BACKGROUND:Gastrostomy tube placement provides long-term enteral access for stroke patients with persistent dysphagia, but the optimal timing of gastrostomy tube placement remains uncertain. Early gastrostomy tube placement may facilitate rehabilitation and discharge, but concerns remain about the necessity of the procedure in patients who may recover swallowing function. METHODS:We conducted a systematic review of studies that evaluated the timing of gastrostomy tube placement in patients with stroke. Early placement was defined as gastrostomy tube placement within 7 days of the qualifying stroke event or admission. Random-effects meta-analysis was used to pool binary outcomes as risk ratios (RRs), and hospital length of stay was pooled as a mean difference (MD). The primary analysis was restricted to studies using a ≤7-day cutoff, with a sensitivity analysis that incorporated one study using a ≤14-day cutoff. RESULTS:Four studies (245,553 patients) using a ≤7-day definition were analyzed, with one additional study (≤14-day definition) included as a sensitivity analysis. Early gastrostomy tube placement was associated with significantly shorter hospital length of stay (4 studies; MD, -11.38 days; 95% CI, -15.56 to -7.20; p < 0.001; I2 = 99.9%). Early placement was also associated with a significantly lower risk of venous thromboembolism (3 studies; RR, 0.47; 95% CI, 0.32-0.69; p < 0.001; I2 = 97.3%). No significant differences were observed for mortality (4 studies; RR, 1.08; 95% CI, 0.61-1.94; p = 0.78; I2 = 99.6%), pneumonia (2 studies; RR, 0.55; 95% CI, 0.23-1.31; p = 0.17; I2 = 83.2%), or discharge to a destination other than home (3 studies; RR, 0.97; 95% CI, 0.89-1.06; p = 0.53; I2 = 99.5%). A sensitivity analysis incorporating the ≤14-day study did not materially change the length-of-stay or mortality estimates. CONCLUSIONS:Early gastrostomy tube placement after stroke was associated with shorter hospitalization and lower risk of venous thromboembolism, without a clear effect on mortality, pneumonia, or discharge disposition.
BACKGROUND:Acute ischemic stroke (AIS) has high disability and mortality. Hemorrhagic transformation (HT) is a critical complication related to astrocyte damage, axonal injury and inflammation. GFAP, NfL and IL-6 are closely associated with HT, but 7-day continuous dynamic data are lacking. OBJECTIVE:To investigate 7-day dynamic changes of serum GFAP, NfL, IL-6 and their predictive value for HT and 3-month functional outcomes in AIS patients. METHODS:A prospective cohort study including 308 AIS patients. Serum biomarkers were measured daily for 7 days. Predictive performance was analyzed by Cox regression, ROC analysis, calibration, and decision curve analysis (DCA). RESULTS:HT occurred in 13.6% (42/308) of patients. The 24-hour GFAP change rate independently predicted HT (HR = 1.041, 95% CI: 1.015-1.069, p = 0.002). The combined model had a bootstrap-corrected C-index of 0.877. Peak GFAP improved 3-month outcome prediction (AUC = 0.850, p = 0.048), outperforming NfL and IL-6. CONCLUSION:The 24-hour GFAP change rate is a potential predictor for HT. Serial GFAP monitoring may provide preliminary evidence for early risk stratification of HT and functional outcomes in AIS patients.
OBJECTIVE:To investigate the independent factors associated with the detection of cerebral microbleeds (CMBs) after intravenous thrombolysis (IVT) in patients with acute ischemic stroke (AIS) based on susceptibility-weighted imaging (SWI). METHODS:This was a retrospective analysis of 157 AIS patients who received IVT. Based on post-thrombolysis SWI findings, patients were divided into a CMBs+ group (n = 75) and a CMBs- group (n = 82). Clinical data were collected. Univariate analysis was used to screen variables, and those with p < 0.05 were incorporated into a multivariate logistic regression model to identify independent factors associated with CMBs. RESULTS:Univariate analysis showed that activated partial thromboplastin time (APTT), international normalized ratio (INR), smoking history, history of lacunar infarction, white matter hyperintensities (WMH), and history of antithrombotic medication use were associated with CMB occurrence (p < 0.05). Multivariate analysis further confirmed that WMH (OR = 29.92, 95% CI: 6.94-128.95), history of lacunar infarction (OR = 17.70, 95% CI: 5.00-62.61), and smoking history (OR = 4.55, 95% CI: 1.37-15.16) were independent factors associated with CMBs (p < 0.05). Age, pre-thrombolysis NIHSS score, and coagulation parameters did not enter the final model. CONCLUSION:Cerebral small vessel disease (manifested as white matter hyperintensities and lacunar infarction) is the most significant factor associated with CMBs detected after IVT, and smoking is an important modifiable behavioral risk factor. Clinical decision‑making should pay particular attention to AIS patients with markers of cerebral small vessel disease.
