Reference Memory Research Articles

Class 1 histone deacetylases differentially modulate memory and synaptic genes in a spatial and temporal manner in aged and APP/PS1 mice

Epigenetics plays a vital role in aging and Alzheimer’s disease (AD); however, whether epigenetic alterations during aging can initiate AD and exacerbate AD progression remains unclear. In this study, using 3-, 12- and 18- month-old APP/PS1 mice and age matched WT littermates, we conducted a series of memory tests, measured synapse-related gene expression, class 1 histone deacetylases (HDACs) abundance, and H3K9ac levels at target gene promoters in the hippocampus and prefrontal cortex (PFC). Our results showed impaired recognition and long-term spatial memory in 18-month-old WT mice and impaired recognition, short-term working, and long-term spatial reference memory in 12-and 18- month-old APP/PS1 mice. These memory impairments are associated with changes of synapse-related gene (nr2a, glur1, glur2, psd95) expression, HDAC abundance, and H3K9ac levels; more specifically, increased HDAC2 was associated with synapse-related gene expression changes through modulation of H3K9ac at the gene promoters during aging and AD progression in the hippocampus. Conversely, increased HDAC3 was associated with synapse-related gene expression changes through modulation of H3K9ac at the gene promoters during AD progression in the PFC. These findings suggest memory impairments in aging and AD may associated with a differential HDAC modulation of synapse-related gene expression in the brain.

Hippocampal cholecystokinin-expressing interneurons regulate temporal coding and contextual learning

Cholecystokinin-expressing interneurons (CCKIs) are hypothesized to shape pyramidal cell-firing patterns and regulate network oscillations and related network state transitions. To directly probe their role in the CA1 region, we silenced their activity using optogenetic and chemogenetic tools in mice. Opto-tagged CCKIs revealed a heterogeneous population, and their optogenetic silencing triggered wide disinhibitory network changes affecting both pyramidal cells and other interneurons. CCKI silencing enhanced pyramidal cell burst firing and altered the temporal coding of place cells: theta phase precession was disrupted, whereas sequence reactivation was enhanced. Chemogenetic CCKI silencing did not alter the acquisition of spatial reference memories on the Morris water maze but enhanced the recall of contextual fear memories and enabled selective recall when similar environments were tested. This work suggests the key involvement of CCKIs in the control of place-cell temporal coding and the formation of contextual memories.

Digestive and Absorptive Properties of the Antarctic Krill Tripeptide Phe-Pro-Phe (FPF) and Its Auxiliary Memory-Enhancing Effect.

Aging and stress have contributed to the development of memory disorders. Phe-Pro-Phe (FPF) was identified with high stability by mass spectrometry from simulated gastrointestinal digestion and everted gut sac products of the Antarctic krill peptide Ser-Ser-Asp-Ala-Phe-Phe-Pro-Phe-Arg (SSDAFFPFR) which was found to have a positive impact on memory enhancement. This study investigated the digestive stability, absorption, and memory-enhancing effects of FPF using nuclear magnetic resonance spectroscopy, simulated gastrointestinal digestion, in vivo fluorescence distribution analysis, mouse behavioral experiments, acetylcholine function, Nissl staining, immunofluorescence, and immunohistochemistry. FPF crossed the blood-brain barrier into the brain after digestion, significantly reduced shock time, working memory errors, and reference memory errors, and increased the recognition index. Additionally, FPF elevated ACh content; Nissl body counts; and CREB, SYN, and PSD-95 expression levels, while reducing AChE activity (P < 0.05). This implies that FPF prevents scopolamine-induced memory impairment and provides a basis for future research on memory disorders.

