Spatial-Temporal Analysis of Neural Desynchronization in Sleeplike States Reveals Critical Dynamics.

Sleep is characterized by nonrapid eye movement sleep, originating from widespread neuronal synchrony, and rapid eye movement sleep, with neuronal desynchronization akin to waking behavior. While these were thought to be global brain states, recent research suggests otherwise. Using time-frequency analysis of mesoscopic voltage-sensitive dye recordings of mice in a urethane-anesthetized model of sleep, we find transient neural desynchronization occurring heterogeneously across the cortex within a background of synchronized neural activity, in a manner reminiscent of a critical spreading process and indicative of an "edge-of-synchronization" phase transition.

Detecting the effect of genetic diversity on brain composition in an Alzheimer's disease mouse model.

Alzheimer's disease (AD) is broadly characterized by neurodegeneration, pathology accumulation, and cognitive decline. There is considerable variation in the progression of clinical symptoms and pathology in humans, highlighting the importance of genetic diversity in the study of AD. To address this, we analyze cell composition and amyloid-beta deposition of 6- and 14-month-old AD-BXD mouse brains. We utilize the analytical QUINT workflow- a suite of software designed to support atlas-based quantification, which we expand to deliver a highly effective method for registering and quantifying cell and pathology changes in diverse disease models. In applying the expanded QUINT workflow, we quantify near-global age-related increases in microglia, astrocytes, and amyloid-beta, and we identify strain-specific regional variation in neuron load. To understand how individual differences in cell composition affect the interpretation of bulk gene expression in AD, we combine hippocampal immunohistochemistry analyses with bulk RNA-sequencing data. This approach allows us to categorize genes whose expression changes in response to AD in a cell and/or pathology load-dependent manner. Ultimately, our study demonstrates the use of the QUINT workflow to standardize the quantification of immunohistochemistry data in diverse mice, - providing valuable insights into regional variation in cellular load and amyloid deposition in the AD-BXD model.

Single-molecule analysis of osmolyte-mediated nanomechanical unfolding behavior of a protein domain.

The small organic molecules, known as osmolytes being ubiquitously present in different cell types, affect protein folding, stability and aggregation. However, it is unknown how the osmolytes affect the nanomechanical unfolding behavior of protein domain. Here, we show the osmolyte-dependent mechanical unfolding properties of protein titin immunoglobulin-27 (I27) domain using an atomic force microscopy (AFM)-based single-molecule force spectroscopy. We found that amines and methylamines improved the mechanical stability of I27 domain, whereas polyols had no effect. Interestingly, glycine betaine (GB) or trimethylamine-N-oxide (TMAO) increased the average unfolding force of the protein domain. The kinetic parameters analyzed at single-molecule level reveal that stabilizing effect of osmolytes is due to a decrease in the unfolding rate constant of I27, which was confirmed by molecular dynamics simulations. Our study reveals different effects that diverse osmolytes have on the mechanical properties of the protein, and suggests the potential use of osmolytes in modulating the mechanical stability of proteins required for various nano-biotechnological applications.

Detecting the effect of genetic diversity on brain composition in an Alzheimer's disease mouse model.

Alzheimer's disease (AD) is characterized by neurodegeneration, pathology accumulation, and progressive cognitive decline. There is significant variation in age at onset and severity of symptoms highlighting the importance of genetic diversity in the study of AD. To address this, we analyzed cell and pathology composition of 6- and 14-month-old AD-BXD mouse brains using the semi-automated workflow (QUINT); which we expanded to allow for nonlinear refinement of brain atlas-registration, and quality control assessment of atlas-registration and brain section integrity. Near global age-related increases in microglia, astrocyte, and amyloid-beta accumulation were measured, while regional variation in neuron load existed among strains. Furthermore, hippocampal immunohistochemistry analyses were combined with bulk RNA-sequencing results to demonstrate the relationship between cell composition and gene expression. Overall, the additional functionality of the QUINT workflow delivers a highly effective method for registering and quantifying cell and pathology changes in diverse disease models.

