The importance of m6A topology in chicken embryo mRNA: a precise mapping of m6A at the conserved chicken ß-actin zipcode.

N6-methyladenosine (m6A) in mRNA regulates almost every stage in the mRNA life cycle, and the development of methodologies for the high-throughput detection of methylated sites in mRNA using m6A-specific methylated RNA immunoprecipitation with next-generation sequencing (MeRIPSeq) or m6A individual-nucleotide-resolution cross-linking and immunoprecipitation (miCLIP) have revolutionized the m6A research field. Both of these methods are based on immunoprecipitation of fragmented mRNA. However, it is well documented that antibodies often have nonspecific activities, thus verification of identified m6A sites using an antibody-independent method would be highly desirable. We mapped and quantified the m6A site in the chicken ß-actin zipcode based on the data from chicken embryo MeRIPSeq results and our RNA-Epimodification Detection and Base-Recognition (RedBaron) antibody-independent assay. We also demonstrated that methylation of this site in the ß-actin zipcode enhances ZBP1 binding in vitro, while methylation of a nearby adenosine abolishes binding. This suggests that m6A may play a role in regulating localized translation of ß-actin mRNA, and the ability of m6A to enhance or inhibit a reader protein's RNA binding highlights the importance of m6A detection at nucleotide resolution.

Extracellular vesicle microRNA-mediated transcriptional regulation may contribute to dementia with Lewy bodies molecular pathology.

OBJECTIVE: Dementia with Lewy bodies (DLB) is the second most common dementia. Advancing our limited understanding of its molecular pathogenesis is essential for identifying novel biomarkers and therapeutic targets for DLB. DLB is an α-synucleinopathy, and small extracellular vesicles (SEV) from people with DLB can transmit α-synuclein oligomerisation between cells. Post-mortem DLB brains and serum SEV from those with DLB share common miRNA signatures, and their functional implications are uncertain. Hence, we aimed to investigate potential targets of DLB-associated SEV miRNA and to analyse their functional implications. METHODS: We identified potential targets of six previously reported differentially expressed miRNA genes in serum SEV of people with DLB (MIR26A1, MIR320C2, MIR320D2, MIR548BA, MIR556, and MIR4722) using miRBase and miRDB databases. We analysed functional implications of these targets using EnrichR gene set enrichment analysis and analysed their protein interactions using Reactome pathway analysis. RESULTS: These SEV miRNA may regulate 4278 genes that were significantly enriched among the genes involved in neuronal development, cell-to-cell communication, vesicle-mediated transport, apoptosis, regulation of cell cycle, post-translational protein modifications, and autophagy lysosomal pathway, after Benjamini-Hochberg false discovery rate correction at 5%. The miRNA target genes and their protein interactions were significantly associated with several neuropsychiatric disorders and with multiple signal transduction, transcriptional regulation, and cytokine signalling pathways. CONCLUSION: Our findings provide in-silico evidence that potential targets of DLB-associated SEV miRNAs may contribute to Lewy pathology by transcriptional regulation. Experimental validation of these dysfunctional pathways is warranted and could lead to novel therapeutic avenues for DLB.

m6 A mRNA methylation in human brain is disrupted in Lewy body disorders.

AIMS: N6 -methyladenosine modification of RNA (m6 A) regulates translational control, which may influence neuronal dysfunction underlying neurodegenerative diseases. METHODS: Using microscopy and a machine learning approach, we performed cellular profiling of m6 A-RNA abundance and YTHDF1/YTHDF3 m6 A reader expression within four regions of the human brain from non-affected individuals and individuals with Parkinson's disease, dementia with Lewy bodies or mild cognitive impairment (MCI). RESULTS: In non-diseased tissue, we found that m6 A-modified RNAs showed cell-type and sub-compartment-specific variation. YTHDF1 and YTHDF3 showed opposing expression patterns in the cerebellum and the frontal and cingulate cortices. Machine learning quantitative image analysis revealed that m6 A-modified transcripts were significantly altered in localisation and abundance in disease tissue with significant decreases in m6 A-RNAs in Parkinson's disease, and significant increases in m6 A-RNA abundance in dementia with Lewy bodies. MCI tissue showed variability across regions but similar to DLB; in brain areas with an overall significant increase in m6 A-RNAs, modified RNAs within dendritic processes were reduced. Using mass spectrometry proteomic datasets to corroborate our findings, we found significant changes in YTHDF3 and m6 A anti-reader protein abundance in Alzheimer's disease (AD) and asymptomatic AD/MCI tissue and correlation with cognitive resilience. CONCLUSIONS: These results provide evidence for disrupted m6 A regulation in Lewy body diseases and a plausible mechanism through which RNA processing could contribute to the formation of Lewy bodies and other dementia-associated pathological aggregates. The findings suggest that manipulation of epitranscriptomic processes influencing translational control may lead to new therapeutic approaches for neurodegenerative diseases.

