Role of the habenulo-interpeduncular system in the neurodevelopmental basis of susceptibility and resilience to stress-induced anxiety

Experiencing stress during sensitive periods of brain development has a major impact on how individuals cope with later stress. Although many become more prone to develop anxiety or depression, some appear resilient. The mechanisms underlying these differences are unknown. Key answers may lie in how genetic and environmental stressors interact to shape the circuits controlling emotions. Here we studied the role of the habenulo-interpeducuncular system (HIPS), a critical node of reward circuits, in early stress-induced anxiety. We found that a subcircuit of this system, characterized by Otx2 expression, is particularly responsive to chronic stress during puberty, which induces HIPS hypersensitivity to later stress and susceptibility to develop anxiety. We further show that Otx2 deletion restricted to the HIPS counteracts these effects of stress. Together, these results demonstrate that Otx2 and stress interact, around puberty, to shape the HIPS stress-response, revealed here as a key modulator of susceptibility/resilience to develop anxiety.

Role of the habenulo-interpeduncular system in the neurodevelopmental basis of susceptibility and resilience to stressinduced anxiety

Experiencing stress during sensitive periods of brain development has a major impact on how individuals cope with later stress. Although many become more prone to develop anxiety or depression, some appear resilient. The mechanisms underlying these differences are unknown. Key answers may lie in how genetic and environmental stressors interact to shape the circuits controlling emotions. Here we studied the role of the habenulo-interpeducuncular system (HIPS), a critical node of reward circuits, in early stress-induced anxiety. We found that a subcircuit of this system, characterized by Otx2 expression, is particularly responsive to chronic stress during puberty, which induces HIPS hypersensitivity to later stress and susceptibility to develop anxiety. We further show that Otx2 deletion restricted to the HIPS counteracts these effects of stress. Together, these results demonstrate that Otx2 and stress interact, around puberty, to shape the HIPS stress-response, revealed here as a key modulator of susceptibility/resilience to develop anxiety.

Alterations in Metabolome and Microbiome Associated with an Early Stress Stage in Male Wistar Rats: A Multi-Omics Approach

Stress disorders have dramatically increased in recent decades becoming the most prevalent psychiatric disorder in the United States and Europe. However, the diagnosis of stress disorders is currently based on symptom checklist and psychological questionnaires, thus making the identification of candidate biomarkers necessary to gain better insights into this pathology and its related metabolic alterations. Regarding the identification of potential biomarkers, omic profiling and metabolic footprint arise as promising approaches to recognize early biochemical changes in such disease and provide opportunities for the development of integrative candidate biomarkers. Here, we studied plasma and urine metabolites together with metagenomics in a 3 days Chronic Unpredictable Mild Stress (3d CUMS) animal approach that aims to focus on the early stress period of a well-established depression model. The multi-omics integration showed a profile composed by a signature of eight plasma metabolites, six urine metabolites and five microbes. Specifically, threonic acid, malic acid, alpha-ketoglutarate, succinic acid and cholesterol were proposed as key metabolites that could serve as key potential biomarkers in plasma metabolome of early stages of stress. Such findings targeted the threonic acid metabolism and the tricarboxylic acid (TCA) cycle as important pathways in early stress. Additionally, an increase in opportunistic microbes as virus of the Herpesvirales was observed in the microbiota as an effect of the primary stress stages. Our results provide an experimental biochemical characterization of the early stage of CUMS accompanied by a subsequent omic profiling and a metabolic footprinting that provide potential candidate biomarkers.

PIWI silencing mechanism involving the retrotransposon nimbus orchestrates resistance to infection with Schistosoma mansoni in the snail vector, Biomphalaria glabrata

