Hippocampal Morphology Research Articles

Evaluation of sea cucumber peptides-assisted memory activity and acetylation modification in hippocampus of test mice based on scopolamine-induced experimental animal model of memory disorder

To investigate the dose-effect relationship of sea cucumber peptides on memory function improvement, animal experiments, behavioral experiments, ACh content, AChE activity, hippocampal morphology, and protein modifications were detected. Sea cucumber peptides (650 mg/kg, 1300 mg/kg, 2600 mg/kg body weight) and piracetam (400 mg/kg) were gavaged into the mice. Scopolamine (5 mg/kg) were administered intraperitoneally to mice. In behavioral experiments, the escape latency and the shocked time of sea cucumber peptides (SCP) groups were significantly reduced (P < 0.05). Determination of biochemical indicators found that ACh content and AChE activity of SCP groups were increased (P < 0.05). The number of neurons in the hippocampus of SCP groups were larger, arranged neatly and intact. The histone acetyltransferases activity of SCP groups may be lower than that of the Scopolamine group, so the acetylation level is down-regulated and approached to dynamic equilibrium, thereby the memory activity of mice was improved.

Impact of JNK and Its Substrates on Dendritic Spine Morphology.

The protein kinase JNK1 exhibits high activity in the developing brain, where it regulates dendrite morphology through the phosphorylation of cytoskeletal regulatory proteins. JNK1 also phosphorylates dendritic spine proteins, and Jnk1-/- mice display a long-term depression deficit. Whether JNK1 or other JNKs regulate spine morphology is thus of interest. Here, we characterize dendritic spine morphology in hippocampus of mice lacking Jnk1-/- using Lucifer yellow labelling. We find that mushroom spines decrease and thin spines increase in apical dendrites of CA3 pyramidal neurons with no spine changes in basal dendrites or in CA1. Consistent with this spine deficit, Jnk1-/- mice display impaired acquisition learning in the Morris water maze. In hippocampal cultures, we show that cytosolic but not nuclear JNK, regulates spine morphology and expression of phosphomimicry variants of JNK substrates doublecortin (DCX) or myristoylated alanine-rich C kinase substrate-like protein-1 (MARCKSL1), rescue mushroom, thin, and stubby spines differentially. These data suggest that physiologically active JNK controls the equilibrium between mushroom, thin, and stubby spines via phosphorylation of distinct substrates.

Astrocyte signaling impacts the effects of human bone marrow mesenchymal stem cells secretome application into the hippocampus: A proliferation and morphometrical analysis on astrocytic cell populations

The central nervous system (CNS) has a limited auto-regeneration capacity, which makes it challenging for the development of new therapies. Previous studies from our lab have demonstrated the applicability of human bone marrow mesenchymal stem cells (hBM-MSCs) secretome as a possible therapeutic tool for CNS. Astrocytes, glial cells present in all brain regions, are important players in brain function through their vast influence in extracellular homeostasis, neuro-vascular regulation, synaptic modulation and neurogenesis. Thus, in the present work, we aimed to evaluate the specific impact of MSCs secretome on hippocampal proliferation and astrocyte morphology, in both WT and dnSNARE mice, a transgenic model that presents impaired astrocytic exocytosis and consequently impaired astrocytic function. Results demonstrated increased levels of proliferation for WT when treated with secretome. Additionally, it was possible to observe that dnSNARE animals injected with hBM-MSCs secretome disclosed increased levels of proliferating GFAP stained cells at the SGZ. Morphometrical evaluation found increased process hypertrophy and branching of dnSNARE astrocytes when treated with secretome. These results are closely related with the trophic factors present in the secretome, namely FGF-2, BDNF, GDNF, IGF-1, VEGF, CADH2, PEDF and miR-16. Moreover, the impaired exocytosis of astrocytes may also have implications for the response to the proliferative stimulus, given the established autocrine signaling through this mechanism.