Modifying the m6A brain methylome by ALKBH5-mediated demethylation: a new contender for synaptic tagging.

Synaptic plasticity processes, which underlie learning and memory formation, require RNA to be translated local to synapses. The synaptic tagging hypothesis has previously been proposed to explain how mRNAs are available at specific activated synapses. However how RNA is regulated, and which transcripts are silenced or processed as part of the tagging process is still unknown. Modification of RNA by N6-methyladenosine (m6A/m) influences the cellular fate of mRNA. Here, by advanced microscopy, we showed that m6A demethylation by the eraser protein ALKBH5 occurs at active synaptic ribosomes and at synapses during short term plasticity. We demonstrated that at activated glutamatergic post-synaptic sites, both the YTHDF1 and YTHDF3 reader and the ALKBH5 eraser proteins increase in co-localisation to m6A-modified RNAs; but only the readers showed high co-localisation to modified RNAs during late-stage plasticity. The YTHDF1 and YTHFDF3 readers also exhibited differential roles during synaptic maturation suggesting that temporal and subcellular abundance may determine specific function. m6A-sequencing of human parahippocampus brain tissue revealed distinct white and grey matter m6A methylome profiles indicating that cellular context is a fundamental factor dictating regulated pathways. However, in both neuronal and glial cell-rich tissue, m6A effector proteins are themselves modified and m6A epitranscriptional and posttranslational modification processes coregulate protein cascades. We hypothesise that the availability m6A effector protein machinery in conjunction with RNA modification, may be important in the formation of condensed synaptic nanodomain assemblies through liquid-liquid phase separation. Our findings support that m6A demethylation by ALKBH5 is an intrinsic component of the synaptic tagging hypothesis and a molecular switch which leads to alterations in the RNA methylome, synaptic dysfunction and potentially reversible disease states.

Fearing the wurst: Robust approach bias towards non-vegetarian food images in a sample of young female vegetarian eaters.

Previous studies have shown that humans show an implicit approach bias toward food related items which is moderated by hunger and properties of the food items displayed (such as their palatability and calorie content). However, little is known about if and how this approach bias is moderated by food preferences and/or diet choices. In this study, we compared approach-avoidance biases in a group of young female omnivore and vegetarian eaters towards images of vegetarian and non-vegetarian food items using a manikin stimulus-response compatibility task. While vegetarian eaters showed a slightly larger approach bias for vegetarian than for non-vegetarian food stimuli, this bias was of similar size to that observed in the omnivorous group. Most interestingly, vegetarian eaters' approach bias towards non-vegetarian food pictures also did not differ from that of the omnivorous group, despite vegetarians rating those pictures as much less pleasant. Our findings suggest that approach biases towards food items are quite robust and do not rapidly change with dietary practice. However, despite approach biases often guiding behaviour, vegetarian eaters successfully withstand these implicit action tendencies and avoid non-vegetarian produce. Potential implications of this finding for the addiction literature are discussed.

St. Luke's Hospice: Prioritizing Comfort, Not Cure, in the Hospital Setting.

The American hospice movement arose in the 1970s as an alternative to standard hospital care for terminally ill patients, emphasizing symptom management and psychological and spiritual care. St. Luke's Hospice of New York City was an outlier in this movement. While other hospices sought to distance themselves from the preexisting healthcare system for fear of its corrupting influence, St. Luke's sought to transform the system from within. While other hospices ultimately accommodated state and federal regulations for terminal care, St. Luke's tried to survive outside of this newly regulated space. This examination of St. Luke's Hospice complicates the preexisting narrative of the hospice movement as a countercultural movement that was subsequently corrupted by integration into mainstream healthcare. It also demonstrates opportunities and challenges in trying to change the structure and culture of the acute care hospital.

