bioRxiv Subject Collection: Neuroscience's Journal

Modeling presynaptic inhibition by the amyloid precursor protein demonstrates one potential mechanism for preventing runaway synaptic modification in Alzheimers disease
INTRODUCTION Previous simulations of Hebbian associative memory models inspired the malignant synaptic growth hypothesis of Alzheimers disease (AD), which suggests that cognitive impairments arise due to runaway synaptic modification resulting from poor separation between encoding and retrieval. METHODS We computationally model presynaptic inhibition by the recently identified interaction of soluble amyloid precursor protein (sAPPalpha) with the gamma-aminobutyric acid type B receptor (GABABR) as one potential biological mechanism which can enhance separation between encoding and retrieval. RESULTS Simulations predict that the dual effect of sAPPalpha on long-term potentiation and presynaptic inhibition of glutamatergic synapses maintains effective associative memory function and prevents runaway synaptic modification. Moreover, computational modeling predicts that sAPPalpha, which interacts with the 1a isoform of GABABR, is more effective at stabilizing associative memory than the GABABR agonist Baclofen. DISCUSSION Molecular mechanisms that enhance presynaptic inhibition, such as sAPPalpha-GABABR1a signaling, are potential therapeutic targets for preventing cognitive impairments in AD.

Epigenetic Shifts Reveal Alzheimer's Origins after Sustained Picomolar Aβ Exposure
Recent advances in sequencing have identified genetic risk factors for Alzheimer's disease (AD), but the molecular mechanisms triggering disease onset remain unclear. While high brain levels of amyloid-beta (A{beta}) impair synaptic function and memory, exposure to low picomolar (pM) A{beta} ; concentrations - typical of healthy brains - enhances these functions, while sustained exposure results in impairment. To investigate this transition from physiological to pathological A{beta} ; activity, we profiled DNA methylation and gene expression in C57B16 mice subjected to prolonged pM A{beta}42 exposure. We identified differentially methylated and expressed genes, including those involved in synaptic function, associated with three phases: memory enhancement (brief exposure), a transitional state with intact memory (intermediate), and memory decline (prolonged). These gene sets may represent early molecular drivers of AD pathogenesis.

Altered molecular signaling pathways in the hippocampus of rhesus monkeys following chronic alcohol use
Context-induced relapse is a significant factor limiting recovery from alcohol use disorder (AUD). However, the molecular processes in the hippocampus, a critical region for contextual memory impacted by chronic alcohol use, remain poorly understood. We used a non-human primate model to test the hypothesis that chronic alcohol use impacts hippocampal molecular pathways that may serve as therapeutic targets for context-induced relapse and memory processing issues associated with chronic alcohol use. We conducted RNAseq profiling on hippocampal samples from adult male rhesus monkeys with chronic alcohol use (n=7) and controls (n=5) from the Monkey Alcohol Tissue Research Resource (MATRR). We identified 2,575 differentially expressed genes (DEGs) in subjects with chronic alcohol use, including genes implicated in genome-wide association studies (GWAS) of alcohol dependence, such as GLP2R and GABBR2. Downregulated pathways included chemical synaptic transmission, trans-synaptic signaling, and neuron development, and upregulated pathways involved mitochondrial function. Targeted pathway analysis highlighted significant downregulation of synaptic signaling (e.g., axonal fasciculation) and upregulation of mitochondrial processes (e.g., electron transport). Leading-edge gene analysis revealed several downregulated genes involved in synaptic signaling including GRIN2B, CACNA1C, and NLGN1 as well as upregulated genes such as NDUFS3 and MT-ND1 involved in mitochondrial processes. Drug repurposing analysis identified several targets including epidermal growth factor receptor (EGFR) inhibitors, and L-type calcium channel blockers as potential therapeutic targets. Our results provide critical insights into molecular pathways underlying hippocampal pathology in chronic alcohol use, emphasizing the roles of mitochondrial function, synaptic regulation and calcium channels, and offering potential novel therapeutic targets.

