Genome-wide association study of drought tolerance in wheat (Triticum aestivum L.) identifies SNP markers and candidate genes.

Drought stress poses a severe threat to global wheat production, necessitating an in-depth exploration of the genetic basis for drought tolerance associated traits. This study employed a 90 K SNP array to conduct a genome-wide association analysis, unravelling genetic determinants of key traits related to drought tolerance in wheat, namely plant height, root length, and root and shoot dry weight. Using the mixed linear model (MLM) method on 125 wheat accessions subjected to both well-watered and drought stress treatments, we identified 53 SNPs significantly associated with stress susceptibility (SSI) and tolerance indices (STI) for the targeted traits. Notably, chromosomes 2A and 3B stood out with ten and nine associated markers, respectively. Across 17 chromosomes, 44 unique candidate genes were pinpointed, predominantly located on the distal ends of 1A, 1B, 1D, 2A, 3A, 3B, 4A, 6A, 6B, 7A, 7B, and 7D chromosomes. These genes, implicated in diverse functions related to plant growth, development, and stress responses, offer a rich resource for future investigation. A clustering pattern emerged, notably with seven genes associated with SSI for plant height and four genes linked to both STI of plant height and shoot dry weight, converging on specific regions of chromosome arms of 2AS and 3BL. Additionally, shared genes encoding polygalacturonase, auxilin-related protein 1, peptide deformylase, and receptor-like kinase underscored the interconnectedness between plant height and shoot dry weight. In conclusion, our findings provide insights into the molecular mechanisms governing wheat drought tolerance, identifying promising genomic loci for further exploration and crop improvement strategies.

The gut microbiome modulates the susceptibility to traumatic stress in a sex-dependent manner.

Post-traumatic stress disorder (PTSD), a psychological condition triggered by exposure to extreme or chronic stressful events, exhibits a sex bias in incidence and clinical manifestations. Emerging research implicates the gut microbiome in the pathogenesis of PTSD and its roles in stress susceptibility. However, it is unclear whether differential gut microbiota contribute to PTSD susceptibility in male and female rats. Here, we utilized the single prolonged stress animal model and employed unsupervised machine learning to classify stressed animals into stress-susceptible subgroups and stress-resilient subgroups. Subsequently, using 16S V3-V4 rDNA sequencing, we investigated the differential gut microbiota alterations between susceptible and resilient individuals in male and female rats. Our findings revealed distinct changes in gut microbiota composition between the sexes at different taxonomic levels. Furthermore, the abundance of Parabacteroides was lower in rats that underwent SPS modeling compared to the control group. In addition, the abundance of Tenericutes in the stress-susceptible subgroup was higher than that in the control group and stress-resilient subgroup, suggesting that Tenericutes may be able to characterize stress susceptibility. What is particularly interesting here is that Cyanobacteria may be particularly associated with anti-anxiety effects in male rats. This study underscores sex-specific variations in gut microbiota composition in response to stress and sex differences should be taken into account when using macrobiotics for neuropsychiatric treatment, highlighting potential targets for PTSD therapeutic interventions.

Sex Differences in Stress Susceptibility as a Key Mechanism Underlying Depression Risk.

PURPOSE OF REVIEW: Although females are at relatively greater risk for a variety of disorders, including depression, the biological mechanisms underlying this striking health disparity remain unclear. To address this issue, we highlight sex differences in stress susceptibility as a key mechanism potentially driving this effect and describe the interacting inflammatory, hormonal, epigenomic, and social-environmental mechanisms involved. RECENT FINDINGS: Using the Social Signal Transduction Theory of Depression as a theoretical framework, women's elevated risk for depression may stem from a tight link between life stress, inflammation, and depression in women. Further, research finds hormonal contraceptive use alters cortisol and inflammatory reactivity to acute stress in ways that may increase depression risk in females. Finally, beyond established epigenetic mechanisms, mothers may transfer risk for depression to their female offspring through stressful family environments, which influence stress generation and stress-related gene expression. Together, these findings provide initial, biologically plausible clues that may help explain the relatively greater risk for depression in females vs. males. Looking forward, much more research is needed to address the longstanding underrepresentation of females in biomedical research on the biology of stress and depression.

Adolescent functional network connectivity prospectively predicts adult anxiety symptoms related to perceived COVID-19 economic adversity.