Kinetics of T-cell subset reconstitution following treatment with bendamustine and rituximab for low-grade lymphoproliferative disease: a population-based analysis.

Delayed lymphocyte and T-cell immune reconstitution following bendamustine-rituximab (BR) for indolent non-Hodgkin lymphoma (iNHL) has been described, but no information is available for chronic lymphocytic leukaemia (CLL). We present a population-based retrospective analysis of immune reconstitution and risk of infection following BR. Outcomes included timing/correlates of CD4+ recovery and risk of ≥grade 3 infections. Consecutively treated patients (1 April 2014 to 31 January 2017) were included (n = 295),with a median age of 65 years (range 33-92); 57% were 1st line treatments. Median cumulative bendamustine dose was 1080 mg/m2 (range 140-1440 mg/m2 ). CD4/CD8/CD19/NK subsets were available for 148 patients. Median follow-up was 24 months. Median times to lymphocyte count (ALC) recovery (≥1 × 109 /l) and CD4+ recovery (≥0·2 × 109 /l) were 26 and 24 months, respectively. Bendamustine total dose >1080 mg/m2 (hazard ratio [HR] 0·4; 95% confidence interval [CI]: 0·2-0·8), end-of-treatment ALC ≤0·4 × 109 /l (HR 0·53; 95% CI: 0·3-0·9) and CD4+ <0·1 × 109 /l 1-year post-BR (HR 0·03; 95% CI: 0·008-0·15) were covariables for delayed CD4+ recovery. ALC-recovery ≥1 × 109 /l was an unreliable predictor of CD4+ recovery (negative predictive vale 74%, positive predictive value 86%, likelihood ratio 3·3). CD4+ lymphopenia >3 years was a significant risk factor for ≥grade 3 infections (Odds ratio 3·4; 95% CI: 1·4-6·9). CD4+ recovery after BR is unexpectedly delayed and late recovery is associated with risk of serious infections. Monitoring CD4+ following BR could identify patients at high risk of delayed infections.

Vitamin intake is associated with improved visuospatial and verbal semantic memory in middle-aged individuals.

OBJECTIVES: Factors maintaining cognitive health are still largely unknown. In particular, the cognitive benefits associated with vitamin intake and vitamin supplementation are disputed. We investigated self-reported vitamin intake and serum vitamin levels with performance in cognitive factors sensitive to dementia progression in two large middle-aged general population cohorts. METHODS: Survey data were used to assess regular vitamin intake in 4400 NCDS 1958 and 1177 TwinsUK cohort members, and serum homocysteine and B vitamin levels were measured in 675 individuals from the TwinsUK study. Principal component analysis was applied to cognitive test performance from both cohorts resulting in two dementia-sensitive cognitive factors reflecting visuospatial associative memory and verbal semantic memory. RESULTS: In both cohorts, individuals who reported regular intake of vitamins, particularly B vitamins, showed significantly better performance in visuospatial associative memory and verbal semantic memory (P < 0.001). A significant association was also found between homocysteine levels, vitamin serum concentration and visuospatial associative memory performance which indicated that individuals with high B vitamin and homocysteine levels showed better visuospatial associative memory performance than individuals with low vitamin B levels (P < 0.05). DISCUSSION: The findings demonstrate that early dementia-sensitive cognitive changes can be identified in middle-aged asymptomatic individuals and that regular vitamin intake is associated with improved cognitive performance. These findings reinforce the potential cognitive benefits of regular vitamin intake, which should be considered as an economically viable therapeutic strategy for maintaining cognitive health.

Using technology to improve end of life care.

As clinical and operations director at East Cheshire Hospice I see the complex and sensitive discussions that my staff have with patients and their loved ones every day.

Retrospective evaluation of palliative care and hospice utilization in hospitalized patients with metastatic breast cancer.