Inhibition of 5α Reductase Impairs Cognitive Performance, Alters Dendritic Morphology and Increases Tau Phosphorylation in the Hippocampus of Male 3xTg-AD Mice

Recent work has suggested that 5α-reduced metabolites of testosterone may contribute to the neuroprotection conferred by their parent androgen, as well as to sex differences in the incidence and progression of Alzheimer’s disease (AD). This study investigated the effects of inhibiting 5α-reductase on object recognition memory (ORM), hippocampal dendritic morphology and proteins involved in AD pathology, in male 3xTg-AD mice. Male 6-month old wild-type or 3xTg-AD mice received daily injections of finasteride (50 mg/kg i.p.) or vehicle (18% β-cyclodextrin, 1% v/b.w.) for 20 days. Female wild-type and 3xTg-AD mice received only the vehicle. Finasteride treatment differentially impaired ORM in males after short-term (3xTg-AD only) or long-term (3xTg-AD and wild-type) retention delays. Dendritic spine density and dendritic branching of pyramidal neurons in the CA3 hippocampal subfield were significantly lower in 3xTg-AD females than in males. Finasteride reduced CA3 dendritic branching and spine density in 3xTg-AD males, to within the range observed in vehicle-treated females. In the CA1 hippocampal subfield, dendritic branching and spine density were reduced in both male and female 3xTg-AD mice, compared to wild type controls. Hippocampal amyloid β levels were substantially higher in 3xTg-AD females compared to both vehicle and finasteride-treated 3xTg-AD males. Site-specific Tau phosphorylation was higher in 3xTg-AD mice compared to sex-matched wild-type controls, increasing slightly after finasteride treatment. These results suggest that 5α-reduced neurosteroids may play a role in testosterone-mediated neuroprotection and may contribute to sex differences in the development and severity of AD.

Effect of α-lipoic acid on spatial memory and structural integrity of developing hippocampal neurons in rats subjected to sodium arsenite exposure

BackgroundExposure to arsenic has been reported to affect the nervous system in a number of ways. Various epidemiological studies suggest cognitive impairment in subjects following exposure to environmental arsenic. The goal of the present study was to determine if supplementation of exogenous α-lipoic acid (ALA) could ameliorate sodium arsenite (NaAsO2) induced adverse effects on learning and memory and synaptic connectivity in rat hippocampus. MethodsAccordingly, NaAsO2 alone (1.5/2.0 mg/kg bw) or NaAsO2 along with ALA (70 mg/kg bw) was administered by intraperitoneal (i.p.) route from postnatal day (PND) 4–17 to Wistar rat pups (experimental groups) and the Control groups received either distilled water or no treatment at all. After carrying out Elevated Plus Maze (EPM) and Morris Water Maze (MWM) test, the fresh brain tissues were collected on PND 18 and processed for Golgi Cox staining. ResultsObservations of MWM test revealed impaired learning and memory in iAs alone treated animals as against those co-exposed to iAs and ALA. In Golgi stained hippocampal sections of iAs alone treated animals, decreased dendritic arborization and reduced number of spines in pyramidal neurons (CA1) and granule cells (DG) was observed whereas neuronal morphology was preserved in the controls and ALA supplemented groups ConclusionsThese observations are suggestive of beneficial effects of ALA on iAs induced effects on learning and memory as well as on hippocampal neuronal morphology.

Simulated spatial radiation impacts learning and memory ability with alterations of neuromorphology and gut microbiota in mice.