BACKGROUND: Stressful events, such as the COVID-19 pandemic, are major contributors to anxiety and depression, but only a subset of individuals develop psychopathology. In a population-based sample (N = 174) with a high representation of marginalized individuals, this study examined adolescent functional network connectivity as a marker of susceptibility to anxiety and depression in the context of adverse experiences. METHODS: Data-driven network-based subgroups were identified using an unsupervised community detection algorithm within functional neural connectivity. Neuroimaging data collected during emotion processing (age 15) were extracted from a priori regions of interest linked to anxiety and depression. Symptoms were self-reported at ages 15, 17, and 21 (during COVID-19). During COVID-19, participants reported on pandemic-related economic adversity. Differences across subgroup networks were first examined, then subgroup membership and subgroup-adversity interaction were tested to predict change in symptoms over time. RESULTS: Two subgroups were identified: Subgroup A, characterized by relatively greater neural network variation (i.e., heterogeneity) and density with more connections involving the amygdala, subgenual cingulate, and ventral striatum; and the more homogenous Subgroup B, with more connections involving the insula and dorsal anterior cingulate. Accounting for initial symptoms, subgroup A individuals had greater increases in symptoms across time (ß = .138, p = .042), and this result remained after adjusting for additional covariates (ß = .194, p = .023). Furthermore, there was a subgroup-adversity interaction: compared with Subgroup B, Subgroup A reported greater anxiety during the pandemic in response to reported economic adversity (ß = .307, p = .006), and this remained after accounting for initial symptoms and many covariates (ß = .237, p = .021). CONCLUSIONS: A subgrouping algorithm identified young adults who were susceptible to adversity using their personalized functional network profiles derived from a priori brain regions. These results highlight potential prospective neural signatures involving heterogeneous emotion networks that predict individuals at the greatest risk for anxiety when experiencing adverse events.

α-MSH-catabolic enzyme prolylcarboxypeptidase in nucleus accumbens shell ameliorates stress susceptibility in mice through regulating synaptic plasticity.

Emerging evidence demonstrates the vital role of synaptic transmission and structural remodeling in major depressive disorder. Activation of melanocortin receptors facilitates stress-induced emotional behavior. Prolylcarboxypeptidase (PRCP) is a serine protease, which splits the C-terminal amino acid of α-MSH and inactivates it. In this study, we asked whether PRCP, the endogenous enzyme of melanocortin system, might play a role in stress susceptibility via regulating synaptic adaptations. Mice were subjected to chronic social defeat stress (CSDS) or subthreshold social defeat stress (SSDS). Depressive-like behavior was assessed in SIT, SPT, TST and FST. Based on to behavioral assessments, mice were divided into the susceptible (SUS) and resilient (RES) groups. After social defeat stress, drug infusion or viral expression and behavioral tests, morphological and electrophysiological analysis were conducted in PFX-fixed and fresh brain slices containing the nucleus accumbens shell (NAcsh). We showed that PRCP was downregulated in NAcsh of susceptible mice. Administration of fluoxetine (20 mg·kg-1·d-1, i.p., for 2 weeks) ameliorated the depressive-like behavior, and restored the expression levels of PRCP in NAcsh of susceptible mice. Pharmacological or genetic inhibition of PRCP in NAcsh by microinjection of N-benzyloxycarbonyl-L-prolyl-L-prolinal (ZPP) or LV-shPRCP enhanced the excitatory synaptic transmission in NAcsh, facilitating stress susceptibility via central melanocortin receptors. On the contrary, overexpression of PRCP in NAcsh by microinjection of AAV-PRCP alleviated the depressive-like behavior and reversed the enhanced excitatory synaptic transmission, abnormal dendritogenesis and spinogenesis in NAcsh induced by chronic stress. Furthermore, chronic stress increased the level of CaMKIIα, a kinase closely related to synaptic plasticity, in NAcsh. The elevated level of CaMKIIα was reversed by overexpression of PRCP in NAcsh. Pharmacological inhibition of CaMKIIα in NAcsh alleviated stress susceptibility induced by PRCP knockdown. This study has revealed the essential role of PRCP in relieving stress susceptibility through melanocortin signaling-mediated synaptic plasticity in NAcsh.

Klotho Regulated by Estrogen Plays a Key Role in Sex Differences in Stress Resilience in Rats.

