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European Journal of Neuroscience

Published by Wiley and Federation Of European Neuroscience Societies

Online ISSN: 1460-9568

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Print ISSN: 0953-816X

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Experimental setup. When participants were ready to complete a trial, they depressed a switch (gray box with a black button) that rendered the occlusion goggles transparent. Participants then lifted either a large or small brick (red cubes) off a switch plate (blue box and plexiglass plate) using a force transducer (black disk underneath the thumb). After the 3‐s trial, the goggles became opaque, occluding the participant's vision between trials.
Rating of perceived heaviness (Scale 1–10) [M ± SD] over the course of the experiment for the large (dark gray circles) and small (gray circles) bricks for the OE (top), MI‐10 (middle) and MI‐2 (bottom) groups. Vertical black lines separate the training block from the pretraining (left) and posttraining blocks (right).
of maximum load forces and load force rates. (A) Maximum load force (N) and (B) maximum load force rate (N/s) [M ± SD] over the course of the experiment for the large (dark gray) and small (light gray) bricks for the OE (top) and MI‐10 (middle) and MI‐2 groups (bottom). Vertical black lines separate the training block from the pretraining (left) and posttraining (right) blocks.
Predicted maximum load force and load force rates in the MI‐2 group's pretraining lifts. (A) Predicted maximum load force (N) and (B) maximum load force rate (N/s) [M ± 60% CI (thick line) and 90% CI (thin line)] on the first lift of the large and small brick in MI‐2 group's pretraining block. The large brick is lifted with a larger force and at a faster load force rate than the smaller brick.
Predicted maximum load force and load force rates in the MI‐10 and OE groups' pretraining lifts. (A) Predicted maximum load force (N) and (B) maximum load force rate (N/s) as predicted by group, exposure, brick size visualizing the three‐way interaction in the OE and MI‐10 groups' pretraining block. The ribbon for each series represents the 95% highest posterior density interval. In OE, participants start by lifting the large brick with more force at a faster rate but converge on similar values for both bricks. In the MI‐10 group, the maximum load forces diverge slightly while the comparison of the rate of applied force remains consistent between bricks across the pretraining block.

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Perceptual and Motor Processes in Motor Imagery

June 2025

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46 Reads

Jack P. Solomon

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Ernest Ng

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David A. Westwood

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Shaun G. Boe
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The European Journal of Neuroscience publishes scientific work in all fields of neuroscience. Our journal supports authors to help them publish high quality research that advances understanding of brain function.
We publish a diverse content, from Research Reports to Reviews, Editorials and Neuro-Opinions on current topics. As the official journal of FENS, profits from EJN are re-invested into the neuroscientific community to serve and support the next generation of neuroscientists.

Recent articles


How Orienting and Defence Drives Oscillatory Responses in Human Visual and Motor Cortical Circuits During Viewing of Threat Pictures: Evidence From ssVEPs and Beta‐Band Desynchronization
  • Article
  • Full-text available

June 2025

Carlota Gil Martín

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Silvia Molina Blanco

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Miriam Díaz Sánchez

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[...]

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Stephan Moratti

When encountering a potential threat, humans and animals engage in different strategic behaviours, such as orienting and defence, depending on the perceived threat imminence. Orienting has been associated with attentional immobility and heightened ‘stimulus intake’, while defence is linked to action preparation and ‘sensory rejection’. First, we replicated previous findings showing that humans exhibit either heart rate (HR) acceleration or deceleration in response to the same threat‐related picture content. Second, we provide direct evidence that orienting, as indexed by increased HR deceleration, leads to enhanced visuocortical processing of threat‐related images, as measured by steady‐state visual evoked potentials (ssVEPs). Excitation of motor‐relevant cortical circuits, assessed by beta‐band desynchronization, was reduced in relation to HR deceleration. Conversely, HR acceleration was associated with a reversed pattern: reduced visual processing and increased excitation of cortical motor circuits, as reflected in ssVEP and beta‐band modulations. While self‐reported measures of state and trait anxiety, along with valence, arousal and dominance ratings, did not account for variations in HR response patterns, shorter self‐paced viewing time of looming threat pictures was linked to defensive HR changes, whereas orienting‐like HR responses were associated with longer avoidance latencies.


Novelty response to change in object configuration across development. (A) Experimental design and timeline. After 10‐min habituation sessions on the first 3 days, the rats were tested in a standard object–place recognition (OPR) task, comprising a 3‐h retention interval between the 5‐min encoding and 5‐min retrieval phases. During the retrieval phase one of the two (identical) objects placed in the arena during encoding was displaced to a novel location (arrow). (B) Illustration of the open field with distal cues at the surrounding walls, along with an illustration of the rat's exploratory rearing and object exploration behaviors. (C) Rats at different ages (juvenile: PD25, peri‐adolescent: PD31; adolescent: PD38, PD48, and young adult: PD84), were tested in the OPR task with the size of the open field being smaller for the younger (PD25, PD31) than older groups (PD38, PD48, PD84). Based on the encoding of a persistent memory during the encoding phase, the change in the spatial configuration of the two objects is expected to induce a novelty response, which expresses itself in an increase in exploratory rearing and an increased exploration of the displaced object. (D) mean rearing duration (%) and (E) total rearing number (% change from encoding phase), (F) Object discrimination index (as a measure of object exploration), and (G) distance travelled (% change from encoding phase) for each of the five age groups during the first 1‐min (white bars) and 3‐min intervals (gray bars) of the retrieval phase. Mean ± SEM values with overlaid dot plots are shown. #p < 0.05, ##p < 0.01, ###p < 0.001 for one sample t‐test against 0. *p < 0.05, **p < 0.01, ***p < 0.001, for Holm–Sidak post hoc tests. Data in F are adapted from Contreras et al. (2019).
Rearing activity in the Never vs Former zones of the arena. (A) For the analyses, the arena as used during the retrieval phase was divided into 4 quadrants (zones): The Same zone was defined by containing the nondisplaced object, the Novel zone by containing the displaced object, the Never zone by containing no object during both the encoding and retrieval phases, and the Former zone by having contained the displaced object during the encoding phase and being empty during the retrieval phase. (B) Mean rearing duration (s) and total rearing number in the Former and Never zones in the different age groups (PD25, PD31, PD38, PD48, PD84) for the first 1 min and (C) 3 min of the retrieval phase. Mean ± SEM values with overlaid dot plots are shown. *p < 0.05, **p < 0.01, for paired samples t‐test.
Rearing duration increases in response to change in the object configuration at OPR retrieval testing. (A) Experimental procedure: Following a within‐subject comparison, adult rats were tested in the standard OPR task condition (the same as in Experiment 1, white bars) and in a “stationary” task control condition (gray bars) where the two objects remained at the same location during the Encoding and Retrieval phases. (B) Mean rearing duration (%) and (C) total rearing number (%) during the Retrieval phase, as percent change from values during encoding (set to 100%). (D) Mean rearing duration (s, left) and total rearing number (right) as absolute values during the retrieval phase. Mean ± SEM values with overlaid dot plots are shown for the first 1 min and 3 min of the Retrieval phase. # p < p < 0.05, ## p < 0.01 for one sample t‐test against 0. *p < 0.05 for paired samples t‐test.
Rearing activity in the four different zones of the arena during the retrieval phase of the OPR task condition. (A) Discrimination of arena zones, see legend to Figure 2A. (B) Mean rearing duration (s, left) and total rearing number (right) in the Former and Never zones for the first 1 min and 3 min of the retrieval phase. (C) The same as in B, for the Same and Novel zones. Mean ± SEM values with overlaid dot plots are shown. *p < 0.05, **p < 0.01, ***p < 0.001 for paired samples t‐test.
Evolution of spatial exploration behavior during early development. The schema illustrates the animal's dominant response to spatial novelty at different developmental stages, that is, with a nonspecific increase in general locomotion around PD16 (blue line, Shan et al. 2022) with an increase in the object discrimination index (ODI) towards familiar object–locations around PD25 (orange line), with a general and persisting increase in rearing at PD31 (purple), with an increase in the ODI towards novel object locations around PD38 (black), and with a zone specific increase in rearing at previously occupied locations (as an indicator of object–location memory) only after PD48 (green).
Rearing Behavior as Indicator of Spatial Novelty and Memory in Developing Rats

