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 5mg 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.

Activation of peroxisome proliferator-activated receptor alpha (PPARα) may attenuate post-ischemic neuroinflammation. This study examined the neuroprotective potential of pemafibrate, a selective PPARα modulator (SPPARMα), in murine cerebral ischemia. Male CB-17 mice underwent transient middle cerebral artery occlusion (MCAO) for 30 min. Pemafibrate (0.1, 0.3, or 1.0 mg/kg) or vehicle was administered orally once daily for 7 days before MCAO and continued for 2 days thereafter. Pemafibrate improved neurological outcomes (median mNSS: 5.5 with vehicle, 5.0 with pemafibrate 0.1 mg/kg, 4.0 with 0.3 mg/kg, and 2.5 with 1.0 mg/kg) and reduced infarct volume (mean, mm[3]: 50.4 with vehicle, 40.3 with pemafibrate 0.1 mg/kg, 34.5 with 0.3 mg/kg, and 24.9 with 1.0 mg/kg) at 48 h in a dose-dependent manner. Plasma triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and glucose levels did not differ between the vehicle and pemafibrate groups. At 3 h post-MCAO, IL-6 and IL-1β mRNA levels were not significantly different between the groups. At 6 h post-MCAO, pemafibrate reduced cortical IL-1β (P = 0.008) and reduced IL-6 in both striatum (P = 0.020) and cortex (P = 0.013), with attenuation of microtubule-associated protein 2 degradation. These findings suggest that selective PPARα activation ameliorates ischemic brain injury, likely through anti-inflammatory rather than systemic metabolic effects.

Stroke is a leading cause of functional impairment. As rehabilitation has a limited effect, it is essential to advance future treatments and enhance the efficacy of rehabilitation. This study focused on the use of astrocytes to augment the efficacy of rehabilitation for strokes. It utilized chemogenetics to specifically activate astrocytes in the peri-infarct region of a mouse photothrombosis model. The mice were subjected to immunohistochemical analysis and behavioral tests to evaluate the effects of astrocytic Gq pathway activation after an induced stroke. The timing of astrocytic activation was separated from that of rehabilitative training. It was observed that chemogenetic astrocytic activation prior to rehabilitation significantly augmented the efficacy of the training and promoted functional motor recovery after the induced stroke. Consequently, a better understanding of this mechanism could be a significant step toward future therapeutic breakthroughs.

Visual abnormalities are common in Lewy body diseases (LBDs), yet Lewy pathology is often sparse in the visual cortex, suggesting that dysfunction of anatomically remote networks may contribute to impaired visual processing. Here we report that α-synuclein (αSyn) expression initiated in the olfactory bulb induces visual abnormalities through remote network dysfunction despite no readily detectable local αSyn in the visual cortex. An adeno-associated virus expressing the A53T mutant αSyn was injected into the right olfactory bulb of mice. αSyn expression remained largely confined to olfactory- and limbic-associated cortices and was not readily detectable in the visual cortex with multiple αSyn and phospho-αSyn antibodies. αSyn-expressing mice exhibited abnormal performance in the visual cliff test and impaired visual discrimination, whereas locomotor activity, anxiety-like behavior, and olfactory performance were not detectably altered. Whole-brain phospho-S6 mapping suggested increased activity in olfactory/limbic-associated cortices and bilateral visual cortices, together with reduced activity in the thalamic reticular nucleus, and these regional changes were confirmed by c-Fos histology. Wide-field calcium imaging showed strengthened functional connectivity across the dorsal cortex, with prominent enhancement in occipital networks. These findings demonstrate a dissociation between αSyn distribution and distal circuit dysfunction, and support large-scale limbic/insular and thalamocortical reorganization as a network-level mechanism linking focal αSyn pathology to remote visual dysfunction. This study advances our pathophysiological understanding of distributed neurological dysfunction in α-synucleinopathies.