Klotho (KL) is a glycosyl hydrolase and aging-suppressor gene. Stress is a risk factor for depression and anxiety, which are highly comorbid with each other. The aim of this study is to determine whether KL is regulated by estrogen and plays an important role in sex differences in stress resilience. Our results showed that KL is regulated by estrogen in rat hippocampal neurons in vivo and in vitro and is essential for the estrogen-mediated increase in the number of presynaptic vesicular glutamate transporter 1 (Vglut1)-positive clusters on the dendrites of hippocampal neurons. The role of KL in sex differences in stress response was examined in rats using 3-week chronic unpredictable mild stress (CUMS). CUMS produced a deficit in spatial learning and memory, anhedonic-like behaviors, and anxiety-like behaviors in male but not female rats, which was accompanied by a reduction in KL protein levels in the hippocampus of male but not female rats. This demonstrated the resilience of female rats to CUMS. Interestingly, the knockdown of KL protein levels in the rat hippocampus of both sexes caused a decrease in stress resilience in both sexes, especially in female rats. These results suggest that the regulation of KL by estrogen plays an important role in estrogen-mediated synapse formation and that KL plays a critical role in the sex differences in cognitive deficit, anhedonic-like behaviors, and anxiety-like behaviors induced by chronic stress in rats, highlighting an important role of KL in sex differences in stress resilience.

Recovery of Human Embryonic Stem Cells-Derived Neural Progenitors Exposed to Hypoxic-Ischemic-Reperfusion Injury by Indirect Exposure to Wharton's Jelly Mesenchymal Stem Cells Through Phosphatidyl-inositol-3-Kinase Pathway.

Increasing evidence suggests that mesenchymal stem cells(MSCs) have beneficial effects in hypoxic ischemic reperfusion injury, but the underlying mechanisms are unclear. Here, we first examined the effect of OGD reperfusion injury on the vulnerability of human NPs derived from human embryonic stem cells (hESCs) with regard to cell survival and oxidative stress. Cellular deregulation was assessed by measuring glutathione levels, basal calcium and intracellular calcium [Ca2+]i response under KCl stimulation, as well as the key parameters of proliferation, glial progenitor marker expression and migration. Next, the influence of WJ-MSCs in recovering these parameters was evaluated, and the role of Phosphatidyl-inositol-3-Kinase(PI3K) pathway in actuating the protective effect was assessed. OGD reperfusion injury induced significant increases in cell death, ROS generation, oxidative stress susceptibility and decreased glutathione levels in NPs, accompanied by rises in basal [Ca2+]i, KCl-induced [Ca2+]i, expression of K+ leak channel(TASK1), and declines in proliferation, migration potential and glial progenitor population. The introduction of WJ-MSCs(after 2 h of reperfusion) through a non-contact method brought about significant improvement in all these cellular parameters as observed after 24hrs, and the PI3K pathway played an important role in the neuroprotection process. Presence of WJ-MSCs increased the expression of survival signals like phosphorylated Akt/Akt and PI3K in the OGD-reperfused NPs. Our data clearly demonstrate for the first time that soluble factors from WJ-MSCs can not only ameliorate survival, proliferation, migration and glial progenitor expression of OGD-reperfused NPs, but also regulate their intracellular Ca2+ response to KCl stimulation and expression of TASK1 through the PI3K pathway.

MicroRNA Let-7e in the Mouse Prefrontal Cortex Differentiates Restraint-Stress-Resilient Genotypes from Susceptible Genotype.

Three strains of mice with various susceptibilities to restraint stress (RS), i.e., mice with a knocked out norepinephrine transporter gene (NET-KO), SWR/J and C57BL/6J (WT) mice were shown to serve as a good model to study the molecular mechanisms underlying different stress-coping strategies. We identified 14 miRNAs that were altered by RS in the PFC of these mice in a genotype-dependent manner, where the most interesting was let-7e. Further in silico analysis of its potential targets allowed us to identify five mRNAs (Bcl2l11, Foxo1, Pik3r1, Gab1 and Map2k4), and their level alterations were experimentally confirmed. A next-generation sequencing (NGS) approach, which was employed to find transcripts differentially expressed in the PFC of NET-KO and WT mice, showed that, among others, two additional mRNAs were regulated by mmu-let-7e, i.e., mRNAs that encode Kmt2d and Inf2. Since an increase in Bcl2l11 and Pik3r1 mRNAs upon RS in the PFC of WT mice resulted from the decrease in mmu-let-7e and mmu-miR-484 regulations, we postulated that MAPK, FoxO and PI3K-Akt signaling pathways were associated with stress resilience, although via different, genotype-dependent regulation of various mRNAs by let-7e and miR-484. However, a higher level of Kmt2d mRNA (regulated by let-7e) that was found with NGS analysis in the PFC of NET-KO mice indicated that histone methylation was also important for stress resilience.