Spatio-temporal analysis of changes occurring in land use and its impact on land surface temperature.

This study shows how remote sensing and Geographic Information System (GIS) can extract land surface temperature (LST) from the Landsat 5, 7, and 8 datasets. In this research, LST over Kharun's lower catchment, located in Chhattisgarh, India, has been estimated. LST data from 2000, 2006, 2011, 2016, and 2021 were analyzed to see how the LULC pattern changed and how that changed LST. In 2000, the average temperature of the study region was 27.73 °C, whereas in 2021, it reached 33.47 °C. When the average temperature values for each class were determined, it was discovered that forest and adjacent waterbodies had the lowest values, with about 24.15 °C in 2000 and 27.65 °C in 2021, whereas urban regions had more variation in values, ranging from 30.15 °C in 2000 to 38.95 °C in 2021. There could be an increase in LST over time because cities are replacing the green cover. For example, there was a notable increase of 5.74 °C in the mean LST over the research area. The findings revealed that places with extensive urban sprawl had LST between 26 and 45°, which was greater than other natural land cover types, such as vegetation and waterbodies, which was between 24 and 35°. These findings support the suggested method's effectiveness for retrieving LST from the Landsat 5, 7, and 8 thermal bands when combined with integrated GIS approaches. So, the goal of this study is to look at Land Use Change (LUC) and changes in LST using Landsat data and figure out how they are related to LST, the Normalized Difference Vegetation Index (NDVI), and the Normalized Built-up Index (NDBI), which are used as major components.

Gate and Temperature Driven Phase Transitions in Few-Layer MoTe2.

MoTe2 has a stable hexagonal semiconducting phase (2H) as well as two semimetallic phases with monoclinic (1T') and orthorhombic (Td) structures. A structural change can thus be accompanied by a significant change in electronic transport properties. The two semimetallic phases are connected by a temperature driven transition and could exhibit topological properties. Here we make extensive Raman measurements as a function of layer thickness, temperature, and electrostatic doping on few layer 2H-MoTe2 and also on 1T'-MoTe2 and Td-WTe2. Recent work in MoTe2 has raised the possibility of a 2H-1T' transition through technology compatible pathways. It has been claimed that such a transition, of promise for device applications, is activated by electrostatic gating. We investigate this claim and find that few-layer tellurides are characterized by high mobility of Te ions, even in ambient conditions and especially through the variation of external parameters like electric field or temperature. These can generate Te clusters, vacancies at crystalline sites, and facilitate structural transitions. We however find that the purported 2H-1T' transition in MoTe2 cannot be obtained by a pure electrostatic field.

Momentum-resolved spin-conserving two-triplon bound state and continuum in a cuprate ladder.

Studying multi-particle elementary excitations has provided unique access to understand collective many-body phenomena in correlated electronic materials, paving the way towards constructing microscopic models. In this work, we perform O K-edge resonant inelastic X-ray scattering (RIXS) on the quasi-one-dimensional cuprate Sr14Cu24O41 with weakly-doped spin ladders. The RIXS signal is dominated by a dispersing sharp mode ~ 270 meV on top of a damped incoherent component ~ 400-500 meV. Comparing with model calculations using the perturbative continuous unitary transformations method, the two components resemble the spin-conserving ΔS = 0 two-triplon bound state and continuum excitations in the spin ladders. Such multi-spin response with long-lived ΔS = 0 excitons is central to several exotic magnetic properties featuring Majorana fermions, yet remains unexplored given the generally weak cross-section with other experimental techniques. By investigating a simple spin-ladder model system, our study provides valuable insight into low-dimensional quantum magnetism.

Synergistic Approach Toward a Reproducible High zT in n-Type and p-Type Superionic Thermoelectric Ag2Te.