June 2025

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13 Reads

Xia Shan

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Anuck Sawangjit

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Jan Born

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Marion Inostroza

Among the various forms of exploration, rearing—where rodents stand on their hind legs—reflects the animal's processing of spatial information and response to environmental novelty. Here, we investigated the developmental trajectory of rearing in response to spatial novelty in a standard object–place recognition (OPR) task, with the OPR retrieval phase allowing for a direct comparison of measures of rearing, object exploration, and locomotion as indicators of spatial novelty and memory. Groups of male rats were tested on postnatal day (PD) 25, PD31, PD38, PD48, and at adulthood (PD84). The OPR task comprised a 5‐min encoding phase with the rat exposed to an arena with two identical objects and, 3 h later, a 5‐min retrieval phase in the same arena with one object being displaced to another arena zone. Rearing increased in response to spatial novelty (i.e., the displaced object) at retrieval relative to encoding, with this increase occurring first on PD31, and thus later than preferential object exploration‐based responses emerging already on PD25. Importantly, zone‐specific analyses during retrieval revealed an increase in rearing events in the (now empty) zone where the displaced object is used to be at encoding. This increase was only observed in adult rats (PD84) and likely indicates the presence of specific object–place associations in memory. These findings evidence rearing as behavior covering aspects of spatial novelty complementary to those of object exploration, thereby enabling a more comprehensive characterization of the emergence of spatial episodic memory during early life.


Red Clover Supplementation Alleviates Neurological Deficits in Estrogen Deficient Rats Exposed to Chronic Unpredictable Mild Stress

Estrogen deficiency after menopause contributes to various neurological disorders, including stress, anxiety, depression, and memory impairment. Hormone replacement therapy (HRT) is commonly used to mitigate menopausal symptoms, but its use is associated with significant adverse effects. As a result, phytoestrogens, plant‐derived estrogens structurally similar to HRTs, are preferred alternatives due to their lack of side effects associated with synthetic HRTs. Among these phytoestrogens, red clover (RC) has emerged as a potent medicinal herb used for the treatment of menopausal symptoms. Thus, the aim of the current study was to evaluate the effects of RC on neurological disorders in estrogen‐deficient rats subjected to chronic unpredictable mild stress (CUMS). Ovariectomy (OVX) was performed to induce estrogen deficiency, a condition that closely mimics menopause in females. CUMS, a model of chronic stress, was employed to mimic the stress and anxiety that commonly accompany menopause. Significant changes in physiological, neurobehavioral, biochemical, molecular, and histopathological alterations in the brain hippocampal region were observed in OVX, CUMS, and OVX + CUMS group rats, indicating enhanced neuronal deficits compared with control group rats. Treatment with RC supplementation, 17‐β estradiol (E2), and fluoxetine (Flx) significantly restored the pathological alterations caused by both CUMS and estrogen deficiency toward normal. E2 and Flx were included in the study to serve as established treatments for postmenopausal symptoms and stress‐related disorders, providing a basis for comparison with RC. In conclusion, our study demonstrated the immense potential of RC in alleviating neurological disorders associated with estrogen deficiency and chronic stress.


Object and task design. Participants performed two tasks: (A,B) reaching to press a left‐ or right‐sided button or (C,D) reaching, grasping, and lifting an object with a left‐ or right‐sided center of mass (CoM) to minimize tilt. To examine repetition‐induced anterograde interference, we varied the number of pre‐switch trials (1, 3, or 5) before switching the button side or CoM side (E, left and middle panels). We compared this design to that of Sager et al. (2024), which had only one post‐switch trial, to assess whether the number of post‐switch trials influenced interference effects (E, right panel).
(A) Reaction time and (B) reach phase. Mean reaction time and reach phase on post‐switch trials on the reach‐to‐button task (solid black line, closed circles) and object‐lift tasks with matched pre‐ and post‐switch trials (solid pink line, solid circles) and with unmatched pre‐ and post‐switch trials (dashed pink line, open circles). Error bars are ± 1 standard error.
(A) Load phase and (B) the difference between grip and lift force initiation. Mean load phase and grip force–lift force coupling on post‐switch trials on the object‐use tasks with matched (solid pink line, solid circles) and unmatched (dashed pink line, open circles) pre‐ and post‐switch trials. Error bars are ± 1 standard error.
Effect of pre‐switch trial repeat on post‐switch performance. Repetition‐induced anterograde interference on performance, quantified as the group mean compensatory torque (MCom), in object‐use tasks with matched pre‐ and post‐switch trials (solid pink line, solid circles) and with unmatched pre‐ and post‐switch trials (dashed pink line, open circles). Statistical significance is shown with an asterisk (*p < 0.05, **p < 0.001). Error bars are ± 1 standard error.
Effect of pre‐switch trial repeat on contributors of compensatory torque on post‐switch trials. Post‐switch digit lift force partitioning by object grip width (A, LFdiff × grip width/2) and grip force by digit positioning (B, GFmean × COPdiff) in object‐use tasks with matched pre‐ and post‐switch trials (solid pink line, solid circles) and with unmatched pre‐ and post‐switch trials (dashed pink line, open circles). Statistical significance is shown with an asterisk (*p < 0.05, **p < 0.001). Error bars are ± 1 standard error.
Repetition Hampers Flexible Object Manipulation Under Visual Uncertainty

Seemingly simple actions, like reaching for and lifting an object, involve the coordination of distinct neural pathways within the dorsal and ventral streams. These components can be differentially affected by repetition‐induced anterograde interference, where extensive practice on one task impairs performance on subsequent tasks. Repetition leads to rigid movement patterns, making it harder to adapt flexibly to new situations, especially in tasks with sensory uncertainty that require the brain to rely more on past experiences (i.e., sensorimotor memories). To explore this, we tested whether object‐use tasks, which depend on the ventral stream, are more affected by this interference than a simpler reach‐to‐button task with helpful visual cues. Participants completed two tasks: a reach‐to‐button task involving pressing buttons on either side of a symmetrical object and an object‐use task where the same object had a hidden, asymmetric center of mass (CoM). To measure interference, we manipulated how many times participants lifted the object with the weight on one side before switching it to the other side. Our results showed that interference was strongest in the object‐use task, where uncertain visual information forced participants to rely on sensorimotor memories. In contrast, the reach‐to‐button task, supported by helpful visual cues, showed no significant interference. This suggests that tasks relying on the ventral stream are more vulnerable to interference, particularly when sensory feedback is unclear. Our findings highlight how repetition affects different movement types and emphasize the need for a balance between repetition and flexibility in motor learning.