The attachment process and physiological properties of Escherichia coli O157:H7 on quartz.

BACKGROUND: Manure application and sewage irrigation release many intestinal pathogens into the soil. After being introduced into the soil matrix, pathogens are commonly found to attach to soil minerals. Although the survival of mineral-associated Escherichia coli O157:H7 has been studied, a comprehensive understanding of the attachment process and physiological properties after attachment is still lacking. RESULTS: In this study, planktonic and attached Escherichia coli O157:H7 cells on quartz were investigated using RNA sequencing (RNA-seq) and the isobaric tagging for relative and absolute quantitation (iTRAQ) proteomic method. Based on the transcriptomic and proteomic analyses and gene knockouts, functional two-component system pathways were required for efficient attachment; chemotaxis and the Rcs system were identified to play determinant roles in E. coli O157:H7 attachment on quartz. After attachment, the pyruvate catabolic pathway shifted from the tricarboxylic acid (TCA) cycle toward the fermentative route. The survival rate of attached E. coli O157:H7 increased more than 10-fold under penicillin and vancomycin stress and doubled under alkaline pH and ferric iron stress. CONCLUSIONS: These results contribute to the understanding of the roles of chemotaxis and the Rcs system in the attachment process of pathogens and indicate that the attachment of pathogens to minerals significantly elevates their resistance to antibiotics and environmental stress, which may pose a potential threat to public health.

Genetic Dissection and Identification of Candidate Genes for Salinity Tolerance Using Axiom®CicerSNP Array in Chickpea.

Globally, chickpea production is severely affected by salinity stress. Understanding the genetic basis for salinity tolerance is important to develop salinity tolerant chickpeas. A recombinant inbred line (RIL) population developed using parental lines ICCV 10 (salt-tolerant) and DCP 92-3 (salt-sensitive) was screened under field conditions to collect information on agronomy, yield components, and stress tolerance indices. Genotyping data generated using Axiom®CicerSNP array was used to construct a linkage map comprising 1856 SNP markers spanning a distance of 1106.3 cM across eight chickpea chromosomes. Extensive analysis of the phenotyping and genotyping data identified 28 quantitative trait loci (QTLs) explaining up to 28.40% of the phenotypic variance in the population. We identified QTL clusters on CaLG03 and CaLG06, each harboring major QTLs for yield and yield component traits under salinity stress. The main-effect QTLs identified in these two clusters were associated with key genes such as calcium-dependent protein kinases, histidine kinases, cation proton antiporter, and WRKY and MYB transcription factors, which are known to impart salinity stress tolerance in crop plants. Molecular markers/genes associated with these major QTLs, after validation, will be useful to undertake marker-assisted breeding for developing better varieties with salinity tolerance.

Chronic social defeat stress increases burst firing of nucleus accumbens-projecting ventral subicular neurons in stress-susceptible mice.

The ventral subiculum (vSub) is the major output structure of the hippocampus and serves as a main limbic region in mediating the brain's response to stress. Previously, we reported that there are three subtypes of vSub neurons based on their firing patterns: regular-spiking (RS), weak-bursting (WB) and strong-bursting (SB) neurons and chronic social defeat stress (CSDS) increased SB neurons especially in the proximal vSub. Here, we found that neurons in the proximal vSub projected to the nucleus accumbens (NAc). CSDS significantly increased SB neurons but decreased RS neurons among the NAc-projecting vSub neuronal population. Interestingly, these changes were only apparent in mice susceptible to CSDS, but not in CSDS-resilient ones. Given that ventral hippocampal inputs to the NAc regulate susceptibility to CSDS, the bursting activity of NAc-projecting vSub neurons might be functionally relevant to behavioral susceptibility to CSDS.

Voluntary wheel running as a promising strategy to promote autonomic resilience to social stress in females: Vagal tone lies at the heart of the matter.

