Detection and tracking of animals is an important first step for automated behavioral studies using videos. Animal tracking is currently done mostly using deep learning frameworks based on keypoints, which show remarkable results in lab settings with fixed cameras, backgrounds, and lighting. However, multi-animal tracking in the wild presents several challenges such as high variability in background and lighting conditions, complex motion, and occlusion. We propose PriMAT, an approach for tracking nonhuman primates in the wild. PriMAT learns to detect and track primates and other objects of interest from labeled videos or single images using bounding boxes instead of keypoints. Using bounding boxes significantly facilitates data annotation and robustness. Our one-stage model is conceptually simple but highly flexible, and we add a classification branch that allows us to train individual identification. To evaluate the performance of our approach, we applied it in two case studies with Assamese macaques (Macaca assamensis) and redfronted lemurs (Eulemur rufifrons) in the wild. Additionally, we show transfer to other settings and species, particularly, Barbary macaques (Macaca sylvanus), Guinea baboons (Papio papio), chimpanzees (Pan troglodytes), and gorillas (Gorilla spp.). We show that with only a few hundred frames labeled with bounding boxes, we can achieve robust tracking results. Combining these results with the classification branch for the lemur videos, the lemur identification model shows an accuracy of 84% in predicting identities. Our approach presents a promising solution for accurately tracking and identifying animals in the wild, offering researchers a tool to study animal behavior in their natural habitats. Our code, models, training images, and evaluation video sequences are publicly available at https://github.com/ecker-lab/PriMAT-tracking, facilitating their use for animal behavior analyses and future research in this field.
Understanding the mechanisms underlying animal cognition requires experimental designs and analyses that respect the biological and perceptual constraints of the species being studied. We address an ongoing debate regarding the role of visual spatial frequency in numerical cognition studies, using honeybees (Apis mellifera) as a model system. Prior analyses that excluded the low spatial frequencies known to be fundamental to how these insects use their spatial vision may have introduced spurious correlations between visual features and numerical cues. By recalculating stimulus properties while incorporating the biologically relevant spectrum of spatial frequencies perceivable by a bee, our results suggest that numerical cognition in honeybees is not driven by spatial frequency but instead reflects true numerosity processing. This work highlights the necessity of aligning experimental design and analysis with the sensory and perceptual abilities of the studied species to ensure biologically meaningful conclusions. To support this goal, we provide a general framework for designing experiments that respect the psychophysical constraints of animal models in numerical cognition studies.
Chemotherapy-induced peripheral neurotoxicity (CIPN) represents a significant clinical burden, affecting 70-80 % of patients during treatment and persisting chronically in 20-30 % of survivors. While peripheral nerve injury is the primary pathological hallmark, emerging evidence demonstrates that central nervous system (CNS) dysregulation plays a crucial role in pain chronification and associated cognitive impairment. This review synthesizes recent findings on cortical and subcortical alterations that drive neuropathic pain processing in CIPN, examining dysregulated glutamatergic and GABAergic neurotransmission, altered voltage-gated ion channel expression, and central sensitization across key pain-modulatory brain regions including the prefrontal cortex, anterior cingulate cortex, somatosensory cortices, and periaqueductal gray. We address chemotherapy-induced cognitive impairment ("chemobrain") as a manifestation of shared neuroinflammatory mechanisms linking peripheral nerve injury to CNS pathology. In fact, peripheral neuropathy-triggered neuroinflammation, characterized by microglial activation and cytokine dysregulation, compromises the blood-brain barrier and impairs hippocampal-dependent memory, synaptic plasticity, and adult neurogenesis. The paper integrates findings from both animal models and human patients and discusses how animal models of CIPN reveal central nervous system engagement beyond peripheral pathology. This review emphasizes CIPN as a disorder profoundly affecting central pain modulation and cognition, requiring integrated therapeutic strategies addressing both peripheral and central nervous system pathology.
