Vocal learning requires juveniles to form auditory representations of adult vocal models that guide vocal practice. The caudomedial nidopallium (NCM), a higher-order auditory pallial region in songbirds, has been implicated in tutor-song memory and receives dopaminergic input, but whether dopamine receptor activation biases the emergence of song-specific selectivity during development remains unclear. We recorded NCM single-unit activity in juvenile male zebra finches with limited tutor-song exposure. One adult song was repeatedly presented after systemic administration of the D1-like receptor agonist SKF-38393, the D2-like receptor agonist quinpirole, or saline, and neural selectivity was assessed before and after pairing. Pairing did not produce a uniform population-wide shift in average selectivity. However, a linear mixed-effects model accounting for pre-pairing selectivity and multiple units per bird revealed significantly higher post-pairing selectivity in SKF-treated units than in saline-treated units. SKF-treated units also differed from quinpirole-treated units, whereas quinpirole and saline did not differ. Among initially non-selective units, threshold-defined gains occurred in 31.3% of SKF, 15.4% of saline, and 10.8% of quinpirole units, with SKF showing the highest gained fraction across all tested thresholds. Although the exact bird-label permutation test was not significant, continuous and threshold-based analyses provided convergent unit-level evidence for an SKF-associated enhancement of paired-song selectivity. These findings support neuromodulatory gating as a potential mechanism by which developmental auditory experience shapes stimulus-specific sensory representations.

Local electrophysiology and microstimulation reveal site-specific neural activity and physiological effects but do not directly link these local effects to whole-brain responses from the same target site. We developed an MRI-compatible electrode implantation system for macaques that enables CT/MRI-based localization, postoperative depth adjustment, neural recording, microstimulation during behavioral testing, and subsequent electrical microstimulation combined with functional MRI (EM-fMRI) using the same implanted electrode. The system supported local field potential recording, a stimulation-induced reduction in pupil size, and distributed stimulation-evoked blood oxygenation level-dependent (BOLD) responses. This approach provides a practical framework for linking local neural activity and stimulation-induced physiological responses with whole-brain responses at the same target site.

Magnetic resonance imaging (MRI) volumetric analysis is among the few tools able to probe the living human brain, offering a route from clinical findings back to basic neuroscience. Here we propose a reverse-translational framework for psychiatric research that links human MRI findings to their underlying molecular mechanisms in model animals. The framework rests on three "liaisons": a species liaison, confirming that a volume change identified in humans is also observed in mice using the same imaging and analytical method; a scale liaison, in which a histological pipeline explains the macroscopic volume change in terms of cell number and cell volume; and a causal liaison, in which molecular or cell-biological intervention converts correlative histological findings into causal evidence by inducing or reversing the volume change. We further propose that unbiased, whole-brain MRI volumetric analysis in mice can serve as an exploratory region-screening method, identifying disease- or treatment-related regions without a predefined region of interest, and capturing the maintained structural outcome of an intervention rather than its immediate functional trace. Together, the three-liaison framework and the region-screening approach outline a general strategy by which MRI-guided reverse and forward translation can uncover the structural and molecular basis of psychiatric diseases and their treatments.

There is a growing need to automate EEG monitoring of preterm-born infants, particularly where expert evaluation is limited. However, existing models necessitate human intervention for comprehensive assessment, thereby limiting the clinical applicability. We collected 165 EEG records from 65 preterm-born infants. 8-channel EEG records were segmented every 30 s and allocated into eight classes (three preterm-equivalent, four term-equivalent, and one noise class). We performed noise detection, sleep state classification, and maturity assessment through the classification. ImageNet pretrained ResNet-50 was finetuned to classify the segmented EEG images. A novel index, named "maturity rate," was calculated as the proportion of term-equivalent labels in each EEG recording. The model achieved a macro F1 score of 0.58 and Cohen's Kappa of 0.58 for the 8-class classification. When the labels were merged into active sleep, quiet sleep, and noise categories, performance improved to an F1 score of 0.84 and Kappa of 0.74. The maturity rate increased continuously with postmenstrual age at the time of recording, reflecting functional brain development beyond the term-preterm dichotomy. Our model enables end-to-end EEG assessment of sleeping newborns by simultaneously performing noise detection, sleep state classification, and maturity assessment, with minimal need for human intervention.

