Statistics of Weighted Brain Networks Reveal Hierarchical Organization and Gaussian Degree Distribution

Whole brain weighted connectivity networks were extracted from high resolution diffusion MRI data of 14 healthy volunteers. A statistically robust technique was proposed for the removal of questionable connections. Unlike most previous studies our methods are completely adapted for networks with arbitrary weights. Conventional statistics of these weighted networks were computed and found to be comparable to existing reports. After a robust fitting procedure using multiple parametric distributions it was found that the weighted node degree of our networks is best described by the normal distribution, in contrast to previous reports which have proposed heavy tailed distributions. We show that post-processing of the connectivity weights, such as thresholding, can influence the weighted degree asymptotics. The clustering coefficients were found to be distributed either as gamma or power-law distribution, depending on the formula used. We proposed a new hierarchical graph clustering approach, which revealed that the brain network is divided into a regular base-2 hierarchical tree. Connections within and across this hierarchy were found to be uncommonly ordered. The combined weight of our results supports a hierarchically ordered view of the brain, whose connections have heavy tails, but whose weighted node degrees are comparable

Tryptophan metabolites in depression: Modulation by gut microbiota

Clinical depression is a multifactorial disorder and one of the leading causes of disability worldwide. The alterations in tryptophan metabolism such as changes in the levels of serotonin, kynurenine, and kynurenine acid have been implicated in the etiology of depression for more than 50 years. In recent years, accumulated evidence has revealed that gut microbial communities, besides being essential players in various aspects of host physiology and brain functioning are also implicated in the etiology of depression, particularly through modulation of tryptophan metabolism. Therefore, the aim of this review is to summarize the evidence of the role of gut bacteria in disturbed tryptophan metabolism in depression. We summed up the effects of microbiota on serotonin, kynurenine, and indole pathway of tryptophan conversion relevant for understanding the pathogenesis of depressive behavior. Moreover, we reviewed data regarding the therapeutic effects of probiotics, particularly through the regulation of tryptophan metabolites. Taken together, these findings can open new possibilities for further improvement of treatments for depression based on the microbiota-mediated modulation of the tryptophan pathway

The effect of different subanesthetic doses of ketamine on BDNF levels in different brain structures in the mouse model of depression

Major depressive disorder (MDD) affects over 300 million people worldwide. The administration of the sub-anaesthetic dose of ketamine, an NMDAr antagonist, was recently approved as highly effective antidepressant whose therapeutic effects are associated with an increase in BDNF levels in the brain. However, lowering the effective dose of ketamine because of its adverse effects is an important goal. We assessed the changes in BDNF levels after the single administration of two subanesthetic doses of ketamine (6mg/kg, Ket6 and 10mg/kg, Ket10) in the chronic unpredictable stress (CUS) mouse model of depression-like behavior in different brain structures. Male C57BL/6J mice exposed to CUS were treated at the postnatal day 70 with either vehicle, Ket6, or Ket10. Following tail suspension test (TST), to assess depressive phenotype at 2- and 7-days post-treatment, animals were sacrificed and the prefrontal cortex (PFC), hippocampus, and striatum were isolated and processed for Western blot analyses. Statistical significance was determined by 1-way ANOVA. Only Ket6 achieved an antidepressant effect that was extinguished at 7 days. Both doses caused a significant increase in BDNF levels in the striatum while neither dose was able to induce BDNF levels in the hippocampus. The increase in BDNF levels in the PFC was observed only 7 days after the treatment and only with Ket10. The increase in BDNF levels was the greatest in the striatum when it correlated with the antidepressive effects of ketamine. Although this increase was sustained for 7 days it did not correlate with the antidepressive behavior which was already extinguished.Poster Session: Brain Metabolism & Dietary Intervention

The effects of a selected methoxy substituted chalcone in human melanoma cells irradiated with γ-rays

Given the well-established potential of chalcones in modulating the response of cancer cells to therapeutic interventions, coupled with the growing imperative to enhance their biological attributes, the objective of this study was to synthesize a methoxy-substituted chalcone (OCH3) and assess its capacity to amplify the inhibitory effects of radiation in melanoma cells known for their resistance to radiotherapy. The A375 melanoma cells were subjected to a clinically relevant dose of 2 Gy gamma irradiation. OCH3 was employed either as a standalone treatment or in conjunction with irradiation. The obtained results unveiled the substantial radiosensitizing potential of OCH3 within this specific cell line. Our subsequent investigations will be designed to investigate the underlying mechanisms that contribute to the radiosensitizing properties of OCH3. Moreover, we intend to evaluate the efficacy of OCH3 against other types of radioresistant cancer cells. The presented data not only illuminates the enhanced therapeutic possibilities offered by OCH3 but also highlights its potential as a valuable agent in addressing a wider array of challenging malignancies.ICCBIKG 2023 : 2nd International Conference on Chemo and Bioinformatics, September 28-29, 2023; Kragujeva

Growth of radiata pine families in nursery and two years after field establishment