Gold nanoparticles (AuNPs) emerge as promising neuromodulatory biomaterials due to their tunable optical properties, biocompatibility, and ability to cross the blood-brain barrier. Here, we investigated the behavioral and neuroprotective effects of citrate-stabilized AuNPs (~ 19 nm) coated with PEG3350 and irradiated under white (AuWL+PEG) or green light (AuGL+PEG), compared with non-irradiated PEGylated AuNPs (AuNP+PEG). Comprehensive physicochemical analyses demonstrated that green-light irradiation enhanced surface plasmon resonance (SPR) activity, improved PEG adsorption, and yielded superior colloidal stability relative to white-light irradiation. In vivo evaluation in Wistar rats revealed that AuGL+PEG produced robust anxiolytic-like effects in the elevated plus maze, significantly enhanced spatial working memory in the Y-maze, and improved performance in the radial arm maze, approaching the efficacy of donepezil. In the forced swimming test, AuGL+PEG also produced the most favorable antidepressant-like profile, reducing immobility without locomotor confounds. Biochemically, AuGL+PEG markedly enhanced antioxidant capacity, increasing SOD, CAT, GPX, and GSH levels while reducing lipid peroxidation (MDA), consistent with restored redox homeostasis. Acetylcholinesterase inhibition was significantly greater in irradiated groups, supporting improved cholinergic signaling. Toxicological evaluation indicated no major systemic or hematological toxicity at the administered doses. Collectively, the findings demonstrate that light-engineered PEGylated AuNPs, particularly those activated with green light, exhibit potent neuroprotective and cognition-enhancing effects mediated by plasmonic surface optimization, antioxidant defense reinforcement, and cholinergic modulation. These results identify AuGL+PEG as a promising candidate nanomaterial for future applications in neuromodulation, cognitive enhancement, and the treatment of neurodegenerative diseases.
Treatment-resistant depression (TRD) is usually defined as an insufficient response to ≥1 treatment considered adequate in terms of dosage, duration, and compliance, or the failure to respond to electroconvulsive therapy (ECT). Cognitive disturbances are the core symptoms of depression and TRD, and they significantly contribute to the poor functional outcomes and treatment resistance. Patients with TRD have moderate to large cognitive deficits in executive function, verbal learning and memory, attention, visual perception, conceptual transformation, attention conversion, logic reasoning, and problem-solving, in processing speed compared to non-TRD patients. The biological underpinning of cognitive deterioration in TRD is diverse, including alterations in different brain regions and circuits, lower levels of N-acetyl aspartate and the important role of inflammatory processes, while animal studies reveal the involvement of 5-HT1A and 5-HT2 serotonergic and α2C-AR adrenergic receptors. It is important to better elucidate the biological background of cognitive dysfunction in TRD to develop more personalized and targeted treatments. Some therapeutic strategies of cognitive dysfunction in TRD include pharmacotherapy, neuromodulation, psychotherapy, and cognitive remediation. Cognitive disturbances in TRD correspond to both obstacles and challenges, but future studies should incorporate cognitive measurements and therapeutic strategies with individual approach to specifically target cognitive impairment in TRD.
The welfare of non-human animals is central to ethical discussions on animal use, with increasing attention to fish welfare across research, aquaria, aquaculture, and fisheries. This paper reviews current theoretical approaches to animal welfare and recent advances in defining and assessing fish welfare since the seminal paper by Huntingford et al. (2006; J Fish Biol 68: 332-372), highlighting the growing role of cognitive and affective processes. It also includes the concept of positive welfare and some of the current research advances in this field. Methods for measuring, monitoring and assessing welfare via the utilisation of outcome- and input-based indicators are outlined, ranging from practical operational tools to laboratory-based measures. Welfare concerns in wild-capture fisheries are examined in relation to stress, flesh quality and sustainability, including the welfare of released fish. Recent advances in fish neurobiology, cognition and pain perception are summarised, together with technological innovations that enhance welfare monitoring and management. The paper also explores the relationship between fish welfare, sustainability, public concerns and consumer demand, and legal and moral recognition across contexts, situating fish welfare within the 'One Health' and 'One Welfare' frameworks that link animal welfare, environmental stewardship and human well-being. Ongoing challenges include climate change, cultural factors and the interpretation of fish sentience and cognition among others.
