Spatial Recognition Memory Research Articles

Melatonin reverses cognitive deficits in streptozotocin-induced type 1 diabetes in the rat through attenuation of oxidative stress and inflammation

Uncontrolled diabetes mellitus (DM) is linked to attentional deficits and cognition deterioration. The neurohormone melatonin is an endogenous synchronizer of circadian rhythms with multiple protective properties. This research was designed to assess its effect against learning and memory decline in streptozotocin (STZ)-induced diabetic rats. Rats were assigned to control, melatonin-treated control, diabetic, and melatonin-treated diabetic groups. Melatonin was administered i.p. at a dose of 10 mg/kg/day for 47 days. Treatment of diabetic rats with melatonin reversed decline of spatial recognition memory in Y maze, performance of rats in novel object discrimination, and retention and recall in passive avoidance tasks. Furthermore, melatonin appropriately attenuated hippocampal malondialdehyde (MDA) and reactive oxygen species (ROS) and improved superoxide dismutase (SOD) activity and improved mitochondrial membrane potential (MMP) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) with no significant effect on nitrite, glutathione (GSH) and catalase activity. Besides, hippocampal level of acetylcholinesterase (AChE), glial fibrillary acidic protein (GFAP), nuclear factor-kappaB (NF-κB), interleukin 6 (IL-6) and tumor necrosis factor α (TNFα) decreased following melatonin treatment. There was also a reduction of dendritic spines of pyramidal neurons of hippocampal CA1 area in diabetic group that was significantly alleviated upon melatonin treatment. Melatonin could ameliorate learning and memory disturbances in diabetic rats through mitigation of cholinesterase activity, astrocytes, oxidative stress and inflammation and also via upregulation of some antioxidants in addition to its prevention of dendritic spine loss.

Nuclear Factor [Erythroid-derived 2]-like 2 and Mitochondrial Transcription Factor A Contribute to Moderate-intensity Swimming Effectiveness against Memory Impairment in Young Mice Induced by Concomitant Exposure to a High-calorie Diet during the Early Life Period

Increased energy food consumption during early-life has been associated with memory impairment. Swimming training has been reported to improve memory processes in rodent models. This study aimed to evaluate whether moderate-intensity swimming training counteracts learning and memory impairment in young mice fed a high-calorie diet during the early-life period. The contribution of hippocampal oxidative stress, as well as nuclear factor [erythroid-derived 2]-like 2/Kelch-like ECH-associated protein (NRF2/Keap-1/HO-1) and peroxisome proliferator-activated receptor gamma co-activator 1-alpha/mitochondrial transcription factor A (PCG-1α/mtTFA) signaling, in memory effects was also investigated. Three-week-old male Swiss mice received a high-calorie diet (20% fat; 20% carbohydrate enriched) or a standard diet from 21 to 49 postnatal days. Mice performed a moderate-intensity swimming protocol (5 days/week) and behavioral tests predictive of memory function. Mice fed a high-calorie diet and subjected to the swimming protocol performed better on short- and long-term spatial and object recognition memory tests than those fed a high-calorie diet. The swimming protocol modulated the hippocampal NRF2/Keap-1/HO-1 and mtTFA pathways in mice fed a high-calorie diet. Swimming training positively affected location and long-term memory, fat mass content, as well as NRF2/Keap-1/HO-1 and mtTFA proteins of control‐diet‐fed mice. In conclusion, a moderate-intensity swimming training evoked an adaptive response in mice fed a high-calorie diet by restoring different types of memory-impaired and hippocampal oxidative stress as well as upregulated the NRF2/Keap-1/HO-1 and mtTFA pathways.

The novel dehydroepiandrosterone (DHEA) derivative BNN27 counteracts cognitive deficits induced by the D1/D2 dopaminergic receptor agonist apomorphine in rats.

Schizophrenia is a devastating mental disease that affects nearly 1% of the population worldwide. It is well documented that the dopaminergic (DAergic) system is compromised in schizophrenia. It is of note that the mixed dopamine (DA) D1/D2 receptor agonist apomorphine induces schizophrenia-like symptoms in rodents, including disruption of memory abilities. Neuroactive steroids, comprising dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulphate (DHEAS), were shown to affect brain DAergic system and to be involved in schizophrenia. BNN27 is a novel DHEA derivative, which is devoid of steroidogenic activity. It has recently been reported that BNN27 counteracted schizophrenia-like behavioural deficits produced by glutamate hypofunction in rats. The aim of the present study was to investigate the ability of BNN27 to attenuate non-spatial, spatial recognition and discrete memory deficits induced by apomorphine in rats. To this end, the object recognition task (ORT), the object location task (OLT) and the step-through passive avoidance test (STPAT) were used. BNN27 (3 and 6mg/kg, i.p.) attenuated apomorphine (0.5mg/kg, i.p.)-induced non-spatial, spatial recognition and discrete memory deficits. Interestingly, the effects of compounds on memory cannot be ascribed to changes in locomotor activity. Our findings suggest that BNN27 is effective to DA dysfunction caused by apomorphine, attenuating cognitive impairments induced by this D1/D2 receptor agonist in rats. Additionally, our findings illustrate a functional interaction between BNN27 and the DAergic system that may be of relevance for schizophrenia-like behavioural symptoms.

