Parkinson's disease (PD) is characterized not only by progressive motor deficits but also by non-motor symptoms, such as depression, which often emerge during the prodromal stage and significantly impair quality of life. While Akkermansia muciniphila (AKK) has shown potential in modulating neuroinflammation, its specific role and underlying mechanisms in alleviating PD-associated non-motor symptoms remain unclear. In this study, we investigated the effects of AKK intervention in 16-month-old female A53T α-synuclein (α-syn) transgenic mice. Behavioral assessments revealed that oral administration of AKK significantly ameliorated depression-like behaviors, evidenced by reduced immobility in the forced swim test and increased sucrose preference, without affecting motor function, spatial memory, or gastrointestinal motility. Mechanistically, the intervention exhibited genotype-specific effects: AKK significantly increased plasma 5-HT levels in C57 mice. This increase was associated with an enrichment of Lactobacillus taiwanensis and metabolic pathways favoring peripheral tryptophan conversion. Conversely, in A53T mice, the treatment specifically elevated hippocampal 5-HT levels without altering plasma concentrations. This central effect correlated with distinct microbial remodeling, characterized by the enrichment of butyrate/propionate-producing Lachnospiraceae and the activation of purine degradation. Collectively, these findings provide novel mechanistic insights into the therapeutic potential of AKK for managing non-motor symptoms in PD. While limited to a female cohort, our results suggest that AKK ameliorates depression-like behaviors in PD through sex-specific remodeling of the gut microbiome and serotonergic signaling.

Rodents, including rats, utilize vocalizations as a primary mode of social communication. While high-frequency ultrasonic vocalizations (USVs) have been extensively explored in laboratory rats, low-frequency (<10kHz) vocalizations (LFVs) were first described only recently, and it is as yet unclear whether these two types of vocalizations are driven by the same behavioral mechanisms. This study investigates the behavioral distinctions between USVs and LFVs in socially interacting rats. In line with previous studies, we found that USVs, mostly associated with social interactions, are emitted during early stages of exhalation and involve complex respiratory modulations. In contrast, LFVs, which correlate with general arousal, occur early at inhalation, show limited deviation from baseline breathing patterns, and are significantly associated with locomotion. Advanced machine learning models, including long short-term memory convolutional neural network frameworks and semiparametric mixed-effects models, were employed to analyze the interplay between vocalizations, respiration, body orientation and locomotion. The results of these analyses demonstrate that USVs are well predicted by the breathing pattern and are associated with social interaction and orientation toward the social stimulus. In contrast, LFVs were predicted poorly from the breathing pattern alone, but are correlated with both breathing rate and locomotion. Moreover, they shared common dynamics with the power of theta oscillations in the nucleus accumbens core, a brain area associated with motivation and emotions. We conclude that these two vocalization types represent distinct communicative and physiological phenomena. These findings advance the understanding of rodent vocal communication and highlight the possible adaptive roles of LFVs in behavioral contexts.

In this study, we demonstrate for the first time that post-injury creatine supplementation (300 mg/kg, p.o.) administered for two weeks attenuates blood-brain barrier disruption, cortical lesion volume (by ∼60%), spatial memory deficits (reducing escape latency by ∼50% in the Barnes maze), hippocampal theta/delta rhythm alterations, and epileptiform activity in 35-day-old male rats subjected to severe fluid percussion injury (FPI). In the hippocampus, the FPI protocol did not cause overt neuronal loss-particularly of parvalbumin-positive neurons in the CA1 and CA2 regions-but it significantly reduced creatine levels and induced marked mitochondrial dysfunction. These alterations were evidenced by impaired MTT reduction, disrupted mitochondrial membrane potential (Δψ), decreased SDH activity, inhibition of respiratory chain complexes I-III, COX, citrate synthase (CS), and CKm activity, together with increased mitochondrial oxidative stress (enhanced DCFH-DA oxidation, elevated 4-hydroxynonenal levels, depletion of free -SH groups, and reduced GSH levels). We propose a mechanistic cascade wherein mitochondrial dysfunction and elevated oxidative stress drive the inhibition of Na[+],K[+]-ATPase, which in turn contributes to neuronal hyperexcitability and cognitive deficits. Creatine's ability to maintain mitochondrial integrity directly interrupts this cascade, protecting against dysfunctions in these essential ion-gradient systems. In conclusion, post-injury creatine supplementation preserves mitochondrial function, maintains Na[+],K[+]-ATPase activity, and prevents epileptiform activity and cognitive deficits, highlighting creatine as a promising strategy to mitigate secondary injury. However, these findings must be interpreted in light of certain limitations, including the use of a male-only cohort, a single time-point assessment, and the correlational nature of the proposed mechanistic pathways, warranting further investigation.