BACKGROUND: Hospitalizations in patients with metastatic cancer occur commonly at the end of life but have not been well-described in individuals with metastatic breast cancer. AIM: To describe the reasons for admission and frequency of palliative care and hospice utilization in hospitalized patients with metastatic breast cancer. DESIGN: This was a retrospective chart review of patients who had their first hospitalization with a diagnosis of metastatic breast cancer between 1 January 2009 and 31 December 2010. To standardize follow-up time, we collected data for 3 years post the index hospitalization. SETTING/PARTICIPANTS: We identified 123 consecutive patients who were hospitalized for the first time with a diagnosis of metastatic breast cancer at a single, tertiary care center. RESULTS: Uncontrolled symptoms accounted for half (50%, 62/123) of index admissions. The majority of patients died during the follow-up period (76%, 94/123), and the median time from index admission to death was 6 months (range: 0-34 months). Approximately half (53%, 50/94) died in the hospital or within 14 days of last hospital discharge, and less than one-third (29%, 27/94) were referred to hospice after their last hospitalization. The inpatient palliative care team evaluated 57% (54/94) of those who died at least once during an admission, but only 17% (16/94) of patients attended an outpatient palliative care appointment. CONCLUSIONS: Hospitalized patients with metastatic breast cancer are commonly admitted for uncontrolled symptoms and have a poor prognosis. However, only a minority receive outpatient palliative care or are referred to hospice during their last hospitalization prior to death.

Cancer care for individuals with schizophrenia.

Individuals with schizophrenia are a vulnerable population that has been relatively neglected in health disparities research. Despite having an equivalent risk of developing most cancers, patients with schizophrenia are more likely to die of cancer than the general population. Cancer care disparities are likely the result of patient-, provider-, and systems-level factors and influenced by the pervasive stigma of mental illness. Individuals with schizophrenia have higher rates of health behaviors linked with cancer mortality including cigarette smoking. They also have significant medical comorbidity, are less likely to have up-to-date cancer screening, and may present at more advanced stages of illness. Patients with schizophrenia may be less likely to receive chemotherapy or radiotherapy, have more postoperative complications, and have less access to palliative care. However, opportunities exist for the interdisciplinary team, including medical, surgical, and radiation oncologists; psychiatrists; and primary care physicians, to intervene throughout the continuum of cancer care to promote survival and quality of life. This review summarizes data on overall and cancer-specific mortality for individuals with schizophrenia and reviews specific disparities across the cancer care continuum of screening, diagnosis, treatment, and end-of-life care. Using a case, the authors illustrate clinical challenges for this population including communication, informed consent, and risk of suicide, and provide suggestions for care. Finally, recommendations for research to address the disparities in cancer care for individuals with schizophrenia are discussed. Despite significant challenges, with collaboration between oncology and mental health teams, individuals with schizophrenia can receive high-quality cancer care.

Perspectives on Transfusions for Hospice Patients With Blood Cancers: A Survey of Hospice Providers.

CONTEXT: Patients with blood cancers have low rates of hospice use. While lack of transfusion access in hospice is posited to substantially contribute to these low rates, little is known about the perspectives of hospice providers regarding transfusion access in hospice. OBJECTIVES: To characterize hospice providers' perspectives regarding care for patients with blood cancers and transfusions in the hospice setting. METHODS: In 2022, we conducted a cross-sectional survey of a sample of hospices in the United States regarding their experience caring for patients with blood cancers, perceived barriers to hospice use, and interventions to increase enrollment. RESULTS: We received 113 completed surveys (response rate = 23.5%). Of the cohort, 2.7% reported that their agency always offers transfusions, 40.7% reported sometimes offering transfusions, and 54.9% reported never offering transfusions. In multivariable analyses, factors associated with offering transfusions included nonprofit ownership (OR 5.93, 95% CI, 2.2-15.2) and daily census >50 patients (OR 3.06, 95% CI, 1.19-7.87). Most respondents (76.6%) identified lack of transfusion access in hospice as a barrier to hospice enrollment for blood cancer patients. The top intervention considered as "very helpful" for increasing enrollment was additional reimbursement for transfusions (72.1%). CONCLUSION: In this national sample of hospices, access to palliative transfusions was severely limited and was considered a significant barrier to hospice use for blood cancer patients. Moreover, hospices felt increased reimbursement for transfusions would be an important intervention. These data suggest that hospice providers are supportive of increasing transfusion access and highlight the critical need for innovative hospice payment models to improve end-of-life care for patients with blood cancers.

Cognitive endophenotypes in a family with bipolar disorder with a risk locus on chromosome 4.

