New conceptual and technological developments bring neuroscientists closer to other disciplines, and to other fields in neuroscience with different traditions, despite having overlapping interests. While some neuroscientists may underrate the potential benefits of successful interdisciplinary collaborations, some may be unaware of the typical difficulties of such collaborations or not trained in skills that render them fruitful. Here, we illustrate how interdisciplinary interactions have long been part of neuroscience, although they are often challenging, because neuroscientists may be confronted with concepts, assumptions, and interpretative horizons that differ from their own. This can lead to misunderstanding and little mutual appreciation. Using the historical development of brain imaging techniques, we distinguish different types of interdisciplinary interactions and illustrate some of their benefits. In addition, we present challenges at the interface between traditional laboratory-type approaches and those of clinical or computational neuroscience, and of ecological field experiments. To address these, we invite neuroscientists to consider philosophers as collaboration partners with complementary expertise, which includes special consideration of language use, underlying assumptions and proficiency in conceptual analysis. This expertise can be used by neuroscientists to increase their understanding and to address some difficulties in interdisciplinary interactions more effectively. The benefits of these interactions can be expected to outweigh some challenges in the dialogue with philosophers. Importantly, neuroscientists can choose between reading philosophical literature, participating in joint events with philosophers, and integrating philosophers into neuroscience projects. This may allow neuroscientists to explore unforeseen possibilities to improve or initiate collaborations with scientists from other fields and disciplines.

It has long been known that the dorsomedial (DMS) and dorsolateral stratium (DLS) mediate distinct forms of action control with DMS mediating goal-directed actions and DLS mediating habits. Recent evidence suggests that, in accord with its role in goal-directed control, unilateral stimulation of dorsomedial striatum (DMS) enhances actions contralateral to the stimulation in a manner that scales with the prior reward history of that action. In the current study we assessed whether the effects of unilateral stimulation of the dorsolateral striatum (DLS) induces a response bias that reflects enhanced habitual control, as measured by the effect of stimulation on on-going goal-directed control. Rats were first trained to press two levers for distinct outcomes in a manner likely to induce goal-directed control of these actions. We then assessed the effects of unilateral hM3D DREADDs-induced stimulation of the DMS or DLS, applied during an outcome devaluation choice test and outcome-mediated reinstatement, both known to depend on DMS activity. DMS stimulation had no impact on choice of either the action ipsilateral or contralateral to the stimulation either during devaluation or reinstatement. In contrast, stimulation of the DLS abolished goal-directed control in both tests, reducing sensitivity to outcome devaluation both on the ipsilateral and contralateral lever. In addition, stimulation both attenuated reinstatement and induced a response bias away from the contralateral lever during reinstated responding. These data suggest that the effects of stimulation of the DLS are modulated by its role in habitual control.

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that can alter the excitability of targeted brain regions and influence motor learning. This study investigates the effects of concurrent M1 anodal and cerebellar cathodal tDCS (M1a+CBc) on motor learning in a complex rhythm-timing video game task. Forty-two participants practiced the game with their non-dominant hand while receiving either M1a+CBc (n = 24) or sham tDCS (n = 18). Performance was assessed using a performance index (PI) incorporating keystroke timing accuracy, tap distribution ratio, and key error rate. A 2 x 5 mixed ANOVA revealed a significant main effect of stimulation group on PI gain scores across practice blocks (P = 0.021, ηp2 = 0.126), with M1a+CBc showing greater gains than sham. An ANCOVA, controlling for baseline performance, showed that the M1a+CBc group had significantly higher post-test PI scores compared to the sham group (P = 0.034, ηp2 = 0.110). These results suggest that concurrent M1a+CBc tDCS significantly enhances motor learning in complex tasks.

Alzheimer’s disease (AD) is the most common age-related dementia. Lifestyle factors, including alcohol use, can increase the risk of AD. While human studies demonstrate that alcohol use can negatively impact AD risk and disease progression, the underlying alcohol-dependent mechanisms that increase neurodegeneration and Aβ burden remain elusive. We have recently shown that alcohol can acutely affect microglial dynamics, which are critical to microglial function, and many other studies have reported inflammatory activation of microglia after long-term alcohol exposure in both humans and animal models. Here, we administered ethanol at dosages that mimic human binge drinking for 4 weeks to 2.5-month-old male 5xFAD mice, a common mouse model of AD. After a two-week abstinence period, we performed behavior assays and analyzed amyloid pathology and microglial morphology in the subiculum where amyloid pathology develops earlier than in other brain regions. We found that ethanol exposure facilitated amyloid pathology and worsened cognitive function in 5xFAD mice, while microglial arborization and phagocytosis appeared unchanged. Overall, our results suggest that pronounced ethanol exposure, when started early in the disease before amyloid pathology is established, can worsen AD progression in an amyloidosis model.