Biplots showing values of principal components 1–4 across groups stratified on sex or familial high‐risk status. The red arrows indicate the relationships between the principal components and the original variables (the scores across the four developmental domains). PC, principal component; M, male; F, female; FHR, familial high‐risk status; SZ, familial high risk of schizophrenia; BP, familial high risk of bipolar disorder; PBC, population‐based controls.
Environmental and Genetic Influences on Developmental Outcomes Across the Domains of Language, Cognition, Motor Function, and Social Behavior

June 2025

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5 Reads

Linguistic, motor, cognitive, and social‐behavioral functions are fundamental facets of a child's neurodevelopment and are influenced by both genetic factors and environmental factors, such as the home environment, including the parents' mental health. However, the nature of these influences remains largely unknown. Using a genotyped cohort of 391 7‐year‐old children with comprehensive phenotype data on linguistic, motor, cognitive, and social‐behavioral performance as well as data on parental mental health and the home environment, we performed regression analyses for the individual neurodevelopmental domains and principal components (PCs) capturing the variance across all domains simultaneously, where these outcomes were regressed on a polygenic score for educational attainment (PGS for EA) as a proxy for genetic factors and the Home Observation for Measurement of the Environment (HOME) as a proxy for environmental factors. HOME was significantly associated with all domains; the PGS for EA was nominally significantly associated (p ≤ 0.05) with cognitive function only. In the principal component analysis, PC1 and PC2 captured 52.57% and 20.73% of the variance in our phenotypic data, respectively. HOME was significantly associated only with PC1, while the PGS for EA was significantly associated only with PC2. Significant differences between familial risk groups were observed for PC1. Our results suggest an important role for potentially modifiable environmental factors on child neurodevelopment across multiple domains. We identified two orthogonal dimensions capturing parts of phenotypic variance that were associated with either environmental or genetic factors, but not both, providing insight into the interplay between genes and the environment in neurodevelopment.


EEG Correlates of Auditory Short‐Term Memory and Dissimilarity Perception in Young and Older Adults

June 2025

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17 Reads

Understanding the neural correlates of short‐term memory is crucial, particularly in the context of aging. In this electroencephalography (EEG) study, we investigated the impact of aging on the brain activity underlying short‐term memory and perception of dissimilarity of auditory sequences. Fifty‐four participants were divided into two groups: (i) 29 young adults (20–30 years old) and (ii) 25 older adults (60–80 years old). We used a variation of the same/different task employing pairs of tone sequences and asking participants to rate the degree of dissimilarity of the second sequence in comparison to the first one. Sequences could be either identical (same), totally different, or with transposed tones. Behavioral results showed a lower level of perceived dissimilarity in different sequences in older compared to young adults. The memory task induced a fronto‐central negative slow wave (NSW) that was significantly higher in the 20–30 group for all three conditions. NSW was higher in the same than in the different and transposed conditions but only in young adults. In transposed sequences, NSW amplitude was modulated by the perception of dissimilarity. The P50 component to first sound of the second sequence was significantly higher in older adults. The N1 was more negative in the same than in the different and transposed conditions. The P2 was higher in the same than in the transposed condition.


Equitable Research Funding: Strategies, Challenges and the Role of Funding Agencies

Ensuring equitable access to research funding is crucial for fostering diversity, innovation and excellence in science. Despite progress, significant disparities remain, with underrepresented researchers—including women, racial and ethnic minorities, LGBTQIA+ individuals and those with disabilities—continuing to receive disproportionately less funding. These disparities not only hinder individual careers but also limit the breadth of perspectives that drive scientific discovery. Through discussions with major funding agencies, including the Dana Foundation, European Research Council (ERC) and ERA‐NET NEURON, we examine how equity, diversity and inclusion (EDI) are integrated into research funding allocation. We focus on three key areas: (1) How EDI is defined and prioritised (2) metrics for assessing and tracking progress and (3) strategies for mitigating bias in selection procedures. While agencies have implemented initiatives such as demographic data transparency, targeted funding mechanisms and bias‐awareness training, systemic challenges remain. Variability in data collection practices, barriers in peer review processes and limitations of interventions like double‐blind reviews highlight the need for ongoing reform. As EDI policies face growing political scrutiny and active efforts to dismantle existing frameworks, reinforcing and expanding strategies to ensure equitable funding distribution has never been more critical. The scientific community must continue advocating for evidence‐based approaches that improve transparency, accountability and fairness in research funding. Without sustained commitment, the progress made over the past decades is at risk of being reversed, undermining the diversity of thought and innovation essential to scientific advancement.


of the study design for the two intervention groups (rTMS: n = 15; sham‐rTMS: n = 16). The colours distinguish between short (red), and longer‐term (blue) effects. Behavioural short‐term adaptations were measured within PRE and POST and behavioural longer‐term adaptations over 4 balance acquisition sessions. Neurophysiological short‐term effects were evaluated twice; in the PRE‐measurement, short‐term adaptations were assessed PRE_1 to PRE_2. In the POST‐measurement, the effects of reactivating the previously learned balance task were investigated from POST_1 to POST_2; ‘reactivation’. Longer‐term adaptations (i.e., four acquisition sessions separated by 2 to 3 days) were assessed from the initial PRE‐measurement (PRE_1) to the POST‐measurement (POST_1). In the figure, ‘Neurophysiology’ stands for the assessment of corticospinal excitability (single pulses with TMS), SICI (short‐interval intracortical inhibition measured by a paired‐pulse TMS‐paradigm), determination of the resting motor threshold (in order to adjust the relative intensity of the rTMS measurements) and the active motor threshold (in order to adjust the relative intensity of the SICI and corticospinal excitability measurements) and Mmax (with peripheral nerve stimulation). S1‐S4 = series one to series four.
Experimental setup for the transcranial magnetic stimulation with the coil fixture and the custom‐made rocker board.
Behavioural data of the balance rocker board task. (A) PRE short‐term balance acquisition normalized to the first PRE series (PRES1). (B) POST short‐term balance acquisition normalized to the first POST series (POSTS1). (C) Longer‐term balance acquisition (solid lines) and consolidation (dotted lines) normalized to the first series of the first acquisition session (A_1S1). Shaded areas indicate consolidation after rTMS or sham‐rTMS. Dev. norm. = normalized mean deviation values of the rocker board task. rTMS = repetitive transcranial magnetic stimulation. A_1S1 = Acquisition_1, Series 1. ***Significant main effect of TIME (p < 0.001). **Significant main effect of TIME (p < 0.01).
Changes in short‐interval intracortical inhibition (SICI) during the balancing condition divided per group. The ANOVA revealed a significant interaction across all time points, indicating that the two groups exhibited distinct patterns of SICI modulation. In the rTMS group, SICI was steadily down‐modulated over time (PRE_1 to PRE_2 = −7.3%; PRE_1 to POST_1 = −14.2% and PRE_1 to POST_2 = −22.0%). Conversely, the sham‐rTMS group showed an initial upregulation of SICI (PRE_1 to PRE_2: +14.0%), which was maintained in the longer term (PRE_1 to POST_1: +9.3%; PRE_1 to POST_2: +9.7%). rTMS = repetitive transcranial magnetic stimulation.
Influence of rTMS on the consolidation process of motor memory. Acquiring a motor task leads to a fragile short‐term memory that stabilizes over time, enabling long‐term storage and retention of the motor memory. However, applying rTMS during this consolidation phase can interfere with long‐term memory, leading to forgetting. These interfering effects might be explained by the suppression of SICI up‐regulation by rTMS over M1. The present study did not investigate the long‐term effects of balance learning (right, lightly coloured box). However, we would expect that with increasing task automatization (i.e., overlearning), the influence of rTMS on motor memory consolidation and on modulation of SICI is reduced as we would assume a shift in movement control from more cortical to more subcortical areas. M1 = primary motor cortex; rTMS = repetitive transcranial magnetic stimulation; SICI = short‐interval intracortical inhibition.
Repetitive Magnetic Stimuli Over the Motor Cortex Impair Consolidation of a Balance Task by Suppressing Up‐Regulation of Intracortical Inhibition

Low‐frequency repetitive transcranial magnetic stimulation (rTMS) over the primary motor cortex (M1) was shown to impair short‐term consolidation of a balance task, emphasizing the importance of M1 in balance skill consolidation. However, the disruptive mechanisms of rTMS on neural consolidation processes and their persistence across multiple balance acquisition sessions remain unclear. GABAergic processes are crucial for motor consolidation and, at the same time, are up‐regulated when learning balance skills. Therefore, this study investigated the impact of rTMS on GABA‐mediated short‐interval intracortical inhibition (SICI) and consolidation of balance performance. Participants (n = 31) underwent six balance acquisition sessions on a rocker board, each followed by rTMS (n = 15) or sham‐rTMS (n = 16). In the PRE‐measurement, SICI was assessed at baseline and after balance acquisition with subsequent rTMS/sham‐rTMS. In the POST‐measurement, this procedure was repeated to assess the influence of motor memory reactivation on SICI. In addition, SICI‐PRE and SICI‐POST were compared to assess longer‐term processes. Both groups achieved similar improvements within the balance acquisition sessions. However, they did not consolidate equally well, indicated by significant declines in performance for the rTMS group (p = 0.003) in the subsequent sessions. Adaptations in SICI were affected by rTMS (p = 0.024): while the sham‐rTMS group up‐regulated SICI, rTMS led to reductions in inhibition. The interfering effect of rTMS on both balance consolidation and up‐regulation of SICI suggests that increased intracortical inhibition is an important factor to protect and consolidate the newly acquired motor memory.