OBJECTIVES: We studied cognitive function in high-risk relatives belonging to a single extended family showing linkage of bipolar disorder to a locus on chromosome 4. High-risk relatives were defined as those that carried the risk haplotype of polymorphic markers, identified in a previous linkage study. This family provided a rare opportunity to characterize a neuropsychological endophenotype in a homogeneous sample of relatives with a common genetic risk factor. METHODS: Fifteen family members carrying the risk haplotype (eight diagnosed with bipolar disorder or depression and seven with no psychiatric diagnosis), unrelated patients with bipolar disorder (n = 36) and major depressive disorder (n = 40), and healthy control subjects (n = 33) were administered the California Verbal Learning Test, Verbal Fluency Test, Hayling Sentence Completion Test, and Brixton Spatial Anticipation Test to assess verbal memory, verbal fluency, and executive function. RESULTS: Compared with healthy controls, family members carrying the risk haplotype were impaired in indices of memory and executive function. There were no significant differences between unaffected and affected haplotype-carrying family members in any cognitive measure. Pronounced deficits in the encoding stage of verbal memory and category verbal fluency were evident in individuals with the risk haplotype. CONCLUSIONS: Verbal learning and semantic verbal fluency impairments may represent a cognitive endophenotype for both bipolar disorder and major depression in relatives of bipolar disorder patients, as impairment was also present in high-risk relatives who had not developed any affective disorder symptoms. These findings suggest that impairment in semantic organization may be linked to the genetic aetiology of bipolar disorder.

Differential expression of m5C RNA methyltransferase genes NSUN6 and NSUN7 in Alzheimer's disease and traumatic brain injury.

Epigenetic processes have become increasingly relevant in understanding disease-modifying mechanisms. 5-Methylcytosine methylations of DNA (5mC) and RNA (m5C) have functional transcriptional and RNA translational consequences and are tightly regulated by writer, reader and eraser effector proteins. To investigate the involvement of 5mC/5hmC and m5C effector proteins contributing to the development of dementia neuropathology, RNA sequencing data of 31 effector proteins across four brain regions was examined in 56 aged non-affected and 51 Alzheimer's disease (AD) individuals obtained from the Aging, Dementia and Traumatic Brain Injury Study. Gene expression profiles were compared between AD and controls, between neuropathological Braak and CERAD scores and in individuals with a history of traumatic brain injury (TBI). We found an increase in the DNA methylation writers DNMT1, DNMT3A and DNMT3B messenger RNA (mRNA) and a decrease in the reader UHRF1 mRNA in AD samples across three brain regions whilst the DNA erasers GADD45B and AICDA showed changes in mRNA abundance within neuropathological load groupings. RNA methylation writers NSUN6 and NSUN7 showed significant expression differences with AD and, along with the reader ALYREF, differences in expression for neuropathologic ranking. A history of TBI was associated with a significant increase in the DNA readers ZBTB4 and MeCP2 (p < 0.05) and a decrease in NSUN6 (p < 0.001) mRNA. These findings implicate regulation of protein pathways disrupted in AD and TBI via multiple pre- and post-transcriptional mechanisms including potentially acting upon transfer RNAs, enhancer RNAs as well as nuclear-cytoplasmic shuttling and cytoplasmic translational control. The targeting of such processes provides new therapeutic avenues for neurodegenerative brain conditions.

Soft, bioresorbable, transparent microelectrode arrays for multimodal spatiotemporal mapping and modulation of cardiac physiology.

Transparent microelectrode arrays (MEAs) that allow multimodal investigation of the spatiotemporal cardiac characteristics are important in studying and treating heart disease. Existing implantable devices, however, are designed to support chronic operational lifetimes and require surgical extraction when they malfunction or are no longer needed. Meanwhile, bioresorbable systems that can self-eliminate after performing temporary functions are increasingly attractive because they avoid the costs/risks of surgical extraction. We report the design, fabrication, characterization, and validation of a soft, fully bioresorbable, and transparent MEA platform for bidirectional cardiac interfacing over a clinically relevant period. The MEA provides multiparametric electrical/optical mapping of cardiac dynamics and on-demand site-specific pacing to investigate and treat cardiac dysfunctions in rat and human heart models. The bioresorption dynamics and biocompatibility are investigated. The device designs serve as the basis for bioresorbable cardiac technologies for potential postsurgical monitoring and treating temporary patient pathological conditions in certain clinical scenarios, such as myocardial infarction, ischemia, and transcatheter aortic valve replacement.

Open thoracic surgical implantation of cardiac pacemakers in rats.

