Translational Psychiatry最新文献

The neuronal ceroid lipofuscinosis family of lysosomal storage diseases, also called CLN1 disease, is characterized by the deficiency of palmitoyl-protein thioesterase 1 (PPT1). In this study, we investigated the impact of PPT1 deficiency on hippocampal GABAergic interneurons (INs) and associated neural network oscillations in a PPT1-KI (CLN1 c.451 C > T (p.R151X)) mouse model. Using a combination of in vivo electrophysiology, immunostaining, and fiber photometry, we observed that PPT1 deficiency led to the activation of caspase 3 in parvalbumin-positive (PV⁺) INs, an increased activity of pyramidal neurons and theta/gamma oscillation power, and the disruption of theta-gamma cross-frequency coupling (CFC) in the early stage of the CLN1 disease model. In the late stage of the CLN1 disease model, we observed the reduced neuronal activity, extensive neuronal loss including PV⁺ INs, and the emergence of spontaneous epileptiform discharges and the pathological ripples. Treatment with diazepam partially restored oscillatory coupling and reduced seizure-like activities. Our research indicated that PPT1 deficiency leads to early selective impairment of PV⁺ INs, triggering overactivation of pyramidal neurons and network dysfunction, which consequently results in seizures and neurodegeneration. This research provides novel insights into the pathogenesis of CLN1 disease and potential therapeutic strategies for the intervention of CLN1 disease by improving the function of inhibitory INs via caspase inhibition.

Postpartum depression (PPD) is linked to neuroimmune dysregulation. Brexanolone, an intravenous formulation of the neurosteroid allopregnanolone and the first FDA-approved treatment for PPD, produces rapid and sustained antidepressant effects. However, its long-term mechanisms of action remain unclear. This study evaluated brexanolone's prolonged impact on two groups of biomarkers in whole blood: inflammatory mediators and growth/differentiation/neurotrophic factors. Whole blood was also maintained in culture (4 h) and subjected to lipopolysaccharide (LPS) stimulation of the TLR4 inflammatory pathway. Ten individuals with moderate-to-severe PPD received brexanolone and were assessed before, and at 6 h, ~7, and ~30 days post-infusion. BDNF significantly increased and remained elevated through 30 days, representing a sustained neurotrophic response. In contrast, inflammatory mediators CCL11, IL-6, TNF-α, and IL-18 showed rapid reductions by 6 h. TNF-α suppression lasted up to 7 days, while CCL11 and IL-6 remained suppressed through 30 days. These changes were associated with reductions in Hamilton Depression Rating Scale (HAM-D) scores over time. LPS-stimulated whole blood cultures revealed suppression of TLR4-induced CCL11, IL-1β, IL-6, IL-8, IL-18, TNF-α, HMGB1, and MIP-1β at 6 h. IL-8, IL-18, and TNF-α remained suppressed through 7 days, while IL-1β and CCL11 remained suppressed through 30 days, aligning with sustained HAM-D score improvements. Biomarker × time interactions suggested dynamic regulation of inflammatory and neurotrophic pathways. Given the small sample size, these findings should be interpreted as a pilot study, but they indicate that brexanolone promotes both rapid and sustained anti-inflammatory and neurotrophic effects supporting lasting symptom remission in PPD.

Cognitive deficits are a hallmark of Alzheimer's disease (AD), and effective treatments remain elusive. Transcranial alternating current stimulation (tACS), a non-invasive technique, has shown potential in improving cognitive function across various populations, but further research is needed to investigate its efficacy in AD. In a randomized, double-blind, sham-controlled pilot trial, 36 mild AD patients received active or sham theta-tACS (8 Hz, 1.6 mA, 20-min daily) during n-back task for two weeks, followed by a 10-week follow-up. Cognitive assessments and resting-state EEG were analyzed at baseline, after-treatment, and follow-up. The results showed that the active group demonstrated significant cognitive improvements after treatment (MMSE: t (15) =-3.273, p = 0.005, Cohen's d = 0.82), particularly in short-term memory (MMSE-recall: Z = -2.11, p = 0.035, r = 0.53), with maintained benefits after 10 weeks. In contrast, the sham group exhibited long-term cognitive decline (MMSE: t (4) = 3.586, p = 0.023, Cohen's d = -1.60). EEG analysis revealed reduced gamma power (t (23) = 2.689, p = 0.013, Cohen's d = 1.077) and theta connectivity in active group, particularly in the frontotemporal regions (F4/F7: t (23) = 2.467, p = 0.021, Cohen's d = 0.988; F4/T3: t (23) = 2.465, p = 0.022, Cohen's d = 0.987), which was correlated with cognitive improvements (R = -0.57, p = 0.043). In conclusion, tACS combining cognitive training may offer cognitive benefits in mild AD by modulating neural activity, though further studies are needed to clarify its mechanisms.