Cognitive decline, Aβ pathology, and blood–brain barrier function in aged 5xFAD mice

BackgroundPatients with Alzheimer's disease (AD) develop blood–brain barrier dysfunction to varying degrees. How aging impacts Aβ pathology, blood–brain barrier function, and cognitive decline in AD remains largely unknown. In this study, we used 5xFAD mice to investigate changes in Aβ levels, barrier function, and cognitive decline over time.Methods5xFAD and wild-type (WT) mice were aged between 9.5 and 15.5 months and tested for spatial learning and reference memory with the Morris Water Maze (MWM). After behavior testing, mice were implanted with acute cranial windows and intravenously injected with fluorescent-labeled dextrans to assess their in vivo distribution in the brain by two-photon microscopy. Images were processed and segmented to obtain intravascular intensity, extravascular intensity, and vessel diameters as a measure of barrier integrity. Mice were sacrificed after in vivo imaging to isolate brain and plasma for measuring Aβ levels. The effect of age and genotype were evaluated for each assay using generalized or cumulative-linked logistic mixed-level modeling and model selection by Akaike Information Criterion (AICc). Pairwise comparisons were used to identify outcome differences between the two groups.Results5xFAD mice displayed spatial memory deficits compared to age-matched WT mice in the MWM assay, which worsened with age. Memory impairment was evident in 5xFAD mice by 2–threefold higher escape latencies, twofold greater cumulative distances until they reach the platform, and twice as frequent use of repetitive search strategies in the pool when compared with age-matched WT mice. Presence of the rd1 allele worsened MWM performance in 5xFAD mice at all ages but did not alter the rate of learning or probe trial outcomes. 9.5-month-old 15.5-month-old 5xFAD mice had twofold higher brain Aβ40 and Aβ42 levels (p < 0.001) and 2.5-fold higher (p = 0.007) plasma Aβ40 levels compared to 9.5-month-old 5xFAD mice. Image analysis showed that vessel diameters and intra- and extravascular dextran intensities were not significantly different in 9.5- and 15.5-month-old 5xFAD mice compared to age-matched WT mice.Conclusion5xFAD mice continue to develop spatial memory deficits and increased Aβ brain levels while aging. Given in vivo MP imaging limitations, further investigation with smaller molecular weight markers combined with advanced imaging techniques would be needed to reliably assess subtle differences in barrier integrity in aged mice.

Tianma-Gouteng pair ameliorates the cognitive deficits on two transgenic mouse models of Alzheimer's disease

Ethnopharmacological relevanceAlzheimer's disease (AD) is a progressive neurodegenerative disease. Tianma-Gouteng Pair (TGP), commonly prescribed as a pair-herbs, can be found in many Chinese medicine formulae to treat brain diseases. However, the neuroprotective effects and molecular mechanisms of TGP remained unexplored. Aim of the studyThis study investigated the difference between the TgCRND8 and 5 × FAD transgenic mice, the anti-AD effects of TGP, and underlying molecular mechanisms of TGP against AD through the two mouse models. MethodsBriefly, three-month-old TgCRND8 and 5 × FAD mice were orally administered with TGP for 4 and 6 months, respectively. Behavioral tests were carried out to determine the neuropsychological functions. Moreover, immunofluorescence and western blotting assays were undertaken to reveal the molecular mechanisms of TGP. ResultsAlthough TgCRND8 and 5 × FAD mice had different beta-amyloid (Aβ) burdens, neuroinflammation status, and cognition impairments, TGP exerted neuroprotective effects against AD in the two models. In detail, behavioral tests revealed that TGP treatment markedly ameliorated the anxiety-like behavior, attenuated the recognition memory deficits, and increased the spatial learning ability as well as the reference memory of TgCRND8 and 5 × FAD mice. Moreover, TGP treatment could regulate the beta-amyloid precursor protein (APP) processing by inhibiting the Aβ production enzymes such as β- and γ-secretases and activating Aβ degrading enzyme to reduce Aβ accumulation. In addition, TGP reduced the Aβ42 level, the ratio of Aβ42/Αβ40, Aβ accumulation, and tau hyperphosphorylation in both the 5 × FAD and TgCRND8 mouse models. Furthermore, TGP ameliorated neuroinflammation by decreasing the densities of activated microglia and astrocytes, and inhibiting the production of inflammatory cytokines. TGP upregulated the SIRT1 and AMPK, and downregulated sterol response element binding protein 2 (SREBP2) in the brain of TgCRND8 mice and deactivation of the EPhA4 and c-Abl in the brain tissues of 5 × FAD mice. ConclusionOur experiments for the first time revealed the neuroprotective effects and molecular mechanism of TGP on 5 × FAD and TgCRND8 transgenic mouse models of different AD stages. TGP decreased the level of Aβ aggregates, improved the tauopathy, and reduced the neuroinflammation by regulation of the SIRT1/AMPK/SREBP2 axis and deactivation of EPhA4/c-Abl signaling pathway in the brains of TgCRND8 and 5 × FAD mice, respectively. All these findings unequivocally confirmed that the TGP would be promising in developing into an anti-AD therapeutic pharmaceutical.