Complex space environments, including microgravity and radiation, affect the body's central nervous system, endocrine system, circulatory system, and reproductive system. Radiation-induced aberration in the neuronal integrity and cognitive functions are particularly well known. Moreover, ionizing radiation is a likely contributor to alterations in the microbiome. However, there is a lacuna between radiation-induced memory impairment and gut microbiota. The present study was aimed at investigating the effects of simulated space-type radiation on learning and memory ability and gut microbiota in mice. Adult mice were irradiated by 60Co-γ rays at 4 Gy to simulate spatial radiation; behavioral experiments, pathological experiments, and transmission electron microscopy all showed that radiation impaired learning and memory ability and hippocampal neurons in mice, which was similar to the cognitive impairment in neurodegenerative diseases. In addition, we observed that radiation destroyed the colonic structure of mice, decreased the expression of tight junction proteins, and increased inflammation levels, which might lead to dysregulation of the intestinal microbiota. We found a correlation between the brain and colon in the changes in neurotransmitters associated with learning and memory. The 16S rRNA results showed that the bacteria associated with these neurotransmitters were also changed at the genus level and were significantly correlated. These results indicate that radiation-induced memory and cognitive impairment can be linked to gut microbiota through neurotransmitters.

Basolateral Amygdala α1-Adrenergic Receptor Suppression Attenuates Stress-Induced Anxiety-Like Behavior and Spine Morphology Impairment on Hippocampal CA1 Pyramidal Neurons

The basolateral amygdala (BLA) and hippocampus are part of the limbic fear–anxiety circuit and have also been implicated in the stress response. The BLA is rich in the expression of α1-adrenoceptors. We hypothesized that α1-adrenoceptors in BLA, may modulate stress-induced anxiety-like behavioral responses and hippocampal CA1 pyramidal neuron spine density. α1-Adrenoceptors agonist, phenylephrine, or antagonist, prazosin, were microinjected bilaterally into BLA of male Wistar rats 5 minutes before foot-shock stress. Then, anxiety-like behavioral responses to stress were measured on the Open Field Test (OFT) and on the Elevated Plus-maze (EPM). Also, Golgi-Cox staining was used to investigate the hippocampal CA1 pyramidal neuron spine density. The results showed that four consecutive day stress reduced the open arm time, and open arm entry in the EPM. Intra-BLA injection of prazosin reversed stress-induced anxiogenic-like behaviors. In the OFT stress decreased the center area entries and time, while intra-BLA injection of phenylephrine or prazosin did not alter these parameters. Stress also reduced the dendritic and axonal arborization in hippocampal CA1 pyramidal neurons. Interestingly, intra-BLA infusion of prazosin blocked the reduction in dendritic and axonal arborization induced by foot-shock stress. Taken together, stress produces anxiogenic-like behaviors and hippocampal CA1 pyramidal neurons morphology changes, which may be mediated through the BLA α1-adrenoceptors mechanism.

Qingxin Kaiqiao Fang Inhibits Aβ 25-35-Induced Apoptosis in Primary Cultured Rat Hippocampal Neuronal Cells via the p38 MAPK Pathway: An Experimental Validation and Network Pharmacology Study.

Qingxin kaiqiao fang (QKF), a traditional Chinese medicine compound, has been applied to treat Alzheimer's disease (AD) for many years and has exhibited remarkable effects. However, the underlying mechanism is still not explicit. The current study aims to investigate whether QKF exerts an antiapoptotic role through the p38 MAPK pathway in the course of AD. Network pharmacology analysis was applied to study the effective components, possible therapeutic targets, and AD-related pathway of QKF. Further, the AD cell model was established using amyloid-beta (Aβ)25-35 peptide and primary hippocampal neuronal cells extracted from newborn Sprague-Dawley rats. Microtubule-associated protein-2 (MAP-2) imaging was used to detect the morphology of hippocampal neurons. Western blot (WB) analysis was applied to detect the protein expression levels of p38 MAPK, p-p38 MAPK, Bcl-2, Bax, caspase-3, and cleaved caspase-3. Cell viability and apoptosis were determined using cell counting kit-8 (CCK-8) and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assays, respectively. SB203580 and U46619 were used to detect changes in cell morphology, cell viability, and apoptosis upon inhibiting or activating p38 MAPK. Our present work showed that QKF protects hippocampal neuronal morphology, enhances cell viability, and reduces the number of TUNEL-positive cells. In addition, our results showed that QKF increased the expression levels of antiapoptotic proteins and decreased the expression of proapoptotic proteins. QKF at 25 mg·mL−1 best inhibited neuronal apoptosis among the three doses of QKF by suppressing p38 MAPK activity. Collectively, QKF plays an antiapoptotic role via the p38 MAPK pathway.