BACKGROUND AND PURPOSE:Vascular Neurology (VN) fellowship education in CTA interpretation is critical, given the increased opportunities for tissue salvage via neurointervention. Holo-Stroke-CTA 3D visualization has already shown improved accuracy and satisfaction for vessel occlusion detection. Our aim in this present analysis was to determine if focused education in CTA reading, including addition of Holo-Stroke-CTA and immediate access to clinical PACS images during team meetings (Holo-PACS), would improve fellow and team education. METHODS:Four VN fellows scored 3 sets of de-identified CTAs (DICOM Group-A (n = 12), DICOM Group-B (n = 12), and Holo-Stroke-CTA Group-C (n = 24) to assess for LVOs/MeVOs. After each set, a training session was given. Concurrently, Holo-PACS, accessing our enterprise PACS system via secure Intranet, was utilized in weekly team conferences. Likert surveys assessed satisfaction. Wilcoxon Signed Rank was used for non-parametric, and Exact Binomial Test was used for preference comparisons. RESULTS:The overall correct percentage was 63% DICOM Group A vs. 97% Group C Holo-PACS. MCA (75%,94%), ICA (75%,100%), and Basilar (100%,100%) locations scored high, with marked improvement for ACA (13%,100%), and PCA (38%,94%). Likert satisfaction overall was 47% DICOM vs. 94% Holo-PACS. 'Satisfaction' scores were (55%,90%), 'Immersion' (34%,96%), 'Ease of Use' (53%,87%), 'Accuracy' (55%,93%), 'Technology Advancement' (42%,98%), and 'Enthusiasm' (45%,97%). CONCLUSIONS:The Holo-PACS initiative, including focused CTA education and implementing both Holo-Stroke-CTA and secure connection to PACS imaging using Holo-PACS during weekly team meetings, resulted in an improved ability to interpret CTAs and robust immersive satisfaction. Holo-PACS is becoming integral to our stroke education and training, and may serve as a model for vascular neurology fellowship training programs.
BACKGROUND:The fetal-type posterior cerebral artery (fPCA) is a circle of Willis variant in which the posterior cerebral artery (PCA) territory is supplied mainly by the internal carotid artery (ICA) through a dominant posterior communicating artery (PComA), with a hypoplastic or absent ipsilateral P1 segment. This carotid dependence alters collateral reserve and the hemodynamics of the ICA-PComA junction, with consequences for aneurysm formation, rupture, and procedural safety. METHODS:We performed a narrative review. We searched PubMed/MEDLINE and Scopus for English-language studies on fPCA and PComA aneurysm formation, rupture, and microsurgical, endovascular, and revascularization outcomes, prioritizing cohort series, comparative studies, and quantitative reports. This is a narrative synthesis and not a systematic review or meta-analysis. RESULTS:fPCA is overrepresented among patients with PComA aneurysms, with a prevalence on the aneurysmal ICA of about 42% versus 19% contralaterally (odds ratio [OR] 3.04), and the association is specific to the ICA-PComA location (OR 2.76). Its effect on rupture is less consistent: fPCA is an independent predictor in some series (OR 2.10) and on radiomic analysis (OR 3.85) but not in others, with a pooled unadjusted OR of 1.57 (95% CI 1.13-2.19) in meta-analysis. Flow diversion achieves complete occlusion in only about 42-44% of fPCA-associated aneurysms versus 78-82% without fPCA. CONCLUSIONS:fPCA is an anatomic modifier of both aneurysm risk and treatment. Preservation of the dominant PComA trunk is the unifying surgical and endovascular principle. Heterogeneous definitions limit cross-study comparison, and standardized reporting of complete versus partial fPCA is needed.