Letrozole delays acquisition of water maze task in female BALB/c mice: Possible involvement of anxiety

Letrozole, an aromatase inhibitor preventing estrogen synthesis from testosterone, is used as an adjuvant therapy in estrogen receptor-positive breast cancer patients. However, like other aromatase inhibitors, it induces many side effects, including impaired cognition. Despite its negative effect in humans, results from animal models are inconsistent and suggest that letrozole can either impair or improve cognition. Here, we studied the effects of chronic letrozole treatment on cognitive behavior of adult female BALB/c mice, a relevant animal model for breast cancer studies, to develop an appropriate animal model aimed at testing therapies to mitigate side effects of letrozole. In Morris water maze, letrozole 0.1 mg/kg impaired reference learning and memory. Interestingly, most of the letrozole 0.1 mg/kg-treated mice were able to learn the new platform position in reversal training and performed similar to control mice in a reversal probe test. Results of the reversal test suggest that letrozole did not completely disrupt spatial navigation, but rather delayed acquisition of spatial information. The delay might be related to increased anxiety as suggested by increased thigmotactic behavior during the reference memory training. The learning impairment was water maze-specific since we did not observe impairment in other spatial tasks such as in Y-maze or object location test. In contrast, the dose of 0.3 mg/kg did not have effect on water maze learning and facilitated locomotor habituation and recognition in novel object recognition test. The current study shows that letrozole dose-dependently modulates behavioral response and that its effects are task-dependent.

Differential contribution of canonical and noncanonical NLGN3 pathways to early social development and memory performance

Neuroligin (NLGN) 3 is a postsynaptic cell adhesion protein organizing synapse formation through two different types of transsynaptic interactions, canonical interaction with neurexins (NRXNs) and a recently identified noncanonical interaction with protein tyrosine phosphatase (PTP) δ. Although, NLGN3 gene is known as a risk gene for neurodevelopmental disorders such as autism spectrum disorder (ASD) and intellectual disability (ID), the pathogenic contribution of the canonical NLGN3-NRXN and noncanonical NLGN3-PTPδ pathways to these disorders remains elusive. In this study, we utilized Nlgn3 mutant mice selectively lacking the interaction with either NRXNs or PTPδ and investigated their social and memory performance. Neither Nlgn3 mutants showed any social cognitive deficiency in the social novelty recognition test. However, the Nlgn3 mutant mice lacking the PTPδ pathway exhibited significant decline in the social conditioned place preference (sCPP) at the juvenile stage, suggesting the involvement of the NLGN3-PTPδ pathway in the regulation of social motivation and reward. In terms of learning and memory, disrupting the canonical NRXN pathway attenuated contextual fear conditioning while disrupting the noncanonical NLGN3-PTPδ pathway enhanced it. Furthermore, disruption of the NLGN3-PTPδ pathway negatively affected the remote spatial reference memory in the Barnes maze test. These findings highlight the differential contributions of the canonical NLGN3-NRXN and noncanonical NLGN3-PTPδ synaptogenic pathways to the regulation of higher order brain functions associated with ASD and ID.

Effect of thymol on oxidative stress and reelin signaling pathway in Alzheimer's disease model.