Functional recovery by transplantation of human iPSC-derived A2B5 positive neural progenitor cell after spinal cord injury in mice
Human induced pluripotent stem cells (hiPSCs) hold great potential for patient-specific therapies. Transplantation of hiPSC-derived neural progenitor cells (NPCs) is a promising reparative strategy for spinal cord injury (SCI), but clinical translation requires efficient differentiation into desired neural lineages and purification before transplantation. Here, differentiated hiPSCs, reprogrammed from human skin fibroblasts using Sendai virus-mediated expression of OCT4, SOX2, KLF4, and C-MYC, into neural rosettes expressing SOX1 and PAX6, followed by neuronal precursors ({beta}-tubulin III+/NESTIN+) and glial precursors (GFAP+/NESTIN+). Both neuronal and glial precursors expressed the A2B5 surface antigen. A2B5+ NPCs, purified by fluorescence-activated cell sorting (FACS), proliferated in vitro with mitogens and differentiated into mature neurons and astrocytes under lineage-specific conditions. NOD-SCID mice received a T9 contusion injury followed by transplantation of A2B5+ NPCs, human fibroblasts, or control medium at 8 days post-injury. At two months, grafted NPCs showed robust survival, progressive neuronal maturation ({beta}-tubulin III+ to doublecortin+ to NeuN+), and astrocytic differentiation (GFAP+), particularly in spared white matter. Transplantation significantly increased spared white matter volume and improved hindlimb locomotor recovery, with no teratoma formation observed. These results demonstrate that hiPSC-derived, FACS-purified A2B5+ NPCs can survive, differentiate into neurons and astrocytes, and enhance functional recovery after SCI. This approach offers a safe and effective candidate cell source for treating SCI and potentially other neurological disorders.

Temporal confounds emulate multivariate fMRI measures of perceptual learning
Human perception inherently involves learning. We can experience the same stimulus completely differently depending on our prior knowledge. Understanding the neural basis of perception therefore requires measurements that capture these temporal dynamics. Multi-voxel pattern analysis (MVPA) approaches are widely used to characterise changes in neural representations over time. A popular example is the perceptual reorganisation paradigm, which investigates the neural correlates of enhanced recognition of distorted images after cueing with the undistorted version. Studies typically report increased representational similarity of these two images in early visual cortex. However, as these paradigms include an inherent ordering of stimuli that precludes trial randomisation or counterbalancing, they are vulnerable to temporal confounds common to fMRI. Here, we investigate how these confounds could influence current understanding of perceptual reorganisation. We tested different perceptual reorganisation paradigm designs derived from published fMRI studies, and found substantial design-driven order effects at the single-subject level for all paradigms. For certain designs, these effects artificially amplified neural indices of perceptual reorganisation at both the single-subject and group levels, emulating widespread signatures of perceptual reorganisation across the brain. To disentangle perceptual learning processes from measurement artefacts, we recommend (i) selecting designs that minimise the effect of stimulus order confounds on contrasts of interest, (ii) correcting for these confounds, and (iii) confirming results are perceptually driven via negative controls, e.g., stimuli or brain areas not expected to produce perceptual effects. Our work demonstrates how current understanding of perceptual learning mechanisms based on multivariate neuroimaging approaches could be influenced by non-obvious design confounds that misdirect interpretations towards distributed neural processing, and offers practical solutions to address this.

Microcephaly-like phenotype triggered by novel reassortant and prototypic Oropouche Virus strains in brain organoids
Oropouche virus (OROV) is an emerging arbovirus currently spreading across South America, with increasing reports of neurological manifestations, severe systemic disease, and congenital abnormalities. Although traditionally associated with mild febrile illness, the recent geographic expansion and surge in OROV outbreaks have prompted attention to its neurotropic potential. Here, we investigated the impact of OROV infection on human neural development using neural stem cells (NSCs) and brain organoids derived from induced pluripotent stem cells. Recent OROV isolates exhibiting genomic reassortment and associated with increased neurological manifestations were compared with a prototypical strain for the ability to infect NSCs, early-stage organoids, and more mature cortical-like tissues. OROV infected NSCs efficiently, leading to widespread cell death, depletion of proliferative progenitors, and disruption of neuroepithelial organization. Transcriptomic profiling of infected NSCs revealed a robust reduction of antiviral response genes and an enrichment of pathways related to viral replication, apoptosis, and the inhibition of stem cell maintenance and neuronal differentiation. These molecular signatures aligned with the phenotypic collapse of progenitor pools and cortical structure observed in organoids. OROV antigens were detected in both astrocytes and neurons, with associated structural degeneration. Although a substantial overlap in differentially expressed genes was observed between the two viral strains, some strain-specific transcriptional responses were detected. However, these modest differences did not translate into distinct cytopathogenic effects between the two viral strains. These phenotypes, including the reduced growth of infected organoids, resemble those previously described with Zika virus in the same cellular models, supporting the hypothesis that OROV may impair brain development. Together, these results reveal a previously unrecognized neuroteratogenic potential of OROV strains and provide mechanistic insight into the potential of OROV to induce microcephaly-like phenotypes, highlighting its relevance as a significant threat to maternal-fetal health.