Immune checkpoint molecules have emerged as regulators of microglial function in neurodegenerative diseases. We previously demonstrated that LAG-3 shapes disease-associated microglial phenotypes in ALS and that germline LAG-3 deletion in SOD1[G93A] mice accelerated disease onset but extended duration, leaving survival unchanged. Here, we investigated the therapeutic efficacy of anti-LAG-3 antibody treatment starting after symptom onset. Anti-LAG-3 treatment extended survival, slowed neurological and motor decline, preserved body weight and motor neurons, and reduced microgliosis. Within microglia, the Axl[+] phagocytic-module fraction increased while the Dectin-1[+] inflammatory-module fraction decreased. These findings indicate that post-onset LAG-3 inhibition is a promising therapeutic strategy for ALS.

The circadian clock regulates a wide range of physiological and behavioral rhythms. Daily variation in nociceptive responsiveness to harmful stimuli has been demonstrated in mammalian models; however, whether such variation is present in non-mammalian species including insects has remained unclear. Here, we found that behavioral responses to noxious heat stimuli in the fruit fly Drosophila melanogaster exhibit significant variation throughout the day. In contrast, null mutants for the clock genes per and tim failed to exhibit daily variation in nociceptive responses. Consistently, we found daily changes of calcium responses toward noxious heat in peripheral nociceptive neurons, which is likely to be under the control of the clock gene. Together, our data show the clock gene-dependent daily variation of nociceptive responses in Drosophila, and support a potential model in which sensory systems, including nociception, operate under distinct temporal dynamics, enabling animals to adjust their behavior in response to environmental changes across the day.

Mammalian neonates are born in an immature state and require caregiving from conspecific adults for survival. A growing body of evidence indicates that multiple neuronal populations and hormonal factors regulate parental caregiving behavior. Among these, arginine vasopressin (AVP) and oxytocin (OT) have received particular attention. While the role of OT has been extensively investigated, the functional contributions of AVP remain comparatively less understood. Recent neurobiological studies in rodents have begun to elucidate the molecular, cellular, and circuit-level mechanisms through which AVP regulates caregiving behavior. In this review, I first summarize the properties of AVP and its receptors, with particular emphasis on vasopressin-to-oxytocin receptor crosstalk, a phenomenon in which AVP can activate non-canonical oxytocin receptors. I then review past and recent findings on the role of AVP signaling in parental caregiving behavior, highlighting evidence that receptor crosstalk contributes to these effects. Based on these findings, I propose a hypothetical circuit model integrating AVP and OT signaling in the regulation of caregiving behavior. Finally, I discuss unresolved questions regarding receptor specificity, temporal dynamics, and circuit mechanisms, as well as the potential relevance of these findings to human parenting.

Social interaction facilitates vocal learning more effectively than passive exposure, but the neural signals that reflect the social context of auditory experience remain unclear. Midbrain dopaminergic circuits broadcast motivational and learning-related signals, raising the possibility that VTA/SNc activity may reflect both tutor-song auditory input and tutor presence during juvenile vocal development. We tested this idea in juvenile zebra finches by recording single-unit activity during the same tutor-song playback under tutor-absent and tutor-present conditions; in the tutor-present condition, a live tutor was present but remained silent. Among 185 VTA/SNc neurons from 8 birds, tutor presence bidirectionally modulated auditory responses. Type-1 neurons showed enhancement (46/185, 24.9%), whereas Type-2 neurons showed suppression (29/185, 15.7%). Both profiles were observed in all birds, and bird-level analyses supported consistent modulation. Type-1 neurons showed increased baseline firing and a further enhancement of baseline-subtracted song-evoked responses, whereas Type-2 suppression occurred without reduced baseline firing. Using spike waveform and firing rate criteria, we found that the tutor-enhanced Type-1 population included neurons with putative dopaminergic features. In naturalistic recordings, these neurons also showed increased activity during live tutor singing. These findings suggest that socially modulated VTA/SNc activity may link tutor presence to auditory processing relevant to vocal learning.