Olfactory coding relies on primary information from olfactory receptor cells, that respond to volatile airborne substances. Despite of extensive efforts, our understanding of odor-response profiles across receptors is still poor, due to the vast number of possible ligands (odorants), the high sensitivity even to trace compounds (creating false positive responses), and the diversity of olfactory receptors. Here, we linked chemical purification with a gas chromatograph to single-receptor type recording with transgenic flies using calcium imaging to record olfactory responses to a large panel of chemicals in 7 Drosophila ORs: Or10a, Or13a, Or22a, Or42b, Or47a, Or56a, Or92a. We analyze the data using linear-non-linear modeling, and reveal that most receptors have “simple” response types (mostly positive: Or10a, Or13a, Or22a, Or47a, Or56a). However, two receptors (Or42b, Or92a) have, in addition to “simple” responses, “complex” response types to some ligands, either positive with a negative rebound, or negative with a positive rebound, suggesting the presence of multiple binding sites and/or transduction cascades. We show that some ligands reported in the literature are false positives, due to contaminations in the stimulus. We record all stimuli across concentrations, showing that at different concentrations different substances appear as best ligands. Our data show that studying combinatorial olfactory coding must consider temporal response properties, and is strongly influenced by the presence of trace amounts of ligands (contaminations) in the samples. These observations have important repercussions for our thinking about how animals navigate their olfactory environment.

Kv2.1 channels have important conducting and nonconducting functions and are regulated by ‘silent’ Kv subunits. One of these is Kv9.1, which is co-expressed with Kv2 channels in sensory neurons, and a common allele which changes Ile489 to Val in human Kv9.1 promotes pain sensitivity. Here we examined the effects of Kv9.1 variants on Kv2 channels expressed in HeLa cells and primary hippocampal neurons. Both Kv9.1Ile and Kv9.1Val were retained within the endoplasmic reticulum when expressed individually, but when co-expressed with either Kv2.1 or Kv2.2 they co-localized with Kv2 within surface clusters. Both variants reduced surface expression of Kv2.1 channels and the size of channel clusters, with Kv9.1Val producing a greater reduction in surface expression in both HeLas and neurons. They both caused a similar hyperpolarizing shift in the voltage-dependence of channel activation and inactivation. Concatamers of Kv2.1 and Kv9.1, suggest both a 3:1 and 2:2 ratio of Kv2.1 to Kv9.1 are permitted, although 2:2 resulted in lower surface expression and function. The AMP kinase activator A769662 produced a strongly hyperpolarizing shift in the voltage-dependence of Kv2.1 and Kv2.1-Kv9.1 channel currents. Onset and recovery kinetics of A769662 were rapid and mutational analysis indicated differences in the regulation of hKv2.1 compared to rKv2.1, with a lack of dependence upon Ser444. In conclusion, the Ile489Val substitution in Kv9.1 did not disrupt its association with Kv2 channels nor its effects on channel gating but it did produce a greater reduction in the Kv2.1 surface expression, suggesting that this underlies its association with pain hypersensitivity.

Different genomes of various organisms imply the creation of anatomical and physiological differences within their nervous systems, which translates into diverse cognitive or broader mental abilities among different species. These changes are largely based on structural mutations, such as duplications or inversions, though smaller changes like single deletions can also occur. The genes affected by these changes are associated with various functions and ultimately lead to different brain development, its structure and function. This work presents the most important type of genes and their changes that may affect the formation of the human brain. In this aspect, we review and discuss genes contribution to brain structures, as well as summarize recent knowledge regarding their involvement in various disorders.

Whether motor imagery (MI) engages the motor system or relies on perceptual/cognitive processes is a matter of debate. Here we used the size weight illusion to create dissociation between perception and action to address the nature of MI. Participants alternated lifting bricks of equal mass but where one brick was larger than the other, resulting in a perceptual illusion. Fifty-seven participants (M=20, F=37, 22.54.4 years; collected 2019-22) were divided into three groups differing in the modality used for training (MI and overt execution; OE) and exposure to the size weight illusion pre-training (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 reverted to the participant’s prior 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 MI, and that the simulation of the motor component of the movement during MI guides the performed action.