The effects of peripherally-subacute treatment with irisin on hippocampal dendritogenesis and astrocyte-secreted factors.

[Purpose]Fibronectin type III domain containing 5 (FNDC5)/irisin is an exercise-induced myokine, which contributes to cognitive functions. However, the relationship between the neuroprotective effects of FNDC5/irisin and hippocampal dendritic remodeling and astrocyte-secreted factors remains unclear. Therefore, we explored whether subchronic recombinant irisin treatment affected hippocampal morphology and some astrocyte-derived molecules.[Methods]Mice were intraperitoneally injected with irisin (0.5 μg/kg/day) for seven days, followed by their sacrifice two days later. Hippocampal morphometric parameters were analyzed and pgc-1a, fndc5, bdnf, and some astrocyte-derived factors mRNA levels were measured.[Results]Dendritic length, arborization, and spine density were enhanced by irisin regimen in hippocampal CA1 and CA3 areas. Hippocampal pgc-1a, fndc5, and bdnf mRNA levels were significantly increased by irisin treatment. Moreover, hevin mRNA levels were significantly enhanced, whereas tgf-b1 levels downregulated by irisin treatment.[Conclusion]FNDC5/irisin has dendritogenic activity probably through hevin induction and TGF-β1 suppression.

MiR-126 suppresses neuronal apoptosis in rats after cardiopulmonary resuscitation via regulating p38MAPK

In this study, we aimed to evaluate the effect of microRNA-126 (miR-126) on neuronal apoptosis in cardiopulmonary resuscitation rats and to explore the related molecular mechanism. The expression of miR-126 in brain tissues of rats after cardiopulmonary resuscitation was measured by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR). The basic parameters of cardiopulmonary resuscitation were recorded by miR-126 mimic injection in rats after cardiopulmonary resuscitation. Hematoxylin-eosin staining was used to observe the pathological changes of hippocampus. Immunohistochemistry was used to observe the expression of p38 and caspase-3 protein. Furthermore, the expression of p38 mitogen-activated protein kinase (p38MAPK), Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase 1/2 (ERK1/2) in rat hippocampus was detected by RT-qPCR and Western blot. In order to confirm whether miR-126 takes part in the p38MAPK pathway in the hippocampus of rats after cardiopulmonary resuscitation, the p38MAPK pathway inhibitor (SB203580) and activator (anisomycin) were added. The results showed overexpression of miR-126 could significantly increase the neurological function score and improve the pathological morphology of hippocampus in rats after cardiopulmonary resuscitation. miR-126 overexpression also could reduce the neuronal apoptosis, p38, and caspase-3 expression in the hippocampus. Moreover, the p38MAPK and JNK expression was downregulated and ERK1/2 expression was upregulated after miR-126 mimic injection (p < 0.05). The results of inhibition of p38MAPK pathway were consistent with those of overexpression of miR-126 (p > 0.05). This study indicated miR-126 could significantly reduce neuronal apoptosis of hippocampus in rats after cardiopulmonary resuscitation, which might be involved in the regulation of p38MAPK pathway.

