of Emotional Behavior in Tryptophan Metabolism: Insights from Novel Kynurenine Aminotransferase Knockout Mice

Szabó,

Spekker,

Szűcs

et al. 2023

Preprint

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Memory and emotion, fundamental components of our mental existence, are highly vulnerable to psychiatric disorders like post-traumatic stress disorder (PTSD). This condition has been linked to serotonin (5-HT) metabolism disruptions. Over 95% of the 5-HT precursor tryptophan (Trp) is metabolized through the Trp-kynurenine (KYN) metabolic pathway, but little is known about its role in behavior. Kynurenine aminotransferases are responsible for the production of the Trp-KYN metabolite kynurenic acid. The gene aadat codes for mitochondrial kynurenine aminotransferase isotype 2. We generated CRISPR/Cas9-induced aadat knockout (kat2−/−) mice to examine the consequence of the gene deletion on negative valence in emotion, memory, and motor function in males 8 weeks of age and compared them to their wild-type counterparts. The forced swim test showed increased depression-like behaviors in transgenic mice. Anxiety and memory tests showed no significant differences. The transgenic mice had fewer center field and corner entries, shorter ambulation distances, and fewer jumping counts in the open field test. Overall, the transgenic mice exhibit depression-like behavior in a learned helplessness model, emotional indifference, and motor deficits. Here we present the first evidence that the deletion of the aadat gene triggers depression-like behaviors, uniquely associated with despair experience rather than fear memory. These findings have profound implications, opening avenues for further exploration into the main causes of experience-based depression linked to despair. This investigation has the potential to advance our understanding of these complex conditions and pave the way for improved therapeutic strategies by elucidating the relationship between Trp metabolism and the pathogenesis of PTSD.

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“…These neuroinflammatory processes are believed to disrupt neurotransmitter signaling, synaptic plasticity, and neuronal function, thereby contributing to the pathogenesis of disorders such as obsessive-compulsive disorder (OCD), MDD and SCZ ( 5 – 8 ). Brain structure and function alternations have also been reported in individuals with chronic inflammation and psychiatric disorders, suggesting a neural basis related to inflammation for the observed behavioral and affective symptoms ( 9 , 10 ). A meta-analysis showed that drugs targeting cytokines treated psychiatric disorders in a subset of patients with chronic inflammation ( 11 ).…”

Section: Introductionmentioning

confidence: 97%

Investigating the shared genetic basis and causal relationships between mucosa-associated lymphoid tissue inflammation and psychiatric disorders

Georgiou,

Voskarides,

Zanos

et al. 2024

Front. Psychiatry

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BackgroundChronic and acute inflammation of the mucosa-associated lymphoid tissue have been positively linked to the development of psychiatric disorders in observational studies. However, it remains unclear whether this association is causal. In the present study, we investigated this association, using as proxies genetically predicted tonsillectomy, appendectomy and appendicitis on psychiatric disorders including major depressive disorder (MDD), schizophrenia (SCZ), bipolar depression (BD) and anxiety (ANX) via a two-sample Mendelian randomization (MR) analysis.MethodsGenetic association summary statistics for tonsillectomy, appendectomy and appendicitis were sourced from FinnGen Consortium, comprising data from 342,000 participants. Genetic correlations between all exposures and outcome were calculated with Linkage Disequilibrium Score (LDSC) Regression analysis. MR estimates were then calculated to assess their impact on the risk of developing psychiatric disorders. Sensitivity analysis was employed to test for any directional pleiotropy.ResultsOur results suggest that there is no direct causal association between tonsillectomy, appendectomy or appendicitis with a heightened risk for development of psychiatric disorders. The robustness of the results of the main MR analysis was further confirmed with additional sensitivity analyses. However, a moderate inverse genetic correlation was observed between tonsillectomy and MDD traits (rg=-0.39, p-value (P)=7.5x10-5).ConclusionOur findings provide, for the first time, evidence that there is no causal association between tonsillectomy or appendectomy on subsequent vulnerability of developing psychiatric disorders. Future studies using larger sample size GWAS should focus on unraveling the confounding factors and mediators to investigate this relationship further.

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Activated Tryptophan-Kynurenine metabolic system in the human brain is associated with learned fear

Cited by 30 publications

References 118 publications

Emerging Translational Research in Neurological and Psychiatric Diseases: From In Vitro to In Vivo Models

Emerging Translational Research in Neurological and Psychiatric Diseases: From In Vitro to In Vivo Models

Exploring the Neurobiological Roots of Emotional Behavior in Tryptophan Metabolism: Insights from Novel Kynurenine Aminotransferase Knockout Mice

Investigating the shared genetic basis and causal relationships between mucosa-associated lymphoid tissue inflammation and psychiatric disorders

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