Post-stroke angiogenesis improves structural and functional recovery, outlining the promises of pro-angiogenic therapies. Unfortunately, vascular endothelial growth factor (VEGF)-A-mediated angiogenesis resulted in mitigated outcomes, as it significantly increases the risk of exacerbating injury via destabilization of the cerebrovascular network. VEGF-E, a non-mammalian VEGF-A homolog, has been reported to promote stable neovascularization upon skin injuries, and thus represents an interesting safe alternative to promote post-stroke angiogenesis. C57BL6/J wildtype mice were subjected to ischemic stroke using transient middle cerebral artery occlusion (MCAo), and recombinant VEGF-E was intranasally delivered throughout the subacute phase. Our results indicate that VEGF-E reduces neuronal loss and improves motor recovery after stroke. VEGF-E attenuates cerebrovascular permeability at the injury site and increases the density of mature CD31+ microvessels. Furthermore, we show that VEGF-E reduces the events of microvascular stalls and improves brain endothelial cell coverage by perivascular cells, required for cerebrovascular stability. VEGF-E increases the density of angiogenic active CD105+ microvessels, while improving the recruitment of CD13+ pericytes, outlining synergistic effects on microvessel formation and stabilization. Using cell-based assays, we demonstrate that VEGF-E activates key pro-survival pathways in brain endothelial cells exposed to ischemia/reperfusion-like conditions, namely extracellular signal-regulated kinase (ERK)1/2 and P38 mitogen-activated protein kinase (MAPK) while preserving the tight junctions. Importantly, we report that the secretome of VEGF-stimulated brain endothelial cells improves perivascular cell migration that is required to mediate the interaction with endothelial cells. Our study indicates that VEGF-E promotes a stable neovascularization after ischemic stroke, paving the way to develop new strategies for therapeutic angiogenesis.

The development of compulsive cue-controlled-incentive-drug-seeking habits, a hallmark of substance use disorder, is predicated on an intrastriatal shift in the locus of control over behaviour from a nucleus accumbens (Nac) core - dorsomedial striatum network to a Nac core - anterior dorsolateral striatum (aDLS) network. Such shift parallels striatal adaptations to chronic drug, including cocaine self-administration, marked by dopamine transporter (DAT) alterations originating in the ventral striatum that spread eventually to encompass the aDLS. Having recently shown that heroin self-administration results in a pan-striatal reduction in astrocytic DAT that precedes the development of aDLS dopamine-dependent incentive heroin-seeking habits we tested the hypothesis that similar adaptations occur following cocaine exposure. We compared DAT protein levels in whole tissue homogenates and astrocytes cultured from ventral and dorsal striatal territories of drug naïve male Sprague Dawley rats to those of rats with a history of cocaine-taking or an aDLS dopamine-dependent incentive cocaine-seeking habit. Cocaine exposure resulted in a decrease in whole tissue and astrocytic DAT across all territories of the striatum. We further demonstrated that compulsive (i.e., punishment-resistant) incentive cocaine-seeking habits were associated with a reduction in DAT mRNA levels in the Nac shell, but not the Nac core-aDLS incentive habit system. Together with the recent evidence of heroin-induced downregulation of striatal astrocytic DAT, these findings suggest that alterations in astrocytic DAT may represent a common mechanism underlying the development of compulsive incentive drug-seeking habits across drug classes.

Exosomes, nanoscale extracellular vesicles (30-150 nm), play a critical role in intercellular communication by transporting bioactive molecules, including proteins, lipids, and nucleic acids. These vesicles have emerged as a transformative tool for drug delivery in brain diseases, particularly due to their ability to cross the blood-brain barrier (BBB), a major challenge in treating central nervous system (CNS) disorders. Recent studies have highlighted the potential of exosome-based therapies in treating neurodegenerative diseases such as Alzheimer’s and Parkinson’s, neuroinflammatory conditions, and brain tumors like glioblastoma. Exosomes can be engineered to enhance their targeting precision by modifying their surface to selectively deliver therapeutic agents to specific brain cells, including neurons, glial cells, and endothelial cells. This review explores the latest advancements in optimizing exosome-mediated drug delivery, focusing on surface modifications and other strategies to improve targeting efficiency and therapeutic outcomes. Additionally, exosomes are being investigated as diagnostic biomarkers for early disease detection and monitoring, offering a non-invasive alternative to traditional methods. Despite their promise, challenges such as large-scale production, cargo loading, safety concerns, and regulatory barriers remain. This review provides an overview of the current state of exosome-based therapies, critically evaluates the ongoing challenges, and explores future directions for optimizing their use in brain disease treatment, emphasizing enhancing targeted delivery and therapeutic efficacy.