Recently, superionic thermoelectrics have attracted enormous attention due to their ultralow thermal conductivity and high figure-of-merit (zT). However, their high zT is generally obtained deep inside the superionic phase, e.g., near 1000 K in Cu2X (X: chalcogen atom) family despite a relatively low superionic transition temperature of ∼400 K. At such high temperatures, the liquid-like flow of the metal ions results in material's degradation. Here, we present thermoelectric properties of superionic Ag2Te synthesized by various methods. The sintered Ag2Te samples are shown to exhibit an unpredictable behavior with respect to the sign of thermopower (S) in the superionic phase and the magnitude of electrical conductivity (σ). We overcome this issue using an all-room-temperature fabrication technique leading to an excellent reproducibility from one sample to another. To improve the zT of Ag2Te beyond the phonon-liquid electron-crystal limit (∼0.64 at 575 K in the ingot samples), we adopted a heirarchical nanostructuring technique, which effectively suppressed the thermal conductivity, leading to a significant improvement in the zT values for both n-type and p-type samples. We obtained zT of 1.2 in the n-type and 0.64 in the p-type Ag2Te at 570 K. These values supersede the zT of any Ag2Te previously reported. At 570 K, for our ball-milled/cold-pressed samples, the critical current density for metal-ion migration exceeds 15 A cm-2, which further confirms that Ag2Te is a promising thermoelectric material. Our results are supported by first-principles density functional theory calculations of the electronic and thermal properties.

Numerical groundwater modelling for studying surface water-groundwater interaction and impact of reduced draft on groundwater resources in central Ganga basin.

Water resources in India's Indo-Gangetic plains are over-exploited and vulnerable to impacts of climate change. The unequal spatial and temporal variation of meteorological, hydrological and hydrogeological parameters has created additional challenges for field engineers and policy planners. The groundwater and surface water are extensively utilized in the middle Gangetic plain for agriculture. The primary purpose of this study is to understand the discharge and recharge processes of groundwater system using trend analysis, and surface water and groundwater interaction using groundwater modelling. A comprehensive hydrological, and hydrogeological data analysis was carried out and a numerical groundwater model was developed for Bhojpur district, Bihar, India covering 2395 km2 geographical area, located in central Ganga basin. The groundwater level data analyses for the year 2018 revealed that depth to water level varies from 3.0 to 9.0 meter below ground level (m bgl) in the study area. The M-K test showed no significant declining trend in the groundwater level in the study area. The groundwater modelling results revealed that groundwater head is higher in the southern part of the district and the groundwater flow direction is from south-west to north-east. The groundwater head fluctuation between the monsoon and the summer seasons was observed to be 2 m, it is also witnessed that groundwater is contributing more to rivers in the monsoon season in comparison with other seasons. Impact of reduction in pumping on groundwater heads was also investigated, considering a 10% reduction in groundwater withdrawal. The results indicated an overall head rise of 2 m in the southern part and 0.2-0.5 m in the middle and northern part of the district.

X-ray photoemission and absorption study of the pyrochlore iridates (Eu1-xBix)2Ir2O7, 0 ⩽x ⩽ 1.

The pyrochlore iridates (Eu1-xBix)2Ir2O7(0⩽x⩽1) undergo an anomalous negative lattice expansion for small Bi-doping (x⩽0.035) (region I) and a normal lattice expansion forx⩾0.1(region II); this is accompanied by a transition from an insulating (and magnetically ordered) to a metallic (and with no magnetic ordering) ground state. Here, we investigate (Eu1-xBix)2Ir2O7(0⩽x⩽1) using hard x-ray photoemission spectroscopy and x-ray absorption fine structure (XAFS) spectroscopy. By analyzing the Eu-L3, Ir-L3and Bi-L2&L3edges x-ray absorption near edge structure spectra and Eu-3dcore-level XPS spectra, we show that the metal cations retain their nominal valence, namely, Ir4+, Bi3+and Eu3+, respectively, throughout the series. The Ir-4fand Bi-4fcore-level XPS spectra consist of screened and unscreened doublets. The unscreened component is dominant In the insulating range (x⩽0.035), and in the metallic region (x⩾0.1), the screened component dominates the spectra. The Eu-3dcore-level spectra remain invariant under Bi doping. The extended XAFS data show that the coordination around the Ir remains well preserved throughout the series. The evolution of the valence band spectra near the Fermi energy with increasing Bi doping indicates the presence of strong Ir(5d)-Bi(6p) hybridization which drives the metal-to-insulator transition.