Sex‐Specific Adaptations to VTA Circuits Following Subchronic Stress

June 2025

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20 Reads

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3 Citations

Dysregulation of the mesolimbic reward circuitry is implicated in the pathophysiology of stress‐related illnesses such as depression and anxiety. These disorders are more frequently diagnosed in females, and sex differences in the response to stress are likely to be one factor that leads to enhanced vulnerability of females. In this study, we use subchronic variable stress (SCVS), a model in which male and female mice exhibit distinct behavioral, transcriptional, and immunological alterations, to investigate sexually divergent mechanisms of regulation of the ventral tegmental area by stress. Using slice electrophysiology, we find that female, but not male, mice have a reduction in the ex vivo firing rate of VTA dopaminergic neurons following SCVS. Surprisingly, both male and female animals show an increase in inhibitory tone onto VTA dopaminergic neurons and an increase in the firing rate of VTA GABAergic neurons. In males, however, this is accompanied by a robust increase in excitatory synaptic tone onto VTA dopamine neurons. This supports a model by which SCVS recruits VTA GABA neurons to inhibit dopaminergic neurons in both male and female mice, but males are protected from diminished functioning of the dopaminergic system by upregulation of excitatory synapses. Thus, SCVS leads to both shared and disparate changes in the organization of the VTA in males and females.


Results of the structural connectivity–psychopathic trait prediction. Line plots (a) showing the predictive accuracy (ρ) across a range of p values for the positive and negative networks, respectively. Scatter plots showing the Spearman correlation between predicted and true psychopathic trait scores using the features from the positive (b), negative (c), and both networks (d). Connectograms (e) showing the edges of the positive and negative networks present in all cross‐validated significant CPM models. The nodes are arranged in two half circles corresponding to the left and right hemispheres (labelled as “L” and “R”). Heatmap (f) showing the number of significant edges connecting the nodes in positive (red) and negative (blue) networks. The nodes from the right and left hemispheres are combined. Fro, frontal lobe; Ins, insular; Lim, limbic; Occ, occipital lobe; Par, parietal lobe; Sub, subcortical; Tem, temporal lobe.
The white matter tracts connecting nodes of each significant edge in the positive and negative network. “L” and “R” corresponding to left and right hemispheres. AF, arcuate fasciculus; IFOF, inferior fronto‐occipital fasciculus; PCS, posterior corticostriatal; SLF_II, the second branch of the superior longitudinal fasciculus; UF, uncinate fasciculus.
Mediation models of structural network connectivity on the relationship between psychopathy and total externalizing behaviors. IFOF_R, the right inferior fronto‐occipital fasciculus; SLF_II_L, the left second branch of the superior longitudinal fasciculus.
The Role of Structural Brain Networks in Psychopathy and Its Relation to Externalizing Behaviors

June 2025

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36 Reads

Externalizing behaviors are particularly pronounced in the context of psychopathy. Recent neurobiological models suggest that psychopathy may be associated with abnormalities in brain network connectivity, which could contribute to its development and its links to externalizing behaviors. However, the specific structural networks contributing to psychopathy and its relation to externalizing behaviors remain poorly understood. In this study, we investigated the structural connectivity associated with psychopathy and its relation to externalizing behaviors in 82 young adults from the MPI Leipzig Mind‐Brain–Body dataset. A structural connectome–based prediction model with leave‐one‐out cross‐validation identified both positive and negative networks associated with psychopathy. Specifically, the positive network involved regions related to social‐affective processing, language, and reward systems, while the negative network was associated with regions involved in attention modulation. Furthermore, mediation analyses revealed two potential neural pathways from psychopathic traits to externalizing behaviors via emotional processing and attention modulation networks. These findings suggest that alterations in structural connectivity play a significant role in psychopathy and may underlie the externalizing behaviors observed in individuals with the disorder.


Schematic of the task blocks. Each of the six task blocks consisted of the performance of five tasks followed by a relaxation period. Each task was performed for 11 s, and the rest between each task was 4 s. The order of the tasks within the task block was randomized, and following each task block, the participants were given 8 s of rest.
(A) Schematic showing the regions and connections included in the sensorimotor network ROI‐to‐ROI functional connectivity analysis. The regions included the supplemental motor area (SMA), left and rigth precentral gyrus (PreCG), and the left and right cerebellum. (B) Schematic showing the regions and connections included in the insular network ROI‐to‐ROI functional connectivity analysis. The regions included the left and right midcigulate cortex (MCC), left and right insular opercular cortex (IOC), and the left and right putamen.
Whole brain activation of both the symptomatic and asymptomatic groups during the bilateral, left, and right bridging tasks. Activation is tresholded at Z > 3. Values at the bottom represent the slice numbers in the z axis.
Brain Activation and Functional Connectivity During Performance of Lumbopelvic Motor Tasks in Individuals With and Without Low Back Pain: A Functional Magnetic Resonance Imaging Study

Mounting evidence suggests that individuals with chronic low back pain exhibit changes in brain activity. However, changes in brain activity during the performance of salient motor tasks have not been fully described. Therefore, the purpose of this study was to investigate the differences in cortical activation and functional connectivity between individuals with and without chronic low back pain while performing condition‐specific motor tasks. Twenty‐three individuals with chronic low back pain and 19 asymptomatic individuals participated in this study. Whole brain activity and functional connectivity were measured, whereas participants performed three lumbopelvic motor tasks: modified bilateral bridge, left unilateral bridge, and right unilateral bridge. Whole‐brain analysis revealed no significant differences in brain activation between the groups when performing lumbopelvic motor tasks. An exploratory region of interest analysis demonstrated that individuals with chronic low back pain had significantly higher activation in the left insular‐opercular cortex, left midcingulate gyrus, right insular‐opercular cortex, right midcingulate gyrus, and right putamen. Functional connectivity analysis revealed significantly higher connectivity between the midcingulate gyrus, putamen, and insular‐opercular cortex in those with chronic low back pain compared to asymptomatic participants. Taken together, this study helps build on the existing literature by providing unique insights into the changes that occur during the performance of salient motor tasks in individuals with chronic low back pain.


Perceptual and Motor Processes in Motor Imagery

June 2025

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46 Reads

The degree to which motor imagery engages the motor system or relies on perceptual/cognitive processes is a continuing debate. Here, we used the size weight illusion to create dissociation between perception and action to address the nature of motor imagery. Participants alternated lifting bricks of equal mass but where one brick was larger than the other, resulting in a perceptual illusion. Fifty‐seven participants were divided into three groups differing in the modality used for training (motor imagery, MI; and overt execution, OE) and exposure to the size weight illusion pretraining, one (MI‐2) and five (MI‐10 and OE) lifts of each brick. We hypothesized that the MI groups would use lifting dynamics post‐training consistent with the illusion, whereas the OE group would maintain accurate lifting forces. Contrary to our hypothesis, the OE and MI‐10 groups maintained the effect of the illusion post‐training. In the MI‐2 group, perception of the bricks' weight changed to reflect the participant's belief that large objects are heavy, and they correspondingly adjusted their lifting force post‐training. These results demonstrate that perceptual and motor processes are engaged during motor imagery and that the simulation of the motor component of the movement during motor imagery guides the performed action.