Abstract: Cognitive flexibility has been shown to be heavily influenced by sequential changes in the amount of reward available. When available reward remains constant, participants favor stability and are more likely to repeat tasks; when available reward changes, they favor flexibility and are more likely to switch tasks. However, past work in this area hasn’t considered what happens when the available reward is not received, e.g., when responses are too slow to receive performance-contingent rewards. If participants are mainly influenced by dynamics in available rewards (rather than outcomes), such outcomes may not affect their behavior. Alternatively, the failure to receive an anticipated reward may be treated as an aversive signal, biasing participants to shift away from the previous task. In the current study, we used EEG and pupillometry to examine the neural response during reward cues and feedback to dissociate these two possibilities. Behaviorally, we found that participants switch more after failing to receive a high reward due to a slow response than after receiving a high reward. Neurally, we found increased pupil dilation and theta power in response to slow response feedback compared to low reward feedback. Taken together, these results suggest that receiving feedback that the response was too slow increases arousal and shifts behavior to favor flexibility.

MicroRNAs (miRNAs) have become essential modulators in many brain disorders, such as neurodegenerative diseases, psychiatry disorders, and chronic pain syndromes, and they play a critical role in controlling gene expression. This review investigates how disorders of the nervous system and pain research are affected by malfunctions in the miRNA biogenesis machinery. Despite tremendous progress, we still don’t fully understand how these molecular regulators affect neuropathological processes. Even with the increasing amount of research, little is known about the malfunctions of the miRNA machinery, especially when it comes to the nervous system and the diseases that are linked to it. The results of recent research are compiled in this review, which emphasizes the role that disruptions in miRNA processing enzymes, including Drosha, Dicer, Argonaute, and RISC proteins, play in neurological conditions like Parkinson’s and Alzheimer’s disease, as well as more general neurodegeneration. We also go over current studies on the stimulus-dependent, temporal, and spatial expression patterns of these essential miRNA biogenesis components in pain. These discoveries broaden our knowledge of the fundamental processes behind pain-related illnesses and present prospective directions for focused therapeutic approaches.

not-yet-known not-yet-known not-yet-known unknown The current lack of diversity in neuroimaging datasets limits the potential generalisability of research findings. This situation is also likely to have a downstream impact on our ability to translate fundamental research into effective interventions and treatments for the global population. We propose that electroencephalography (EEG) is viable for delivering truly inclusive and global neuroscience. Over the past two decades, advances in portability, affordability, and computational sophistication have created a tool that can readily reach underrepresented communities and scale across low-resource contexts—advantages that surpass those of other neuroimaging modalities. However, skepticism persists within the neuroscience community regarding the feasibility of realizing EEG’s full potential for studying the brain on a global scale shortly. We highlight several challenges impeding progress, including the need to amalgamate large-scale, harmonized datasets to provide the statistical power and robust computational frameworks necessary for examining subtle differences between populations; the advancement of EEG technology to ensure high-quality data acquisition from all individuals—irrespective of hair type—and operable by non-specialists; and the importance of engaging directly with communities to co-create culturally sensitive and ethically appropriate research methodologies. By tackling these technical and social challenges and building on initiatives dedicated to inclusivity and collaboration, we can harness EEG’s potential to deliver neuroscience genuinely representative of the global population.

Neuroinflammation plays a significant role in pathogenesis of hepatic encephalopathy (HE). Radiotracer [18F]PBR146 is used for in-vivo imaging of neuroinflammation. Bifidobacterium (BIF) and fecal microbiota transplantation (FMT) are emerging as promising therapeutic approaches for HE. The objective of this study was to monitor and compare the treatment efficiencies of BIF and FMT on neuroinflammation in chronic HE rats [bile duct ligation (BDL) operation] by [18F]PBR146 micro-PET/CT. Thirty rats were divided into Sham+NS, BDL+NS, BDL+BIF, and BDL+FMT groups. Behavioral assessments, fecal samples collections, and micro-PET/CT scans were conducted sequentially following the successful establishment of the chronic HE model. The study analyzed average %ID/g values of whole brain, brain regions, and main organs across each group, complemented by biochemical and pathological analysis. Behavioral results, IL-1β, IL-6, IL-10, and TNF-α levels showed no significant differences among four groups. Although there was no significant difference in global brain uptake values of [18F]PBR146 among four groups (P=0.053), regional brain comparisons revealed significant discrepancies in bilateral accumbens, retrosplenial cortex, posterior hippocampus, left striatum, cingulate cortex, right frontal association cortex, and antero-dorsal hippocampus (all P<0.05). Sham+NS group was mainly enriched with Parasutterella, Streptococcus, and Anaeroplasma, the BDL+FMT group with Enterococcus, Aestuariispira, Lactobacillus, Pseudomonas, and Globicatella, and the BDL+BIF group with Enterorhabdus. The results suggested that BIF had inhibitory effect on neuroinflammation in BDL rats, whereas FMT did not demonstrate positive effects on the chronic HE model rats, might because of dysbiosis. [18F]PBR146 could effectively and noninvasively monitor the efficacy of gut-targeted treatment in chronic HE model.