The purpose of this study was to investigate how thymol affects cognitive functions and the levels of MDA, GSH, Aβ1-42, ApoE, reelin, and LRP8 in an AD model induced in male Wistar albino rats with the application of D-galactose (D-gal) and aluminum chloride (AlCl3). In this work, 3-month-old male Wistar albino rats were used. Group 1 served as the Control, Group 2 received 0.5 mL/day saline + 0.5 mL/day sunflower oil, Group 3 was administered 200 mg/kg/day AlCl3 + 60 mg/kg/day D-gal, Group 4 received 30 mg/kg/day thymol, and Group 5 was administered 200 mg/kg/day AlCl3 + 60 mg/kg/day D-gal + 30 mg/kg/day thymol. At the end of the 10-week experimental period, behavioral and memory tests were performed. GSH and MDA levels were measured in the obtained serum and brain tissue samples, while Aβ1-42, ApoE, reelin, and LRP8 levels were measured in brain tissue samples. Statistical analyses were performed using ANOVA test in Graphpad Prism V8.3 program. A p-value <0.05 was considered significant in intergroup analyses. When the novel object recognition test (NORT) results were evaluated, the Alzheimer + thymol (ALZ+TYM) group showed a significant increase in the recognition index (RI) and discrimination index (DI) compared to the Alzheimer (ALZ) group at the 24th hour. Thymol reduced working memory errors (WME), reference memory errors (RME), and maze completion time at 48, 72, and 96 hours when evaluated in terms of spatial memory in rats with Alzheimer's disease. Furthermore, Aβ1-42 and ApoE levels were increased in the ALZ group compared to the control (C), while reelin and LRP8 levels were decreased in the ALZ group compared to the C group. The data we obtained suggest that thymol may play an effective role in cognitive processes against AD and have an anti-Alzheimer's disease effect.

Metabolic dysfunction induced by HFD + L-NAME preferentially affects hippocampal mitochondria, impacting spatial memory in rats.

High-fat diet-induced metabolic changes are not restricted to the onset of cardiovascular diseases, but also include effects on brain functions related to learning and memory. This study aimed to evaluate mitochondrial markers and function, as well as cognitive function, in a rat model of metabolic dysfunction. Eight-week-old male Wistar rats were subjected to either a control diet or a two-hit protocol combining a high fat diet (HFD) with the nitric oxide synthase inhibitor L-NAME in the drinking water. HFD plus L-NAME induced obesity, hypertension, and increased serum cholesterol. These rats exhibited bioenergetic dysfunction in the hippocampus, characterized by decreased oxygen (O2) consumption related to ATP production, with no changes in H2O2 production. Furthermore, OPA1 protein expression was upregulated in the hippocampus of HFD + L-NAME rats, with no alterations in other morphology-related proteins. Consistently, HFD + L-NAME rats showed disruption of performance in the Morris Water Maze Reference Memory test. The neocortex did not exhibit either bioenergetic changes or alterations in H2O2 production. Calcium uptake rate and retention capacity in the neocortex of HFD + L-NAME rats were not altered. Our results indicate that hippocampal mitochondrial bioenergetic function is disturbed in rats exposed to a HFD plus L-NAME, thus disrupting spatial learning, whereas neocortical function remains unaffected.

Neurotrophin-3 from the dentate gyrus supports postsynaptic sites of mossy fiber-CA3 synapses and hippocampus-dependent cognitive functions.

At the center of the hippocampal tri-synaptic loop are synapses formed between mossy fiber (MF) terminals from granule cells in the dentate gyrus (DG) and proximal dendrites of CA3 pyramidal neurons. However, the molecular mechanism regulating the development and function of these synapses is poorly understood. In this study, we showed that neurotrophin-3 (NT3) was expressed in nearly all mature granule cells but not CA3 cells. We selectively deleted the NT3-encoding Ntf3 gene in the DG during the first two postnatal weeks to generate a Ntf3 conditional knockout (Ntf3-cKO). Ntf3-cKO mice of both sexes had normal hippocampal cytoarchitecture but displayed impairments in contextual memory, spatial reference memory, and nest building. Furthermore, male Ntf3-cKO mice exhibited anxiety-like behaviors, whereas female Ntf3-cKO showed some mild depressive symptoms. As MF-CA3 synapses are essential for encoding of contextual memory, we examined synaptic transmission at these synapses using ex vivo electrophysiological recordings. We found that Ntf3-cKO mice had impaired basal synaptic transmission due to deficits in excitatory postsynaptic currents mediated by AMPA receptors but normal presynaptic function and intrinsic excitability of CA3 pyramidal neurons. Consistent with this selective postsynaptic deficit, Ntf3-cKO mice had fewer and smaller thorny excrescences on proximal apical dendrites of CA3 neurons and lower GluR1 levels in the stratum lucidum area where MF-CA3 synapses reside but normal MF terminals, compared with control mice. Thus, our study indicates that NT3 expressed in the dentate gyrus is crucial for the postsynaptic structure and function of MF-CA3 synapses and hippocampal-dependent memory.