The consumption of caffeine-containing products such as coffee and energy drinks is highly prevalent among medical students, particularly during exams, due to their stimulating effects. The primary objective of the study was to assess the effect of energy drinks and caffeine consumption on cognitive performance, perceived stress, and sleep quality among medical students during examination periods in Mauritius. An observational, cross-sectional, mixed-methods study was carried out at Sir Seewoosagur Ramgoolam Medical College, Mauritius, from November 12 to November 30, 2025, during the university examination phases. Quantitative data were collected via Google Forms (Google, Mountain View, CA) shared through the class WhatsApp group (Meta, Menlo Park, CA), while qualitative data were obtained through one-on-one interviews that were audio-recorded and manually transcribed. A convenience sampling technique was used to select the participants of the study. The data were entered and analyzed using SPSS version 31 (IBM Corp., Armonk, NY). The qualitative data were collected through one-on-one, face-to-face interviews conducted by the research team and were analyzed using NVivo 15 (Windows) software (QSR International, Melbourne, Australia). Braun and Clarke's six-step thematic analysis method was used for data analysis. The quantitative study design and reporting were done according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. A total of 69 students participated in the study, among whom 44 (63.8%) were females, and 25 (36.2%) were males. The mean age was found to be 21.67 ± 1.86 SD years. Consumption rates are high across all years, ranging from 65.5% to 84.2%. Higher daily intake (≥3 servings) is linked to a greater frequency of reported "caffeine crash" symptoms (55.6%), compared to moderate intake (one to two servings), where only 15.4% report such symptoms (p = 0.031). A higher percentage of caffeine consumers (42.0%) fall into the "High Stress" category compared to non-consumers (21.1%). Consuming caffeine after 6 pm is strongly associated with longer sleep onset latency (>30 minutes), reported by 64.0% of this group, compared to only 28.0% of those who stop consumption before 6 pm (p = 0 .009). A descriptive qualitative study was conducted with eight participants. Phenomenological thematic analysis was performed, which generated five themes as follows: academic influences, cognitive boosting, consumption patterns, sleep disruption, and risk-benefit perception. Each theme had different categories: exam pressure, perceived control, alertness, focus, productivity, and other variables. During the examination period, caffeine usage was common among medical students across the years. Consuming caffeine after 6 pm was strongly linked to longer sleep latency, indicating that the timing of consumption influences sleep outcome. Overall, sleep quality is low, emphasizing their susceptibility to low-quality sleep during exams, and higher perceived stress was linked to changes in confidence levels.