Social valence is the directional emotional significance affiliated with social experiences. Maladaptive social information processing has been linked to mood disorder susceptibility, which is more prevalent in women. To determine whether there are sex differences in social valence processing, we employed behavioral tasks that associated conspecific identity recognition with either positive or negative valence, as well as tasks in which valence information originated from social targets. Male mice demonstrated identity recognition regardless of social valence. While male and female mice performed similarly in the positive social valence task, female mice did not show identity recognition following the negative social valence task. In vivo calcium imaging of the dorsal CA1 further revealed sex differences in negative social valence processing with reduced hippocampal representation of social information in female mice. Finally, enhancing dorsal CA1 neuronal activity by ampakine rescued identity recognition in female mice. These results suggest that sex differences in social valence processing may contribute to the heightened vulnerability to social stress-related mood disorders in women.

Cognitive deficits across multiple domains are prevalent in patients with schizophrenia (PWS), and metabolic syndrome (MetS) may significantly contribute to this impairment. To clarify the complex relationships between individual MetS components and multidimensional cognitive dysfunction in PWS, we conducted a multicenter study involving 727 clinically stable patients recruited from ten psychiatric hospitals. Cognitive function was assessed using the Chinese Brief Cognitive Test (C-BCT). We employed network analysis and structural equation modeling (SEM) to explore these associations, with machine learning techniques applied for further validation. The results revealed statistically significant differences in several cognitive domains between patients with and without dyslipidemia (DL). Patients with hypertension (HT) also exhibited overall poorer cognitive performance. Network analysis indicated meaningful distinctions between patients presenting two or more MetS components (MetS-2+) and those without, showing a sparser network configuration in the MetS-2+ group. Across both groups, the Symbol Coding task demonstrated the highest strength centrality. SEM indicated that metabolic indicators, specifically DL and HT, mediated the relationship between clinical symptoms and cognitive function. Furthermore, a transformer-based machine learning model performed effectively in predicting cognitive dimensions, supporting the predictive utility of MetS components for multidimensional cognitive outcomes. In summary, specific MetS components, particularly DL and HT, show intricate associations with cognitive function in stable-phase PWS. Our findings suggest that management of HT in this population may represent a potential pathway for cognitive enhancement and improved social functioning. Trial registration: MR-11-23-007343.

Oral cannabidiol (CBD) treatment has been suggested to alleviate severe symptoms of autism spectrum disorder (ASD). While many CBD preparations have been studied in clinical trials involving ASD, none has used purified CBD preparations or preparations approved by the U.S. Food and Drug Administration, nor have they focused on children with ASD with higher support needs. Previous studies have identified several candidate electrophysiological biomarkers of cognitive and behavioral disabilities in ASD, with emerging biomarkers including periodic (oscillatory) and aperiodic measures of neural activity. We analyzed electroencephalography (EEG) recordings from 24 boys with ASD and higher support needs (aged 7-14 years) from a prior double-blind, placebo-controlled, crossover Phase II Clinical Trial (NCT04517799) that investigated whether 8 weeks of daily CBD treatment (up to 20 mg/kg/day) improved severe behavioral problems, measured at baseline, post-CBD, post-placebo, and post-washout. Using linear mixed effect models, we found that aperiodic EEG measures varied with CBD metabolite levels in blood, as evidenced by a larger aperiodic offset across the scalp and a decreased aperiodic exponent across occipital electrodes. Furthermore, CBD metabolite levels in blood had a positive association with receptive vocabulary, nonverbal intelligence and visuomotor coordination. Our data suggest that this daily CBD preparation and administration schedule produced mixed effects, with some children showing improvements in cognitive and behavioral abilities while others demonstrated limited changes. Our findings support the inclusion of aperiodic EEG measures alongside traditional oscillatory EEG measures as candidate biomarkers for tracking the variable clinical impact of purified CBD treatment in children with ASD.