Dusp8 affects hippocampal size and behavior in mice and humans

Dual-specificity phosphatase 8 (Dusp8) acts as physiological inhibitor for the MAPKs Jnk, Erk and p38 which are involved in regulating multiple CNS processes. While Dusp8 expression levels are high in limbic areas such as the hippocampus, the functional role of Dusp8 in hippocampus morphology, MAPK-signaling, neurogenesis and apoptosis as well as in behavior are still unclear. It is of particular interest whether human carriers of a DUSP8 allelic variant show similar hippocampal alterations to mice. Addressing these questions using Dusp8 WT and KO mouse littermates, we found that KOs suffered from mildly impaired spatial learning, increased locomotor activity and elevated anxiety. Cell proliferation, apoptosis and p38 and Jnk phosphorylation were unaffected, but phospho-Erk levels were higher in hippocampi of the KOs. Consistent with a decreased hippocampus size in Dusp8 KO mice, we found reduced volumes of the hippocampal subregions subiculum and CA4 in humans carrying the DUSP8 allelic variant SNP rs2334499:C > T. Overall, aberrations in morphology and behavior in Dusp8 KO mice and a decrease in hippocampal volume of SNP rs2334499:C > T carriers point to a novel, translationally relevant role of Dusp8 in hippocampus function that warrants further studies on the role of Dusp8 within the limbic network.

Impaired memory and marble burying activity in deformed epidermal autoregulatory factor 1 (Deaf1) conditional knockout mice

Deleterious mutations within the DNA binding domain of the transcription factor deformed epidermal autoregulatory factor 1 (DEAF1) result in a phenotypic spectrum of neurodevelopmental disorders including intellectual disabilities and autism spectrum disorders. While whole animal deletion of Deaf1 in mice is lethal, mice with conditional disruption of the gene in neuronal precursor cells can display memory deficits and increased anxiety-like behavior. This study aimed to further characterize learning and memory alterations and assess changes in marble burying activity and hippocampal size in mice with conditional deletion of Deaf1. Mice lacking DEAF1 in the CNS (NKO) displayed reduced memory in both contextual fear conditioning and a 3-day massed trials Morris water maze paradigm. NKO mice had reduced marble burying activity in full cage marble burying tests. Using a half-cage marble test, NKO mice again buried fewer marbles and spent significantly more time on the side of the cage away from the marbles compared to control animals. The area of the dorsal hippocampus of NKO mice was decreased compared to control and animals with a single Deaf1 allele. These results continue to establish the importance of DEAF1 in cognitive behavior and provide new evidence that DEAF1 regulates hippocampal morphology.

Gpr158 Deficiency Impacts Hippocampal CA1 Neuronal Excitability, Dendritic Architecture, and Affects Spatial Learning.

G-protein-coupled receptor 158 (Gpr158) is highly expressed in striatum, hippocampus and prefrontal cortex. It gained attention as it was implicated in physiological responses to stress and depression. Recently, Gpr158 has been shown to act as a pathway-specific synaptic organizer in the hippocampus, required for proper mossy fiber-CA3 neurocircuitry establishment, structure, and function. Although rodent Gpr158 expression is highest in CA3, considerable expression occurs in CA1 especially after the first postnatal month. Here, we combined hippocampal-dependent behavioral paradigms with subsequent electrophysiological and morphological analyses from the same group of mice to assess the effects of Gpr158 deficiency on CA1 physiology and function. We demonstrate deficits in spatial memory acquisition and retrieval in the Morris water maze paradigm, along with deficits in the acquisition of extinction memory in the passive avoidance test in Gpr158 KO mice. Electrophysiological recordings from CA1 pyramidal neurons revealed normal basal excitatory and inhibitory synaptic transmission, however, Schaffer collateral stimulation yielded dramatically reduced post-synaptic currents. Interestingly, intrinsic excitability of CA1 pyramidals was found increased, potentially acting as a compensatory mechanism to the reductions in Schaffer collateral-mediated drive. Both ex vivo and in vitro, neurons deficient for or with lowered levels of Gpr158 exhibited robust reductions in dendritic architecture and complexity, i.e., reduced length, surface, bifurcations, and branching. This effect was localized in the apical but not basal dendrites of adult CA1 pyramidals, indicative of compartment-specific alterations. A significant positive correlation between spatial memory acquisition and extent of complexity of CA1 pyramidals was found. Taken together, we provide first evidence of significant disruptions in hippocampal CA1 neuronal dendritic architecture and physiology, driven by Gpr158 deficiency. Importantly, the hippocampal neuronal morphology deficits appear to support the impairments in spatial memory acquisition observed in Gpr158 KO mice.