Kinase signalling networks involved in Alzheimer's disease pathogenesis. This schematic illustrates the complex interplay among key kinases implicated in ad, including GSK3β, CDK5, p38 MAPK, Fyn, AMPK, PKA, CK1 and TTBK1. GSK3β contributes to tau phosphorylation at Thr231 and Nrf2 regulation, promoting oxidative stress and NFT formation. The pathological CDK5/p25 complex—formed via cleavage of CDK5/p35 by Aβ, Ca²⁺ and calpain‐1—drives mitochondrial dysfunction, apoptosis and aberrant cell cycle re‐entry. p38 MAPK exacerbates inflammation and synaptic damage, whereas Fyn phosphorylates APP and NMDA receptor subunits, contributing to excitotoxicity. Reduced AMPK activity promotes Aβ accumulation via mTOR activation and impaired autophagy. Kinases such as PKA and CK1 also modulate synaptic plasticity, BDNF signalling and downstream kinase pathways. Collectively, these pathways form a tightly interconnected regulatory network central to ad progression. Adapted with permission from Wu et al. (2025) (Signal Transduction and Targeted Therapy, 10.1038/s41392‐025‐02179‐x).
Potential therapeutic targets in Alzheimer's disease.
Kinase signalling networks involved in Parkinson's disease pathogenesis. This schematic illustrates the interplay between key kinases involved in mitochondrial quality control, autophagy and neuronal survival in PD. Mutations in PINK1 and LRRK2 impair mitophagy and lysosomal clearance, leading to mitochondrial dysfunction and aggregation of α‐synuclein into Lewy bodies. PINK1 accumulation at the outer mitochondrial membrane recruits Parkin, initiating mitophagy and promoting cell survival. Mutant LRRK2 fails to activate AKT, resulting in reduced FOXO1 inhibition and increased cell death. In parallel, LRRK2 and stress signals activate the ASK1–MAP 2K–JNK/p38 axis, amplifying proapoptotic signalling. Phosphorylation of α‐synuclein by kinases such as CK, PLK, GRK5 and c‐Abl enhances its aggregation, promoting neuroinflammation and oxidative stress (ROS). The dysregulation of these signalling cascades contributes to dopaminergic neurodegeneration and disease progression. Adapted with permission from Wu et al. (2025) (Signal Transduction and Targeted Therapy, 10.1038/s41392‐025‐02179‐x).
Kinase signalling pathways dysregulated in Huntington's disease (HD). This schematic illustrates the central role of mutant huntingtin (mHTT) in modulating kinase‐driven neurodegenerative processes. mHTT promotes neuronal apoptosis and inflammation by activating pro‐death kinases (p38, JNK and IKKβ) and inhibiting prosurvival pathways such as ERK. Its interactions with HTT via AKT and MEK/ERK pathways regulate autophagy, neuroprotection and glucose metabolism. mHTT aggregation contributes to DNA damage, pancreatic β‐cell dysfunction and activation of CDK5 via IRS‐2. CDK5 overactivation destabilizes microtubules, further exacerbating mHTT toxicity. In parallel, IKKβ activation by AKT promotes neuroinflammatory signalling through NF‐κB, whereas AKT also counters JNK‐mediated apoptosis. Adapted with permission from Wu et al. (2025) (Signal Transduction and Targeted Therapy, 10.1038/s41392‐025‐02179‐x).
The Role of Kinases in Neurodegenerative Diseases: From Pathogenesis to Treatment

Neurodegenerative diseases are characterized by progressive neuronal loss and dysfunction, with protein kinases playing crucial roles in their pathogenesis. This article explores the involvement of protein kinases in these disorders, focusing on their contributions to disease mechanisms, potential as therapeutic targets and challenges in developing effective treatments. In Alzheimer's disease, kinases such as CDK5, GSK3β and MARK4 are implicated in tau hyperphosphorylation and the formation of neurofibrillary tangles. Kinases also regulate amyloid‐β processing and plaque formation. In Parkinson's disease, LRRK2, PINK1 and other kinases contribute to α‐synuclein pathology, mitochondrial dysfunction and neuroinflammation. LRRK2 inhibitors and PROTACs have shown promise in preclinical models. Huntington's disease involves altered kinase activity, with CK2, GSK3 and MAPK pathways influencing mutant huntingtin toxicity and aggregation. Kinases are also implicated in less common neurodegenerative diseases, such as ALS and spinocerebellar ataxias. Despite the therapeutic potential of targeting kinases, challenges remain, including the complexity of kinase networks, blood–brain barrier permeability and the lack of robust biomarkers. Emerging technologies, such as covalent inhibitors, targeted protein degradation and combination therapies, offer new avenues for addressing these challenges and developing more effective treatments for neurodegenerative diseases.



BSD: A Bayesian Framework for Parametric Models of Neural Spectra

May 2025

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14 Reads

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1 Citation

The analysis of neural power spectra plays a crucial role in understanding brain function and dysfunction. While recent efforts have led to the development of methods for decomposing spectral data, challenges remain in performing statistical analysis and group‐level comparisons. Here, we introduce Bayesian spectral decomposition (BSD), a Bayesian framework for analysing neural spectral power. BSD allows for the specification, inversion, comparison and analysis of parametric models of neural spectra, addressing limitations of existing methods. We first establish the face validity of BSD on simulated data and show how it outperforms an established method [fit oscillations and one‐over‐f (FOOOF)] for peak detection on artificial spectral data. We then demonstrate the efficacy of BSD on a group‐level study of electroencephalography (EEG) spectra in 204 healthy subjects from the LEMON dataset. Our results not only highlight the effectiveness of BSD in model selection and parameter estimation but also illustrate how BSD enables straightforward group‐level regression of the effect of continuous covariates such as age. By using Bayesian inference techniques, BSD provides a robust framework for studying neural spectral data and their relationship to brain function and dysfunction.


Functional connectivity for nucleus accumbens and ventral caudate seeds. Functional connectivity (FC) of the left and right nucleus accumbens (L and R NAc) is illustrated in the top eight panels. Left NAc shows significant FC to the left parietal operculum (yellow‐red). Right NAc exhibits prominent FC to the contralateral ventral putamen, bilateral precuneus, medial postcentral gyrus and posterior and anterior cingulate cortex (blue‐light blue). The ventral caudate (vCau) seeds (bottom eight panels) show largely symmetric and overlapping FC pattern, with the most prominent FC to the anterior cingulate cortex. For details, see Table S1. Displayed at voxel‐level pFWE < 0.05, k = 250. FWE = family‐wise error corrected. k = minimum cluster size (in mm³). t‐Statistic range in the colour bars is 5.34–8.
Functional connectivity (FC) strength between the left ventral caudate seed and the left middle frontal gyrus (MFG) is negatively associated with the total Slips of Action Task (SOAT) score. The cluster, indicated by a light blue circle, has the primary peak in the MFG ([−31, 0, 55]) that extends into the left superior frontal gyrus (peak at [−24, 0, 63]). Overlap (green) of the cluster (blue‐light blue) and dorsal attention network (yellow). L = left. Fit line represents bivariate correlation and is shown for illustration purposes only.
Functional connectivity (FC) strength between the left nucleus accumbens (NAc) seed and the right central operculum (CO, light green circle) is positively associated with the total Slips of Action Task (SOAT) score. Overlap of the SOA cluster (red‐yellow) and somatomotor network (green). L = left. Fit line represents bivariate correlation and is shown for illustration purposes only.
Parallel mediation model on average drinks per drinking day. CO = central operculum; MFG = middle frontal gyrus; NAc = nucleus accumbens; SOAT = Slips of Action Task. Solid arrow indicates a significant association. Dashed arrow indicates nonsignificant association.
Parallel mediation model on cumulative work for alcohol. CAT = constant attention task; CO = central operculum; MFG = middle frontal gyrus; NAc = nucleus accumbens; SOAT = Slips of Action Task. Solid arrow indicates a significant association. Dashed arrow indicates nonsignificant association.
Left Ventral Caudate Functional Connectivity Mediates the Relationship Between Habitual Responding and Alcohol Use

