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.

Diet Prevents Social Stress-Induced Maladaptive Neurobehavioural and Gut Microbiota Changes in a Histamine-Dependent Manner

Exposure to repeated social stress may cause maladaptive emotional reactions that can be reduced by healthy nutritional supplementation. Histaminergic neurotransmission has a central role in orchestrating specific behavioural responses depending on the homeostatic state of a subject, but it remains to be established if it participates in the protective effects against the insults of chronic stress afforded by a healthy diet. By using C57BL/6J male mice that do not synthesize histamine (Hdc−/−) and their wild type (Hdc+/+) congeners we evaluated if the histaminergic system participates in the protective action of a diet enriched with polyunsaturated fatty acids and vitamin A on the deleterious effect of chronic stress. Behavioural tests across domains relevant to cognition and anxiety were performed. Hippocampal synaptic plasticity, cytokine expression, hippocampal fatty acids, oxylipins and microbiota composition were also assessed. Chronic stress induced social avoidance, poor recognition memory, affected hippocampal long-term potentiation, changed the microbiota profile, brain cytokines, fatty acid and oxylipins composition of both Hdc−/−and Hdc+/+ mice. Dietary enrichment counteracted stress-induced deficits only in Hdc+/+ mice as histamine deficiency prevented almost all of the diet-related beneficial effects. Interpretation: Our results reveal a previously unexplored and novel role for brain histamine as a mediator of many favorable effects of the enriched diet. These data present long-reaching perspectives in the field of nutritional neuropsychopharmacology.

Neuronal Yin Yang1 in the prefrontal cortex regulates transcriptional and behavioral responses to chronic stress in mice

Although the synaptic alterations associated with the stress-related mood disorder major depression has been well-documented, the underlying transcriptional mechanisms remain poorly understood. Here, we perform complementary bulk nuclei- and single-nucleus transcriptome profiling and map locus-specific chromatin interactions in mouse neocortex to identify the cell type-specific transcriptional changes associated with stress-induced behavioral maladaptation. We find that cortical excitatory neurons, layer 2/3 neurons in particular, are vulnerable to chronic stress and acquire signatures of gene transcription and chromatin structure associated with reduced neuronal activity and expression of Yin Yang 1 (YY1). Selective ablation of YY1 in cortical excitatory neurons enhances stress sensitivity in both male and female mice and alters the expression of stress-associated genes following an abbreviated stress exposure. These findings demonstrate how chronic stress impacts transcription in cortical excitatory neurons and identify YY1 as a regulator of stress-induced maladaptive behavior in mice.

Corticosterone-mediated regulation and functions of miR-218-5p in rat brain

Chronic stress is one of the key precipitating factors in major depressive disorder (MDD). Stress associated studies have underscored the mechanistic role of epigenetic master players like microRNAs (miRNAs) in depression pathophysiology at both preclinical and clinical levels. Previously, we had reported changes in miR-218-5p expression in response to corticosterone (CORT) induced chronic stress. MiR-218-5p was one of the most significantly induced miRNAs in the prefrontal cortex (PFC) of rats under chronic stress. In the present report, we have investigated how chronic CORT exposure mechanistically affected miR-218-5p expression in the rat brain and how miR-218 could trigger molecular changes on its downstream regulatory pathways. Elevated expression of miR-218-5p was found in the PFC of CORT-treated rats. A glucocorticoid receptor (GR) targeted Chromatin-Immunoprecipitation (ChIP) assay revealed high GR occupancy on the promoter region of Slit3 gene hosting miR-218-2 in its 3rd intron. RNA-sequencing data based on RNA Induced silencing Complex Immunoprecipitation (RISC-IP) with AGO2 in SH-SY5Y cells detected six consistent target genes of miR-218-5p (APOL4, DTWD1, BNIP1, METTL22, SNAPC1, and HDAC6). The expression of all five genes, except APOL4, was successfully validated with qPCR in CORT-treated rat PFC. Further, Hdac6-based ChIP-seq experiment helped in mapping major genomic loci enriched for intergenic regions in the PFC of CORT-treated rat. A proximity-based gene ontology (GO) analysis revealed a majority of the intergenic sites to be part of key genes implicated in central nervous system functions, notably synapse organization, neuron projection morphogenesis, and axonogenesis. Our results suggest that the upregulation of miR-218-5p in PFC of CORT-treated rats possibly resulted from GR biding in the promoter region of Slit3 gene. Interestingly, Hdac6 was one of the consistent target genes potentially found to regulate CNS related genes by chromatin modification. Collectively, these findings establish the role of miR-218-5p in chronic stress and the epigenetic function it plays to induce chromatin-based transcriptional changes of several CNS genes in triggering stress-induced disorders, including depression. This also opens up the scope to understand the role of miR-218-5p as a potential target for noncoding RNA therapeutics in clinical depression.

Brief Report: Above and Beyond Safety: Psychosocial and Biobehavioral Impact of Autism-Assistance Dogs on Autistic Children and their Families

Autism-Assistance Dogs (AADs) are highly-skilled service animals trained primarily to ensure the safety of an autistic child by preventing elopement and mitigating ‘meltdowns’. Although anecdotal accounts and case-studies have indicated that AADs confer benefits above and beyond safety, empirical support anchored in validated clinical, behavioral, and physiological measures is lacking. To address this gap, we studied children and their families before and after receiving a well-trained AAD using a within-subject, repeated-measures design. Notably, this study is the first to assess change in a biomarker for chronic stress in both autistic children and their parents. Final analyses included pre-/post-AAD data from 11 triads (parent/handler-dog-child) demonstrating significantly positive psychosocial and biobehavioral effects of AADs.

The Psychological and Biological Impact of “In-Person” vs. “Virtual” Choir Singing in Children and Adolescents: A Pilot Study Before and After the Acute Phase of the COVID-19 Outbreak in Austria

Psychobiological responses to music have been examined previously in various naturalistic settings in adults. Choir singing seems to be associated with positive psychobiological outcomes in adults. However, evidence on the effectiveness of singing in children and adolescents is sparse. The COVID-19 outbreak is significantly affecting society now and in the future, including how individuals engage with music. The COVID-19 pandemic is occurring at a time when virtual participation in musical experiences such as singing in a virtual choir has become more prevalent. However, it remains unclear whether virtual singing leads to different responses in comparison with in-person singing. We evaluated the psychobiological effects of in-person choral singing (7 weeks, from January to March 2020, before the COVID-19 outbreak) in comparison with the effects of virtual choral singing (7 weeks, from May to July 2020, after schools partly re-opened in Austria) in a naturalistic pilot within-subject study. A group of children and young adolescents (N = 5, age range 10–13, female = 2) from a school in Salzburg, Austria were recruited to take part in the study. Subjective measures (momentary mood, stress) were taken pre- and post-singing sessions once a week. Additionally, salivary biomarkers (cortisol and alpha-amylase) and quantity of social contacts were assessed pre- and post-singing sessions every second week. Psychological stability, self-esteem, emotional competences, and chronic stress levels were measured at the beginning of in-person singing as well as at the beginning and the end of the virtual singing. We observed a positive impact on mood after both in-person and virtual singing. Over time, in-person singing showed a pre-post decrease in salivary cortisol, while virtual singing showed a moderate increase. Moreover, a greater reduction in stress, positive change in calmness, and higher values of social contacts could be observed for the in-person setting compared to the virtual one. In addition, we observed positive changes in psychological stability, maladaptive emotional competences, chronic stress levels, hair cortisol, self-contingency and quality of life. Our preliminary findings suggest that group singing may provide benefits for children and adolescents. In-person singing in particular seems to have a stronger psychobiological effect.