Trim46 knockout impaired neuronal architecture and caused hypoactive behavior in rats.

Tripartite motif (TRIM46) is a relatively novel protein that belongs to tripartite motif family. TRIM46 organizes parallel microtubule arrays on the axons, which are important for neuronal polarity and axonal function. TRIM46 is highly expressed in the brain, but its biological function in adults has not yet been determined. Trim46 knockout (KO) rat line was established using CRISPR/cas9. Trim46 KO rats had smaller hippocampus sizes, fewer neuronal dendritic arbors and dendritic spines, and shorter and more distant axon initial segment. Furthermore, the protein interaction between endogenous TRIM46 and FK506 binding protein 5 (FKBP5) in brain tissues was determined; Trim46 KO increased hippocampal FKBP5 protein levels and decreased hippocampal protein kinase B (Akt) phosphorylation, gamma-aminobutyric acid type A receptor subunit alpha1 (GABRA1) and glutamate ionotropic receptor NMDA type subunit 1 (NMDAR1) protein levels. Trim46 KO rats exhibited hypoactive behavioral changes such as reduced spontaneous activity, social interaction, sucrose preference, impaired prepulse inhibition (PPI), and short-term reference memory. These results demonstrate the significant impact of Trim46 KO on brain structure and behavioral function. This study revealed a novel potential association of TRIM46 with dendritic development and neuropsychiatric behavior, providing new insights into the role of TRIM46 in the brain.

Maze-Based Scalable Wireless Power Transmission Experimental Arena for Freely Moving Small Animals Applications.

This paper presents an innovative T/Y-maze-based wireless power transmission (WPT) system designed to monitor spatial reference memory and learning behavior in freely moving rats. The system facilitates uninterrupted optical/electrical stimulation and neural recording experiments through the integration of wireless headstages or implants in T/Y maze setups. Utilizing an array of resonators covering the entire underneath of the mazes, the wireless platform ensures scalability with various configurations. The array is designed to ensure a natural localization mechanism to localize the Tx power toward the location of the Rx coil. The system is analyzed and modeled using ANSYS HFSS software to optimize design. The primary goal was to achieve uniform wireless power delivery throughout the mazes through a comparative study of different transmitter (Tx) array configurations, such as float, series, and parallel resonators. The calculated Specific Absorption Rate (SAR) in rat tissue model equals 1.7 W/kg at the power carrier frequency of 13.56 MHz. A prototype of the proposed maze-based WPT design, featuring 8 Tx resonators, a Tx coil and power amplifier, and a headstage power harvesting unit, is successfully implemented and its performance characterized for all three resonator configurations. The implemented T maze-based WPT system has a total length of 128 cm. In the overlapping Tx resonators configuration, a homogeneity of 94% is achieved for the measured power transfer efficiency at over 30%, while continuously delivering over 60 mW for series configuration.

Brain-enriched guanylate kinase-associated protein, a component of the post-synaptic density protein complexes, contributes to learning and memory

Brain-enriched guanylate kinase-associated protein (BEGAIN) is highly enriched in the post-synaptic density (PSD) fraction and was identified in our previous study as a protein associated with neuropathic pain in the spinal dorsal horn. PSD protein complexes containing N-methyl-d-aspartate receptors are known to be involved in neuropathic pain. Since these PSD proteins also participate in learning and memory, BEGAIN is also expected to play a crucial role in this behavior. To verify this, we first examined the distribution of BEGAIN in the brain. We found that BEGAIN was widely distributed in the brain and highly expressed in the dendritic regions of the hippocampus. Moreover, we found that BEGAIN was concentrated in the PSD fraction of the hippocampus. Furthermore, immunoelectron microscopy confirmed that BEGAIN was localized at the asymmetric synapses. Behavioral tests were performed using BEGAIN-knockout (KO) mice to determine the contribution of BEGAIN toward learning and memory. Spatial reference memory and reversal learning in the Barns circular maze test along with contextual fear and cued fear memory in the contextual and cued fear conditioning test were significantly impaired in BEGAIN-KO mice compared to with those in wild-type mice. Thus, this study reveals that BEGAIN is a component of the post-synaptic compartment of excitatory synapses involved in learning and memory.

