bioRxiv Subject Collection: Neuroscience's Journal

A non-invasive test for stria vascularis dysfunction
Age-related hearing loss is common in the human population but it is highly heterogeneous in aetiology which has hampered efforts to develop ways of stopping its progression. Three major sites of the initial dysfunction are the sensory hair cells, their innervation, and the stria vascularis which generates the high potassium endolymph maintained at a high endocochlear potential bathing the apical surface of hair cells. Treatments aimed at the initial site-of-lesion may be useful, and diagnostic tools to distinguish the primary site would help stratify clinical trials and facilitate selection of the most suitable treatment for each person. Here we report a new non-invasive test that distinguishes mutant mice with known stria vascularis dysfunction and reduced endocochlear potential from mice with sensory hair cell or neural defects but with normal endocochlear potential. It is based on measuring inter-trial coherence in auditory brainstem responses to individual stimuli. Mice with reduced strial function show good inter-trial coherence compared with the amplitude of the averaged response, while mice with sensory or neural deficits show poor coherence. This method might be useful in humans to predict whether they have reduced strial function, which cannot be measured directly, and identify who would benefit from treatments aimed at boosting strial function.

A neuropeptide-specific signaling pathway for state-dependent regulation of the mesolimbic dopamine system
Dopamine (DA)-producing neurons of the ventral tegmental area (VTA) regulate consummatory behavior in a state-dependent manner (e.g. when hungry or thirsty). The mechanisms by which and extent to which DA neurons are regulated by these interoceptive signals are poorly understood. Here, we identify transient receptor potential canonical type 6 (TRPC6) channels as selective mediators of neuropeptide receptor-induced calcium signaling in VTA-DA neurons. These channels regulate DA neuron activity and consummatory behavior in a state-dependent manner. We find that TRPC6 channels regulate distinct aspects of neuropeptide-induced calcium signals in DA neurons but make little contribution to calcium dynamics associated with metabotropic neurotransmitter receptor signaling. We further show that TRPC6 channels regulate scalable reward valuation and consummatory behavior in hungry but not thirsty mice. These findings demonstrate that neuropeptide- and neurotransmitter-activated G-protein coupled receptors (GPCRs) regulate cellular calcium dynamics through distinct mechanisms, and that TRPC6 channels are important determinants of how animals respond to different homeostatic demands.

Principles of neocortical organisation and behaviour in primates
The development and evolution of neocortical organisation is typically explained by the interaction of two fundamental factors: genetics and experience-dependent processes. Morphogens and signalling molecules would orchestrate the formation of neocortical areas and connection networks, which are later refined through exposure to environmental stimuli. Evolutionary changes to these genetic programs are thought to account for the diversity of brains and behaviours observed in extant species. However, our phylogenetic comparative study of primate neuroanatomy and behaviour shows this view is incomplete. Using brain MRI from 70 primate species we observed that not only the degree of folding but also the folding pattern changes continuously with brain volume, independently of phylogenetic position. To better understand the consequences of this continuity we focused on New and Old World monkeys which diverged approximately 47 million years ago. Large New World monkeys, such as capuchins, have a significantly larger and more folded neocortex than many of their close phylogenetic relatives, whose brains are barely folded. Notably, in addition to folding, their thickness and connectivity patterns were almost identical to those of phylogenetically distant Old World monkeys. Combined analyses of MRI and endocasts from 105 primate species indicated that the highly folded neocortex of large New World monkeys evolved independently from a common ancestor with a small, unfolded brain. Remarkably, across all 70 species, behavioural similarity correlated substantially more with neuroanatomical similarity than with phylogenetic similarity. Our results challenge the prevailing explanation of the development and evolution of neocortical organisation. We propose that the "capuchin anomaly" can be resolved by incorporating mechanical morphogenesis, alongside genetics and experience, as a third fundamental factor. Growth-driven mechanical instabilities would produce similar neuroanatomical organisation patterns and behaviours, emerging independently of the specific genetic determinants of that growth.