This research investigated two maternal processes that affect neurodevelopment: 1) the prenatal endowment of maternal iron that supports growth-related iron needs, and 2) the exposure to maternal bacteria and breast milk that shape the postnatal assemblage of the infant's gut microbiota. A primary aim was to extend prior results indicating that the bacterial profile of nursing infant monkeys should normally be dominated by a high abundance of Bifidobacteria (Phylum Actinomycetota), and that the presence of higher abundance of taxa in the Phylum Pseudomonadota provides a sentinel indicator of slower brain maturation. This perspective was applied to additional infants who became anemic subsequently at the end of the nursing period. Fecal and blood specimens were collected from 41 infant rhesus monkeys; diffusion tensor imaging scans were acquired at one year of age. Atlas-based fiber tract analyses examined fractional anisotropy (FA) values in three major myelinated projections: the cingulum (CG), uncinate fascicularis (UF), and inferior longitudinal fascicularis (ILF). Fecal samples were collected from nursing infants at 2 months postpartum, prior to the onset of infantile anemia, and analyzed with 16S ribosomal RNA gene amplicon sequencing. The analysis focused on the 4 most abundant phyla. Pseudomonadota were inversely associated with FA in the cingulum tract. Sixteen of the 41 infants subsequently became iron deficient between 4 and 8 months of age and there was an overall trend for a negative influence on FA values. The findings convey that both gut bacterial profiles and iron status during infancy can influence the myelination of important tracts connecting the temporal lobe with other cortical areas.
INTRODUCTION:A 3D interactive report is a state-of-the-art artificial intelligence (AI) tool that integrates a patient's imaging history into an intuitive visualisation. Yet, despite the many potential benefits to patients, referring physicians, and the healthcare system, a substantial gap exists between such AI developments and their clinical implementation. The goal of this study was to evaluate physicians' attitudes towards AI and their readiness to implement new AI-technologies in different practice settings. MATERIALS AND METHODS:A 15-question cross-sectional online survey addressing AI in Radiology was distributed to physicians through professional networks and at a national neuroscience conference. Results were summarized using descriptive statistics, as appropriate for the type and distribution of the data. Group comparisons were made using Chi-square or Fisher's test, as appropriate. RESULTS:75 physicians completed the survey between September-December 2025, 52 (69%) being hospital physicians and the rest private practitioners. Response rate was 17%. Hospital physicians were significantly more likely to implement a 3D interactive report in daily practice (Hospital: 82.4% vs. Private Practice: 36.8%; p < 0.001). Private practitioners more often believed that of AI-based radiology aids must be explicitly disclosed (82.6%), compared to hospital physicians (76.9%; p = 0.007). CONCLUSION:Hospital physicians were more receptive for use of AI technologies in radiology compared to private practitioners. Practice patterns, economic factors, doctor-patient relationships, and frequency of interaction with the radiology department likely influence how AI use in radiology is perceived.
Protein kinase C alpha (PKCα), encoded by Prkca, has been implicated in neuronal signaling, plasticity, and memory. Human genetic studies identify PRKCA as a candidate locus relevant to memory and posttraumatic stress disorder (PTSD), but the physiological functions of PKCα remain incompletely defined. Here, we examined the anatomical distribution, signaling function, and behavioral phenotypes associated with constitutive global PKCα deficiency in Prkca-/- mice. PKCα was enriched in forebrain regions, including the hippocampus and prefrontal cortex. It was detected in MAP2-positive neurons and was not detected in GFAP-positive astrocytes. In cultured hippocampal neurons, PKC activation induced redistribution of PKCα to dendritic and membrane-associated compartments, including PSD95-positive postsynaptic sites. PKCα deficiency did not alter gross hippocampal morphology or the basal abundance of major neuronal and synaptic marker proteins, but it reduced basal phosphorylation of pan-PKC, CaMKIIα, and the AMPA receptor subunit GluR1 at Ser831. Male Prkca-/- mice showed impaired hippocampus-dependent spatial memory, increased anxiety-like behavior, and a marked deficit in contextual fear extinction. These findings identify PKCα as part of a signaling program associated with synaptic function and support a role for PKCα-dependent processes in adaptive updating of learned fear.