Targeting intracellular tau with a gene-encoded single-chain antibody promotes neuronal homeostasis and ameliorates tau pathology
The intraneuronal aggregation of tau is a key driver of pathogenesis in tauopathies such as Alzheimer's disease. Passive immunotherapy is a promising strategy for targeting tau, with several tau-specific antibodies having demonstrated the ability to reduce tau pathology and improve behavioural deficits in tau transgenic mouse models. Despite preclinical promise, however, conventional antibodies have limited access to the cell cytoplasm where tau pathology itself originates and accumulates to cause downstream neuronal dysfunction. As such, conventional antibodies are typically limited to targeting extracellular tau, failing to address the primary site of tau pathogenesis. This challenge can be overcome by intracellular antibodies or intrabodies, small antibody fragments that can be expressed within cells to target intracellular antigens like tau. Here, we have generated a single-chain variable fragment (scFv) derived from the N-terminal tau-specific antibody, RNJ1, and investigated its potential as an intrabody to reduce tau pathology and restore neuronal function in a tau transgenic mouse model. The RNJ1 intrabody successfully engaged intracellular tau and reduced total tau and phosphorylated tau inclusions in brains of tau transgenic mice. Furthermore, treatment with the RNJ1 intrabody in female tau transgenic mice induced restoration of various protein pathways important for cellular homeostasis, thus promoting the restoration of neuronal function. Our findings underscore the therapeutic utility of targeting intracellular tau in disease, providing novel insights into the potential mechanisms by which intrabodies ameliorate tau pathology.

GIP receptor agonism suppresses inflammation-induced aversion and food intake via distinct circuits
Glucose-dependent insulinotropic polypeptide (GIP) is a gut-derived incretin hormone, and pharmacologic modulation of central GIP receptors (GIPR) improves energy homeostasis. Recent reports have demonstrated that GIPR agonism is also anti-aversive. However, the mechanisms by which GIPR signaling impact food intake and aversion are incompletely understood. Here, we show that GIPR agonism abrogatesthe aversive and enhances the anorexigenic effects of the pro-inflammatory cytokine interleukin-1{beta} (IL-1{beta}). Aversion-encoding parabrachial calcitonin-gene related peptide (CGRP) neurons were required for IL-1{beta}-induced conditioned taste avoidance (CTA) but not anorexia. Moreover, systemic IL-1{beta} increased in vivo CGRP neural activity, and this was significantly attenuated by co-administration of a GIPR agonist. By contrast, GIPR in the dorsal vagal complex were required for the acute anorectic effect of GIPR agonism but not its anti-aversive effect. Taken together, our data suggest that GIPR agonism reduces food intake and prevents aversion via distinct circuits, and that GIPR agonism may represent an effective approach to alleviate inflammation-induced aversion.

Circular continuum of alpha motoneuron types
Alpha-motoneurons ( - MNs) are traditionally classified into slow (S), fast fatigue-resistant (FR), and fast-fatigable (FF), which exist along a continuum of properties between slow and fast, enabling the generation of graded force and seamless movement. Using combinations of markers, we developed novel immunohistochemistry protocols that enabled co-labeling of six major and transitional - MN types throughout the mouse lumbar spinal cord with unprecedented detail. Intriguingly, our protocols labeled for the first time: - MNs of the fast fatigue intermediate (FI) type; a previously undescribed transitional - MN subtype (FR/FI); and a novel subtype of - MNs exhibiting hybrid characteristics of both S and FF types -- termed S/FF -- which resist ALS degeneration. Electrophysiological recordings confirmed FR/FI and S/FF subtypes, both exhibiting mixed traits. The discovery of S/FF subtype reveals that - MNs exist along a circular continuum between slow and fast types, challenging the traditional linear model and reshaping our understanding of their role in motor control.