Rats emit ultrasonic vocalizations (USVs) that function as affective and social acoustic cues. In adults, 50-kHz USVs are associated with appetitive states, whereas 22-kHz USVs are associated with aversive or defensive contexts. However, developmental changes in receiver responses to these calls remain unclear. Here, we compared sound-source approach behavior and c-Fos expression in juvenile and adult male rats exposed to playback of 50-kHz USVs, 22-kHz USVs, or control sounds. Each rat was assigned to one playback condition and perfused after the behavioral test for c-Fos immunohistochemistry. Playback condition significantly affected approach time. Adult rats showed selective approach to 50-kHz USVs, with longer approach time to 50-kHz USVs than to 22-kHz USVs or control sounds. In contrast, juvenile rats showed a broader, less differentiated pattern of approach times across the two USV conditions. Direct age-group comparisons showed that adults approached 22-kHz USVs less than juveniles. USV playback increased c-Fos expression in several affect- and reward-related regions, including the agranular insular cortex, anterior cingulate cortex, nucleus accumbens core, and basolateral amygdala. Following playback of 50-kHz USVs, adults showed higher c-Fos expression than juveniles in the nucleus accumbens core and basolateral amygdala. Moreover, c-Fos expression in the nucleus accumbens core and central amygdala was positively correlated with approach behavior. These findings suggest that responses to USVs involve distributed sensory-affective processing and adult-biased recruitment of reward- and affect-related regions following playback of 50-kHz USVs.

Personality disorders (PDs) are increasingly recognized and highly prevalent, yet remarkably poorly understood, diagnosed and treated mental conditions. Common PDs include antisocial, avoidant, borderline, dependent, histrionic, narcissistic, obsessive-compulsive personality, and paranoid disorders. Experimental (animal) models are a valuable tool to study various brain illnesses, including PDs. However, characterized by complex and frequently overlapping aberrant behaviors, PDs pose major challenges for their preclinical modeling. Here, we discuss the potential utility of zebrafish (Danio rerio) as complementary translational models relevant to studying PDs. Paralleling clinical symptoms and traits of PDs to specific behavioral phenotypes, biomarkers and paradigms in these fish, we critically evaluate the existing challenges and limitations of such models, and provide a conceptual framework for further research in this field. Despite clear conceptual and practical challenges, we argue that zebrafish models not only provide a powerful platform for elucidating neurobiological mechanisms of a wide range of key PD traits (e.g., impulsivity, aggression, emotional dysregulation), but may markedly accelerate both translational modeling of these disorders and therapeutic discovery.

Falls are a common and debilitating feature of Parkinson's Disease (PD) patients. Prefrontal acetylcholine (ACh) deficits, as well as nigrostriatal dopamine deficits, are implicated in vulnerability to falls. PD patients with loss of cortical ACh and associated cognitive dysfunction experience a higher rate of falls than PD patients without cortical ACh loss. In addition, chemogenetic inhibition of basal forebrain (BF) neurons in rats increases the vulnerability to falls on a balance beam task. Here, the impact of transient optogenetic inhibition specifically of BF cholinergic neurons was assessed in rats with dorsomedial striatal dopamine lesions during traversal of straight or zig-zag balance beams using the Michigan Complex Movement Control Task (MCMCT). Adding transient optogenetic inhibition of BF cholinergic neurons with striatal dopamine lesions elevated falls above the level produced by striatal dopamine lesions or BF ACh inhibition alone, especially on the challenging zig-zag task. These results support the critical role of BF-cortical cholinergic circuits in alleviating vulnerability to falls in PD patients with striatal dopamine loss, suggesting that it is combined loss of BF cholinergic activity and striatal dopamine that leads to greatest vulnerability to falls and related complex movement impairments.