Sex-specific variations in spatial reference memory acquisition: Insights from a comprehensive behavioral test battery in C57BL/6JRj mice

Sex differences in declarative memory are described in humans, revealing a female or a male advantage depending on the task. Specifically, spatial memory (i.e., spatial navigation) is typically most efficient in men. This sexual dimorphism has been replicated in male rats but not clearly in mice. In this study, sex differences in spatial memory were assessed in thirty-six C57BL/6 J mice (Janvier Labs; i.e., C57BL/6JRj mice), a widely used mouse substrain. Both male and female mice (12 weeks-old) were subjected to standard behavioral paradigms: the elevated plus maze, the open field test, the novel object and place tests, the forced swimming test, and the water maze test for spatial navigation. Across assessment, no sex differences were found in measures of locomotor activity, emotional and behavioral responses, and object and place recognition memories. In the water maze, male mice were faster in learning the platform location in the reference memory training and used more spatial strategies during the first training days. However, both sexes reached a similar asymptotic performance and performed similarly in the probe trial for long-term memory consolidation. No sex differences were found in the cued training, platform inversion sessions, or spatial working memory sessions. Hippocampal expression of the brain-derived neurotrophic factor was similar in both sexes, either in basal conditions or after performing the behavioral training battery. Importantly, female mice were not more variable than males in any measure analyzed. This outcome encourages the investigation of sex differences in animal models and the usefulness of including female mice in behavioral research.

Utilization of the novel adeno‐associated virus PHP.eB serotype to modulate Intersectin 1 expression in the Ts65Dn mouse model of Down syndrome

AbstractBackgroundDown Syndrome (DS) and Alzheimer’s disease (AD) include cholinergic neurodegeneration which parallels cognitive decline. Triplicated genes in DS are thought to play a role in basal forebrain cholinergic neuron (BFCN) pathology; one avenue to assess triplicated genes’ role is to normalize their expression in DS mouse models by stereotaxic injection of adeno‐associated viruses (AAVs) carrying silencing constructs such as single hairpin mRNA (shRNA). However, stereotaxic surgeries have drawbacks particularly when targeting areas lying deep within the brain. The introduction of the AAV‐PHP.eB serotype, which can cross the blood‐brain‐barrier when introduced into peripheral vasculature, has been shown to vary in efficiency depending on mouse background. Here, we investigated tropism of the AAV‐PHP.eB serotype in the Ts65Dn mouse, the most commonly used DS mouse model. We then used AAV‐PHP.eB to assess our ability to globally modulate expression of intersectin 1 (ITSN1), a protein triplicated in DS that may relate to BFCN dysfunction and memory impairments.MethodsWe retro‐orbitally injected N = 16 4‐4.5 month‐old male mice, (C57Bl, Ts65Dn trisomic and normosomic) with AAV‐PHP.eB‐CamKII‐GFP‐scrmble‐shRNA, to assess tropism and optimize virus concentration (2, 5, and 10µL). Four weeks post injection we imaged for GFP expression in 50µm coronal sections. To knock down ITSN1 globally, we injected N = 58 Ts65Dn mice (3 months, balanced by sex, genotype, virus) with either 5μl AAV‐PHP.eB‐U6‐scrmble‐GFP (control) or AAV‐PHP.eB‐U6‐shITSN1‐GFP (ITSN1); mice were behaviorally tested at 7 months and euthanized at 8 months followed by tissue collection.ResultsMice injected with AAV‐PHP.eB‐CamKII‐GFP‐scrmble‐shRNA showed GFP expression 4 weeks following injection, with robust expression visible with 5µL virus. Mice subsequently injected with control and ITSN1 AAVs showed significant effects of ITSN1 knockdown, including increased tremors, increased latency in the radial arm water maze – suggesting impaired spatial reference learning and memory – decreased brain weight, and altered weight change.ConclusionThe AAV‐PHP.eB serotype shows successful CNS tropism in the Ts65Dn mouse model, with 5µL of AAV providing the best efficiency throughout key brain regions affected in DS and AD. Furthermore, the AAV‐PHP.eB serotype can be used to modulate expression of genes triplicated in DS to investigate their mechanistic role in neurodegeneration both molecularly and behaviorally.