S-Adenosylmethionine Rescues Cognitive Deficits in the rTg4510 Animal Model by Stabilizing Protein Phosphatase 2A and Reducing Phosphorylated Tau.

Alterations in the methionine cycle and abnormal tau phosphorylation are implicated in many neurodegenerative diseases, including Alzheimer's disease and frontotemporal dementia. rTg4510 mice express mutant human P301L tau and are a model of tau hyperphosphorylation. The cognitive deficit seen in these animals correlates with a burden of hyperphosphorylated tau and is a model to test therapies aimed at lowering phosphorylated tau. This study aimed to increase protein phosphatase 2A activity through supplementation of S-adenosylmethionine and analyze the effect on spatial memory and tau in treated animals. 6-month-old rTg4510 mice were treated with 100 mg/kg S-adenosylmethionine by oral gavage for 3 weeks. Spatial recognition memory was tested in the Y-maze. Alterations to phosphorylated tau and protein phosphatase 2A were explored using immunohistochemistry, western blot, and enzyme-linked immunosorbent assays. Treatment with S-adenosylmethionine increased the Y-maze novel arm exploration time and increased both the expression and activity of protein phosphatase 2A. Furthermore, treatment reduced the number of AT8 positive neurons and reduced the expression of phosphorylated tau (Ser202/Thr205). S-adenosylmethionine contributes to multiple pathways in neuronal homeostasis and neurodegeneration. This study shows that supplementation with S-adenosylmethionine stabilizes the heterotrimeric form of PP2A resulting in an increase the enzymatic activity, a reduced level of pathological tau, and improved cognition.

The effects of dietary edible bird nest supplementation on learning and memory functions of multigenerational mice.

IntroductionEdible bird nest (EBN) is a natural food product produced from edible nest swiftlet's saliva which consists of glycoproteins as one of its main components; these glycoproteins contain an abundant of sialic acid. The dietary EBN supplementation has been reported to enhance brain functions in mammals and that the bioactivities and nutritional value of EBN are important during periods of rapid brain growth particularly for preterm infant. However, the effects of EBN in maternal on multigeneration learning and memory function still remain unclear. Thus, the present study aimed to determine the effects of maternal EBN supplementation on learning and memory function of their first (F1)‐ and second (F2)‐generation mice.MethodsCJ57BL/6 breeder F0 mice were fed with EBN (10 mg/kg) from different sources. After 6 weeks of diet supplementations, the F0 animals were bred to produce F1 and F2 animals. At 6 weeks of age, the F1 and F2 animals were tested for spatial recognition memory using a Y‐maze test. The sialic acid content from EBN and brain gene expression were analyzed using HPLC and PCR, respectively.ResultsAll EBN samples contained glycoprotein with high level of sialic acid. Dietary EBN supplementation also showed an upregulation of GNE, ST8SiaIV, SLC17A5, and BDNF mRNA associated with an improvement in Y‐maze cognitive performance in both generations of animal. Qualitatively, the densities of synaptic vesicles in the presynaptic terminal were higher in the F1 and F2 animals which might derive from maternal EBN supplementation.ConclusionThis study provided a solid foundation toward the growing research on nutritional intervention from dietary EBN supplementation on cognitive and neurological development in the generation of mammals.

Age-Related Changes in Audiovisual Simultaneity Perception and Their Relationship With Working Memory.

Perceiving simultaneity of a visual and an auditory signal is critical for humans to integrate these multisensory inputs effectively and respond properly. We examined age-related changes in audiovisual simultaneity perception, and the relationships between this perception and working memory performances with aging. Audiovisual simultaneity perception of young, middle-aged, and older adults was measured using a simultaneity judgment (SJ) task, in which a flash and a beep were presented at 1 of 11 stimulus-onset asynchronies (SOAs). Participants judged whether these two stimuli were perceived simultaneously. Precision of simultaneity perception, the SOA corresponding to the point of subjective simultaneity (PSS), and response errors at each SOA were estimated using model fitting. The precision and PSS are associated with multisensory perception per se, whereas the response error reflects executive ability when performing the SJ task. Visual working memory of the same middle-aged and older adults was measured using the Cambridge Neuropsychological Test Automated Battery (CANTAB) beforehand. Compared to young adults' performances, middle-aged and older adults showed a decreased precision, a shift of PSS toward the visual-leading SOAs, and increased response errors at the visual-leading SOAs. Among these changes, only the increased response errors correlated with worse spatial recognition memory in middle-aged and older adults. Age-related decrements in audiovisual simultaneity perception start from middle age and are manifested in both perceptual and executive parameters. Furthermore, higher-order executive ability is plausibly a common cause for age-related degenerations in the audiovisual simultaneity perception and visual working memory.