Sigma-band activity of the electroencephalogram during non-rapid eye movement (NREM) sleep exhibits infraslow fluctuations. These sigma-power fluctuations (SPFs) contain recurring local waveform periods, including ascending, high, descending, and low-sigma-power portions, which can be operationally categorized as SPF states. Although some SPF states are associated with arousal-related processes and sleep fragility, how the prevalence of SPF states changes within a continuous sleep episode remains unknown. Resolving this question requires a reliable analysis pipeline, yet it has been difficult to determine which pipeline best identifies SPF states. Here, we present the Simulation of SPF and SPF-State Identification (SSSI) framework, which generates simulated SPFs with known reference SPF states and uses them to evaluate candidate SPF-state identification pipelines. With a pipeline selected through SSSI, mouse NREM and human N2 sleep showed within-episode changes in SPF-state proportions in both species, with additional age-dependent variation in humans. Pipeline evaluation further showed that the detection of these effects can depend on the pipeline. Together, these findings establish SSSI as a framework for evaluating and interpreting within-episode temporal changes in SPFs while assessing pipeline-dependent methodological bias.

Human induced pluripotent stem cells (iPSCs) and organoids are increasingly important components of new approach methodologies because they provide experimentally accessible human systems that preserve patient-specific genetic backgrounds and can be differentiated into disease-relevant cell types. Genomic imprinting disorders are particularly attractive targets for this approach because their pathogenesis depends not only on DNA sequence but also on parent-of-origin-specific epigenetic regulation. Prader-Willi syndrome (PWS) and Angelman syndrome (AS), which arise from distinct disruptions within the same imprinted domain on chromosome 15q11.2-q13, illustrate both the opportunities and the complexity of therapeutic epigenetic manipulation. Recent studies using PWS patient-derived iPSCs have shown that disease-associated imprinting states are largely retained after reprogramming and can be experimentally reversed by locus-specific epigenome editing. Targeted demethylation of the PWS imprinting control region restored multiple paternally expressed genes, and the corrected state persisted after differentiation into hypothalamic organoids, partially normalizing disease-associated transcriptomic and functional phenotypes. Here, we discuss how iPSC-based disease modeling is evolving from a platform for mechanism discovery toward a test bed for therapeutic epigenome engineering and outline the major challenges that must be addressed before epigenome editing can be translated to patients with imprinting disorders.

The optokinetic reflex stabilizes retinal images during global motion and depends on retinal direction-selective (DS) circuits. Although mutant mouse strains exhibit impaired DS circuits via distinct mechanisms, how these circuit disruptions produce distinct visually evoked eye movement phenotypes remain unclear. Here, we developed a behavioral system to quantify mouse eye movements under opposite-direction and same-direction visual stimuli. Using this platform, we examined eye movement responses in wild-type (WT) mice and two DS circuit mutants: Frmd7™ mice, which lack horizontal DS tuning and horizontal eye movement responses, and Chrnb2™ mice, which have disrupted β2-nAChR-dependent cholinergic spontaneous activity during development. Consistent with previous research, both mutants lacked horizontal eye movement responses across conditions, while vertical responses remained detectable. We found that Chrnb2™ mice exhibited spontaneous horizontal eye oscillations regardless of visual input. This phenotype was absent in Frmd7™ mice, suggesting that defective retinal waves in Chrnb2™ mice may induce instability distinct from the loss of horizontal DS tuning alone. In addition, binocular opposite-direction stimulation enhanced vertical responses only in WT mice. Together, these findings provide a functional comparison of Frmd7™ and Chrnb2™ mice and establish a quantitative framework for dissecting how genetic perturbations alter the retinal computations underlying horizontal and vertical eye movements.

Leaky gut, defined as increased intestinal permeability, has been associated with many diseases. Recent studies suggest the brain is involved in maintaining gut barrier function. Since tofogliflozin, a sodium/glucose cotransporter 2 (SGLT2) inhibitor acts centrally to increase food intake, and feeding and gut functions are deeply associated, this study aimed to clarify the hypothesis that gut barrier function is influenced by centrally administered SGLT2 inhibitors in rats using Evans blue method. Intracisternal SGLT2 inhibitor blocked colonic hyperpermeability in response to lipopolysaccharide dose-dependently (15 μg-). The blockade was cancelled by atropine, vagotomy, intracisternal orexin receptor antagonist, intracisternal compound C, an adenosine monophosphate-activated protein kinase (AMPK) inhibitor, or subcutaneously injected sulpiride, a dopamine D2 receptor antagonist. Subcutaneous SGLT2 inhibitor at much higher doses of 5 mg or more could improve colonic hyperpermeability, and the improvement was also blocked by atropine or intracisternal orexin receptor antagonist or compound C. These results indicate SGLT2 inhibitor administered centrally or peripherally reduces colonic hyperpermeability through the vagal pathway although we could not exclude the possibility that peripherally administered SGLT2 inhibitor might act first in periphery. Brain orexin, AMPK and dopamine D2 signaling are involved in this process. SGLT2 inhibitors may be useful to treat leaky gut-related diseases.