ATHENA: Automatically Tracking Hands Expertly with No Annotations
Studying naturalistic hand behaviours is challenging due to the limitations of conventional marker-based motion capture, which can be costly, time-consuming, and encumber participants. While markerless pose estimation exists - an accurate, off-the-shelf solution validated for hand-object manipulation is needed. We present ATHENA (Automatically Tracking Hands Expertly with No Annotations), an open-source, Python-based toolbox for 3D markerless hand tracking. To validate ATHENA, we concurrently recorded hand kinematics using ATHENA and an industry-standard optoelectronic marker-based system (OptiTrack). Participants performed unimanual, bimanual, and naturalistic object manipulation and we compared common kinematic variables like grip aperture, wrist velocity, index metacarpophalangeal flexion, and bimanual span. Our results demonstrated high spatiotemporal agreement between ATHENA and OptiTrack. This was evidenced by extremely high matches (R2 > 0.90 across the majority of tasks) and low root mean square differences (< 1 cm for grip aperture, < 4 cm/s for wrist velocity, and < 5-10 degrees for index metacarpophalangeal flexion). ATHENA reliably preserved trial-to-trial variability in kinematics, offering identical scientific conclusions to marker-based approaches, but with significantly reduced financial and time costs and no participant encumbrance. In conclusion, ATHENA is an accurate, automated, and easy-to-use platform for 3D markerless hand tracking that enables more ecologically valid motor control and learning studies of naturalistic hand behaviours, enhancing our understanding of human dexterity.

Longitudinal three-photon imaging for tracking amyloid plaques and vascular degeneration in a mouse model of Alzheimer's disease
Significance: Vascular abnormalities may contribute to amyloid-beta accumulation and neurotoxicity in Alzheimer's disease (AD). The ability to monitor vascular degeneration as AD progresses is essential. Three-photon fluorescence microscopy (3PM) enables high-resolution deep tissue imaging with minimal invasiveness and photodamage. Aim: This study established a longitudinal 3P imaging pipeline to quantify vascular degeneration and amyloid plaque formation in the APP NL-G-F mouse model. Approach: A cranial window allowed repeated 3P imaging at four-week intervals beginning at five weeks after surgery. Vessels labelled with Texas-Red were segmented using DeepVess, while plaques labelled with methoxy-XO4 were segmented using custom scripts. Quantitative analyses assessed vascular parameters (diameter, density, tortuosity, length, inter-vessel distance) and plaque metrics (radius, nearest plaque-to-vessel distance). Results: We imaged the same field over 4 weeks quantifying a decrease in vasculature and increase in amyloid plaque formation with age. Significant decreases in vessel diameter, increases in inter-vessel distance, and alterations in vessel length were observed. Changes in vessel tortuosity, plaque radius, and plaque proximity to vessels were not significant. Conclusions: This pipeline tracks vascular remodeling and amyloid pathology in deep cortical structures. It offers a tool for studying the interplay between vascular and amyloid pathologies in AD, supporting future research into disease mechanisms and therapeutic strategies.

Semaglutide drives weight loss through cAMP-dependent mechanisms in GLP1R-expressing hindbrain neurons
Glucagon-like peptide 1 receptor (GLP1R) agonists like semaglutide drive weight loss through the brain, but insights into their intracellular signaling mechanisms are lacking. Although canonically GLP1Rs signal through the stimulatory alpha Gs protein, we find that semaglutide utilizes both Gs- and Gq-signaling pathways in GLP1Rs in the area postrema (AP)--the primary site of semaglutide action in the brain--to differentially regulate neuronal activation across distinct neuronal clusters. Semaglutide also drives graded increases of the essential secondary messenger cyclic adenosine monophosphate (cAMP) in Glp1r-expressing AP neurons (APGlp1r) through Gs-dependent and -independent manners. Inhibition of the cAMP-degradation enzyme phosphodiesterase 4 (PDE4) can enhance and sustain these cAMP responses, whereas disruption of Gs or cAMP signaling in APGlp1r neurons abolishes semaglutide-induced weight loss and downstream brain-wide activation. Our systematic characterization of semaglutide's signaling mechanisms in the brain provides avenues for improving the performance of obesity therapeutics.