Putative long-range mossy fiber sprouting and regional hypermetabolic capacity in the hippocampus of patients with mesial temporal lobe epilepsy
Mesial temporal lobe epilepsy (MTLE) is pathologically characterized by neuronal loss in the dentate hilus, CA3 and CA1 regions, and mossy fiber (MF) sprouting into the inner molecular layer (iML). The latter forms aberrant excitatory circuities that are considered to facilitate recurrent seizures, with the subiculum also being related to epileptogenic activation. We recently identified a distinct expression of -smooth muscle actin (SMA) at the MF terminals in human hippocampus. This prompted us to explore MF sprouting in resected hippocampi (n=20) from patients with MTLE relative to postmortem control (n=20) using SMA along with reference markers for pathological cross-validation. Compared to control, neuronal loss assessed with neuron-specific nuclear antigen and sortilin immunolabeling reached CA1 in all resected hippocampi. SMA, zinc transporter 3 and -secretase 1 immunolabeling in the iML tended to be increased. The MF-related markers also revealed a preserved fibrous band extending across CA1 to subiculum. Cytochrome c oxidase immunolabeling also increased in iML and subiculum in the MTLE group. Taking together, the current findings point to the existence of long-range MF sprouting and a regional hypermetabolic compacity in the hippocampal formation of patients with drug resistant MTLE.

The effect of psychedelics on associative learning: a systematic review
Introduction: Psychedelics are emerging as potential treatments for neuropsychiatric conditions, with evidence suggesting a single administration can lead to enduring behavioural changes. While the underlying putative mechanism(s) remain unclear, there is evidence supporting altered learning as a key candidate. Aim: This systematic review examined studies assessing the effects of psychedelics on associative learning in both humans and animals. Methods: Electronic databases were searched up until 13/01/2025 for studies investigating any difference in learning after psychedelic administration. Results: 31 studies were included (29 in animals, 2 in humans). Classical and operant conditioning paradigms were employed, including fear extinction, conditioned avoidance, and reversal learning. Studies assessed acute and post-acute effects, however repeated dosing paradigms often obscured this distinction. There was considerable heterogeneity in study designs, paradigms, drug administration timings and doses, and behavioural effects appeared to be influenced by dose, timing, training intensity, and sex. Due to between-study heterogeneity, a meta-analysis was not possible. Evidence suggests that psychedelic administration enhances associative learning in animals across paradigms, although findings were not entirely consistent. Possible mechanisms identified were increased prediction error sensitivity, serotonin receptor agonism, and structural plasticity. Learning enhancements may extend into the post-acute phase and appear to depend on active environmental engagement during this window. Conclusion: Studies suggest that psychedelics enhance associative learning in animals; however, these findings are yet to be translated into humans. Understanding whether a period of enhanced learning follows the psychedelic experience may have important implications for psychedelic-assisted psychotherapy, where behavioural changes must generalise and persist beyond the drug-induced state.

Death receptor 6 does not regulate axon degeneration and Schwann cell injury responses during Wallerian degeneration
Axon degeneration (AxD), accompanied by glial remodeling, is a pathological hallmark of many neurodegenerative diseases, leading to the disruption of neuronal connectivity [1-3]. Understanding the mechanisms in neurons and glia that regulate AxD is essential for developing therapeutic strategies to prevent or mitigate axon loss. Wallerian degeneration (WD) is a well-established model to study the mechanisms of nerve injury-induced AxD, glial responses, and axon-glia interactions. We recently showed that Schwann cells (SCs), the axon-associated glia of the peripheral nervous system, exert protective effects on axons through their rapid metabolic injury response [4]. Enhancing this SC response promotes axon protection during WD [4]. A prior study reported that eliminating the orphan tumor necrosis factor receptor DR6 (death receptor 6, Tnfrsf21) strongly delays AxD and alters SC injury responses during WD, suggesting a possible intersection with our findings [5]. Here, we rigorously revisit the role of DR6 in WD using two independent DR6 knockout mouse lines including the same model used in the previous study. Surprisingly, in striking contrast to the earlier report, we observed no impact of DR6 deletion on AxD kinetics or SC injury responses across a range of WD assays. Moreover, injured axons in primary neuronal cultures lacking DR6 degenerated at a similar rate as wild-type axons. We conclude that DR6 is dispensable for the regulation of AxD and glial nerve injury responses during WD. Our data argue that any therapeutic benefit from DR6 suppression in neurodegeneration models occurs through mechanisms independent of WD.