Cognitive training increases dendritic arborization in the dorsal hippocampal CA1 and CA3 neurons of female and male Long-Evans rats.

Experiences influence the development of the central nervous system. Cognitive training promotes changes in the structure of the brain, such as in its weight and number of cells, as well as ability to perform dendritic remodeling. The present study was designed to detect possible differences in the neuronal morphology of the dorsal hippocampus between female and male Long-Evans rats after cognitive training (CT). CT was promoted through three learning and memory tests: the Morris water maze, the Barnes circular maze, and Novel object recognition tests. Our data revealed no differences in learning or memory capacities between female and male rats; rats of the two sexes solved the behavioral test with equal efficiency. CT caused an increase in the basilar and apical dendritic arborization of CA1 neurons in male rats, whereas female rats that underwent CT presented only remodeling in the apical arbors of CA1 neurons. The basilar arbors of CA3 neurons of female rats showed an increase in arborization, but their apical arbors were not modified; the arbors of CA3 neurons of male rats submitted to CT were not modified. Total dendritic length was modified by CT in the apical arbors of CA1 neurons of female and male rats and in the basilar CA1 arbors of male rats. There was a significant increase in dendritic spine density in all arbors of CA1 and CA3 neurons of females and males subjected to CT. These results suggest that dendritic remodeling after CT is similar between female and male rats.

Dorsal Hippocampal Actin Polymerization Is Necessary for Activation of G-Protein-Coupled Estrogen Receptor (GPER) to Increase CA1 Dendritic Spine Density and Enhance Memory Consolidation.

Activation of the membrane estrogen receptor G-protein-coupled estrogen receptor (GPER) in ovariectomized mice via the GPER agonist G-1 mimics the beneficial effects of 17β-estradiol (E2) on hippocampal CA1 spine density and memory consolidation, yet the cell-signaling mechanisms mediating these effects remain unclear. The present study examined the role of actin polymerization and c-Jun N-terminal kinase (JNK) phosphorylation in mediating effects of dorsal hippocampally infused G-1 on CA1 dendritic spine density and consolidation of object recognition and spatial memories in ovariectomized mice. We first showed that object learning increased apical CA1 spine density in the dorsal hippocampus (DH) within 40 min. We then found that DH infusion of G-1 increased both CA1 spine density and phosphorylation of the actin polymerization regulator cofilin, suggesting that activation of GPER may increase spine morphogenesis through actin polymerization. As with memory consolidation in our previous work (Kim et al., 2016), effects of G-1 on CA1 spine density and cofilin phosphorylation depended on JNK phosphorylation in the DH. Also consistent with our previous findings, E2-induced cofilin phosphorylation was not dependent on GPER activation. Finally, we found that infusion of the actin polymerization inhibitor, latrunculin A, into the DH prevented G-1 from increasing apical CA1 spine density and enhancing both object recognition and spatial memory consolidation. Collectively, these data demonstrate that GPER-mediated hippocampal spinogenesis and memory consolidation depend on JNK and cofilin signaling, supporting a critical role for actin polymerization in the GPER-induced regulation of hippocampal function in female mice.SIGNIFICANCE STATEMENT Emerging evidence suggests that G-protein-coupled estrogen receptor (GPER) activation mimics effects of 17β-estradiol on hippocampal memory consolidation. Unlike canonical estrogen receptors, GPER activation is associated with reduced cancer cell proliferation; thus, understanding the molecular mechanisms through which GPER regulates hippocampal function may provide new avenues for the development of drugs that provide the cognitive benefits of estrogens without harmful side effects. Here, we demonstrate that GPER increases CA1 dendritic spine density and hippocampal memory consolidation in a manner dependent on actin polymerization and c-Jun N-terminal kinase phosphorylation. These findings provide novel insights into the role of GPER in mediating hippocampal morphology and memory consolidation, and may suggest first steps toward new therapeutics that more safely and effectively reduce memory decline in menopausal women.