Social stress is a major risk factor for comorbid conditions including cardiovascular disease and depression. While women exhibit 2-3× the risk for these stress-related disorders compared to men, the mechanisms underlying heightened stress susceptibility among females remain largely unknown. Due to a lack in understanding of the pathophysiology underlying stress-induced comorbidities among women, there has been a significant challenge in developing effective therapeutics. Recently, a causal role for inflammation has been established in the onset and progression of comorbid cardiovascular disease/depression, with women exhibiting increased sensitivity to stress-induced immune signaling. Importantly, reduced vagal tone is also implicated in stress susceptibility, through a reduction in the vagus nerve's well-recognized anti-inflammatory properties. Thus, examining therapeutic strategies that stabilize vagal tone during stress may shed light on novel targets for promoting stress resilience among women. Recently, accumulating evidence has demonstrated that physical activity exerts cardio- and neuro-protective effects by enhancing vagal tone. Based on this evidence, this mini review provides an overview of comorbid cardiovascular and behavioral dysfunction in females, the role of inflammation in these disorders, how stress may impart its negative effects on the vagus nerve, and how exercise may act as a preventative. Further, we highlight a critical gap in the literature with regard to the study of females in this field. This review also presents novel data that are the first to demonstrate a protective role for voluntary wheel running over vagal tone and biomarkers of cardiac dysfunction in the face of social stress exposure in female rats.

Hippocampal HDAC5-mediated histone acetylation underlies stress susceptibility in mice exposed to chronic social defeat stress.

Chronic stress leads to social avoidance and anhedonia in susceptible individuals, a phenomenon that has been observed in both human and animal models. Nevertheless, the underlying molecular mechanisms underpinning stress susceptibility and resilience remain largely unclear. There is growing evidence that epigenetic histone deacetylase (HDAC) mediated histone acetylation is involved in the modulation of depressive-related behaviors. We hypothesized that histone deacetylase 5 (HDAC5), which is associated with stress-related behaviors and antidepressant response, may play a vital role in the susceptibility to chronic stress. In the current study, we detected the levels of HDAC5 and acetylation of histone 4 (H4) in the hippocampus subsequent to chronic social defeat stress (CSDS) in C57BL/6J mice. We found that CSDS induces a notable increase in HDAC5 expression, concomitant with a reduction in the acetylation of histone H4 at lysine 12 (H4K12) in the hippocampus of susceptible mice. Meanwhile, intrahippocampal infusion of HDAC5 shRNA or HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) both reversed the depression susceptibility in susceptible mice that subjected to CSDS. Furthermore, HDAC5 overexpression was sufficient to induce depression susceptibility following microdefeat stress, accompanied by a significant reduction in H4K12 level within the hippocampus of mice. Additionally, the Morris water maze (MWM) results indicated that neither CSDS nor HDAC5 exerted significant effects on spatial memory function in mice. Taken together, these investigations indicated that HDAC5-modulated histone acetylation is implicated in regulating the depression susceptibility, and may be serve as potential preventive targets for susceptible individuals.

Inflammation and Connexin 43 profiles in the prefrontal cortex are relevant to stress susceptibility and resilience in mice.

Depression is a major chronic mental illness worldwide, characterized by anhedonia and pessimism. Exposed to the same stressful stimuli, some people behave normally, while others exhibit negative behaviors and psychology. The exact molecular mechanisms linking stress-induced depressive susceptibility and resilience remain unclear. Connexin 43 (Cx43) forms gap junction channels between the astrocytes, acting as a crucial role in the pathogenesis of depression. Cx43 dysfunction could lead to depressive behaviors, and depression down-regulates the expression of Cx43 in the prefrontal cortex (PFC). Besides, accumulating evidence indicates that inflammation is one of the most common pathological features of the central nervous system dysfunction. However, the roles of Cx43 and peripheral inflammation in stress-susceptible and stress-resilient individuals have rarely been investigated. Thus, animals were classified into the chronic unpredictable stress (CUS)-susceptible group and the CUS-resilient group based on the performance of behavioral tests following the CUS protocol in this study. The protein expression of Cx43 in the PFC, the Cx43 functional changes in the PFC, and the expression levels including interleukin (IL)-1ß, tumor necrosis factor-α, IL-6, IL-2, IL-10, and IL-18 in the peripheral serum were detected. Here, we found that stress exposure triggered a significant reduction in Cx43 protein expression in the CUS-susceptible mice but not in the CUS-resilient mice accompanied by various Cx43 phosphorylation expression and the changes of inflammatory signals. Stress resilience is associated with Cx43 in the PFC and fluctuation in inflammatory signaling, showing that therapeutic targeting of these pathways might promote stress resilience.