Cerebral small vessel disease (CSVD) leads to vascular cognitive impairment, gait disturbances, and disability in later life. Common observations include white matter hyperintensities, lacunar infarcts, increased perivascular gaps, and microhemorrhages. The condition progresses gradually as a result of endothelial and microvascular dysfunction, diminished blood flow, compromised lymphatic clearance, and neuroinflammation. Contemporary medicine has enhanced risk management; yet, no medication substantially postpones disease progression, underscoring the necessity for alternative treatment strategies. Traditional Chinese Medicine (TCM), characterized by its holistic approach and classification of conditions, provides a distinctive perspective on complex diseases, including cerebral small vessel disease. In TCM, theories such as "blood stasis obstructing collaterals", "toxin impairing collaterals" and "kidney deficiency leading to marrow degeneration" are highly consistent with the contemporary pathophysiological theories of CSVD. This review uniquely synthesizes TCM theories with contemporary mechanistic evidence, encompassing clinical trials and network pharmacology, thereby establishing a comprehensive framework for the prospective application of TCM in CSVD and filling a void in prior research in this domain. This study assesses TCM for CSVD, elucidates its mechanisms of action and clinical efficacy, and synthesizes recent research to evaluate TCM's significance and potential in the management of CSVD. In accordance with the PRISMA guidelines, we conducted a systematic search of major scientific databases (PubMed, Web of Science, Embase, Cochrane Library, Wanfang and CNKI), with the search time range spanning from the establishment of each database to October 2025. Predefined keywords were adopted, including cerebral small vessel disease, white matter hyperintensities, lacunar cerebral infarction, traditional Chinese medicine, Chinese herbal medicine, acupuncture, and traditional Chinese herbal prescriptions. The literatures included in the analysis were qualified original studies (covering clinical trials, observational studies, and experimental studies involving human subjects or animal/cell models). These studies adopted any intervention measures of TCM and reported outcome indicators related to efficacy, mechanisms or safety. Reviews, commentaries and case reports were excluded. Two reviewers independently screened the titles, abstracts and full texts. Discrepancies were resolved through consensus negotiation or by a third reviewer. Standardized forms were used for data extraction. Meta-analysis was not performed due to the significant heterogeneity among the included studies. The quality of clinical studies was evaluated using the Cochrane Risk of Bias Assessment Tool, and the quality of animal studies was assessed with the SYRCLE Risk of Bias Assessment Tool. The evaluation results were applied to assist in interpreting the research findings, rather than serving as the basis for excluding relevant studies. Based on clinical trials, animal models, and in vitro investigations, this study describes several TCM therapies that may benefit CSVD. These therapies protect the endothelium, stabilize the BBB, reduce neuroinflammation, increase microcirculation, and clear lymphatics. These effects match CSVD's complex pathology, but the research deserves scrutiny. Animal models have shown that TCM formulations regulate vascular homeostasis and reduce white matter injury via PI3K/Akt, NF-κB, and Wnt/β-catenin pathways. These interesting discoveries need clinical validation to be relevant. However, some clinical investigations demonstrate that specific formulations increase cognition and daily life, indicating their therapeutic efficacy, particularly in patients with cognitive impairments or neurodegenerative conditions. Numerous experiments have limited sample sizes and short durations. Modern formulations increase drug absorption and brain targeting, yet most research is preclinical. Mechanisms are diverse, but evidence varies. Confirming these preliminary findings requires larger, more thorough clinical investigations. In conclusion, TCM may target the intricate network associated with persistent stroke-related vascular illness. Specific herbal formulations have demonstrated the ability to enhance endothelial function and diminish blood-brain barrier (BBB)permeability. They additionally mitigate neuroinflammation, enhance hypoperfusion, and facilitate the clearance of metabolic waste. Contemporary formulation techniques improve the precision and efficacy of TCM. Collectively, these data indicate novel approaches for the management of CSVD as a chronic condition. Nonetheless, obstacles in standardization and reproducibility necessitate additional investigation to facilitate clinical translation and wider acceptability.
Understanding chicken cognition is essential for improving welfare in production systems, as it reveals how animals perceive and respond to their environment. Barren housing can compromise welfare, including negative affective states and cognitive deficits, but previous research mostly focused on effects of barren environments on young animals. Here, we investigated whether hens moved to battery cages once adults show lower cognitive performance than those kept cage-free. Because stable inter-individual differences (personality traits) can modulate how animals respond to environmental changes, we also explored whether personality modulates this effect. Sixty hens were reared in enriched aviary pens; at 18 weeks, half were transferred to battery cages (456 cm² per hen) and the rest remained cage-free (5,333 cm² per hen) for 64 days before testing. Personality was assessed through four standardised tests, and spatial memory was evaluated with a modified hole-board task. Working memory (WM), general working memory (GWM), and reference memory (RM) were calculated from visit ratios. Behaviours after birds consumed all baited rewards were recorded to assess responses to reward omission (e.g. extinction learning). Battery hens outperformed cage-free hens in all memory metrics and were more active during the post-reward period, showing more empty-cup visits. While the enhanced memory performance of battery hens is likely driven by increased reward motivation and greater engagement with the task, our results also suggest these birds showed a deficit in extinction learning. Personality also influenced performance: more fearful hens had lower WM and GWM and were slower to find baited cups. Housing and personality jointly shaped cognition in laying hens, highlighting that enhanced performance under poor conditions may not indicate better welfare, but rather a shift in motivation for food rewards.