Pinus radiata D. Don is the most widely planted exotic species in Australia, Chile, New Zealand and Spain. In this study, growth and survival of P. radiata were compared in 30 open pollinated families grown under two contrasting watering regimes in nursery (well-watered cf. water-stress conditions) and planted on a drought-prone site with Mediterranean climate in central Chile. This study assessed phenotypic plasticity in growth and survival at nursery stage and two years after establishment in the field. Family plasticity at nursery stage was estimated by the angular phenotypic change index (APCI), while the relationship between nursery and field traits was estimated by genetic correlations (rg ) and the Pearson coefficient of correlation (rxy). Families presented high plasticity in diameter, height, and survival at nursery stage. Out of 30 families, eight exhibited over 80 % survival in the well-watered treatment, but less than 20 % survival in the water-stress treatment. As expected, growth traits and survival were positively correlated (rg and rxy > 0.65) between both nursery environments. However, for growth, most genetic and phenotypic correlations between combinations of nursery treatments versus the field test were negative or not significant. As there was no detectable pattern of nursery–field correlations regarding to combinations of nursery treatments and test site, the need to include more stable families and genotypes to an appropriate developmental stage at nursery is discussed

Ketamine ameliorates fear extinction learning in adolescent males via hippocampal mTOR signaling

Adolescence is a developmental stage characterized by impaired fear extinction learning, which is a significant contributing factor for the high incidence of fearrelated disorders observed across this period. Ketamine is a noncompetitive N-methyl D-aspartate receptor antagonist that targets glutamatergic transmission and mammalian target of rapamycin (mTOR) signaling pathway, synaptic plasticity mediators known to be involved in fear extinction processes. Therefore, we aimed to explore ketamine’s potential to boost fear extinction of adolescent males, as well as to identify the associated molecular mechanisms. Adolescent male mice (C57BL/6) received an i.p. ketamine injection (10 mg/kg) 1h prior to each cued fear extinction session for 4 consecutive days. Protein expression levels of synaptic plasticity markers in hippocampal synaptosomal fractions were subsequently detected by Western blot analysis. Our results revealed that ketamine significantly improved overall fear extinction learning, as well as extinction memory consolidation/retention. Our data also showed that ketamine upregulated protein kinase B (Akt), mTOR and glutamate receptor 1 (GluR1) protein levels in the hippocampus. Interestingly, we detected no changes in the levels of extracellular signal-regulated kinase 1/2. These results suggest that ketamine ameliorates longterm fear extinction of adolescent males via hippocampal Akt-mTOR-GluR1 signaling, highlighting this pathway as an important therapeutic target for improving extinction learning in the adolescent population.Poster Session: Brain Metabolism & Dietary Intervention

Chronic unpredictable stress in adolescence causes disruption of colon morphology that is associated with depressive phenotype in adult mice

Adolescence is a critical period for neurodevelopment, and exposure to chronic stress during this stage can have long-lasting effects on physiological systems and mental health, particularly on depression. Recent studies report that stress affects the gutbrain axis, leading to changes in gut morphology and motility, nutrient absorption, and gut microbiome, which can be associated with development of depression. We investigated the impact of chronic unpredictable stress (CUS) in adolescence on depressive-like behavior and colon in adult mice. Male C57BL/6 mice were exposed to CUS, including different daily stressors such as social isolation, forced swim, and restraint stress, and others, during postnatal days 28-40. Control mice were housed under standard conditions. Behavioral assessments were conducted during adulthood (postnatal day 70), to evaluate depressive-like behavior. Alterations in mice colon were assessed by histopathological analysis. Our results revealed that mice exposed to CUS during adolescence have disrupted colon, including loss of colonic crypts and significantly increased presence of mucosa and submucosa in respect to controls. Changes in colon were associated with increased depressive-like behavior in CUS-mice compared to control mice. These findings suggest that CUS experienced in adolescence can disrupt colon morphology that is associated with depressive phenotype in adult mice, highlighting the importance of understanding the long-term consequences of chronic stress during this critical period of development as a potential risk for development of depression. Further research is needed to elucidate the underlying mechanisms and potential therapeutic interventions to mitigate the effects of stress on mental health and gut functionPoster Session: Brain Metabolism & Dietary Intervention

Ketamine’s Amelioration of Fear Extinction in Adolescent Male Mice Is Associated with the Activation of the Hippocampal Akt-mTOR-GluA1 Pathway

Fear-related disorders, including post-traumatic stress disorder (PTSD), and anxiety disorders are pervasive psychiatric conditions marked by persistent fear, stemming from its dysregulated acquisition and extinction. The primary treatment for these disorders, exposure therapy (ET), relies heavily on fear extinction (FE) principles. Adolescence, a vulnerable period for developing psychiatric disorders, is characterized by neurobiological changes in the fear circuitry, leading to impaired FE and increased susceptibility to relapse following ET. Ketamine, known for relieving anxiety and reducing PTSD symptoms, influences fear-related learning processes and synaptic plasticity across the fear circuitry. Our study aimed to investigate the effects of ketamine (10 mg/kg) on FE in adolescent male C57 BL/6 mice at the behavioral and molecular levels. We analyzed the protein and gene expression of synaptic plasticity markers in the hippocampus (HPC) and prefrontal cortex (PFC) and sought to identify neural correlates associated with ketamine’s effects on adolescent extinction learning. Ketamine ameliorated FE in the adolescent males, likely affecting the consolidation and/or recall of extinction memory. Ketamine also increased the Akt and mTOR activity and the GluA1 and GluN2A levels in the HPC and upregulated BDNF exon IV mRNA expression in the HPC and PFC of the fear-extinguished mice. Furthermore, ketamine increased the c-Fos expression in specific brain regions, including the ventral HPC (vHPC) and the left infralimbic ventromedial PFC (IL vmPFC). Providing a comprehensive exploration of ketamine’s mechanisms in adolescent FE, our study suggests that ketamine’s effects on FE in adolescent males are associated with the activation of hippocampal Akt-mTOR-GluA1 signaling, with the vHPC and the left IL vmPFC as the proposed neural correlates