Activation of NOP receptor increases vulnerability to stress: role of glucocorticoids and CRF signaling.

RATIONALE: Recently, we demonstrated that the activation of the nociceptin/orphanin FQ (N/OFQ) receptor (NOP) signaling facilitates depressive-like behaviors. Additionally, literature findings support the ability of the N/OFQ-NOP system to modulate the hypothalamic-pituitary-adrenal (HPA) axis. OBJECTIVES: Considering that dysfunctional HPA axis is strictly related to stress-induced psychopathologies, we aimed to study the role of the HPA axis in the pro-depressant effects of NOP agonists. METHODS: Mice were treated prior to stress with the NOP agonist Ro 65-6570, and immobility time in the forced swimming task and corticosterone levels were measured. Additionally, the role of endogenous glucocorticoids and CRF was investigated using the glucocorticoid receptor antagonist mifepristone and the CRF1 antagonist antalarmin in the mediation of the effects of Ro 65-6570. RESULTS: The NOP agonist in a dose-dependent manner further increased the immobility of mice in the second swimming session compared to vehicle. By contrast, under the same conditions, the administration of the NOP antagonist SB-612111 before stress reduced immobility, while the antidepressant nortriptyline was inactive. Concerning in-serum corticosterone in mice treated with vehicle, nortriptyline, or SB-612111, a significant decrease was observed after re-exposition to stress, but no differences were detected in Ro 65-6570-treated mice. Administration of mifepristone or antalarmin blocked the Ro 65-6570-induced increase in the immobility time in the second swimming session. CONCLUSIONS: Present findings suggest that NOP agonists increase vulnerability to depression by hyperactivating the HPA axis and then increasing stress circulating hormones and CRF1 receptor signaling.

Neurobiological basis of stress resilience.

A majority of humans faced with severe stress maintain normal physiological and behavioral function, a process referred to as resilience. Such stress resilience has been modeled in laboratory animals and, over the past 15 years, has transformed our understanding of stress responses and how to approach the treatment of human stress disorders such as depression, post-traumatic stress disorder (PTSD), and anxiety disorders. Work in rodents has demonstrated that resilience to chronic stress is an active process that involves much more than simply avoiding the deleterious effects of the stress. Rather, resilience is mediated largely by the induction of adaptations that are associated uniquely with resilience. Such mechanisms of natural resilience in rodents are being characterized at the molecular, cellular, and circuit levels, with an increasing number being validated in human investigations. Such discoveries raise the novel possibility that treatments for human stress disorders, in addition to being geared toward reversing the damaging effects of stress, can also be based on inducing mechanisms of natural resilience in individuals who are inherently more susceptible. This review provides a progress report on this evolving field.

The double-edged sword of the hippocampus-ventromedial prefrontal cortex resting-state connectivity in stress susceptibility and resilience: A prospective study.

The hippocampus has long been considered a pivotal region implicated in both stress susceptibility and resilience. A wealth of evidence from animal and human studies underscores the significance of hippocampal functional connectivity with the ventromedial prefrontal cortex (vmPFC) in these stress-related processes. However, there remains a scarcity of research that explores and contrasts the roles of hippocampus-vmPFC connectivity in stress susceptibility and resilience when facing a real-life traumatic event from a prospective standpoint. In the present study, we investigated the contributions of undirected and directed connectivity between the hippocampus and vmPFC to stress susceptibility and resilience within the context of the COVID-19 pandemic. Our findings revealed that the left hippocampus-left vmPFC connectivity prior to the pandemic exhibited a negative correlation with both stress susceptibility and resilience. Specifically, individuals with stronger left hippocampus-left vmPFC connectivity reported experiencing fewer stress-related feelings during the outbreak period of the epidemic but displayed lower levels of stress resilience five months later. Our application of spectral dynamic causal modeling unveiled an additional inhibitory connectivity pathway from the left hippocampus to the left vmPFC in the context of stress susceptibility, which was notably absent in stress resilience. Furthermore, we observed a noteworthy positive association between self-inhibition of the vmPFC and stress susceptibility, with this effect proving substantial enough to predict an individual's susceptibility to stress; conversely, these patterns did not manifest in the realm of stress resilience. These findings enrich our comprehension of stress susceptibility and stress resilience and might have implications for innovative approaches to managing stress-related disorders.