Progressive balance exercises may change corticomotor excitability during the learning process of postural stability control. The primary purpose of the present study was to assess corticomotor excitability corresponding to the peroneus longus muscle under transcranial magnetic stimulation following 6 weeks of progressive balance exercises in individuals suffering from functional ankle instability. Eligible volunteers with functional ankle instability were randomly and equally assigned to either the intervention or control groups. The intervention group participated in progressive balance exercises every other day for 6 weeks, while the control group continued their daily activities and refrained from new physical activities. The variables were measured in the intervention group before and after the progressive balance exercises, and in the control group twice at an interval of 6 weeks. The primary variables included the active and resting corticomotor thresholds, motor evoked potential, and cortical silent period, which were measured using an electromyography device under a transcranial magnetic stimulator. The corticomotor thresholds and cortical silent period of the peroneus longus muscle significantly decreased in the intervention group following progressive balance exercises (p-value < 0.001), whereas the normalized motor evoked potential significantly increased in the same group (p-value < 0.001). Conversely, no significant changes were detected in the control group (p-value > 0.086). The present study revealed, for the first time, that 6 weeks of progressive balance exercises significantly increased corticomotor excitability corresponding to the peroneus longus muscle and improved balance control in individuals suffering from functional ankle instability.

Abstract Our principal was to demonstrate the convergence of the trigeminal ganglion population from the transversal meningeal sinus and the infraorbital nerve. Recent data suggest that some trigeminal ganglion cells simultaneously send neuronal projections to craniofacial structures via the V1 and V2 trigeminal branches; however, no conclusive evidence exists. Hence, immunohistological assays using retrograde neural tracers injected at the V1 (meningeal dura mater at the transverse sinus level; true-blue, (TB) and V2 (infraorbital nerve; fluoro-gold, (FG) branches were performed to test the hypothesis regarding the convergence of different trigeminal branches to one trigeminal ganglion cell. Besides, bifurcated labeled sensory trigeminal nerves were quantified in adult (60 days old) and young rats (30 days old). The correlation between oxytocin receptor (OTR), calcitonin gene-related peptide (CGRP), and IB4 was analyzed. Cells were labeled concomitantly with FG and TB neuro tracers at the trigeminal ganglion. Interestingly, young animals showed more labeled cells than did adult rats. Triple-labeled neurons (i.e., CGRP/FG/TB and OTR/FG/TB) were found in trigeminal ganglion cells, implying that CGRPergic fibers can be modulated by OTR activation in meningeal or infraorbital nerve fibers. These data support the contention that bifurcated trigeminal ganglion cells simultaneously run via two trigeminal branches (V1 and V2). Finally, the significant decrease in labeled ganglionic cells at 60 days compared to rats 30 days old needs to be followed to understand the developmental process of the orofacial system.

The release of synaptic vesicles (SVs) at the synaptic junction is a complex process involving various specialized proteins that work in unison. Among these, Bassoon has emerged as a significant protein, particularly noted for its association with various neurological and aging-related diseases. Due to its structural and functional roles, Bassoon has become a focus of recent research, especially in understanding its implications in neurodegenerative and psychiatric disorders. In this narrative review, we explore Bassoon’s structure, function, and its role across a spectrum of neurological disorders. Neurotransmission is a tightly regulated process that relies on specialized structures within the presynaptic terminal, such as the presynaptic active zone (AZ), to precisely control SV release in response to incoming signals. The AZ comprises a complex network of large, multidomain proteins, with Bassoon playing a crucial role in this arrangement. Bassoon facilitates the tethering and reloading of SVs, ensuring responsiveness to high-frequency signals, while also maintaining proteostasis at the presynapse. This involves orchestrating the localization of proteins essential for neuronal development and plasticity. Bassoon’s large size and unique structural features enable it to interact with and regulate the function of multiple proteins, making it integral to presynaptic functioning. Variants in the Bassoon gene have been linked to a variety of neurodegenerative and psychiatric conditions, including Progressive Supranuclear Palsy, multiple system atrophy (MSA), epilepsy, schizophrenia, bipolar disorder, and Parkinson’s disease. This review delves into Bassoon’s pivotal role in preserving presynaptic integrity and how disruptions in its functions may contribute to these disorders.