Ac-SDKP ameliorates the progression of experimental autoimmune encephalomyelitis via inhibition of ER stress and oxidative stress in the hippocampus of C57BL/6 mice

Despite the attention given to the treatment of multiple sclerosis (MS), still no certain cure is available. The main purpose of MS drugs is acting against neuroinflammation which underlies the pathology of MS. Neuroinflammation is associated with endoplasmic reticulum (ER) stress that mediates neural apoptosis. In the present study, we hypothesized that the tetrapeptide N-acetyl-ser-asp-lys-pro (Ac-SDKP) with the previously described anti-fibrotic effects might have anti-inflammatory, anti-oxidative and anti-ER stress roles in the hippocampus.We used myelin oligodendrocyte glycoprotein (MOG) to induce experimental autoimmune encephalomyelitis (EAE), a widely-accepted animal model of MS, in C57BL/6 mice. The protein levels of ER stress-related molecules including caspase-12, C/EBP homologous protein (CHOP), and protein disulfide isomerase (PDI) in the hippocampus were examined by immunoblotting. Hence, reactive oxygen species (ROS) production, lipid peroxidation and antioxidant capacity of the hippocampus were studied. Moreover, hippocampal morphology changes, leukocytes infiltration, and the levels of IL-6 and IL-1β pro-inflammatory cytokines were evaluated.Our results displayed that Ac-SDKP down regulates caspase-12 and CHOP expression in the hippocampus-resident oligodendrocytes of EAE mice. Further, treatment with Ac-SDKP decreased oxidative stress markers and caspase-3 activation in the hippocampus of EAE mice.According to our findings, Ac-SDKP showed beneficial effects against ER stress and oxidative stress in addition to inflammation in the hippocampus of EAE mice. The present study provides the basis for further research on the therapeutic applications of Ac-SDKP to reduce ER stress and oxidative stress-induced apoptosis in neurodegenerative disorders.

Normalization of hippocampal retinoic acid level corrects age-related memory deficits in rats

Dietary micronutrients constitute a major environmental factor influencing aging processes. Vitamin A (vit. A) is the precursor of retinoic acid, a bioactive molecule that controls the expression of several genes involved in brain function. Evidence suggests a reduction of vit. A bioavailability with aging, but its impact on neuronal network is poorly understood. We investigated the mechanisms linking memory impairments with specific alterations of retinoic acid metabolism in the hippocampus. We compared young (10 weeks) and aged (16 months) rats, supplemented or not with dietary vit. A (20 IU retinol/g) for 4 weeks. Our study reveals that aging induced dysregulation of gene expression involved in vit. A and retinoic acid metabolism in the liver. Furthermore, vit. A supplementation restored the integrity of the hippocampal neuronal morphology altered by aging. Importantly, we found a high correlation between hippocampal levels of retinoic acid and memory performance. The present work establishes the link between collapse of retinoid metabolism and age-related cognitive decline, highlighting the role of vit. A in maintaining memory through aging.

Early and reversible changes to the hippocampal proteome in mice on a high-fat diet