May 2025

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21 Reads

Preclinical studies posit that habitual behaviour is an important mechanism in the development of alcohol use disorder (AUD), but human findings are unclear. The goals of this study were to test a behavioural measure of habit formation, the Slips of Action Task (SOAT), in humans and identify brain‐based mechanisms explaining the relationship between habit and alcohol use. Thirty‐six participants (63.9% female, mean age = 30.58, SD = 9.73, 69.4% White, 83.3% Not Hispanic/Latino) who endorsed heavy drinking completed self‐report measures, the SOAT (lower scores = higher habit formation), a 2.5‐h intravenous alcohol self‐administration session, and a resting‐state functional magnetic resonance imaging scan. Three seed regions—bilateral ventral caudate, nucleus accumbens and dorsal caudate—were assessed for significant whole brain functional connectivity (FC) associations with SOAT (cluster‐level pFWE < 0.05 at a cluster‐forming threshold p = 0.001). Two clusters survived Bonferroni correction (cluster pFWE = 0.008): FC between the left ventral caudate and the left middle frontal gyrus correlated negatively, while FC between the left NAc and the right central operculum correlated positively, with SOAT score. SOAT score was unrelated to drinking outcomes; however, there was a significant indirect relationship between SOAT and average drinks per drinking day through FC between the left ventral caudate and the left middle frontal gyrus. A similar trend seen with cumulative work for alcohol fell short of significance. Habit formation's relationship with alcohol use may function through neuroadaptations in the ventral caudate. More work is needed to better characterize objective habit formation in the human alcohol laboratory with additional laboratory‐, alcohol‐specific, imaging‐ and ambulatory‐based alcohol use metrics.


Intraperitoneal Single Injection of Dexamethasone Leads to Region‐Specific Changes in the Profile of Neuron‐Specific Proteins in the Rat Brain

This study aims to investigate the effect of dexamethasone (DEX) injection on the production of growth‐associated protein 43 (GAP‐43), the protein that promotes calpain‐2 activation. Increased levels of GAP‐43 in the central nervous system can stimulate plastic and regenerative processes in the brain, which can be used to treat neurodegenerative diseases. However, GAP‐43 is a target for the specific apoptotic protease calpain‐2, whose hyperactivation may have negative consequences for the CNS. We found that DEX stimulates GAP‐43 mRNA and protein production in the rat hippocampus. DEX administration at a dose of 8 mg/kg (once intraperitoneally) leads to an increase in GAP‐43 protein levels and calpain‐2 activation in the striatum and prefrontal cortex of rats; however, calpain‐2 protein production is increased in the striatum and decreased in the prefrontal cortex. Our data support the hypothesis that DEX can be used to enhance the production of GAP‐43 and other proteins crucial for brain function, such as tyrosine hydroxylase and calpains. This approach could potentially be employed to stimulate regenerative processes in the brain following acute injury or as a pulse therapy for chronic neurodegenerative conditions.


Experimental manipulations used in Study 1 (top) and Studies 2 and 3 (bottom).
(A) Average normalized reaction times for correct keypresses for the 200‐ and 500‐ms interstimulus interval conditions across the five blocks. (B) Average error rates for the 200‐ and 500‐ms conditions across the five blocks. Error bars represent the within‐participant standard errors (Morey 2008).
(A) Average normalized reaction times for correct keypresses for the four groups across the five blocks. (B) Average error rates for the four groups across the five blocks. Error bars represent the within‐participant standard errors (Morey 2008). Note that errors do not contribute to the normalized reaction time calculations.
(A) Average normalized reaction times for correct keypresses for the (bimodal) Informative and Uninformative conditions across the five blocks. (B) Average error rates for the (bimodal) Informative and Uninformative conditions across the five blocks. Error bars represent the within‐participant standard errors (Morey 2008). Note that errors do not contribute to the normalized reaction time calculations.
Informative Auditory Cues Enhance Motor Sequence Learning

Motor sequence learning, or the ability to learn and remember sequences of actions, such as the sequence of actions required to tie one's shoelaces, is ubiquitous to everyday life. Contemporary research on motor sequence learning has been largely unimodal, ignoring the possibility that our nervous system might benefit from sensory inputs from multiple modalities. In this study, we investigated the properties of motor sequence learning in response to audiovisual stimuli. We found that sequence learning with auditory–visual stimuli showed a hallmark feature of traditional unimodal sequence learning tasks: sensitivity to stimulus timing, where lengthier interstimulus intervals of 500 ms improved sequence learning compared to briefer interstimulus intervals of 200 ms. Consistent with previous findings, we also found that auditory–visual stimuli improved learning compared to a unimodal visual‐only condition. Furthermore, the informativeness of the auditory stimuli was important, as auditory stimuli which predicted the location of visual cues improved sequence learning compared to uninformative auditory stimuli which did not predict the location of the visual cues. Our findings suggest a potential utility of leveraging audiovisual stimuli in sequence learning interventions to enhance skill acquisition in education and rehabilitation contexts.


Nano‐Chaperones: Bridging Therapeutics for Amyloid Aggregation in Alzheimer's Disease and Type‐2 Diabetes Mellitus

May 2025

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29 Reads

Nano‐chaperones represent an innovative therapeutic approach targeting amyloid aggregation in Alzheimer's disease ( AD ) and Type‐2 diabetes mellitus (T2DM), two diseases linked by similar pathogenic mechanisms involving protein misfolding and insulin resistance. Current treatments primarily address symptoms, yet nano‐chaperones can potentially intervene at the molecular level by mimicking natural chaperone proteins to prevent or reverse amyloid aggregation. In AD , nano‐chaperones target amyloid‐beta (Aβ) peptides, reducing neurotoxicity and preserving neuronal function, while in T2DM, they inhibit islet amyloid polypeptide (IAPP) aggregation, alleviating cytotoxic stress on pancreatic β‐cells. These nanoparticles exhibit a dual capacity for cellular penetration and selectivity in interacting with misfolded proteins, showing promise in mitigating the shared amyloidogenic pathways of both diseases. Preclinical studies have demonstrated significant reductions in amyloid toxicity with potential applications in crossing the blood–brain barrier (BBB) to enhance central nervous system (CNS) delivery. Nano‐chaperones transformative role in developing multi‐targeted precision therapies for complex diseases is highlighted, underscoring their capacity to modulate disease progression through targeted biomimetic interactions. Nano‐chaperone designs for clinical application focus on enhancing therapeutic efficacy and safety. This innovative approach may redefine treatment paradigms for amyloid‐related diseases, offering a new frontier in personalized medicine.