Class 1 HDACs Modulate Synapse‐Related Genes in Mouse Models of Aging and Alzheimer’s Disease

AbstractBackgroundStudies have demonstrated that epigenetics plays an important role in both aging and Alzheimer’s disease (AD) pathogenesis, however, whether epigenetic dysregulation during aging can initiate AD development and/or exacerbate AD progression remains unclear. Given aging is the major risk factor of AD, it is critical to determine the epigenetic alterations occurring during aging and how these changes influence AD pathogenesis.MethodsIn this study, 3, 12, and 18‐month‐old APP/PS1 mice and WT littermates were used for a series of behavioral tests to evaluate and compare different memory domains, including recognition, short‐term working, and long‐term spatial reference memory in aging and AD progression. After behavioral testing, the hippocampus and prefrontal cortex (PFC) were collected for biochemical assessment to determine the dynamic changes of class 1 HDACs globally and at gene promoters that are associated with synaptic structure and function, namely Nr2a, GluR1 Glur2, and Psd95. Additionally, synaptic gene expression and H3K9ac levels at the gene promoters were evaluated during aging and AD progression.ResultsOur results showed that recognition and short‐term working memory declined in WT mice only at 18 months of age, but significantly declined in the three memory domains of APP/PS1 mice at both 12 and 18 months of age. Moreover, 18 months of age APP/PS1 mice showed exacerbated recognition and spatial working memory deficits. We also found HDACs modulate the synaptic‐related genes in a genotype and regional manner. More specifically, HDAC 2 modulated synaptic gene expression through dysregulations of H3K9ac levels at the gene promoters in the hippocampus during aging and AD progression. While HDAC 3 modulated synaptic gene expression through dysregulations of H3K9ac levels at gene promoters in the prefrontal cortex during AD progression. The dynamic changes of HDACs and H3K9ac levels during aging and AD progression are associated with specific declines in memory.ConclusionOur findings suggest a potential differential HDAC modulation of synaptic gene expression in aging and AD progression, which impacts the decline of different memory domains. Future work will confirm our findings and will begin using genetic manipulation approaches to dissect individual class 1 HDAC contributions to aging and/or AD progression in the hippocampus and PFC.

The Effect of Fat Intake with Increased Omega-6-to-Omega-3 Polyunsaturated Fatty Acid Ratio in Animal Models of Early and Late Alzheimer’s Disease-like Pathogenesis

This work aims to clarify the effect of dietary polyunsaturated fatty acid (PUFA) intake on the adult brain affected by amyloid pathology. McGill-R-Thy1-APP transgenic (Tg) rat and 5xFAD Tg mouse models that represent earlier or later disease stages were employed. The animals were exposed to a control diet (CD) or an HFD based on corn oil, from young (rats) or adult (mice) ages for 24 or 10 weeks, respectively. In rats and mice, the HFD impaired reference memory in wild-type (WT) animals but did not worsen it in Tg, did not cause obesity, and did not increase triglycerides or glucose levels. Conversely, the HFD promoted stronger microglial activation in Tg vs. WT rats but had no effect on cerebral amyloid deposition. IFN-γ, IL-1β, and IL-6 plasma levels were increased in Tg rats, regardless of diet, while CXCL1 chemokine levels were increased in HFD-fed mice, regardless of genotype. Hippocampal 3-nitrotyrosine levels tended to increase in HFD-fed Tg rats but not in mice. Overall, an HFD with an elevated omega-6-to-omega-3 ratio as compared to the CD (25:1 vs. 8.4:1) did not aggravate the outcome of AD regardless of the stage of amyloid pathology, suggesting that many neurobiological processes relevant to AD are not directly dependent on PUFA intake.