Nicotine exposure during pregnancy interferes with critical periods of foetal brain development, disrupting the timing and functioning of neurodevelopment. This systematic review and meta-analysis aims to evaluate the effect of prenatal nicotine exposure on postnatal cognitive outcomes. Web of Science, PubMed, PsycINFOand OpenGrey databases were searched, with no date restrictions. Human (k = 1) and animal research (k = 8) was included. Studies were required to include at least one postnatal cognitive measure during the pre-weaning period. Exposure to nicotine during pregnancy negatively impacted postnatal outcomes of spatial memory (Cohen's d = -1.117; 95% CI [-2.112, -0.123]), centre exploration in animal studies (d = -1.054; 95% CI [-1.659, -0.449]), and reflex development in human and animal studies (d = -1.126; 95% CI [-1.737, -0.514]). Prenatal nicotine exposure did not have a significant effect on ambulation (d = -0.044; 95% CI [0.485, 0.397]) and rearing (d = -0.45; 95% CI [-1.042, 0.142]) in animals. Findings suggest that certain domains may be especially vulnerable to prenatal nicotine exposure, with reflex development showing the strongest effect. The scarcity of human studies underscores an urgent need for further research to ensure informed recommendations on nicotine intake during pregnancy.
Neuroinflammation is a chronic inflammatory response that contributes to synaptic dysfunction and neuronal damage, it is a common feature among various neurodegenerative diseases such as Alzheimer's Disease (AD), Parkinson's Disease (PD) and Huntington's Disease (HD). Tocotrienol-rich fraction (TRF) is a form of vitamin E that is known for its anti-inflammatory, antioxidant and neuroprotective properties. Yet, it has not been adequately investigated in both cellular and animal neuroinflammation models. In this study, the potential therapeutic effects of TRF were investigated in-vitro using BV2 microglial cells and also in-vivo in a pilot study using Sprague Dawley rats. TRF at 5 and 10 µg/mL were found to reduce nitric oxide (NO) and reactive oxygen species (ROS) levels. Furthermore, in-vivo treatment with TRF significantly increases the recognition index implying improvement in cognition ability. Gene expression analysis showed downregulation of RelA, TNF-α and IL-6 while NFE2L2 and BDNF were upregulated. These findings suggests that TRF may help mitigates neuroinflammation and oxidative stress, indicating its potential as a candidature for further investigation in neurodegenerative diseases associated with chronic neuroinflammation.
Effective pharmacological treatments for Post-Stroke Cognitive Impairment (PSCI) remain elusive. Preclinical studies have shown that phosphodiesterase 4 (PDE4) inhibition improved cognition, particularly memory, in post-stroke animal models and in healthy young and elderly individuals. This study tested whether the PDE4 inhibitor roflumilast could improve memory in PSCI patients. A double-blind randomized placebo-controlled trial (RCT) included 100 community-dwelling participants receiving roflumilast (100 µg q.d.) or placebo (N = 50 per group). Participants were 41-70 years and had suffered a cerebrovascular accident more than a year ago. They had subjective memory complaints and scored below the normative score on the delayed recall of the verbal learning test (VLT). After the RCT, 42 placebo group participants completed a 3-month open label extension (OLE). The primary outcome was the VLT delayed recall score. Roflumilast efficacy in the RCT was estimated through analysis of covariance (ANCOVA) with (post hoc) and without adjustment for baseline prognostic covariates defined a priori. In the OLE, general linear model repeated measures analyses were used. Secondary outcomes related to cognition, mood, and daily functioning. Of the 97 participants completing the study (roflumilast: 48; placebo: 49), primary ANCOVA indicated a larger response in the roflumilast group on VLT and Rivermead Behavioural Memory Test (stories) at endpoint with non-significant moderate effect sizes (Cohen's d: 0.31-0.36). When post hoc adjusting for prognostic baseline covariates, effect sizes (0.33-0.40) became significant. Adverse events were similar in both groups. In the OLE, all memory test scores improved with medium to large significant effect sizes (Partial η2: 0.079-0.171). Roflumilast appeared to improve memory and was not associated with adverse effects. Results support further clinical studies.