Age‐Related Differences in Neural Correlates of Auditory Spatial Change Detection in Real and Virtual Environments

May 2025

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14 Reads

Although virtual environments are increasingly used in research, their ecological validity in simulating real‐life scenarios, for example, to investigate cognitive changes in aging populations, remains relatively unexplored. This study aims to evaluate the validity of a virtual environment for investigating auditory spatial change detection in younger and older adults. This evaluation was performed by comparing behavioral and neurophysiological responses between real and virtual environments. Participants completed an auditory change detection task, identifying sound source position changes relative to a reference position. In the real environment, sounds were presented through physical loudspeakers in a reverberant room. In the virtual environment, stimuli were delivered through headphones, accompanied by a head‐mounted display showing a visual replica of the room. Participants showed higher accuracy for azimuth than for distance changes, regardless of age or environment, emphasizing humans' larger sensitivity to lateralized sounds. Event‐related potentials were mostly consistent across environments, with significantly higher N1 and P2 amplitudes in older compared with younger adults. Mismatch negativity was reduced in older adults, and both reduced and delayed in the virtual environment. The P3b showed larger amplitudes and shorter latencies for azimuth changes, reflecting greater salience of directional cues, whereas responses in the virtual environment were slightly diminished, especially among older adults. Bayesian analyses validated the observed effects. Results support virtual environments as reliable tools for exploring spatial perception and underlying neural and behavioral processes in realistic contexts. Furthermore, differences in the processing of spatial changes in azimuth and distance, as well as age‐related effects, could be highlighted.


FIGURE 2 | Comparison of differentially expressed genes in the choroid plexus and cortex of P5 pups following foetal valproate exposure. (A) Overlaps of differentially expressed genes between choroid plexus and cortex. (B) Histogram of the number of differentially expressed genes across −log10 (adjusted p values) in choroid plexus (CP) and cortex. (C) Top enrichment clusters for common differentially expressed genes between the two tissues.
FIGURE 5 | Expression of drug transfer mechanisms in the choroid plexus of P5 pups following foetal valproate exposure. (A) Pie chart of the proportion of genes analysed which were upregulated (red), downregulated (blue) or showed no changes (grey) in their expression. Transporters include ABC transporters and solute carriers. DMEs: drug-metabolising enzymes. (B) Counts per million (CPM) of differentially expressed drug transporting ABC transporters in control (filled circles • ) and valproate-exposed P5 pups (open circles ○ ). (C) Counts per million (CPM) of differentially expressed drug transporting solute carriers in control and valproate-exposed P5 pups. Mean ± standard deviation; n = 4. *p-adj < 0.05, **p-adj < 0.01, ***p-adj < 0.001, **** p-adj < 0.0001. (D) Fold changes of differentially expressed drug-metabolising enzymes (DMEs). Red and blue indicate up-or downregulation respectively.
FIGURE 8 | Expression of immune response-related genes in P5 pups following foetal valproate exposure. Volcano plot showing log2 fold changes and −log10 adjusted p values of differentially expressed genes in (A) cortex and (B) choroid plexus. Red and blue indicate up-or downregulation respectively. (C) Overlaps of differentially expressed genes between cortex and choroid plexus, with the list of shared genes.
Gestational Valproate Exposure Induces Tissue‐Specific Transcriptomic Changes in the Neonatal Brain and Choroid Plexus in a Rat Model of Epilepsy, GAERS

May 2025

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4 Reads

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1 Citation

Valproate is an antiseizure drug required by many epileptic patients to manage their symptoms. During pregnancy, its use has been shown to increase the risk of neurobehavioral deficits in the offspring. The present study used a rat model of absence epilepsy, Genetic Absence Epilepsy Rat from Strasbourg (GAERS), to investigate the effects of gestational valproate exposure on early postnatal brain cortex and lateral choroid plexus transcriptomes. Females were provided with either a control diet or a valproate‐laced diet (20 g/kg) from 2 weeks prior to mating and throughout gestation. At parturition, all dams received a control diet. Pups at Postnatal Day 5 were used for RNA sequencing. Differential expression analyses were conducted between transcriptomes from valproate‐exposed and control animals. In the choroid plexus, 5694 genes significantly altered their expression compared to 214 in the cortex, a difference of nearly 25 times. Dysregulation was identified in choroidal expression of ion channels and metal transporters including six members of the Slc4a family, Cacna1h and Kcne2 . Several drug transporting ATP‐binding cassette transporters and solute carriers were significantly upregulated and drug‐metabolising enzymes downregulated. In the cortex, 11 genes associated with the development of the central nervous system were differentially expressed. Finally, in both tissues, foetal valproate exposure appeared to result in dysregulation of genes related to adaptive and innate immune responses. These results indicated that gestational exposure to valproate resulted in distinct and greater effects on the choroid plexus transcriptome compared to the cortex, potentially suggesting additional targets related to developmental valproate neurotoxicity.


FIGURE 1 | Female hormone and neurotransmitter levels. Estrogen, progesterone and dopamine levels throughout the female lifespan (A), human menstrual (B) and rodent estrous (C) cycles, and DA transporter and receptor expression throughout the estrous cycle (D). DAT, dopamine transporter; H:L D2, high:low dopamine 2 receptor affinity ratio; VMAT, vesicular monoamine transport. Created with BioRender.com.
FIGURE 2 | Estrogen's modulation of DA synapses in dorsal and ventral striatum. Indirect estrogen effects in the dorsal (A, B) and ventral (C, D) striatum during metestrus/diestrus (A, C) and proestrus/estrus (B, D). (A) In the dorsal striatum, estrogen receptors are only expressed postsynaptically on spiny projection neurons (SPNs), and DA release is indirectly modulated by local GABA release. (B) When estrogen concentration is high in proestrus/estrus in the dorsal striatum, GABA release from SPNs decreases, and DA release increases. (C) Estrogen receptors in the ventral striatum are expressed presynaptically and postsynaptically, modulating DA release directly and indirectly. (D) During proestrus/estrus, DA release increases by increasing VMAT activity, decreasing DAT activity, decreasing DA autoreceptor activity, and decreasing local GABA release. Note: DA receptors are not divided into D1/D2 because that would require discussing direct or indirect pathways, respectively. Created with BioRender.com.
FIGURE 3 | Proposed mechanism of increased LID in postmenopausal women. (A) In premenopausal women, estrogen controls DA surges generated by levodopa administration via increased DAT activity, decreased D2 autoreceptor activity, and increased postsynaptic binding. (B) Following menopause, when estrogen levels have declined, extracellular DA concentration surges and LID symptoms occur because DA spillover activates receptors on other spiny projection neurons. Note: Synapses are related to Figure 2 but have been simplified for clarity. Created with BioRender.com.
Sexual Dimorphism in Levodopa‐Induced Dyskinesia Following Parkinson's Disease: Uncharted Territory

Sexual dimorphism is well‐documented in Parkinson's disease (PD); however, when it comes to levodopa‐induced dyskinesia (LID), epidemiological and clinical findings are scarce. This is an oversight because recent studies show significant correlations between LID risk and female sex. Estrogen strongly impacts neuronal function, affecting cognitive tasks such as movement, object recognition, and reward. In movement pathways, estrogen increases dopamine synthesis, transmission, and regulation, resulting in neuroprotection for PD in women. However, following menopause, PD prevalence, symptom severity, and LID risk increase for women. Consequently, early to mid‐life estrogen state is neuroprotective, but later in life becomes a risk factor for PD and LID. This review explores estrogen's action in the brain, specifically within the dopamine system. Sexual dimorphism is described for the prevalence and onset of PD and LID. We examine the cellular basis of estrogen's role in sexual dimorphism and integrate these ideas to hypothesize why the risk for LID is higher for women, than men, with PD. Lastly, this review proposes that women with PD need their symptoms to be considered and managed differently to males. Treatment of women with PD should be based on their menopausal stage, as estrogen may be masking, exacerbating, or complicating symptoms. Importantly, we present these concepts to stimulate discussion among clinical and bench scientists so that key experiments can be conducted to examine the mechanisms underlying LID, so they can be prevented to improve the quality of life for women and men living with PD in the future.