Engraftment of aging-related human gut microbiota and the effect of a seven-species consortium in a pre-clinical model

ABSTRACT Human aging is characterized by gut microbiome alteration and differential loss of gut commensal species associated with the onset of frailty. The administration of cultured commensal strains to replenish lost taxa could potentially promote healthy aging. To investigate the interaction of whole microbiomes and administered strains, we transplanted gut microbiota from a frail or healthy elderly subject into germ-free mice. We supplemented the frail-donor recipient group with a defined consortium of taxa (the “S7”) that we identified by analyzing healthy aging subjects in our previous studies and whose abundance correlated with health-promoting dietary intervention. Inoculation with a frail or a healthy donor microbiome resulted in differential microbiota compositions in murine recipients 5 weeks post-transplantation. Fecal acetate levels were significantly higher in healthy donor recipient mice than in frail donor recipient mice after 4 weeks. However, the frailty-related phenotype was not replicated in recipient mice with single-dose microbiota transplantation from a healthy and a frail donor. Five S7 species colonized successfully in germ-free mice, with a relatively high abundance of Barnesiella intestinihominis and Eubacterium rectale. The engraftment of five S7 species in germ-free mice increased fecal acetate levels and reduced colon permeability and plasma TNF-ɑ concentration. Supplementation with the S7 in frail-microbiota recipient mice did not increase alpha-diversity but significantly increased the abundance of Barnesiella intestinihominis. S7 supplementation showed the potential for improving spatial reference memory in frail-microbiota recipient mice. Collectively, these data highlight the challenge of elderly microbiota engraftment in the germ-free mouse model but show promise for modulating the gut microbiome of frail elderly subjects by administering an artificial gut microbe consortium associated with healthy aging.

Hyperbaric Oxygen Therapy Alleviates Memory and Motor Impairments Following Traumatic Brain Injury via the Modulation of Mitochondrial-Dysfunction-Induced Neuronal Apoptosis in Rats.

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality in young adults, characterized by primary and secondary injury. Primary injury is the immediate mechanical damage, while secondary injury results from delayed neuronal death, often linked to mitochondrial damage accumulation. Hyperbaric oxygen therapy (HBOT) has been proposed as a potential treatment for modulating secondary post-traumatic neuronal death. However, the specific molecular mechanism by which HBOT modulates secondary brain damage through mitochondrial protection remains unclear. Spatial learning, reference memory, and motor performance were measured in rats before and after Controlled Cortical Impact (CCI) injury. The HBOT (2.5 ATA) was performed 4 h following the CCI and twice daily (12 h intervals) for four consecutive days. Mitochondrial functions were assessed via high-resolution respirometry on day 5 following CCI. Moreover, IHC was performed at the end of the experiment to evaluate cortical apoptosis, neuronal survival, and glial activation. The current result indicates that HBOT exhibits a multi-level neuroprotective effect. Thus, we found that HBOT prevents cortical neuronal loss, reduces the apoptosis marker (cleaved-Caspase3), and modulates glial cell proliferation. Furthermore, HBO treatment prevents the reduction in mitochondrial respiration, including non-phosphorylation state, oxidative phosphorylation, and electron transfer capacity. Additionally, a superior motor and spatial learning performance level was observed in the CCI group treated with HBO compared to the CCI group. In conclusion, our findings demonstrate that HBOT during the critical period following the TBI improves cognitive and motor damage via regulating glial proliferation apoptosis and protecting mitochondrial function, consequently preventing cortex neuronal loss.

Intermittent working memory training during adulthood protects against age-related long-term spatial reference memory decline in rats.

Engagement in cognitive activity in adulthood is one of the factors that enable successful cognitive aging, both in humans and rodents. However, some studies emphasize that the beneficial effect on cognition of such an activity may reflect carry over from one test situation to another, including memory for procedural aspects of the behavioral tasks, and thus question whether this effect can be limited to the trained cognitive domain or whether it can be transferred to an untrained ones. In the current study, we assessed whether adulthood intermittent working memory training has beneficial effect on long-term memory of aged rats using two very different test situations. To this aim, rats trained in a delayed non-matching to position task in operant box at 3 and 15months of age were tested in a place learning task in water maze when they were 24months. The two tasks differ with regard to the cognitive domain but also in their spatial ability requirement and the nature of the reinforcer used. During the memory tests, accuracy of the platform search indicated age-related impairment only in the aged-untrained group. Thus, intermittent training during adult life in a task involving working memory protects aged animals from the deleterious effects of aging on spatial reference memory. This result highlights the long-term beneficial effects of training on a working memory task on an untrained cognitive domain.