Number sense is the intuitive, non-verbal ability to perceive and process numerical quantities without formal counting. This evolutionarily conserved trait, shared by different animal species, is supported by two mechanisms: the object tracking system (OTS) for small sets and the approximate number system (ANS) for larger quantities. Although historically viewed as distinct, these systems interact dynamically; their disruption is implicated in developmental dyscalculia and disorders such as Williams-Beuren syndrome (WBS), a chromosome microdeletion characterised by marked numerical and visuospatial deficits. Here, we synthesise neurobiological advances to provide an integrative perspective on the neural substrates of number sense. Field studies provide ecological validity, while laboratory procedures offer tighter precision; together, they illuminate the biological foundations of numerical cognition. Although number sense is conserved, human studies indicate only moderate heritability likely reflecting directional selection. Nonetheless, genetic findings converge on neurodevelopmental and synaptic mechanisms. Zebrafish (Danio rerio) offer a powerful platform to bridge genes, circuits and behaviour. For instance, manipulating zebrafish genes linked to WBS reveals gene-specific effects on quantity processing. At the neural level, numerical cognition is largely supported by specialised number-selective neurons. Whole-brain calcium imaging in larval zebrafish demonstrates that these neurons emerge by 3 days postfertilisation and follow a trajectory where representations of small numerosities precede larger ones. Altogether, integrating genetic, behavioural and circuit-level approaches provides a powerful framework for uncovering conserved mechanisms of numerosity supporting higher-level cognitive functions, including mathematics.
The ability to discriminate numbers is widespread across taxonomically diverse animals. Some animals may have evolved enhanced numerical abilities to cope with specific social or ecological challenges. Peafowl (Pavo cristatus) are one example in which enhanced numerical abilities could be useful because peacocks have colorful trains that exhibit many eyespot feathers and females may evaluate the number of eyespot feathers to assess their mates. We therefore tested the numerical discrimination abilities of captive peafowl using a custom touchscreen apparatus. Peafowl were presented with two squares that contained a different number of circles (one to eight) and they received a reward for pecking on the square that contained more circles. To examine whether quantity factors aside from numerosity were influencing their performance, we varied the size, density or surface area of the circles. We found that the peafowl's performance was largely driven by numerosity rather than the other quantity factors. The peafowl generally performed at levels above chance regardless of the size, density or surface area of the circles. Their performance was also consistent with the Weber-Fechner Law, in which numerical discrimination is related to the ratio between numbers rather than the absolute difference. The results suggest that peafowl can discriminate among numbers and they could potentially use that ability during courtship or other contexts.