Extreme Small-World, Modular, and Rich-Club Topology of Single-Neuron Networks in Mouse Primary Visual Cortex
Understanding whether the canonical topologies of macroscale connectomes, such as small-world architecture, hub dominance, rich-club cores, and modularity, extend to local cortical microcircuitry has remained challenging due to limitations in simultaneously recording large neuronal populations in vivo. Here, using ultra-large-scale, high-resolution calcium imaging, we tracked spontaneous activity from approximately 2,000 neurons across the mouse primary visual cortex (V1). Across multiple mice and correlation thresholds, V1 neuronal networks exhibited hallmark characteristics of efficient brain organization, but in a markedly intensified form compared to macroscopic brain networks. Local clustering coefficients remained an order of magnitude above random levels, while characteristic path lengths approached those observed in random networks, yielding an exceptionally high small-world index that substantially exceeded typical values previously reported at macroscopic scales. Degree distributions followed a power-law, identifying highly connected hub neurons whose interconnections formed a robust rich-club integrative core. Community detection analyses showed robust modularity upon pruning weak connections, indicating functionally specialized neuronal clusters interconnected predominantly through hubs. These findings provide one of the first direct in vivo evidence that single cortical microcircuits not only recapitulate but intensify network topologies observed at macroscopic scale, implying evolutionarily conserved design principles underlying brain organization from neurons to systems.

PHA-4/FoxA controls the function of pharyngeal and extrapharyngeal enteric neurons of C. elegans
FoxA transcription factors pattern gut tissue across animal phylogeny. Beyond their early patterning function, little is known about whether they control the terminal differentiation and/or function of the fully mature enteric nervous system, the intrinsic nervous system of the gut. We show here that the expression and function of the sole C. elegans FoxA homolog, PHA-4, reaches beyond its previously described pioneer factor roles in patterning the foregut. Through the engineering of neuron-specific cis-regulatory alleles, Cre-mediated cell-specific knockouts and degron-mediated, temporally controlled PHA-4/FoxA removal in postmitotic neurons, we found that PHA-4/FoxA is required not only to initiate the terminal differentiation program of foregut-associated enteric neurons, but also to maintain their functional properties throughout the life of the animal. Moreover, we discovered novel sites of expression of PHA-4/FoxA in extrapharyngeal enteric neurons that innervate the hindgut (AVL and DVB), a GABAergic interneuron that controls foregut function during sleep (RIS), and a peptidergic neuron, PVT, which we implicate here in controlling defecation behavior. We show that while PHA-4/FoxA is not required for the developmental specification of AVL, DVB, RIS, and PVT, it is required to enable these neurons to control enteric functions. Taken together, pha-4 is the only transcription factor known to date that is expressed in and required for the proper function of all distinct types of enteric neurons in a nervous system.

Indirect pathway neurons in the tail of the striatum regulate inhibitory control over sensory driven behavior
Inhibitory control, or the ability to withhold action in certain situations, is behaviorally essential. Disrupted inhibitory control is linked to various neuropsychiatric symptoms, making it critical to understand the underlying neural basis. We examined how the tail of the striatum (TS), a major basal ganglia sensory hub, regulates actions to sensory stimuli. Mice performed an auditory Go/NoGo task where we recorded cell-specific activity of TS neurons. Both major striatal types were active during target sounds, but non-target sounds preferentially engaged indirect pathway neurons. Temporarily silencing this activity increased errors to non-target stimuli, indicating a role in suppressing inappropriate action. In mice deficient for the synaptic adhesion molecule Neurexin1, a gene linked to autism spectrum disorder and ADHD, TS indirect pathway recruitment was reduced, and these mice demonstrated auditory-specific inhibitory control deficits. Altogether, these findings highlight a subcortical target to potentially improve attentional and behavioral regulation in neurodevelopmental disorders.