Leveraging genetic diversity in mice to inform individual differences in brain microstructure and memory.

In human Alzheimer's disease (AD) patients and AD mouse models, both differential pre-disease brain features and differential disease-associated memory decline are observed, suggesting that certain neurological features may protect against AD-related cognitive decline. The combination of these features is known as brain reserve, and understanding the genetic underpinnings of brain reserve may advance AD treatment in genetically diverse human populations. One potential source of brain reserve is brain microstructure, which is genetically influenced and can be measured with diffusion MRI (dMRI). To investigate variation of dMRI metrics in pre-disease-onset, genetically diverse AD mouse models, we utilized a population of genetically distinct AD mice produced by crossing the 5XFAD transgenic mouse model of AD to 3 inbred strains (C57BL/6J, DBA/2J, FVB/NJ) and two wild-derived strains (CAST/EiJ, WSB/EiJ). At 3 months of age, these mice underwent diffusion magnetic resonance imaging (dMRI) to probe neural microanatomy in 83 regions of interest (ROIs). At 5 months of age, these mice underwent contextual fear conditioning (CFC). Strain had a significant effect on dMRI measures in most ROIs tested, while far fewer effects of sex, sex*strain interactions, or strain*sex*5XFAD genotype interactions were observed. A main effect of 5XFAD genotype was observed in only 1 ROI, suggesting that the 5XFAD transgene does not strongly disrupt neural development or microstructure of mice in early adulthood. Strain also explained the most variance in mouse baseline motor activity and long-term fear memory. Additionally, significant effects of sex and strain*sex interaction were observed on baseline motor activity, and significant strain*sex and sex*5XFAD genotype interactions were observed on long-term memory. We are the first to study the genetic influences of brain microanatomy in genetically diverse AD mice. Thus, we demonstrated that strain is the primary factor influencing brain microstructure in young adult AD mice and that neural development and early adult microstructure are not strongly altered by the 5XFAD transgene. We also demonstrated that strain, sex, and 5XFAD genotype interact to influence memory in genetically diverse adult mice. Our results support the usefulness of the 5XFAD mouse model and convey strong relationships between natural genetic variation, brain microstructure, and memory.

Sex-Dependent Effects of Intestinal Microbiome Manipulation in a Mouse Model of Alzheimer's Disease.

Mechanisms linking intestinal bacteria and neurodegenerative diseases such as Alzheimer's disease (AD) are still unclear. We hypothesized that intestinal dysbiosis might potentiate AD, and manipulating the microbiome to promote intestinal eubiosis and immune homeostasis may improve AD-related brain changes. This study assessed sex differences in the effects of oral probiotic, antibiotics, and synbiotic treatments in the AppNL-G-F mouse model of AD. The fecal microbiome demonstrated significant correlations between bacterial genera in AppNL-G-F mice and Aß plaque load, gliosis, and memory performance. Female and not male AppNL-G-F mice fed probiotic but not synbiotic exhibited a decrease in Aß plaques, microgliosis, brain TNF-α, and memory improvement compared to no treatment controls. Although antibiotics treatment did not produce these multiple changes in brain cytokines, memory, or gliosis, it did decrease Aß plaque load and colon cytokines in AppNL-G-F males. The intestinal cytokine milieu and splenocyte phenotype of female but not male AppNL-G-F mice indicated a modest proinflammatory innate response following probiotic treatment compared to controls, with an adaptive response following antibiotics treatment in male AppNL-G-F mice. Overall, these results demonstrate the beneficial effects of probiotic only in AppNL-G-F females, with minimal benefits of antibiotics or synbiotic feeding in male or female mice.