BackgroundThe rise in global obesity makes it crucial to understand how diet drives obesity-related health conditions, such as premature cognitive decline and Alzheimer’s disease (AD). In AD hippocampal-dependent episodic memory is one of the first types of memory to be impaired. Previous studies have shown that in mice fed a high-fat diet (HFD) episodic memory is rapidly but reversibly impaired.MethodsIn this study we use hippocampal proteomics to investigate the effects of HFD in the hippocampus. Mice were fed either a low-fat diet (LFD) or HFD containing either 10% or 60% (Kcal) from fat for 3 days, 1 week or 2 weeks. One group of mice were fed the HFD for 1 week and then returned to the LFD for a further week. Primary hippocampal cultures were challenged with palmitic acid (PA), the most common long-chain saturated FA in the Western diet, and with the anti-inflammatory, n-3 polyunsaturated FA, docosahexaenoic acid (DHA), or a combination of the two to ascertain effects of these fatty acids on dendritic structure.ResultsHFD-induced changes occur in hippocampal proteins involved in metabolism, inflammation, cell stress, cell signalling, and the cytoskeleton after 3 days, 1 week and 2 weeks of HFD. Replacement of the HFD after 1 week by a low-fat diet (LFD) for a further week resulted in partial recovery of the hippocampal proteome. Microtubule-associated protein 2 (MAP2), one of the earliest proteins changed, was used to investigate the impact of fatty acids (FAs) on hippocampal neuronal morphology. PA challenge resulted in shorter and less arborised dendrites while DHA had no effect when applied alone but counteracted the effects of PA when FAs were used in combination. Dendritic morphology recovered when PA was removed from the cell culture media.ConclusionThis study provides evidence for the rapid and reversible effects of diet on the hippocampal proteome and the impact of PA and DHA on dendritic structure.

Interval and continuous exercise overcome memory deficits related to β-Amyloid accumulation through modulating mitochondrial dynamics

Exercise is a non-pharmacological strategy that may help to protect against cognitive decline and reduce the risk of Alzheimer’s disease. However, the optimal exercise modes for cognitive benefits are controversial. Mitochondrial function has been related to both exercise and cognition. The present study aimed to investigate the effects of two exercise modes on cognitive function and mitochondrial dynamics in APP/PS1 transgenic mice. The results showed that 12-week high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) could improve exploratory behavior, spatial learning and memory ability of APP/PS1 transgenic mice. Both HIIT and MICT interventions significantly alleviated the hippocampal β-Amyloid (Aβ) burden and mitochondrial fragmentation and improved mitochondrial morphology in hippocampus. Furthermore, both HIIT and MICT interventions down-regulated dynamin-related protein 1 (DRP1) and fission 1 (FIS1), whereas mitofusin 1 (MFN1), mitofusin 2 (MFN2) and optic atrophy 1 (OPA1) were up-regulated. Hippocampal levels of total reactive oxygen species (ROS), malondialdehyde (MDA) and hydrogen peroxide (H2O2) were decreased, whereas activities of superoxide dismutase (SOD) and catalase (CAT) were elevated by HIIT and MICT. The study suggests that both HIIT and MICT alleviate cognitive decline and down-regulat Aβ level in the hippocampus in APP/PS1 transgenic mice, which may be mediated by improvements in mitochondrial morphology and dynamics.

Metabolomic profiling on rat brain of prenatal malnutrition: implicated for oxidative stress and schizophrenia.

Schizophrenia is a kind of neurodevelopmental disease. Epidemiological data associates schizophrenia with prenatal exposure to famine. Relevant prenatal protein deprivation (PPD) rodent models support this result by observing decreasing prepulse inhibition, altered hippocampal morphology and impaired memory in offspring. All these abnormalities are highly consistent with the pathophysiology of schizophrenia. We developed a prenatal famine rat model by restricting daily diet of the pregnant rat to 50% of low protein diet. A metabolomics study of prefrontal cortex was performed to integrate GC-TOFMS and UPLC-QTOFMS. Thirteen controls and thirteen famine offspring were used to differentiate in PLS-DA (partial least squares-discriminate analysis) model. Furthermore, metabolic pathways and diseases were enriched via KEGG and HMDB databases, respectively. A total of 67 important metabolites were screened out according to the multivariate analysis. Schizophrenia was the most statistical significant disease (P = 0.0016) in our famine model. These metabolites were enriched in key metabolic pathways related to energy metabolism and glutamate metabolism. Based on these important metabolites, further discussion speculated famine group was characterized by higher level of oxidized damage compared to control group. We proposed that oxidative stress might be the pathogenesis of prenatal undernutrition which is induced schizophrenia.