European Journal of Neuroscience

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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 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.

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.

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.

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.

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

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.

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.