Antiarthritic activity of OA-DHZ; a gastroprotective NF-κB/MAPK/COX inhibitor.

Arthritis, a primary autoimmune disorder having a global incidence of 2.03% person/year, is presently being treated by many commercially available drugs that treat symptomatically or improve the disease's clinical state; however, all the therapies pose varying amount of side effects. Therefore, it has become a fundamental need to search for therapeutics that offer better efficacy and safety profile, and the natural or nature-derived products are known for their outstanding performance in this arena. OA-DHZ, known to possess anti-inflammatory and analgesic properties, when explored for its efficacy against arthritis in adjuvant-induced arthritis (AIA) model, was found to inhibit paw edema by 34% and TNF-α, IL-6, and IL-1ß by 67%, 39%, and 45% respectively when compared to diseased control. It was also able to reduce the inflamed spleen size by 45% and successfully normalized biochemical and hematological changes that followed arthritis. In vitro studies revealed that the underlying mechanism for inhibiting arthritis progression might be due to NF-κB /MAPK pathway modulation. OA-DHZ also showed selective inhibition of COX-2 in vitro while showing gastroprotective effects when evaluated for ulcerogenic and antiulcer potential in vivo. In contrast to the results obtained from in vivo experimentation, there is a disparity in the pharmacokinetic profile of OA-DHZ, where it showed low oral exposure and high clearance rate. OA-DHZ being antiarthritic acting via NF-κB /MAPK/ COX inhibition while showing gastroprotective effects, can be a suitable candidate to be in the drug pipeline and further exploration.

Isotopes (δ18O, δD and 3H) variations in groundwater with emphasis on salinization in the state of Punjab, India.

The state of Punjab has a dominant agrarian economy and is considered India's bread basket. However, it is now under the problem of falling agro-economy primarily because of pervasive depletion of groundwater levels and deteriorating groundwater quality in south-west Punjab, but increasing salinity is a major concern. The irrigation requirements of crops are fulfilled by groundwater and canal water but the introduction of canal irrigation has led to waterlogging and subsequent salinization rendering large fertile-land areas becoming unproductive mainly in the south-western part of Punjab. There was an apprehension that excessive withdrawal of groundwater might have caused a reversal of natural groundwater flow pattern that might have caused ingress of saline water into fresh groundwater region of central Punjab. To address the apprehension related to the rise in groundwater salinity and its subsequent ingression in the fresh-water zone and suggest suitable management solutions, a study was undertaken to analyse the data related to salinity, isotopes, land-use and land cover (LULC) along with field and laboratory experimental results. The depth-wise isotope analysis shows that there is a large variation in isotopic signatures of shallow and intermediate aquifers and it decreases with the depth of aquifers (150-250 m). It appears that very deep groundwater (>250 m) is relatively isolated and does not show a large variation or mixing effect. Tritium analysis shows that dynamic groundwater is actively recharged through canal, river, and/or rain. The presence of modern groundwater at deeper depth indicates a good interconnection between shallow and deep groundwater. Interpretations of the results show that the canal is the main source of groundwater recharge in south-west Punjab and the evaporation process is responsible for increasing the salinity hazard. In the central parts of Punjab, groundwater and rain are the main sources of groundwater recharge, while rain is the main source of groundwater recharge in the Kandi area. In the south-west Punjab, some primary salinity has formed as a result of mineral dissolution which has further increased due to evaporative enrichment.

Floodplains landforms, clay deposition and irrigation return flow govern arsenic occurrence, prevalence and mobilization: A geochemical and isotopic study of the mid-Gangetic floodplains.