Although increased maternal androgens, such as those in polycystic ovary syndrome (PCOS), are associated with a higher incidence of autism spectrum disorder (ASD) in offspring, a causal link has yet to be established. We assessed whether perinatal hyperandrogenization in a murine model recapitulates core ASD traits and compared this model to the maternal immune activation (MIA) model of ASD. Both models produced ASD-like phenotypes, yet they exhibited distinct behavioral subtypes and neurodevelopmental trajectories. Hyperandrogenized offspring showed greater reductions in social communication (neonatal USVs, d = 0.633-0.773; juvenile USVs, d = 1.103-1.216; social preference, d = 0.715), whereas only MIA offspring showed increased repetitive behaviors (d = 0.599). Ex vivo magnetic resonance imaging revealed volume increases in specific cortical regions in both models, with MIA additionally showing absolute cingulate cortex enlargement, and hyperandrogenized mice displaying focal increases in sexually dimorphic regions, despite a 36% reduction in overall brain volume (FDR 10%). Placentas from both groups showed reduced LIX (CXCL5), but distinct immune shifts also emerged: MIA placentas exhibited elevated IL-4 and IL-1β, whereas hyperandrogenized placentas showed increased TNFα. In neonatal brains, both conditions were associated with reduced IL-2, with MIA additionally decreasing IL-17A and IL-12p70, suggesting suppression of Th1/Th17-type cytokine signaling that normally supports proinflammatory and immune-neural interactions. DRD2 and BDNF protein were upregulated in hyperandrogenized fetal brains but downregulated with MIA. These results suggest that hyperandrogenization and MIA act through distinct mechanisms, producing subtle neurodevelopmental and behavioral differences consistent with human ASD subtypes.

Insensitivity to costs during cost-benefit decision-making consistently has been related to substance use severity. However, little work has manipulated cost information to examine how people evaluate and compare multiple costs. Further, no work has examined how the consideration of cost information varies across different contexts. We administered a new loss-frame variant of a probabilistic learning task in a diverse community sample enriched for substance use (N = 137). Individuals with more years of regular substance use tended not to repeat choices after they avoided losses, choosing similarly regardless of whether they had avoided or incurred a loss. Computational modeling parameters indicated that they were more inconsistent in their use of expected values to guide choice. These results contribute to our conceptualization of substance use severity by suggesting that inconsistency in using cost information, rather than insensitivity to costs, may inform choices to continue using substances despite incurring negative consequences.

The glucagon-like peptide-1 receptor (GLP-1R) has emerged as a promising therapeutic option for alcohol use disorder (AUD), yet the underlying mechanisms and neurocircuitry involved remain unclear. This study aimed to analyze GLP-1R gene expression changes in brain regions associated with alcohol's effects, including the prefrontal cortex (PFC), nucleus accumbens (NAc), and hippocampus (HIP), in mice following 42 days of voluntary ethanol consumption (VEC; 10% v/v) and postmortem samples from 18 patients with AUD. Additionally, we examined the expression of OPRM1 (mu-opioid receptor) and BDNF (brain-derived neurotrophic factor), key targets related to alcohol intake and reward, in the NAc and HIP, respectively. GLP-1R gene expression was significantly reduced in all brain regions of ethanol-exposed mice and AUD patients. These reductions paralleled decreased OPRM1 and BDNF expression in the NAc and HIP, respectively. Pearson and Spearman correlation analyses revealed no significant associations between gene expression and age, RIN, pH, postmortem interval (PMI), body mass index (BMI), smoking status, age of onset of alcohol use, or years of drinking. In summary, chronic alcohol consumption in humans or mice was associated with decreased GLP-1R gene expression in brain regions involved in the reinforcing effects of ethanol. These findings open new avenues for further research into how this emerging receptor could serve as a potential biomarker and therapeutic target in AUD.