Procrastination partly reflects an evolutionary byproduct of non-planning impulsivity
Procrastination has immediately visible repercussions on health and survival resilience, yet shows stably heritable and remains increasingly pervasive across human societies. Despite a paradox, this behavior is theoretically explained to represent a byproduct of evolutionary advantages underlying impulsivity, yet not deciphered well by scientific evidences. After adjusting psychometric endogeneity, we demonstrate the unique predictive roles of non-planning impulsivity (NPI) during late adolescence and early adulthood uniquely predicts procrastination in later adulthood in a twin cohort (N = 154). This association was further replicated in two independent cohorts (N = 327, N = 1,543). Using AE models, in conjunction of single-paper meta-analytic synthesis (N = 3,656 twin pairs), we observed significant shared genetic contributions underlying this NPI-procrastination association (rg = 0.51, 95% CI: 0.18 - 0.84). Beyond to the phenotypic heritability, employing a Genome-Wide-Association Study (GWAS), six NPI-procrastination overlapping SNPs are identified, functionally accounting for neural dysregulation. Thus, leveraging neurodevelopmental normative modelling (N = 37,407), online meta-analytic estimations (k = 198, loci = 5,855) and seed-based d mapping estimates (N = 893), cortical deviations in the left dorsolateral prefrontal cortex (DLPFC) - the brain region showing highest probabilistic overlap mapping NPI to procrastination, partly explains their shared genetic variants, but are substantially independent in genetic contribution. Mendelian Randomization analysis finally indicates causal roles of NPI and procrastination both, to DLPFC deviations. Our findings empirically clarified this theory that procrastination partly derives from NPI as an evolutionary byproduct indeed, but is still unique in neurogenetic entities.

The Amplified Burden of Depression in Drug-Resistant Epilepsy: Role of Limbic Network Dynamic Reconfiguration
Objectives: To explore potential associations between drug resistance and limbic network (LN) dynamic functional interactions in temporal lobe epilepsy (TLE), whether these LN alterations are associated with and potentially mediate comorbid depression severity, and their potential neurochemical and transcriptomic underpinnings. Methods: This cross-sectional study included 49 patients in the Responsive group, 33 patients in the Resistant group, and 50 healthy controls (HCs). Using resting-state fMRI, we derived LN dynamic integration coefficients and used non-negative matrix factorization (NMF) to identify coactivation patterns. Depressive symptoms (Self-Rating Depression Scale, SDS), LN integration, and NMF pattern expression were compared across groups (ANOVA) and correlated. Mediation analysis tested if LN integration mediated the relationship between drug resistance status and SDS scores. LN integration differences were spatially correlated with neurotransmitter receptor density and Allen Human Brain Atlas transcriptomic data. Results: Patients in the Resistant group reported significantly higher SDS scores than patients in the Responsive group (p = 0.008). LN integration with the dorsal attention network (DAN) and fronto-parietal network (FPN) was significantly lower in the Resistant group compared to the Responsive group (p = 0.001; p < 0.001). NMF analysis identified key LN-DAN (p = 0.013) and LN-FPN (p < 0.001) coactivation patterns. In TLE patients, DAN-LN integration was negatively correlated with depressive symptoms (r = -0.28, p = 0.01), and lower integration levels significantly mediated the relationship between group status (Resistant vs. Responsive) and increased symptom severity (p < 0.001). These LN integration coefficient differences (Responsive group vs. Resistant group) were associated with 5-hydroxytryptamine 1B (5-HT1B; r = 0.29, p = 0.036) and dopamine D2 (D2; r = -0.29, p = 0.034) receptor densities, and linked to gene expression pathways including telomerase activity regulation (p < 0.001). Interpretation: This study identifies dynamic LN dysregulation, supported by distinct neurochemical and transcriptomic profiles, as a core bridging mechanism potentially contributing to comorbid depression linked to drug response status in TLE patients.