This article attempts to understand the evolution of groundwater chemistry in the mid Gangetic floodplain through the identification of hydrogeochemical processes including the impact of surface recharge and geological features. Isotopic investigations identified that irrigation return flow is partly responsible for arsenic (As) enrichment through preferential vertical recharge. Further, the floodplain geomorphological attributes and associated As hydrogeochemical behaviour traced through isotopes tracers highlighted that meandering and ox-bow like geomorphological features owing to clay deposition leads to the anoxic condition induced reductive microbial dissolution of As-bearing minerals causing the arsenic contamination in the investigated aquifer of the mid-Gangetic plain (MGP). To achieve the objectives, 146 water samples for water chemistry and 62 samples for the isotopic study were collected from Bhojpur district, Bihar (district bounded by the river Ganges in the north and Son in the east) located in MGP during the pre-monsoon season of 2018. The chemical results revealed high arsenic concentration (BDL to 206 µg.L-1, 32% samples are exceeding the 10 µg.L-1 limit) in the Holocene recent alluviums which are characterized by various geomorphological features such as meander scars and oxbow lake (northern part of the district). Arsenic is more concentrated in the depth range of 15-40 m below ground surface. All other trace metals viz. Ni, Pb, Zn, Cd and Al were found in low concentration except Fe and Mn. The geochemical analyses suggest that rock-water interaction is controlling the hydro-geochemistry while the chemical constituent of the groundwater is mainly controlled by carbonate weathering with limited contribution from silicate weathering. The isotopic signatures revealed that the Son river is recharging groundwater while the groundwater is contributing to the Ganges river. A clear pattern of fast vertical recharge in the arsenic contaminated area is observed in the proximity to the river Ganges with an elevated nitrate concentration resulted from the reduced As dissolution. The origin of groundwater is local precipitation with low to high evaporation enrichment effect which is further indicating the vertical mixing of groundwater from the irrigation return flow and/or recharge from domestic discharge causing enhanced As mobilization through microbial assisted reductive dissolution of As-bearing minerals.

Prenatal stress dysregulates resting-state functional connectivity and sensory motifs.

Prenatal stress (PS) can impact fetal brain structure and function and contribute to higher vulnerability to neurodevelopmental and neuropsychiatric disorders. To understand how PS alters evoked and spontaneous neocortical activity and intrinsic brain functional connectivity, mesoscale voltage imaging was performed in adult C57BL/6NJ mice that had been exposed to auditory stress on gestational days 12-16, the age at which neocortex is developing. PS mice had a four-fold higher basal corticosterone level and reduced amplitude of cortical sensory-evoked responses to visual, auditory, whisker, forelimb, and hindlimb stimuli. Relative to control animals, PS led to a general reduction of resting-state functional connectivity, as well as reduced inter-modular connectivity, enhanced intra-modular connectivity, and altered frequency of auditory and forelimb spontaneous sensory motifs. These resting-state changes resulted in a cortical connectivity pattern featuring disjoint but tight modules and a decline in network efficiency. The findings demonstrate that cortical connectivity is sensitive to PS and exposed offspring may be at risk for adult stress-related neuropsychiatric disorders.

Safranal inhibits NLRP3 inflammasome activation by preventing ASC oligomerization.