BACKGROUND:Symptomatic extracranial vertebral artery stenosis (EVAS) is associated with recurrent vertebrobasilar arterial ischemic stroke, but recurrence under medical management remains unclear. We describe the 4-year frequency and timing of recurrent non-fatal vertebrobasilar arterial ischemic stroke among patients with EVAS who did not undergo vertebral artery stent placement. METHODS:We conducted a retrospective cohort study using the HealthVerity Launch Sample, an administrative claims database. Eligible patients had an institutional claim from January 2020 through June 2021 containing both diagnoses and continuous enrollment for 1,461 days. The primary outcome was a new vertebrobasilar arterial ischemic stroke hospitalization as the primary or admitting diagnosis at least 30 days after index and within 4 years. Analyses were descriptive and exploratory and included Wilson confidence intervals (CIs), person-time incidence, Kaplan-Meier estimation, post hoc beta-binomial Monte Carlo simulation, and sensitivity analyses. RESULTS:Among 43 patients, mean age was 71.5 ± 15.2 years, and 33 (76.7%) were men. Seven patients experienced recurrence within 4 years, corresponding to an event rate of 16.3% (95% CI, 8.1%-30.0%) and 4.71 events per 100 person-years. The posterior mean recurrence probability was 17.0% (95% uncertainty interval, 7.6%-29.3%). Cumulative incidence was 11.6% at 1 year, 14.0% at 2 years, and 16.3% at 3 and 4 years. Four recurrences occurred between days 33 and 45; none occurred after day 732. CONCLUSIONS:In this small cohort, qualifying recurrences occurred predominantly early, but the estimates were imprecise. Without a stent placement comparator, the findings are hypothesis-generating and cannot establish comparative effectiveness or guide treatment selection.
Objectives: Neuroinflammation and oxidative stress following cerebral ischemia contribute to neuronal damage and cognitive dysfunction. Dexpanthenol, an antioxidant and neuroprotective derivative of pantothenic acid, may attenuate these pathological processes. This study investigated the neuroprotective effects of dexpanthenol following cerebral ischemia in rats.Methods: Cerebral ischemia was induced using the two-vessel occlusion model, and a single intraperitoneal dose of dexpanthenol (500 mg/kg) was administered after ischemia. Behavioral assessments, including the open-field test, elevated plus maze test, forced swim test, and novel object recognition test, were performed to evaluate anxiety-like and depressive-like behaviors and cognitive performance. Enzyme-linked immunosorbent assay was used to quantify brain-derived neurotrophic factor, vascular endothelial growth factor A, hypoxia-inducible factor-1 alpha, tumor necrosis factor alpha, caspase-3, and myeloperoxidase levels. Histopathological and immunohistochemical analyses were performed to assess neuronal damage and neuroinflammatory changes.Results: Dexpanthenol treatment increased brain-derived neurotrophic factor, vascular endothelial growth factor A, and hypoxia-inducible factor-1 alpha levels while reducing tumor necrosis factor alpha, caspase-3, and myeloperoxidase levels. Behavioral and histological findings demonstrated attenuation of neuroinflammation, neuronal loss, and cognitive deficits.Conclusions: Dexpanthenol exerted neuroprotective effects following cerebral ischemia, accompanied by favorable changes in neurotrophic, inflammatory, apoptotic, and oxidative stress-related parameters and improvements in behavioral and histopathological outcomes. The use of a single dexpanthenol dose and an acute ischemia model represents a limitation; further dose-response and chronic studies are required to support translational relevance.
BACKGROUND:Subthalamic nucleus deep brain stimulation (STN-DBS) is an established treatment for motor symptoms in Parkinson's disease (PD), but its effects on sleep remain uncertain. This study evaluated changes in nocturnal sleep quality and daytime sleepiness following STN-DBS. METHODS:Four databases were searched for longitudinal studies assessing sleep outcomes after STN-DBS in PD. Sleep was evaluated using the Parkinson's Disease Sleep Scale (PDSS) and Epworth Sleepiness Scale (ESS). Study quality was assessed with the Newcastle-Ottawa Scale. Pooled mean differences (MDs) were calculated using inverse-variance fixed-effects models, and heterogeneity was assessed with I2 statistics. RESULTS:Nine studies reporting PDSS outcomes (n = 286) and eight reporting ESS outcomes (n = 190) were included. Most patients underwent bilateral STN-DBS (93.7%). Pooled analyses demonstrated significant improvements in PDSS scores (MD 21.23 points, 95% CI 11.59-30.87; p < 0.01) and reductions in ESS scores (MD - 3.62 points, 95% CI - 5.09 to -2.14; p < 0.01). Heterogeneity was negligible for both outcomes (τ = 0; I2 = 0%). The 95% prediction intervals remained favorable for PDSS (9.61-32.86) and ESS (-5.46 to -1.77), suggesting consistent findings across studies. CONCLUSION:Current evidence suggests that STN-DBS is associated with improved subjective sleep quality and reduced daytime sleepiness in patients with PD. However, these findings should be interpreted cautiously because they are derived primarily from observational studies with limited sample sizes and potential confounding factors. Prospective studies specifically designed to evaluate sleep outcomes are needed to clarify the independent effects of STN-DBS on sleep.