Tongue-Palate Electromyographic Synchronization Related to Swallowing, Mastication, and Speech
The specific oscillatory dynamics of intermuscular coupling involved in swallowing, mastication, speech production, and respiration have not been elucidated. This study aimed to explore intermuscular coupling between the tongue and palate that underlies oral functions by analyzing the event-related coherence (ERC) of electromyography (EMG) signals before swallowing, mastication, and speech production. Twenty-two healthy participants performed three oral tasks: swallowing, speech production, and mastication. Sixteen of these participants also completed a combined task involving swallowing immediately after speech. EMG signals were recorded from the tongue and palate, and ERC between tongue and palate EMG was analyzed. Peak ERC was compared across tasks for alpha (8-14 Hz), beta (16-30 Hz), and gamma (32-46 Hz) frequency bands. In all participants, ERC showed significant peaks in all frequency bands before the onset of swallowing, mastication, and speech. Only the ERC values in the beta band were significantly larger for swallowing than for mastication, but not for speech. Moreover, the ERC values for the combined task of swallowing after speech production were significantly smaller than those for the simple swallowing task in the alpha, beta, and gamma bands. The intermuscular oscillatory regulation is more critical for swallowing than for mastication.

Distinct Neurogenic Dynamics of Cortico-cortical Neuronal Subtypes in Layer 2/3 of the Mouse Visual Cortex
In the mammalian cerebral cortex, the birthdates of excitatory projection neurons are closely linked to their laminar positions, which are often associated with distinct long-range projection targets. Although broad relationships between neurogenic timing, laminar position, and projection patterns are well established, the degree to which birthdate specifies projection identity within the same cortical layer remains unclear. In the mouse primary visual cortex (V1), neurons projecting to lateral higher visual areas are relatively evenly distributed throughout layer 2/3, whereas those projecting to medial areas are biased toward more superficial sublayers. To determine whether these projection identities are linked to neurogenic timing, we combined EdU birthdating with retrograde viral tracing. Notably, we found that V1 layer 2/3 neurons projecting to lateral higher visual areas are preferentially born at embryonic day 15.5 (E15.5) compared to E16.5, whereas V1 neurons projecting to medial higher visual areas show no significant birthdate bias between E15.5 and E16.5. These findings suggest that distinct cortico-cortical projection subtypes in layer 2/3 are generated on different temporal schedules, linking neurogenic timing to fine-scale projection identity.

Different dopaminergic circuits defined by D2/D3 receptor availablity patterns show structure-specific links to memory in ageing
Cognitive ageing is marked by progressive decline in episodic memory and dopaminergic function, yet the extent to which individual differences in dopaminergic system integrity influence memory under motivational contexts remains unclear. In this study, we investigated how baseline D2/D3 receptor availability (BPND0) in key dopaminergic pathways relates to reward-modulated memory performance in healthy older adults. Thirty-three healthy seniors (aged 64-85) underwent two session concurrent MR-PET imaging with [18F]fallypride involving scene categorisation task with high- and low-motivational contexts. We quantified BPND0 across nine dopaminergic regions of interest and examined their relationships with recognition memory performance at short (~15m) and long (~24h) delays. Baseline D2/D3 receptor availability showed high test-retest reliability and regionally distinct profiles, suggesting it reflects a stable neurochemical characteristic in healthy ageing, and principal axis factor analysis revealed two partially independent dopaminergic subsystems (dorsal striatal vs mesolimbic) based on interindividual patterns in receptor densities. Region-specific associations further linked D2/D3 receptor availability to distinct memory outcomes. Higher caudate D2/D3 receptor availability was associated with a liberal response bias (increased hits and false alarms both), whereas higher putamen D2/D3 predicted more durable long-term memory retention. Greater thalamic D2/D3 receptor availability correlated with fewer short-term false memories, while greater D2/D3 receptor availability in the amygdala was associated with better recognition at longer delays. In contrast, higher midbrain (substantia nigra and ventral tegmental area) D2/D3 availability which was linked to poorer reward-related memory performance. These findings suggest several complementary dopaminergic circuits supporting episodic memory. Our results highlight dopaminergic neuromodulation as a key factor in cognitive ageing and a potential target for interventions to bolster memory in late life.