Neural correlates of motor sequence learning and enhanced offline consolidation in 7- to 11-year-old children
Intro: Many daily activities involve series of interrelated movements and thus the capacity to learn new motor sequences is vital for everyday functioning. Although learning new skills is especially prominent throughout childhood, remarkably few studies have examined the neural underpinnings of motor sequence learning (MSL) in children. Methods: Twenty-two children (7-11 years) and 23 adults (18-30 years) underwent functional magnetic resonance imaging while completing two sessions of a MSL task, separated by a 5-hour offline period of wakefulness. Results: Analyses of the behavioral data revealed comparable initial learning in children and adults. However, and consistent with previous research, children exhibited superior motor memory consolidation over the 5-hour offline epoch. Neuroimaging analyses revealed that children exhibited smaller modulations in brain activity between task and rest epochs in a widespread network of areas, including the sensorimotor cortex, supplementary motor area, cerebellum, putamen and regions associated with the default mode network. Similar levels of activity during task and rest epochs in the hippocampus, dorsolateral prefrontal cortex and somatosensory cortex were associated with better motor memory consolidation in children. Conclusion: Results potentially suggest that the continued engagement of the developing brain during interleaved rest contributes to the childhood advantage in motor memory consolidation.

E/I ratio and net E+I strength are differentially affected across brain disorders
Neuronal oscillations wax and wane near criticality, switching between high- and low-power states. However, the link between this bistability and excitation-inhibition balance is not well understood. Using a computational model, we demonstrate that bistability is influenced by two key factors: the excitatory-inhibitory (E/I) ratio and the combined strength of excitatory and inhibitory activity (E+I). We developed algorithms to infer both metrics from electrophysiological data and validated them in vivo. In intracranial recordings from epilepsy patients, both E/I and E+I increased during seizures, while interictally, E+I remained elevated in seizure zones as E/I decreased, consistent with compensatory inhibition. Extending the framework to scalp EEG from eight disorders, we found that Alzheimer's disease is better classified by E/I changes, whereas autism spectrum disorder and ADHD are distinguished by E+I alterations. Our findings highlight the importance of bistability in understanding EI regulation and offer handles for diagnostic and treatment decision support.

O-GlcNAcase promotes dendritic spine morphogenesis while downregulating their GluA2-containing AMPA receptors
Dendritic spines are essential for synaptic transmission, neural circuit organization, and cognitive function. Their morphology and density influence synaptic plasticity, learning, and memory. Many proteins in dendritic spines are modified with O-GlcNAc, a monosaccharide that can be attached and removed from serines and threonines. O-GlcNAc has been implicated in multiple brain disorders, yet the role of O-GlcNAcase (OGA), the enzyme that removes O-GlcNAc modification from proteins, in dendritic spine regulation remains unclear. This study examines the role of OGA in spine and synapse morphogenesis. Immunohistochemical and biochemical analyses reveal OGA present in dendritic spines. Functional assays show that OGA promotes spine maturation, increases spine density, and alters synapse size. Additionally, OGA modulates the -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), down-regulating GluA2-containing receptors in developing and mature neurons. These findings highlight OGA as a key regulator of excitatory synaptic remodeling and a therapeutic target for synapse-related pathologies such as Alzheimer's disease and autism.