Introduction:Hypothalamic-pituitary-adrenal (HPA) axis dysregulation has been implicated in obsessive-compulsive disorder (OCD), but epigenetic changes in HPA axis-related genes remain poorly understood. We investigated whether DNA methylation of the glucocorticoid receptor gene (NR3C1), particularly within exon 1F, is associated with OCD and examined its relationship with stress resilience and early-life trauma. Methods:A total of 275 patients with OCD and 200 healthy controls (aged 19-40 years) were recruited. DNA methylation at three CpG sites within NR3C1 exon 1F was measured using pyrosequencing. Group differences were examined using multivariate analysis of covariance (MANCOVA), and structural equation modeling (SEM) was conducted to evaluate resilience-mediated pathways linking NR3C1 methylation, early-life trauma, and OCD status. Results:Compared to healthy controls, DNA methylation at NR3C1 exon 1F was significantly reduced in women with OCD (p < 0.001), which remained significant in a drug-naïve or drug-free subset. No overall multivariate difference was observed in men. SEM revealed that stress resilience partially mediated the association between NR3C1 methylation and OCD status (indirect β = -0.117, p = 0.014). While early-life trauma was associated with lower methylation at a specific CpG site, the mediation effect of DNA methylation between trauma and OCD did not reach statistical significance. Conclusion:These findings suggest that epigenetic alterations of NR3C1 may contribute to stress-related vulnerability in OCD, with resilience representing a key psychological pathway linking stress-related biological processes, including HPA-axis regulation, to clinical outcomes.
OBJECTIVES:Peripheral nerve injuries impose substantial functional morbidity and long-term neurological impairment, yet electrodiagnostic severity assessment remains dependent on specialized expertise and susceptible to inter-examiner variability. This study proposes a supervised machine learning framework for automated four-class severity classification of upper-extremity peripheral nerve impairment using integrated electromyography (EMG) and nerve conduction study (NCS) features. METHODS:Five classifiers were evaluated using stratified five-fold cross-validation: support vector machine (SVM), random forest, LightGBM, XGBoost, and tabular prior-data fitted network (TabPFN). Feature selection combined Kruskal-Wallis and Chi-square statistical testing with Fisher score ranking. For the integrated EMG-NCS configuration, Gaussian Copula-based synthetic augmentation addressed the scarcity of paired electrodiagnostic samples (28 records). RESULTS:On the EMG dataset (n = 912), the ensemble of SVM, random forest, and TabPFN achieved the highest accuracy (73.77%) and macro-F1 (72.64%). On the NCS dataset (n = 1020), TabPFN achieved 98.04% accuracy and a macro-F1 of 98.60%, with the ensemble model producing comparable performance. On the augmented training distribution, SVM and TabPFN achieved 100% accuracy and macro-F1 on an independent held-out test set. Given the limited test size (n = 9), these findings are presented as proof of concept pending validation on larger paired clinical cohorts. SHAP-based explainability identified MUAP polyphasia percent as the primary EMG predictor, and sensory latency and motor conduction velocity as the key NCS predictors. DISCUSSION:These findings demonstrate the feasibility of interpretable machine learning for multimodal electrodiagnostic analysis and support its potential as a scalable decision-support tool for objective peripheral nerve impairment severity grading.