Transcriptional Dysregulation in the Hippocampus of a murine model for Parkinson's Disease Cognition Impairment is Driven by Sex, Age, and Alpha-synuclein overexpression
Cognitive impairment is the most common and detrimental, but understudied non-motor symptom of Parkinson's disease (PD). Neuropathologically, it is associated with alpha-synuclein (Syn) misfolding and synapse loss in hippocampus and prefrontal cortex, leading to cognition loss and ultimately dementia. The molecular underpinnings of PD-associated cognitive dysfunction are unknown. In the present study, longitudinal gene expression profiling was performed to characterise molecular hippocampal alterations in a transgenic mouse overexpressing E46K mutated Syn, a model of early PD with loss of synaptophysin, a proxy marker of cognition, in hippocampus and cortex. Comparing 4 different ages of mice from both sexes showed that hippocampal gene expression changes were sexually dimorphic and strongly modulated by age and Syn overexpression. Pathways that emerged across different comparisons were connected to a variety of neuronal functions, collagen synthesis/remodelling, cellular stress, and inflammatory responses. The findings indicate that sex and age are essential covariates to consider when studying PD-associated cognitive decline. The uncovering of early events leading to disease in an animal model is an essential step toward prognostic biomarker identification and early interventions, which may have implications for monitoring, and for timing of therapeutic approaches.

Skeletal muscle TDP-43 aggregation drives progressive motor dysfunction and neurodegeneration with potential for functional recovery after clearance
Understanding the mechanisms driving TDP-43 pathology is essential for combating amyotrophic lateral sclerosis and other neurodegenerative diseases. To investigate the contribution of skeletal muscle to disease onset, progression, and recovery, we generated an inducible, muscle-specific TDP-43 mouse model. Cytoplasmic aggregation of endogenous human TDP-43 protein in skeletal muscle led to muscle dysfunction, denervation, motor neuron loss, and dysregulation of mRNA markers related to myogenesis and neuromuscular junction stress at disease early-stage, along with muscle atrophy, neurodegeneration, and fatal motor decline at disease late-stage. Notably, this exogenous TDP-43 propagated from skeletal muscle to the spinal cord and brain, underscoring the vulnerability of the central nervous system to muscle-derived TDP-43 toxicity. Suppression of cytoplasmic TDP-43 in skeletal muscle improved survival and promoted substantial recovery of muscle dysfunction, motor deficits and neurodegeneration. These findings highlight the therapeutic potential of targeting skeletal muscle-derived TDP-43 toxicity as an approach to delaying neurodegenerative disease.

Modulation of huntingtin S421 phosphorylation in a Huntington's disease mouse model and its detection in nonhuman primate cerebrospinal fluid
Huntington's disease (HD) is a progressive neurodegenerative disease caused by the pathologic expansion of a CAG repeat in the first exon of the huntingtin (HTT) gene, resulting in a huntingtin (HTT) protein with an expanded polyglutamine (polyQ) tract. Phosphorylation at residue S421 (pS421) is one of the post-translational modifications proposed to influence the biology of wild-type and mutant (m)HTT, such as HTT stability and clearance, HTT subcellular localization, mHTT toxicity, and regulation of HTT function in axonal transport. However, the detection and quantification of S421-HTT phosphorylation in relevant biological contexts have remained challenging and the consequences of pS421 in HD pathogenesis remains unclear. Here we report the development of a novel ultrasensitive immunoassay enabling the specific and sensitive detection of pS421-HTT in a variety of biologically relevant contexts. With this assay we conducted a longitudinal assessment of pS421 levels in tissues from a mouse model of HD to investigate the relationship between S421 phosphorylation and phenotypic progression. We also identified PRKACA, the cAMP-regulated catalytic subunit of PKA, as a kinase capable of phosphorylating S421-HTT, demonstrating its ability to regulate endogenous pS421 in human cells. Finally, we exploited the sensitivity of the assay to detect endogenous pS421-HTT in cerebrospinal fluid (CSF) from nonhuman primates, showing for the first time that phosphorylation at S421-HTT can be detected in this bio-fluid. These reagents and assay will enable investigation of the biological consequence and the relevance of pS421 in the natural history of HD.