Mapping social relevance in affective scenes: A large-scale multidimensional rating study
Understanding how individuals evaluate social content in affective scenes is crucial for research in emotion, social cognition, and decision-making. However, standardized image databases often lack fine-grained ratings of social dimensions beyond basic emotional content. We present a normative dataset of 296 affective scenes rated by 424 adult participants across six social-affective dimensions: social relevance, emotion sharing, action sharing, interpersonal equality, scene pleasantness, and participatory arousal. Each image was independently coded for objective features such as number of people, face visibility, and gaze direction. All rating dimensions showed excellent interrater reliability. Pleasantness ratings demonstrated strong convergent validity with established valence norms from the International Affective Picture System (IAPS), while arousal ratings differentiated between experienced and participatory arousal, suggesting that the latter captures a distinct affective component. Correlation analyses revealed that social relevance was strongly predicted by scene pleasantness and a composite "engagement" factor combining emotion sharing, action sharing, and equality. Notably, the association between pleasantness and social relevance was especially pronounced in scenes depicting single individuals. Linear mixed models further indicated that extraversion modestly amplified the relationship between engagement and social relevance, while other personality traits and empathy did not significantly affect ratings. This open-access dataset provides a reliable, multidimensional tool for selecting affective scenes based on both emotional and social-interpersonal features. It supports improved stimulus control and design in a wide range of behavioral and neurocognitive research. By systematically mapping social meaning in static affective scenes, our study advances existing methodological resources and offers empirical insight into the structure of social-affective appraisals. All image codes, mean ratings, and analysis scripts are publicly available via the Open Science Framework.

Comparison of the effects of lithium orotate and lithium carbonate on locomotion and memory in a Drosophila melanogaster model of Alzheimer's disease
Alzheimer's disease (AD) is a terminal neurodegenerative disease characterized by cognitive decline and memory loss resulting from the buildup of amyloid-beta plaques and tau protein tangles. Lithium salts, particularly lithium carbonate (Li2CO3), inhibit the enzyme Glycogen Synthase Kinase-3, which is upregulated in AD, reducing tau and amyloid-beta accumulation, inflammation, and oxidative stress. However, Li2CO3 has declined in use due to long-term neurotoxicity. Lithium orotate (LiOr), an alternative lithium salt, has greater bioavailability--delivering more ions to the brain--but was discontinued in the 1970s due to toxicity concerns at equivalent doses. It was hypothesized that LiOr would be more effective than Li2CO3 at lower doses (5 mM) due to higher lithium ion transfer, while Li2CO3 may outperform LiOr at higher doses (10 mM) due to LiOr's toxicity. This study compares LiOr and Li2CO3 in treating locomotion and memory in a Drosophila melanogaster model produced by crossing UAS amyloid-beta 42 and Act5c GAL4 flies via the GAL4/UAS system. Once aged to 25 days, flies were assessed for locomotion using the negative geotaxis assay and for short-term memory using the aversive phototaxic suppression (APS) assay. These behavioral assays aim to quantify changes in cognitive and motor function resulting from treatment. Results suggest Li2CO3 improves cognitive and motor performance in healthy flies, but LiOr was not found to be significantly more effective. This study offered a novel comparison of two lithium compounds in an Alzheimer's model and may guide research into safer, more effective AD and lithium treatments.

Blunted response of caudal locus coeruleus to arousing stimuli in Parkinson's Disease
Parkinson's disease (PD) causes progressive degeneration of noradrenergic neurons in the locus coeruleus (LC), contributing to non-motor symptoms. Using neuromelanin-sensitive ultra-high field (7T) MRI, we previously identified a reduction in neuromelanin signal in the caudal LC, indicating a rostro-caudal gradient of noradrenergic cell loss. Caudal LC degeneration was associated with greater severity of non-motor symptoms such as orthostatic hypotension and apathy. In the current study, we expanded the PD cohort to further validate the structure-symptom relationships within the LC and investigate how degeneration along the rostro-caudal LC axis affects arousal-related functional responsivity. To this end, 71 people with PD in the ON-medication state and 40 age- and sex-matched healthy controls underwent clinical assessments and 7T magnetization transfer-weighted (MTw) MRI to quantify structural changes along the rostro-caudal LC axis. A subgroup of 30 people with PD and 27 controls underwent 7T fMRI to assess LC responsivity to arousing auditory and visual stimuli in two fMRI sessions on separate days. Healthy controls were scanned twice without medication, while people with PD were studied on and off dopaminergic medication in counterbalanced order. In the PD group, MTw MRI confirmed a significant reduction of the regional neuromelanin signal in caudal LC relative to the control group (P = 0.0099). This structural disintegration correlated with orthostatic hypotension (P = 0.0087) and cognitive impairment (P = 0.036), corroborating its clinical relevance. Functional MRI revealed reduced activation of the caudal LC to arousing visual and auditory stimuli in people with PD relative to controls (P = 0.012). This difference reached statistical significance only in the ON-medication state, with a similar but non-significant trend in the OFF-medication state (P = 0.10). In an exploratory analysis of a smaller sub-sample, structural and functional caudal LC signals were significantly correlated in both people with PD and healthy controls (P = 0.0069). Together, the findings provide evidence for a rostro-caudal gradient of LC pathology in PD at both structural and functional levels. While structural MRI provides fine-grained insights into spatial gradients of disease-related pathology, functional MRI captures impaired functional responsivity of caudal LC. The presence of arousal-induced hypoactivation of caudal LC in the ON-medication state indicates that LC dysfunction extends beyond dopamine deficits in PD, highlighting complex interactions between dopaminergic and noradrenergic systems.