The mineralocorticoid receptor (MR) plays a pivotal role in modulating the neuroendocrine stress response and cognitive function. While recent evidence highlights the importance of MRs in glutamatergic neurons in regulating anxiety-like behavior, the specific contribution of MRs within inhibitory networks remains incompletely understood. To address this gap, we generated a mouse model with targeted ablation of MR in forebrain GABAergic neurons (MRDlx). Comprehensive behavioral profiling revealed a profound, state-dependent cognitive phenotype in male MRDlx mice. Under non-stressful baseline conditions, these mice exhibited impaired object recognition memory, while under aversive learning paradigms, such as the Morris water maze and fear conditioning, they displayed enhanced spatial and contextual memory. Furthermore, male MRDlx mice demonstrated significant behavioral lack of adaptation to 21 days of chronic social defeat stress (CSDS). Notably, these changes were highly sex-influenced, as female MRDlx mice did not exhibit the same baseline cognitive deficits or subsequent stress resistance. Mechanistically, in vitro hippocampal electrophysiological recordings from male mice showed that acute corticosterone (CORT) application, which typically suppresses long-term potentiation (LTP), failed to impair LTP in MRDlx slices, indicating a marked resistance to CORT-induced suppression. Together, our findings suggest that MRs in GABAergic neurons normally function as critical constraints on excitatory synaptic plasticity during high-stress states. Ablating this regulatory mechanism confers robust behavioral and synaptic stress resistance, underscoring that adaptive stress responses rely on a finely tuned, cell-type-specific balance of corticosteroid signaling within limbic microcircuits.
BACKGROUND AND AIMS:The impact of atrial fibrillation (AF) on outcomes of endovascular thrombectomy (EVT) in patients with acute ischemic stroke (AIS) caused by large vessel occlusion (LVO) has been studied, with no definitive characterization of how AF might influence the technical and clinical outcomes of EVT. We aimed to perform a meta-analysis to assess the effects of AF on the outcomes of EVT for AIS patients. METHODS:We searched PubMed, Scopus, and WOS till May 2026 for studies comparing outcomes of EVT for AIS among patients with and without AF. Our primary outcome was the rate of a favorable functional outcome (mRS score 0-2) at 90 days. Secondary outcomes included rates of successful reperfusion, 90-day mortality, and symptomatic intracranial hemorrhage. We pooled odds ratio (OR) with 95% confidence interval (CI). RESULTS:We included 19 studies comprising 16,094 patients (6,283 with AF versus 9,811 without AF). The odds of 90-day mRS 0-2 was significantly lower among patients with AF (OR = 0.79, 95% CI 0.67-0.95; p = 0.01), with significant heterogeneity among the included studies. Mortality was significantly higher in the AF group (OR = 1.3, 95% CI 1.14-1.63, p < 0.01). A random-effects model was used for all outcomes. CONCLUSIONS:Current observational evidence suggests that EVT may remain effective and safe in patients with AF. However, the certainty of evidence is very low, and the findings should be interpreted cautiously. Further research is needed to understand the potential pathophysiological mechanisms that could be implicated in these associations.
Chronic stress is a major risk factor for anxiety disorders and is often accompanied by disruptions in female reproductive cyclicity, but the stress-responsive neural populations that shape these comorbid behavioral and physiological outcomes remain poorly defined. The bed nucleus of the stria terminalis (BNST) is a major node for sustained anxiety and stress integration, yet the contribution of genetically defined BNST neurons to restraint stress is not fully resolved in females. Here, we identify proenkephalin-expressing neurons in the anterior dorsal BNST (adBNSTPENK) as a restraint-responsive population that constrains anxiety-like behaviors and modulates cytology-based estrous cycle organization. Acute chemogenetic inhibition of adBNSTPENK neurons produced anxiety-like behaviors in females, whereas activation attenuated acute restraint stress (ARS)-induced anxiety-like behaviors. Female mice subjected to chronic restraint stress (CRS) exhibited both anxiety-like avoidance and disrupted estrous-cycle organization, which can be mitigated by sustained activation of adBNSTPENK neurons. These findings suggest that adBNSTPENK neurons form a stress-recruited limbic circuit node that buffers stress-induced anxiety-like behaviors and is associated with improved vaginal cytology-based estrous-cycle organization under chronic stress.