Background Schistosomiasis remains widespread in many regions despite efforts at its elimination. By examining changes in the transcriptome at the host-pathogen interface in the snail Biomphalaria glabrata and the blood fluke Schistosoma mansoni, we previously demonstrated that an early stress response in juvenile snails, manifested by induction of heat shock protein 70 (Hsp 70) and Hsp 90 and of the reverse transcriptase (RT) domain of the B. glabrata non-LTR- retrotransposon, nimbus, were critical for B. glabrata susceptibility to S. mansoni. Subsequently, juvenile B. glabrata BS-90 snails, resistant to S. mansoni at 25°C become susceptible by the F2 generation when maintained at 32°C, indicating an epigenetic response. Methodology/Principal findings To better understand this plasticity in susceptibility of the BS-90 snail, mRNA sequences were examined from S. mansoni exposed juvenile BS-90 snails cultured either at 25°C (non-permissive temperature) or 32°C (permissive). Comparative analysis of transcriptomes from snails cultured at the non-permissive and permissive temperatures revealed that whereas stress related transcripts dominated the transcriptome of susceptible BS-90 juvenile snails at 32°C, transcripts encoding proteins with a role in epigenetics, such as PIWI (BgPiwi), chromobox protein homolog 1 (BgCBx1), histone acetyltransferase (BgHAT), histone deacetylase (BgHDAC) and metallotransferase (BgMT) were highly expressed in those cultured at 25°C. To identify robust candidate transcripts that will underscore the anti-schistosome phenotype in B. glabrata, further validation of the differential expression of the above transcripts was performed by using the resistant BS-90 (25°C) and the BBO2 susceptible snail stock whose genome has now been sequenced and represents an invaluable resource for molecular studies in B. glabrata. A role for BgPiwi in B. glabrata susceptibility to S. mansoni, was further examined by using siRNA corresponding to the BgPiwi encoding transcript to suppress expression of BgPiwi, rendering the resistant BS-90 juvenile snail susceptible to infection at 25°C. Given transposon silencing activity of PIWI as a facet of its role as guardian of the integrity of the genome, we examined the expression of the nimbus RT encoding transcript at 120 min after infection of resistant BS90 piwi-siRNA treated snails. We observed that nimbus RT was upregulated, indicating that modulation of the transcription of the nimbus RT was associated with susceptibility to S. mansoni in BgPiwi-siRNA treated BS-90 snails. Furthermore, treatment of susceptible BBO2 snails with the RT inhibitor lamivudine, before exposure to S. mansoni, blocked S. mansoni infection concurrent with downregulation of the nimbus RT transcript and upregulation of the BgPiwi encoding transcript in the lamivudine-treated, schistosome-exposed susceptible snails. Conclusions and significance These findings support a role for the interplay of BgPiwi and nimbus in the epigenetic modulation of plasticity of resistance/susceptibility in the snail-schistosome relationship.

Central role of the habenulo-interpeduncular system in the neurodevelopmental basis of susceptibility and resilience to anxiety

Experiencing stress during sensitive periods of brain development has a major impact on how individuals cope with later stress. Although many become more prone to develop anxiety or depression, some appear resilient. The mechanisms underlying these differences are unknown. Key answers may lie in how genetic and environmental stressors interact to shape the circuits controlling emotions. Here we studied the role of the habenulo-interpeducuncular system (HIPS), a critical node of reward circuits, in early stress-induced anxiety. We found that a subcircuit of this system, characterized by Otx2 expression, is particularly responsive to chronic stress during puberty, which induces HIPS hypersensitivity to later stress and susceptibility to develop anxiety. We further show that Otx2 deletion restricted to the HIPS counteracts these effects of stress. Together, these results demonstrate that Otx2 and stress interact, around puberty, to shape the HIPS stress-response, revealed here as a key modulator of susceptibility/resilience to develop anxiety.

Individuals with Adverse Childhood Experiences Explore Less and Underweight Positive Reward Feedback

Adverse Childhood Experiences (ACEs) are extreme stressors that lead to negative psychosocial outcomes in adulthood. Non-human animals explore less after exposure to early stress. Therefore, in this pre-registered study we hypothesised that reduced exploration following ACEs would also be evident in human adults. Further, we predicted that adults with ACEs, in a foraging task, would adopt a decision-making policy that relies on the most recent reward feedback, a rational strategy for unstable environments. We analysed data from 145 adult participants, 47 with four or more ACEs and 98 with fewer than four ACEs. In the foraging task, participants evaluated the trade-off between exploiting a known patch with diminishing rewards and exploring a novel one with a fresh distribution of rewards. Using computational modelling, we quantified the degree to which participants’ decisions weighted recent feedback. As predicted, participants with ACEs explored less. However, contrary to our hypothesis, they underweighted recent feedback. These unexpected findings might have occurred due to early adversity causing adults exposed to these experiences to use reward feedback less when making decisions. Our results may help to identify cognitive mechanisms that link childhood trauma to the onset of psychopathology.

Detailed Investigation of Spectral Vegetation Indices for Fine Field-Scale Phenotyping

Spectral vegetation indices (VIs) are a well-known and widely used method for crop state estimation. These technologies have great importance for plant state monitoring, especially for agriculture. The main aim is to assess the performance level of the selected VIs calculated from space-borne multispectral imagery and point-based field spectroscopy in application to crop state estimation. The results obtained indicate that space-borne VIs react on phenology. This feature makes it an appropriate data source for monitoring crop development, crop water needs and yield prediction. Field spectrometer VIs were sensitive for estimating pigment concentration and photosynthesis rate. Yet, a hypersensitivity of field spectral measures might lead to a very high variability of the calculated values. The results obtained in the second part of the presented study were reported on crop state estimated by 17 VIs known as sensitive to plant drought. An alternative approach for identification early stress by VIs proposed in this study is Principal Component Analysis (PCA). The results show that PCA has identified the degree of similarity of the different states and together with reference stress states from the control plot clearly estimated stress in the actual irrigated field, which was hard to detect by VIs values only.

Connect-the-DOT from early stress to depression

Targeting the epigenetic enzyme DOT1L may reverse some behavioral effects of early-life stress.