NLRP3 inflammasome is involved in several chronic inflammatory diseases. The inflammatory effect of the NLRP3 inflammasome is executed through IL-1ß and IL-18. Therefore, IL-1ß is one of the primary targets in chronic inflammatory conditions. However, current treatment regimens are dependent on anti- IL-1ß biologicals. The therapies targeting IL-1ß through inhibition of NLRP3 inflammasome are thus being actively explored. We identified safranal, a small molecule responsible for the essence of saffron as a potential inhibitor of the NLRP3 inflammasome. Safranal significantly suppressed the release of IL-1ß from ATP stimulated J774A.1 and bone marrow-derived macrophages (BMDMs) by regulating CASP1 and CASP8 dependent cleavage of pro-IL-1ß. Safranal markedly suppressed the expression of NLRP3 and its ATPase activity. Safranal treatment enhanced the expression of NRF2, whereas, si-RNA mediated silencing of Nrf2 abrogated the anti-NLRP3 effect of safranal. Furthermore, safranal inhibited ASC oligomerization and formation of ASC specks. Safranal also displayed anti-NLRP3 activity in multiple mice models. Treatment of animals with safranal reduced the production of IL-1ß in ATP elicited peritoneal inflammation, MSU induced air pouch inflammation, and MSU injected foot paw edema in mice. Thus, our data projects safranal as a potential preclinical drug candidate against NLRP3 inflammasome triggered chronic inflammation.

Gut microbiome-mediated epigenetic regulation of brain disorder and application of machine learning for multi-omics data analysis.

The gut-brain axis (GBA) is a biochemical link that connects the central nervous system (CNS) and enteric nervous system (ENS). Clinical and experimental evidence suggests gut microbiota as a key regulator of the GBA. Microbes living in the gut not only interact locally with intestinal cells and the ENS but have also been found to modulate the CNS through neuroendocrine and metabolic pathways. Studies have also explored the involvement of gut microbiota dysbiosis in depression, anxiety, autism, stroke, and pathophysiology of other neurodegenerative diseases. Recent reports suggest that microbe-derived metabolites can influence host metabolism by acting as epigenetic regulators. Butyrate, an intestinal bacterial metabolite, is a known histone deacetylase inhibitor that has shown to improve learning and memory in animal models. Due to high disease variability amongst the population, a multi-omics approach that utilizes artificial intelligence and machine learning to analyze and integrate omics data is necessary to better understand the role of the GBA in pathogenesis of neurological disorders, to generate predictive models, and to develop precise and personalized therapeutics. This review examines our current understanding of epigenetic regulation of the GBA and proposes a framework to integrate multi-omics data for prediction, prevention, and development of precision health approaches to treat brain disorders.

Effects of Probiotic Supplementation on Short Chain Fatty Acids in the AppNL-G-F Mouse Model of Alzheimer's Disease.

BACKGROUND: The intestinal microbiota and its metabolites, particularly short-chain fatty acids (SCFAs), have been implicated in immune function, host metabolism, and even behavior. OBJECTIVE: This study was performed to investigate whether probiotic administration influences levels of intestinal microbiota and their metabolites in a fashion that may attenuate brain changes in a mouse model of Alzheimer's disease (AD). METHODS: C57BL/6 wild-type (WT) mice were compared to AppNL-G-Fmice. The animals were treated with either vehicle or probiotic (VSL#3) for 8 weeks. Fecal microbiome analysis along with Aß, GFAP, Iba-1, c-Fos, and Ki-67 immunohistochemistry was done. SCFAs were analyzed in serum and brains using UPLC-MS/MS. RESULTS: Probiotic (VSL#3) supplementation for 2 months resulted in altered microbiota in both WT and AppNL-G-Fmice. An increase in serum SCFAs acetate, butyrate, and lactate were found in both genotypes following VSL#3 treatment. Propionate and isobutyrate were only increased in AppNL-G-Fmice. Surprisingly, VSL#3 only increased lactate and acetate in brains of AppNL-G-Fmice. No significant differences were observed between vehicle and VSL#3 fed AppNL-G-Fhippocampal immunoreactivities of Aß, GFAP, Iba-1, and Ki-67. However, hippocampal c-Fos staining increased in VSL#3 fed AppNL-G-Fmice. CONCLUSION: These data demonstrate intestinal dysbiosis in the AppNL-G-Fmouse model of AD. Probiotic VSL#3 feeding altered both serum and brain levels of lactate and acetate in AppNL-G-Fmice correlating with increased expression of the neuronal activity marker, c-Fos.