Studies linking mitochondrial DNA (mtDNA) variants to cognition yielded inconsistent findings, and the underlying mechanisms remain unclear. We investigated whether mtDNA heteroplasmic variants were associated with cognitive outcomes, including the Montreal Cognitive Assessment (MoCA), in 197 late midlife adults from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort with complete data. MtDNA was sequenced from blood using targeted deep sequencing. Adjusted linear and mixed-effects models examined the associations by functional regions, genes, total variant burden, nonsynonymous variants, and control regions. Heteroplasmic variants in the control region (β = -0.44, 95% CI: -0.83, -0.05, p = 0.027) and transfer RNA (tRNA) genes (β = -1.34, 95% CI: -2.58, -0.11, p = 0.034) were associated with MoCA baseline scores. Individual variants in cytochrome c oxidase subunit 1 (CO1) (β = -1.51, 95% CI: -2.54, -0.47, p = 0.005), NADH dehydrogenase subunit 1 (ND1) (β = -2.63, 95% CI: -4.56, -0.70, p = 0.008), and Displacement Loop (D-LOOP2) (β = -2.25, 95% CI: -4.20, -0.30, p = 0.025) was associated with reduced baseline MoCA scores. The ND6 (β = −1.23, 95% CI: −2.09, − 0.37, p = 0.006), ND4 (β = −1.11, 95% CI: −2.02, − 0.20, p = 0.018), ATP Synthase Membrane Subunit 8 (ATP8; β = −1.38, 95% CI: −2.63, − 0.13, p = 0.031), and D-LOOP1 (β = −0.61, 95% CI: −1.20, − 0.01, p = 0.045) genes suggested a potential association with executive function. Longitudinal Animal Fluency Test (AFT) scores were inversely associated with heteroplasmic variants in coding regions (β = -0.10, 95% CI: -0.19, -0.006, p = 0.049), the total number of variants (β = -0.06, 95% CI: -0.11, -0.003, p = 0.037) and total nonsynonymous variants (β = -0.11, 95% CI: -0.21, -0.01, p = 0.040). Variants in the control region were associated with the greatest decline in verbal fluency (β = −0.20, 95% CI: −0.39 to − 0.002, p = 0.049). No associations were observed between mitochondrial variants and verbal memory performance or the MoCA composite scores. Our study indicates that mitochondrial variants measured in blood may provide insight into cognitive function during midlife. However, additional studies are needed to validate these associations and to address potential power limitations in our study. The online version contains supplementary material available at 10.1186/s12883-026-04857-x.
There is increasing evidence of microglia participation in Alzheimer's disease (AD), which incentives their modulation to intercept the disease. Here, we describe a new mechanism by which the recently AD-associated Peptidase M20 Domain Containing 1 (PM20D1) instructs microglia to tackle AD. We show that the PM20D1-derived N-oleoyl-Leucine (OLE) improves AD pathologies in two animal models of AD. OLE induces microglia association with amyloid beta (Aβ) plaques, reduce their size, number and toxicity, and leads to enhanced neuroprotection and cognition. Furthermore, OLE also increases Aβ chemotaxis and clearance in microglia cultures and enhances cell viability in neurons subjected to AD-related stressors. Finally, we also find evidence for a PM20D1- and OLE-mediated microglia association with amyloid plaques and neuroprotection in human AD brains. In sum, our results provide further insight into the protective role of PM20D1 in AD and support the use of OLE as a microglia-modifying treatment for AD.
Physical exercise acutely improves hippocampus-dependent memory. Whereas animal studies have offered cellular- and synaptic-level accounts of these effects, human neuroimaging studies show that exercise improves hippocampal-cortical connectivity at the macroscale level. However, the neurophysiological basis of exercise-induced effects on hippocampal-cortical circuits remains unknown. Experimental evidence supports the idea that hippocampal sharp wave-ripples (SWR) play a critical role in learning and memory. Coupling between SWRs in the hippocampus and neocortex may reflect modulations in inter-regional connectivity required by mnemonic processes. Here, we examine the hypothesis that exercise modulates hippocampal-cortical ripple dynamics in the human brain. We performed intracranial recordings in epilepsy patients undergoing pre-surgical evaluation, during awake resting state, before and after an exercise session. Exercise increased ripple rate in the hippocampus. Exercise also enhanced the coupling and phase-synchrony between cortical ripples in the limbic and the default mode (DM) cortical networks and hippocampal SWRs. Further, a higher heart rate during exercise, reflecting exercise intensity, was related to a subsequent increase in resting state ripples across specific cortical networks, including the DM network. These results offer the first direct evidence that a single exercise session elicits changes in ripple events, a well-established neurophysiological marker of mnemonic processing. The characterisation and anatomical distribution of the described modulation points to hippocampal ripples as a potential mechanism by which exercise elicits its reported short-term effects in cognition.