Ejaculation latency determines susceptibility to stress in the male rat.

Stress induces diverse effects on sexual behavior, ranging from enhanced execution to the complete abolishment of sexual interaction. However, it is not clear whether some characteristics intrinsic to the individual that experiences stress could also explain this differential effect. This study seeks to relate sexual execution to susceptibility to stress (as post-stress sexual motivation). To this end, we designed a three-session experimental paradigm. In the first session, male rats were allowed to copulate with a female. In the second, the male rats received electric foot shocks as they attempted to approach the female. The third and final session was used to determine the effects of stress on sexual behavior by separating the rats into two groups: a motivation-impaired group (rats that did not cross to achieve copulation), and an unimpaired group (rats that did cross). Mount latency was affected immediately by stress in both groups, though only the non-crossing group presented a reduced number of copulatory events. The rats that did not cross showed slower-paced sexual execution even before stress was applied compared to the rats that crossed. These results show that rats that are more susceptible to stress present higher ejaculation latency even before the application of stress.

A thalamic circuit facilitates stress susceptibility via melanocortin 4 receptor-mediated activation of nucleus accumbens shell.

AIMS: Central melanocortin 4 receptor (MC4R) has been reported to induce anhedonia via eliciting dysfunction of excitatory synapses. It is evident that metabolic signals are closely related to chronic stress-induced depression. Here, we investigated that a neural circuit is involved in melanocortin signaling contributing to susceptibility to stress. METHODS: Chronic social defeat stress (CSDS) was used to develop depressive-like behavior. Electrophysiologic and chemogenetic approaches were performed to evaluate the role of paraventricular thalamus (PVT) glutamatergic to nucleus accumbens shell (NAcsh) circuit in stress susceptibility. Pharmacological and genetic manipulations were applied to investigate the molecular mechanisms of melanocortin signaling in the circuit. RESULTS: CSDS increases the excitatory neurotransmission in NAcsh through MC4R signaling. The enhanced excitatory synaptic input in NAcsh is projected from PVT glutamatergic neurons. Moreover, chemogenetic manipulation of PVTGlu -NAcsh projection mediates the susceptibility to stress, which is dependent on MC4R signaling. Overall, these results reveal that the strengthened excitatory neurotransmission in NAcsh originates from PVT glutamatergic neurons, facilitating the susceptibility to stress through melanocortin signaling. CONCLUSIONS: Our results make a strong case for harnessing a thalamic circuit to reorganize excitatory synaptic transmission in relieving stress susceptibility and provide insights gained on metabolic underpinnings of protection against stress-induced depressive-like behavior.

Adolescent neurodevelopment and psychopathology: The interplay between adversity exposure and genetic risk for accelerated brain ageing.

In adulthood, stress exposure and genetic risk heighten psychological vulnerability by accelerating neurobiological senescence. To investigate whether molecular and brain network maturation processes play a similar role in adolescence, we analysed genetic, as well as longitudinal task neuroimaging (inhibitory control, incentive processing) and early life adversity (i.e., material deprivation, violence) data from the Adolescent Brain and Cognitive Development study (N = 980, age range: 9-13 years). Genetic risk was estimated separately for Major Depressive Disorder (MDD) and Alzheimer's Disease (AD), two pathologies linked to stress exposure and allegedly sharing a causal connection (MDD-to-AD). Adversity and genetic risk for MDD/AD jointly predicted functional network segregation patterns suggestive of accelerated (GABA-linked) visual/attentional, but delayed (dopamine [D2]/glutamate [GLU5R]-linked) somatomotor/association system development. A positive relationship between brain maturation and psychopathology emerged only among the less vulnerable adolescents, thereby implying that normatively maladaptive neurodevelopmental alterations could foster adjustment among the more exposed and genetically more stress susceptible youths. Transcriptomic analyses suggested that sensitivity to stress may underpin the joint neurodevelopmental effect of adversity and genetic risk for MDD/AD, in line with the proposed role of negative emotionality as a precursor to AD, likely to account for the alleged causal impact of MDD on dementia onset.