Deep Brain Stimulation rescues the homeostasis disruption of circulating D- and L-amino acids level in men with Parkinson's Disease.
In a comprehensive study of genetically and clinically characterized male and female Parkinson's disease (PD) patients and healthy controls, we recently reported a marked downregulation in blood D- and L-amino acids level that regulate glutamatergic NMDAR function, particularly in idiopathic male cases. However, the extent to which disease progression and antiparkinsonian therapies contribute to this systemic dysregulation remains unclear. To address these issues, in the present study we measured by High Performance Liquid Chromatography the concentrations of glutamatergic system-related D- and L-amino acids and their precursors in the plasma of male and female healthy controls (HC) and PD patients across three distinct clinical stages and treatment conditions: (1) early stage L-DOPA naive patients treated with MAO-B inhibitors; (2) mid-stage patients treated with L-DOPA; and (3) advanced stage patients receiving Deep Brain Stimulation in the subthalamic nucleus (STN-DBS) plus L-DOPA. Our results reveal notable reduction of circulating neuroactive D- and L-amino acids exclusively in male PD patients, while female patients remain unaffected regardless of disease stage or treatment. In male patients, this dysregulation manifests early, with L-DOPA-naive individuals showing decreased plasma levels of L-glutamate and L-aspartate. In mid stage L-DOPA-treated PD patients, amino acid reductions extend to L-alanine, L-serine, L-glutamine, L-asparagine, and L-threonine. Remarkably, in advanced PD patients, with a median disease duration of ~23 years, STN-DBS normalizes the blood concentrations of these amino acids to those observed in HC. In conclusion, our study highlights the potential of circulating D- and L-amino acid dysregulation as an early biomarker of PD and demonstrates that, in contrast to L-DOPA therapy, the STN-DBS confers systemic metabolic benefits even at advanced stages of the disease.

Age-related cognitive decline in house crickets reveals conserved patterns of sensory and learning deficits across the lifespan
Cognitive decline with age is characterized by impairments in learning, sensory discrimination, and decision-making. While mammalian models have advanced understanding of the neural substrates of aging, their use in large-scale behavioral studies is limited. Invertebrate models, such as the house cricket (Acheta domesticus), offer short lifespans, high throughput, and conserved neurobiological pathways but remain underexplored in geroscience. We developed a dual behavioral paradigm integrating an olfactory discrimination Y-maze and an escape learning task requiring crickets to override innate odor preferences. Adult, mid-age, and geriatric crickets were tested for sensory discrimination, associative learning, and decision speed. Morphological traits, including antennal and femoral metrics, were quantified to evaluate their influence on cognitive outcomes. Data were analyzed using ANOVA, ANCOVA, and logistic regression models. Aging impaired olfactory preference and learning success, with geriatric crickets showing reduced task acquisition and memory retention. Mid-age individuals exhibited the slowest decision-making, suggesting an early onset shift in behavioral strategy. Morphological traits predicted aspects of sensory performance and physiological resilience, such as reduced weight loss in crickets with larger femoral dimensions but did not explain age-related cognitive deficits. Olfactory decline was particularly pronounced in males, mirroring sex differences observed in human cognitive aging. House crickets exhibit hallmark features of cognitive aging, including sensory decline, learning impairments, and reduced resilience, independent of morphological deterioration. These findings establish the house cricket as a scalable invertebrate model for dissecting conserved mechanisms of neural aging and testing interventions to promote cognitive health.