Attention impairment constitutes a primary cognitive deficit following subconcussive head impacts. However, the underlying neural mechanisms remain unclear. This study investigated neural alterations in attention networks associated with repetitive subconcussive exposure by integrating source-level electroencephalography (EEG) functional connectivity analysis with the Attention Network Test (ANT). Source-level functional connectivity matrices were constructed using the phase-locking value (PLV) to characterize connectivity patterns across multiple frequency bands (delta, theta, alpha, and beta), and graph-theoretical analysis was subsequently performed to assess network topological properties. At the behavioral level, attention network efficiency did not differ significantly between groups; however, compared with healthy controls, the subconcussion group exhibited increased functional connectivity across attention networks. Specifically: (1) Within the alerting network, connectivity increased in the delta and alpha bands; exploratory correlations analyses indicated that stronger connectivity between the rolandic operculum (ROL) and the inferior parietal lobule, as well as between the ROL and the angular gyrus, was associated with better alerting efficiency, whereas stronger connectivity between the middle frontal gyrus and the supplementary motor area (SMA) was associated with poorer alerting efficiency. (2) Within the orienting network, widespread increases in connectivity were observed across the delta, alpha, and beta bands, and stronger connectivity between the supramarginal gyrus and the middle temporal pole was associated with better orienting efficiency. (3) Within the executive control network, right-hemisphere-predominant enhancement of connectivity in the alpha and beta bands was accompanied by significant alterations in network topological organization. Collectively, these findings reveal frequency-specific functional hyperconnectivity and selective topological reorganization within attention networks following repetitive subconcussion, providing insights into subconcussion-related neural alterations and potential neurophysiological signatures for further investigation.

The gut microbiota has emerged as a key regulator of central nervous system development and function. Accumulating experimental and clinical evidence demonstrates that microbial signals influence brain activity through integrated neural, immune, neuroendocrine, and metabolic pathways. These pathways converge on core mechanisms of synaptic plasticity, including neurotrophic signaling, glutamatergic transmission, dendritic remodeling, and adult neurogenesis, thereby shaping learning, memory, executive function, and emotional regulation. Disruption of microbiota-brain communication is implicated in a range of neurodevelopmental and neurodegenerative disorders, including autism spectrum disorder (ASD), major depressive disorder (MDD), Alzheimer's disease (AD), and Parkinson's disease (PD), suggesting shared systems-level vulnerabilities across conditions and highlighting the translational potential of microbiota-targeted interventions such as probiotics, dietary modulation, postbiotics, and precision microbiome-based strategies. Overall, the gut microbiota functions as a dynamic regulator of brain plasticity and cognitive resilience across the lifespan. Future progress will require identification of causal mechanisms at the level of specific microbial metabolites, neural circuits, and developmental windows using integrated multi-omics and spatially resolved approaches, alongside translation into targeted therapeutic strategies.

Anxiety disorders represent a major psychiatric burden, yet their molecular underpinnings remain poorly understood. While observational studies have linked circulating lipids and proteins to mental health, causal inference is hampered by confounding and reverse causation. Here, we leveraged two-sample Mendelian randomization (MR) to systematically evaluate the causal effects of 179 plasma lipid species and 4907 plasma proteins on anxiety disorders, using two large-scale independent GWAS datasets for replication. Significant findings from the primary inverse variance weighted analysis were validated using Bayesian Weighted MR and MR Robust Adjusted Profile Score methods to mitigate potential pleiotropy. Sensitivity analyses and reverse MR assessed robustness and directionality. Mediation analyses further explored whether protein signatures mediate lipid-anxiety associations. We identified three lipids with robust causal effects, with sterol ester (27:1/20:5) consistently conferring a protective effect across both cohorts. Additionally, 31 proteins showed significant causal links to anxiety. Notably, the protective effect of sterol ester (27:1/20:5) was partially mediated by the upregulation of SERPINA4 and ICT1, both of which exhibited protective associations. Our findings provide genetic evidence for causal roles of the plasma lipidome and proteome in anxiety disorders, and unveil a specific lipid-protein-anxiety pathway that may offer novel biomarkers and therapeutic targets. These results underscore the value of integrating multi-omic MR to dissect psychiatric disease mechanisms.

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social behavior and cognition. Increasing evidence suggests that alterations in dopaminergic neurotransmission, including changes in dopamine transporter (DAT) function, may contribute to ASD-related behavioral abnormalities. This study investigated whether selective DAT inhibition during early postnatal development influences behavioral and molecular alterations in a rat model of ASD induced by prenatal exposure to sodium valproate (NaVP). Pregnant Wistar rats received NaVP (600 mg/kg, i.p.) on gestational day 12.5. Male offspring were treated with the selective DAT inhibitor CE-123 (10 mg/kg, i.p.) once daily from postnatal day (PND) 10-23. Behavioral assessments during adolescence (PND25-42) evaluated social interaction, recognition memory, spatial preference, anxiety-like behavior, locomotor activity, and aversive memory. DAT, dopamine D2 receptor, brain-derived neurotrophic factor (BDNF), and interleukin-1β (IL-1β) protein expression were assessed in selected brain regions. Prenatal NaVP exposure impaired social novelty discrimination, declarative, spatial, and aversive memory, reduced locomotor activity, and increased anxiety-like behavior. These behavioral alterations were accompanied by elevated DAT and dopamine D2 receptor expression. Early postnatal CE-123 treatment attenuated several ASD-like behavioral abnormalities, normalized DAT and dopamine D2 receptor expression, increased BDNF levels in the prefrontal cortex (PFC), and increased IL-1β expression, without inducing non-specific locomotor stimulation. Together, these findings demonstrate that early postnatal CE-123 treatment was associated with long-lasting behavioral improvements accompanied by alterations in dopaminergic markers and BDNF expression. Although these findings support a role for dopaminergic regulation and neuroplasticity in the observed behavioral effects, the underlying mechanisms require further investigation.