Reward seeking is an essential component of human behavior. Anhedonia (reduced motivation for and pleasure in reward) is a core feature of several mental illnesses. Early life adversity associates with later impairments in reward behaviors and related psychopathology; however, specific aspects of early adversity that lead to disrupted reward behaviors are unknown. Capitalizing on evidence that unpredictable signals to the developing brain constitute adversity and influence neurodevelopment, we examined whether exposure to perinatal unpredictable maternal signals associated with diminished reward responsivity, and probed causality using experiments in mice. We analyzed a longitudinal human study (N=158 mother/child dyads) and a controlled prospective mouse study (N=111 pups; 17 litters). In humans, exposure to unpredictable signals during late gestation was assessed by maternal mood entropy (a measure of how disordered or random signals are). In mice, unpredictable maternal care behaviors were experimentally induced during the neonatal period, and maternal care entropy was similarly computed. Aspects of anhedonia were determined by adolescent self-report and diminished behavioral responses to palatable food in young adult mice. Across species, unpredictable maternal signals were associated with reduced reward responsivity in males, but not females. Associations persisted after accounting for income and maternal psychopathology in humans, and for cohort and litter effects in mice. These findings indicate a robust, sex-dependent link between early exposure to maternal unpredictability and disrupted reward processing. The convergence of cross-species results indicates that unpredictability of maternal signals plays a role in shaping reward behaviors in males, with implications for the developmental origins of mental illness.
Mitochondrial dysfunction is increasingly implicated in stress-related disorders, including post-traumatic stress disorder (PTSD) and depression, but its relationship to inflammatory signalling and circuit-level vulnerability remains unclear. Here, we investigated region-specific mitochondrial adaptations across two experimental approaches of stress in rodents: stress-enhanced fear learning (SEFL) and chronic unpredictable stress (CUS), modelling PTSD- and depression-like phenotypes, respectively. Behavioural data were analysed using a novel, data-driven clustering approach to define stress-responsive phenotypes (e.g., susceptible, resilient, depressive), alongside quantification of mitochondrial oxidative phosphorylation (OXPHOS) markers across the hippocampus, basolateral amygdala, and prefrontal cortex (prelimbic and infralimbic subregions), and circulating plasma inflammatory markers. Hippocampal mitochondrial adaptations diverged between experimental approaches, with SEFL-susceptible animals showing broad upregulation of OXPHOS complexes, whereas CUS-depressive animals exhibited more restrictive mitochondrial alterations. In contrast, the basolateral amygdala showed convergent mitochondrial adaptations across models, with increased Complex V expression observed in vulnerable phenotypes. Within the prefrontal cortex, stress effects were regionally dissociable, with the prelimbic cortex showing SEFL-specific, phenotype-dependent mitochondrial alterations, implicating it as a putative node in stress sensitisation in PTSD-like phenotypes. Plasma TNF-α levels were significantly elevated in a phenotype- and time-dependent manner and were associated with regional mitochondrial adaptations, consistent with a role for systemic inflammatory signalling in modulating stress-related neurobiological plasticity and energy states. These data support a multi-level model in which behavioural phenotypes reflect underlying inflammatory-mitochondrial states distributed across hippocampal, amygdala, and prefrontal circuits, providing a potential explanatory framework linking systemic inflammatory signalling, circuit-specific mitochondrial function, and vulnerability to PTSD- and depressive-like pathology.
Maternal separation is a widely used early-life stress (ELS) paradigm in rodents. Disrupted maternal care by separation of pups from the dam for several hours per day across neonatal and juvenile development has been found to alter hypothalamic-pituitary-adrenal axis function, molecular and circuit-level brain development and function, and behaviors associated with anxiety, depression, and cognition. However, dams have been found to temporarily increase their care towards pups upon reunion - typically associated with positive outcome measures - calling into question whether this increase in care compensates for care lost during separation. Using a mouse model of ELS, we quantified maternal home cage behaviors from postnatal day P2-16 across three observation periods per day (prior to maternal separation, immediately following reunion, and several hours following reunion), with maternal separation beginning on P10. Four composite variables of home cage behavior frequency were created: total dam-pup contact, rough contact, no contact, and dam self-care. Consistent with previous reports, we found a transient increase in care upon reunion, along with an increase in rough contact and a decrease in dam self-care. We then calculated geometric area-under-curve across the day and found that the increase in total contact among ELS litters does not result in overall more care, as indicated in previous publications, but rather a temporal reorganization of care. These findings provide important nuance to understand how maternal separation disrupts offspring care.