A Bioinformatic Analysis of BAG Protein Interactors and Pathways in Alzheimers and Parkinsons Disease
Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common neurodegenerative disorders. While the symptoms and general etiology may be different, these two diseases share significant common features in terms of their disease pathogenesis. Within the scope of neurodegenerative disorders, the Bcl-2 associated athanogene (BAG) family proteins and associated interactors have been a key area of focus. The BAG family is a group of proteins that contain at least one evolutionarily conserved BAG domain. Despite this similarity, their interactions and functions can vary widely. So far, research has predominantly scrutinized individual BAG proteins, rather than explore potential cooperative actions among family members. Some BAG family members may function together thereby indicating potential interactions within this family. Although connections among BAG members have been observed, their role in neurodegenerative disorders, such as AD and PD, remains largely uncharacterized. This mini review explores the common pathways, intersections, and differences within these interactions as well as their link to AD and PD. Using computational techniques to mine transcriptomic data, several groupings of pathways that these BAG family members are involved in were identified in the context of AD and PD. Understanding these pathways and their relationships may uncover potential gaps in current research and help identify novel therapeutic targets for the treatment of these neurodegenerative diseases.

Dynamic prioritization reshapes neural geometries for action in human working memory
Prior work has shown that control brain regions encode upcoming novel instructed actions. Similarly, visual working memory (WM) representations can reflect different priority states. However, it remains unknown whether the priority status of WM-guided novel actions similarly modulates their neural coding format, and how such dynamics unfold over time. We addressed these questions using EEG while human participants performed two consecutive choice reaction tasks. At the start of each trial, participants encoded two novel stimulus-response (S-R) mappings. A cue then indicated whether these mappings would be relevant immediately ("current" condition), later after an intervening task ("prospective"), or after a free delay ("delayed"). Using multivariate pattern analysis, we found that the S-R category was decodable in all conditions during relevant time windows. Critically, pattern similarity analyses revealed that while mere maintenance demands allow for temporary preservation of neural codes (i.e., between current and delayed trials), shielding from interference (i.e., prospective trials) induced significant alterations to the neural code. Further exploration of the representational geometry revealed that priority status gained prominence dynamically over S-R category coding when preparing for such shielding demands. Importantly, some of these changes emerged anticipatorily, prior to target onset. Overall, our results show that, similar to visual WM, the priority of intended actions dynamically and anticipatorily reshapes their neural format. They further reveal how different demands induce content geometries compatible with previously proposed coding schemes, and that such representational changes can be implemented flexibly in time.

Distinct neurogenic pathways shape the diversification and mosaic organization of cortical output channels
A hallmark of the mammalian cerebral cortex is its vast and diverse efferent projections across cortical areas mediated by extratelencephalic (ET) neurons that broadcast to myriad subcortical regions. ET neurons are generated from two fundamentally distinct neurogenic pathways: direct neurogenesis (dNG-ETd) from radial glia progenitors and indirect neurogenesis (iNG-ETi) from intermediate progenitors, but the contribution of ETd and ETi to the organization of cortical output channels is unknown. Leveraging a novel lineage-based genetic strategy enabling differential viral access to ETd and ETi in the same mouse, we show that iNG-ETi massively amplifies and diversifies dNG-ETd across the cortex. While ETd projections are largely restricted to the forebrain and midbrain structures, ETi greatly amplifies and diversifies these projections and overwhelmingly dominates the innervation of hindbrain and spinal cord. This is exemplified in an area-specific pattern by ETi dominance to brainstem and spinal action diversification and execution centers from motor areas, to major sensory processing stations along lemniscal pathways from sensory areas, and to pallial, hypothalamic and neuromodulatory structures from high order areas. Corticofugal subpopulations in multiple areas are derived from only ETi, indicating the generation of novel projection types by iNG over dNG. Furthermore, area-specific ETi, but not ETd, spinal projection pattern is sculpted from the massive pruning of an early cortex-wide population during postnatal development. Together, these results uncover that two foundational neurogenic pathways with distinct evolutionary history differentially shape the area-specific diversification and mosaic organization of cortical output channels.