Mindfulness meditation has been studied for its many health benefits, yet the neural mechanisms that facilitate these benefits are still opaque. The present review examines adaptive attention processes and associated dynamic brain networks (e.g., executive control network, default mode network) that are engaged during mindfulness meditation, demonstrating emerging evidence of durable neuroplasticity linked to beneficial psychological outcomes. Electroencephalography (EEG) methods offer high-resolution chronometry of cortical neural processes and are necessary to investigate the rapid dynamics of adaptive attention processes that are changed due to mindfulness meditation. Here we review EEG methodologies that have been used to investigate attention processes in the context of mindfulness meditation, and discuss how malleable attention networks, in particular the executive control network, and the default mode network influence adaptive attention processes, which in turn leads to reduced psychological distress and improved emotional wellbeing. This review emphasizes an interdisciplinary perspective on bridging neurocognitive methodologies of attention processes with clinical outcomes on which to build future evidenced-based mindfulness meditation strategies and interventions.

In Parkinson's disease (PD), dopaminergic (DA) neurons deteriorate within the substantia nigra pars compacta (SNc), causing movement difficulties. This deterioration can be modeled in rats given large, unilateral DA-depleting lesions of the nigrostriatal pathway using the neurotoxin 6-hydroxydopamine. The behavioral benefits promoted by classic L-DOPA pharmacotherapy typically do not include skilled limb use restoration. Among deteriorative diseases, the single neurotransmitter loss in PD allows for a more discrete or focused replacement goal. Stem cell therapy (SCT) would be more likely to help restore skilled limb use if it integrates successfully into the host. We surmise that more stable or persistent PD SCT will require active guidance or context signaling while connecting within a hospitable host environment to integrate successfully and ensure behavior-responsive host control. To explore this, we examined the supportive effects of swimming exercise alone or exercise with transplantation of modified LMO3-containing mesenchymal stem cell (MSC)-derived dopaminergic transplants, and, in both cases with or without varying degrees of swim-correlated direct chemogenic activated optogenetic stimulation of the transplanted cells. We were interested in whether increasing selective and behavior-correlated transplant stimulation more than once during early integration might guide reconstructive events and enhance behavioral improvement following DA loss without producing undesirable repercussions. Our study evaluated forelimb cooperative control in rats using a recorded swimming task to assess exercise/transplant/stimulation-related improvements. Combined transplant stimulation and swimming facilitated transplant-derived forelimb cooperation during swimming after a single exposure. Two distinct stimulations supported this recovery both safely, and more effectively, than just one.

Problematic smartphone use (PSU) has emerged as a significant concern, associated with disruptions in cognitive function, emotional regulation, and neural processing. Previous studies have shown that the global signal (GS) in resting-state functional magnetic resonance imaging (fMRI) influences neuronal activity within the 0.01-0.1 Hz frequency range, yet its spatial pattern in PSU remains poorly understood. In this study, we examined frequency-specific alterations in GS topography in 78 participants (41 PSU and 37 nonPSU individuals) across four frequency bands: slow-2 (0.198-0.25 Hz), slow-3 (0.073-0.198 Hz), slow-4 (0.027-0.073 Hz), and slow-5 (0.01-0.027 Hz). Significant group differences in GS topography were observed, particularly in the left calcarine region. Additionally, significant interaction effects between group and frequency band were identified in the supplementary motor area (SMA). Correlation analyses revealed associations between GS alterations and clinical measures, including the pop-up notification frequency and smartphone usage frequency, especially in the higher frequency bands (slow-2 and slow-3). These findings suggest that PSU is associated with frequency-dependent alterations in GS topography, as supported by a significant Group × Frequency interaction in the SMA-particularly in regions implicated in cognitive control and visual processing. The observed alterations in GS coherence, particularly the elevated coherence at slow-5 and correlations in higher bands, may reflect neural dysfunctions related to attentional control and self-regulation, which are central to the behavioral manifestations of PSU. These results enhance our understanding of the neural mechanisms underlying PSU and emphasize the importance of considering frequency-specific brain activity in PSU research.