Figure 1. Simulated trajectories of molecules or ions over a 50-second period as they cross a fluid channel lined with alternating surface charge domains. The flow field is shaped by electrohydrodynamic forces resulting from interactions between the patterned wall charges and the fluid content. The colored lines trace the paths of individual particles. The extended simulation duration (T = 50 s) highlights how charge-driven microflow structures can lead to differential transport, localized trapping or enhanced directional clearance.
Figure 2. Simulated trajectories of molecules or ions advected through a CSF microchannel bounded by alternating positive and negative surface charge domains on the top and bottom walls. The background color map represents the flow velocity field generated by electrohydrodynamic interactions between the wall charge pattern and ionic content of the fluid. Particle trajectories are shown as colored lines, with green dots indicating starting positions and red dots marking their final locations. Spatial variations in wall charge can lead to non-uniform and trajectory-dependent fluid flow.
Figure 3. Brain-relevant parameters influencing CSF flow dynamics. Left Panel: Effect of electrostatic coupling strength (ionic strength). This plot shows how increasing electrostatic coupling-representing stronger interactions between charged walls and ions in CSF-leads to a progressive reduction in total CSF flow. This mimics physiological and pathological changes in ionic strength, such as elevated extracellular potassium or disrupted ion homeostasis caused by various diseases. Middle Panel: Effect of wall charge amplitude. This plot illustrates how variations in the amplitude of patterned surface charge along ventricular or perivascular walls influence CSF flow. Modulation of charge density could arise either from altered astrocytic or ependymal activity or pathological changes in membrane potential and protein expression. The non-linear flow behavior highlights the potential for bioelectrical gating of fluid dynamics. Right Panel. Effect of pressure gradient. This panel shows the linear relationship between the applied pressure gradient and CSF flow rate, modeling physiological drivers such as cardiac and respiratory cycles, as well as pathological changes in intracranial pressure.
Figure 4. Conceptual workflow of a hybrid computational model combining near-wall and bulk flow simulations to investigate electrohydrodynamic CSF dynamics. The upper section represents the near-wall simulation zone, where Dissipative Particle Dynamics (DPD) or Molecular Dynamics (MD) are used to capture fine-scale electrostatic interactions, ion layering and local electro-osmotic effects near charged glial or ependymal surfaces. The lower section depicts the bulk flow simulation domain, modeled using Lattice Boltzmann Method (LBM) or Finite Element Method (FEM), which handles pressure-driven flow and global CSF transport in anatomically relevant structures. The central coupling interface enables dynamic data exchange between the two regions. Velocity and ionic flux data from the particlebased simulation may inform boundary conditions, macroscopic pressure and shear feedbacks.
Charged Interfaces in the Brain: How Electrostatic Forces May Guide Cerebrospinal Fluid Dynamics

Cerebrospinal fluid (CSF) flows play a main role in maintaining brain homeostasis, supporting waste clearance, nutrient delivery and interstitial solute exchange. Although current models emphasize mechanical drivers like cardiac pulsation, respiration and ciliary motion, these mechanisms alone fall short of explaining the nuanced spatiotemporal regulation of CSF flow observed under physiological and pathological conditions-even when accounting for the glymphatic framework. We hypothesize that electrostatic forces arising from charged cellular interfaces may contribute to CSF movement through electro-osmotic mechanisms. We begin by examining the biological basis for surface charge in the brain, highlighting the presence of charged glycoproteins, ion channels and dynamic membrane potentials on ependymal/glial cells interfacing directly with CSF pathways. Next, we describe key electro-osmotic principles in confined geometries, emphasizing how nanoscale surface charges can modulate fluid motion without mechanical input. Drawing from nanofluidic research, biophysics and electrohydrodynamic theory, we argue that the conditions required for electro-osmotic coupling, i.e., ionic fluid, narrow conduits and patterned surface charge, are present within brain microenvironments. To test plausibility, we present computational simulations demonstrating that surface charge patterns alone can induce structured fluid flow/solute transport, including nonlinear transitions and oscillatory behaviours that resemble physiological rhythms. These findings support the idea that electrostatics may play a modulatory role in CSF regulation, complementing mechanical drivers. By integrating different disciplines, we propose a testable, mechanistically grounded hypothesis reframing CSF dynamics as electrohydrodynamically sensitive processes. Our approach could inspire novel diagnostics/therapeutic strategies in hydrocephalus and neurodegenerative disease and inform the design of targeted drug delivery systems. Below is the unedited draft of the article that has been accepted for publication © European Journal of Neuroscience, 2025. 2 GRAPHICAL ABSTRACT This illustration visualizes the hypothesis that cerebrospinal fluid (CSF) flow within the brain may be modulated not only by mechanical forces, but also by electrostatic interactions. The image depicts CSF flowing through confined perivascular and ventricular spaces lined with glial and ependymal cells, which display patterned surface charges. These charges interact with the ionic constituents of the CSF, generating electro-osmotic forces that may drive directional or oscillatory fluid movement. The conceptual model bridges neuroscience, nanofluidics and electrohydrodynamics to propose that surface charge dynamics at cellular interfaces could contribute to localized CSF regulation, potentially influencing solute clearance, signaling and pathological states. 3


Changes of the Primary Cilia in Alzheimer's Disease Pathogenesis

May 2025

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10 Reads

Alzheimer's disease (AD), a neurodegenerative disorder intricately linked with aging, poses an escalating global health challenge. Currently, no effective treatment exists for AD. Although the pathological characteristics of AD predominantly emerge in older age, numerous structural and functional alterations in the nervous system may commence early in life or even during developmental stages. Primary cilia, organelles associated with age‐related diseases, have not been extensively studied in the context of AD progression. This study initiated an examination of the common pathological features of AD and identified that amyloid‐beta (Aβ) plaque deposition resulted in the shortening of primary cilia. In the hippocampus of familial AD mice, there was a significant upregulation of somatostatin receptor 3 (SSTR3) expression. To further elucidate the role of SSTR3 in AD pathology, we knocked out SSTR3 expression in 5 × FAD mice, which resulted in an exacerbation of AD‐related pathological features. Our study offers novel insights into the pathological alterations associated with AD.


Pallidal Deep Brain Stimulation Enhances Habitual Behavior in a Neuro‐Computational Basal Ganglia Model During a Reward Reversal Learning Task

May 2025

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21 Reads

Deep brain stimulation (DBS) within the basal ganglia is a widely used therapeutic intervention for neurological disorders; however, its precise mechanisms of action remain unclear. This study investigates how DBS may affect decision‐making processes through computational modeling of the basal ganglia. A rate‐coded model incorporating direct, indirect, and hyperdirect pathways was utilized alongside a cortico‐thalamic shortcut known for promoting habitual behavior. Simulations of a two‐choice reward reversal learning task were conducted to replicate data from patients with dystonia in ON and OFF DBS conditions. We demonstrate that plasticity in the cortico‐thalamic shortcut, which bypasses the basal ganglia, is crucial for reproducing the patients' behavioral data, emphasizing the role of habit formation. Simulated DBS increased habitual behavior following reward reversal. Integrating different DBS mechanisms revealed that suppression of stimulated neurons, stimulation of efferent axons, and a combined variant promoted habitual behavior. Analyses of thalamic inputs showed that, despite differing effects on the model's activity and plasticity, these DBS variants consistently reduced the influence of the basal ganglia while enhancing the role of the cortico‐thalamic shortcut. Notably, the DBS variants were distinguishable by their divergent behavioral effects following discontinued stimulation. These findings underscore the potential multifaceted effects of DBS on decision‐making processes. In particular, our model proposes that DBS modulates the balance between reward‐guided and habitual behavior.


Journal metrics


2.7 (2023)

Journal Impact Factor™


35%

Acceptance rate


7.1 (2023)

CiteScore™


33 days

Submission to first decision


0.898 (2023)

SNIP


$3,560.00 / £2,380.00 / €2,980.00

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