Reduced Model-Based Control in Gambling Disorder Despite Intact Neural Value and Task Structure Representations
Disordered gambling has been linked to impairments in goal-directed (model-based) control and reinforcement learning. Here we investigated the potential neural basis of this impairment using a sequential reinforcement learning task (modified two-step-task), computational modeling, and functional magnetic resonance imaging (fMRI) in individuals exhibiting symptoms of disordered gambling (GD) and matched healthy controls (HC, n=30 per group). Model-agnostic analyses replicated the effects of reduced performance and reduced model-based control in the gambling group, both in terms of choice and response time effects. Computational modeling of choice behavior confirmed that this effect was due to reduced model-based control in the gambling group. Analyses of choices and response times using drift diffusion modeling revealed a more complex pattern, where behavioral impairments in the gambling group were linked to changes across several parameters reflecting drift rate modulation and asymptote, as well as non-decision time. Despite these pronounced behavioral differences, the gambling group exhibited largely intact neural effects related to the task transition structure, reward feedback and trial-to-trial behavioral adjustments. Results are discussed with respect to current neurocomputational models of behavioral dysregulation in disordered gambling.

Complexes between Netrin G Ligands and Chiral Nanoparticles Promote Axons Regeneration under Near-Infrared Illumination
Chiral nanoparticles combine functionalities of inorganic materials and large biomacromolecules enabling stimulation of neurons. However, multiple challenges remain in their use for central nervous system including identifying suitable cell signaling pathways and traversing the blood-brain barrier. In this study, we show that glutathione-coated Ni(OH)2; nanoparticles form nanoscale complexes with netrin-G1 ligands (NGL-1), critical for neuronal regeneration. NGL-1 features a semispherical pocket with a 2.5 nm radius of curvature, fitting well with nanoparticles sized ca. 3 nm. D-NPs with D-glutathione surface ligands activate D-glutathione receptors on epithelial cells, facilitating their transport into the brain. When illuminated with 980 nm light, the nanoparticle-protein complex stimulates axon regeneration through localized IGF-1 production. This approach successfully regenerated (a) hippocampal neurons in Alzheimer's disease mice and (b) dorsal root ganglion neurons in spinal cord-injured mice. The nanoparticles were thoroughly tested for safety and excreted intact. The local, rather than systemic, IGF-1 up-regulation minimizes its side effects.

Mild subcortical stroke induces widespread astrogliosis independent of microglia and age
Ischemic stroke induces a plethora of pathophysiological changes, including neuroinflammation and chronic cerebrovascular dysfunction. In humans, even small, silent strokes can trigger these pathologies, which can spread to brain regions far beyond the infarct and persist chronically, ultimately worsening prognosis and increasing the risk for vascular dementia and Alzheimers disease. The cause of this extensive pathology is unknown, but reactive astrocytes and microglia are likely contributors. Here, we describe an optimized short-duration middle cerebral artery occlusion model that produces a clinically relevant small stroke confined to subcortical regions, similar to most silent strokes in humans. We termed this model the mild subcortical infarct (MSCI). We then mapped the spatiotemporal extent of reactive astrocytes and microglia during the sub-acute period (1, 3, and 7 days) following MSCI. We observed that reactive astrogliosis develops more rapidly and spreads more extensively, permeating the entire middle cerebral artery territory, compared to the reactive microglial response following this small infarct. Microglial depletion resulted in larger infarct sizes but did not prevent the reactive astrocytes, suggesting that ischemia-driven astrogliosis is largely microglia-independent. Lastly, we show that aging mice exposed to MSCI exhibit a comparably strong response of reactive astrocytes and microglia as young mice. We propose that MSCI is a novel and valuable model for examining the subtle yet highly important chronic effects of stroke. It may be especially useful for investigating the influence of reactive astrogliosis on pathologies like neuroinflammation and cerebrovascular dysfunction in regions distal from the primary injury site.