Receiving timely Alzheimer's disease (AD) diagnosis is often delayed due to long waitlists for specialists. Our study aimed to bridge the gap between the timeliness and complexity of diagnosing AD by developing a scoring system with interpretable machine learning using variables that are obtainable at integrated primary care settings. We trained the model using 666 participants with normal cognition or mild cognitive impairment at baseline visit from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and externally validated the scorecard using 4,876 participants from the National Alzheimer's Coordinating Center (NACC). We integrated cognitive measures, daily functioning measured with Functional Assessment Questionnaire (FAQ), and demographics into FasterRisk algorithm. Combinations of 4 separate measures were selected to generate 10 scorecards, showing strong performance (area under the curve [AUC] = 0.868-0.892) in ADNI and remaining robust when externally validated in NACC (AUC = 0.795). The features were Category Animal ≤ 20 (2 points), Trail Making Test B ≤ 143 (-3 points), Logical Memory Delayed ≤ 3 (4 points), Logical Memory Delayed ≤ 8 (3 points), and FAQ ≤ 2 (-5 points). The probable AD risk increased correspondingly with higher total points: 7.4% (-8), 25.3% (-4), 50% (-1), 74.7% (2), and >90% (>6). We refer to this model as the (F)unctioning, (LA)nguage, (M)emory, and (E)xecutive functioning or FLAME scorecard. Our findings highlight the potential to predict AD development using obtainable information, allowing for implementation into integrated primary care workflows to initiate early intervention. While our scope centers on AD, this established foundation paves the way for other types of dementia.
Mutations in human LIS1 cause lissencephaly, a severe developmental brain malformation. Although most studies focus on development, LIS1 is also expressed in adult mouse tissues. We previously induced LIS1 knockout (iKO) in adult mice using a Cre-Lox approach with an actin promoter driving CreERT2 expression. This proved to be rapidly lethal, with evidence pointing toward nervous system dysfunction. CreERT2 activity was observed in astrocytes, brainstem and spinal motor neurons, and axons and Schwann cells in the sciatic and phrenic nerves, suggesting dysfunctional cardiorespiratory and motor circuits. However, it is unclear how LIS1 knockout in these different cell types contributes to the lethal phenotype. We now report that LIS1 depletion from astrocytes is not lethal to mice (male or female), although glial fibrillary protein (GFAP) expression is increased in all LIS1-depleted astrocytes. In contrast, LIS1 depletion from projection neurons causes motor deficits and rapid lethality in both males and females. This is accompanied by progressive, widespread axonal degeneration along the entire length of both motor and sensory axons. Interestingly, sensory neurons harvested from iKO mice initially extend axons in culture but soon develop axonal swellings and fragmentation, indicating axonal degeneration. LIS1 is a prominent regulator of cytoplasmic dynein 1 (dynein, hereafter), a microtubule motor whose disruption can cause both cortical malformations and later-onset neurodegenerative diseases, such as Charcot-Marie-Tooth disease. Our results raise the possibility that LIS1 depletion, through disruption of dynein function in mature axons, may lead to Wallerian-like axon degeneration without traumatic nerve injury.Significance Statement A healthy nervous system requires that proper brain wiring is maintained throughout the life of the animal. Connectivity often involves the long axons of projection neurons. Some axons drive cognition, others contribute to sensory and motor systems, while still others subserve vitally important cardiorespiratory processes. We show that LIS1, a protein linked to congenital brain abnormalities, also plays a crucial role in fully developed projection neurons in the adult mouse. LIS1 depletion from these cells causes severe axonal degeneration resembling the Wallerian degeneration that occurs in response to nerve injury. Because LIS1 regulates dynein, and because defective dynein can cause neurodegenerative disorders in humans, our study suggests that drugs targeting Wallerian degeneration may have therapeutic potential for dynein-related diseases.