Vector autoregressive modeling (VAR) is a powerful method for estimating dynamic functional connectivity (dFC) from resting-state functional magnetic resonance imaging (fMRI) data. However, VAR-based dFC can become unstable when only limited data are available. We compared multiple regularization approaches (PLS, PCA, Ridge, and Lasso) to examine whether they can stabilize VAR-based dFC without substantially compromising behaviorally relevant information. All regularization methods improved stability. Behavioral measure prediction improved and reached a level comparable to Pearson correlation-based FC, except Lasso. These findings suggest that regularized VAR-based dFC can provide behaviorally relevant information about temporal dynamics not represented in Pearson correlation-based FC.

Writer's cramp (WC) is a task-specific arm dystonia with involuntary contractions during writing. While motor circuit dysfunction is well-characterized in WC, the roles of motor learning and error processing remain unclear. We investigated implicit motor sequence learning in WC patients using fMRI during Serial Reaction Time Task (SRTT), focusing on cerebellar activity and error-related processing. 25 WC patients and 17 healthy controls were compared. Both groups showed a comparable sequence-specific advantage with faster reaction times and lower error rates in sequence versus random blocks. WC patients showed significantly higher combined error rates than controls, whereas group differences in reaction time did not reach significance. Speed-accuracy analysis revealed greater accuracy deterioration during fast responses in WC patients. Error trials elicited increased cerebellar activation (right lobule VIII, left lobule IX) in patients. Exploratory analysis revealed absent amygdala deactivation in patients during errors, contrasting the suppression observed in controls, an effect that did not survive whole-brain correction. Our findings indicate preserved implicit sequence learning alongside reduced accuracy of motor execution in WC, particularly under speed demands. Altered cerebellar and amygdala error responses suggest that WC pathophysiology extends beyond traditional motor networks, encompassing disrupted error salience processing.

The frontal cortex contains multiple motor areas, including the caudal cingulate motor area (CMAc), supplementary motor area (SMA), and primary motor cortex (M1). Although neurons in these areas exhibit activity related to both contralateral and ipsilateral limb movements, whether their contributions to movement initiation differ across areas and effectors remains unclear. Here, we recorded single-neuron activity from the CMAc, SMA, and M1 in monkeys performing a button-press task with either hand and quantified trial-by-trial correlations between spike counts and reaction times to assess initiation-related signals. For contralateral movements, both the proportion of neurons with significant correlations and the magnitude of the correlation increased from the CMAc through the SMA to M1. Among neurons showing significant correlations during contralateral movements, correlation strength remained greater in M1 than in the SMA and CMAc, whereas no difference was observed between the SMA and CMAc. In contrast, for ipsilateral movements, areal differences were weak or absent, with no differences in correlation strength across areas among neurons showing significant correlations during ipsilateral movements. These findings indicate that contralateral movement initiation is associated with both increased neuronal recruitment and stronger single-neuron signaling in M1 than in the CMAc and SMA, whereas ipsilateral movement initiation is associated with more comparable initiation-related signaling across the three motor areas.

How the medullary nucleus tractus solitarius (NTS) and hypoglossal nucleus (HN) respond when peripheral input or output is lost is unclear. In adult mice, we unilaterally transected the superior laryngeal (input) and hypoglossal (output) nerves and mapped c-Fos in the NTS and HN at 12, 24 and 72 h. Both nuclei showed a transient c-Fos increase relative to sham. In the HN, c-Fos shifted over time from the ipsilateral to the intact contralateral side, whereas the NTS responded bilaterally. Because the contralateral HN response arose in non-axotomized neurons, it reflects an activity-dependent component, not injury alone.

Metabolic alterations in early-stage psychosis may provide insights into disease pathophysiology and potential biomarkers. We performed targeted metabolomic and lipidomic profiling of plasma samples from 31 patients with early-stage psychosis (onset within 24 months) and 22 healthy controls using a liquid chromatography-mass spectrometry (LC-MS) platform. Of 523 compounds analyzed, 16 (3 metabolites, 13 lipids) were significantly altered in patients compared with controls, with a significant enrichment of glycerolipids (69%). Within patients, glycerolipids significantly correlated with symptom severity and cognitive performance. These findings highlight the involvement of glycerolipid metabolism in early psychosis and clinical outcomes.