Genetic engineering and implantable bioelectronics have transformed investigations of cardiovascular physiology and disease. However, the two approaches have been difficult to combine in the same species: genetic engineering is applied primarily in rodents, and implantable devices generally require larger animal models. We recently developed several miniature cardiac bioelectronic devices suitable for mice and rats to enable the advantages of molecular tools and implantable devices to be combined. Successful implementation of these device-enabled studies requires microsurgery approaches that reliably interface bioelectronics to the beating heart with minimal disruption to native physiology. Here we describe how to perform an open thoracic surgical technique for epicardial implantation of wireless cardiac pacemakers in adult rats that has lower mortality than transvenous implantation approaches. In addition, we provide the methodology for a full biocompatibility assessment of the physiological response to the implanted device. The surgical implantation procedure takes ~40 min for operators experienced in microsurgery to complete, and six to eight surgeries can be completed in 1 d. Implanted pacemakers provide programmed electrical stimulation for over 1 month. This protocol has broad applications to harness implantable bioelectronics to enable fully conscious in vivo studies of cardiovascular physiology in transgenic rodent disease models.

A cytogenetic abnormality and rare coding variants identify ABCA13 as a candidate gene in schizophrenia, bipolar disorder, and depression.

Schizophrenia and bipolar disorder are leading causes of morbidity across all populations, with heritability estimates of approximately 80% indicating a substantial genetic component. Population genetics and genome-wide association studies suggest an overlap of genetic risk factors between these illnesses but it is unclear how this genetic component is divided between common gene polymorphisms, rare genomic copy number variants, and rare gene sequence mutations. We report evidence that the lipid transporter gene ABCA13 is a susceptibility factor for both schizophrenia and bipolar disorder. After the initial discovery of its disruption by a chromosome abnormality in a person with schizophrenia, we resequenced ABCA13 exons in 100 cases with schizophrenia and 100 controls. Multiple rare coding variants were identified including one nonsense and nine missense mutations and compound heterozygosity/homozygosity in six cases. Variants were genotyped in additional schizophrenia, bipolar, depression (n > 1600), and control (n > 950) cohorts and the frequency of all rare variants combined was greater than controls in schizophrenia (OR = 1.93, p = 0.0057) and bipolar disorder (OR = 2.71, p = 0.00007). The population attributable risk of these mutations was 2.2% for schizophrenia and 4.0% for bipolar disorder. In a study of 21 families of mutation carriers, we genotyped affected and unaffected relatives and found significant linkage (LOD = 4.3) of rare variants with a phenotype including schizophrenia, bipolar disorder, and major depression. These data identify a candidate gene, highlight the genetic overlap between schizophrenia, bipolar disorder, and depression, and suggest that rare coding variants may contribute significantly to risk of these disorders.

GRIK4/KA1 protein expression in human brain and correlation with bipolar disorder risk variant status.

The kainate class of ionotropic glutamate receptors is involved in the regulation of neuronal transmission and synaptic plasticity. Previously we reported that a deletion variant within the gene GRIK4, which encodes the KA1 kainate receptor subunit, was associated with a reduced risk of bipolar disorder and increased GRIK4 mRNA abundance. Using a high resolution immunohistochemistry technique, we characterized KA1 protein localization in human brain and performed a genotype-protein expression correlation study. KA1 was expressed in specific populations of neuronal cells in the cerebellum and all layers of the frontal and parahippocampal cortices. In the hippocampus, strong KA1 expression was observed in the stratum pyramidale and stratum lucidum of CA3 and CA2, in cell processes in CA1, in the neuropil of the CA4 region, in polymorphic cells including mossy fiber neurons in the hilus, and dentate gyrus (DG) granule cells. Mean counts of KA1 positive DG granule cells, hippocampal CA3 pyramidal cells, and layer 1 of the frontal cortex were significantly increased in subjects with the deletion allele (P = 0.0005, 0.018, and 0.0058, respectively) compared to subjects homozygous for the insertion. Neuronal expression levels in all regions quantified were higher in the deletion group. These results support our hypothesis that the deletion allele affords protection against bipolar disorder through increased KA1 protein abundance in neuronal cells. Biological mechanisms which may contribute to this protective effect include KA1 involvement in adult hippocampal neurogenesis, HPA axis activation, or plasticity processes affecting neuronal circuitry.