Recovery of High Interference Memory in Spite of Lingering Cognitive Deficits in a Longitudinal Pilot Study of Hospitalized Depressed Patients.

BackgroundMajor depressive disorder has deleterious impacts on mood, cognition, and many functions of daily life. Even after remission of mood symptoms, patients frequently report persistent cognitive deficits. By contrast, the neurogenic theory of depression posits that recovery from depression is dependent upon a restoration of neurogenesis. The present study was designed to test this prediction by assessing performance in MDD in-patients on a broad battery of cognitive tasks including the Mnemonic Similarity Task, a high interference memory test that is a putative correlate of neurogenesis. We predicted that remitted patients should exhibit recovery of function on this task, even though they may show residual deficits on other cognitive tasks.Methods18 hospitalized patients diagnosed with MDD and 22 healthy control participants matched for age, sex, and education completed a battery of mood and cognitive tests at two time points. Patients completed their baseline assessments when first admitted to hospital and repeated the same assessments upon remission, typically 4–5 weeks later and just prior to their release from hospital. Control participants were tested at baseline and 4–5 weeks later on the same assessment battery, which included the BDI-II, BAI, Cohen’s PSS, Mnemonic Similarity Task, and several sub-tests adapted from the CANTAB.ResultsAt baseline, MDD patients were impaired relative to controls on the MST and many other cognitive tasks. Upon remission, patients’ MST scores did not differ from those of healthy controls, although patients were still impaired on Pattern Recognition Memory, Spatial Recognition Memory, Delayed Matching to Sample and Paired Associates Learning relative to healthy control participants.ConclusionThe lingering memory deficits observed in remitted patients with MDD observed here are broadly consistent with findings in the literature. Importantly, however, remitted patients showed recovery of cognitive function on the Mnemonic Similarity Task. This is the first study that we are aware of to report recovery of function on a high interference, putatively neurogenesis-dependent memory test in a longitudinal sample of hospitalized MDD patients from admission to remission. Our findings are consistent with the neurogenic theory of depression, which posits that a restoration of neurogenesis is linked to recovery from depression.

COX5A Plays a Vital Role in Memory Impairment Associated With Brain Aging via the BDNF/ERK1/2 Signaling Pathway.

Cytochrome c oxidase subunit Va (COX5A) is involved in maintaining normal mitochondrial function. However, little is known on the role of COX5A in the development and progress of Alzheimer’s disease (Martinez-Losa et al., 2018). In this study, we established and characterized the genomic profiles of genes expressed in the hippocampus of Senescence-Accelerated Mouse-prone 8 (SAMP8) mice, and revealed differential expression of COX5A among 12-month-aged SAMP8 mice and 2-month-aged SAMP8 mice. Newly established transgenic mice with systemic COX5A overexpression (51% increase) resulted in the improvement of spatial recognition memory and hippocampal synaptic plasticity, recovery of hippocampal CA1 dendrites, and activation of the BDNF/ERK1/2 signaling pathway in vivo. Moreover, mice with both COX5A overexpression and BDNF knockdown showed a poor recovery in spatial recognition memory as well as a decrease in spine density and branching of dendrites in CA1, when compared to mice that only overexpressed COX5A. In vitro studies supported that COX5A affected neuronal growth via BDNF. In summary, this study was the first to show that COX5A in the hippocampus plays a vital role in aging-related cognitive deterioration via BDNF/ERK1/2 regulation, and suggested that COX5A may be a potential target for anti-senescence drugs.

Modeling human age-associated increase in Gadd45γ expression leads to spatial recognition memory impairments in young adult mice

Aging is associated with the progressive decay of cognitive function. Hippocampus-dependent processes, such as the formation of spatial memory, are particularly vulnerable to aging. Currently, the molecular mechanisms responsible for age-dependent cognitive decline are largely unknown. Here, we investigated the expression and function of the growth arrest DNA damage gamma (Gadd45γ) during aging and cognition. We report that Gadd45γ expression is increased in the hippocampus of aged humans and that Gadd45γ overexpression in the young adult mouse hippocampus compromises cognition. Moreover, Gadd45γ overexpression in hippocampal neurons disrupted cAMP response element-binding protein signaling and the expression of well-established activity-regulated genes. This work shows that Gadd45γ expression is tightly controlled in the hippocampus and its disruption may be a mechanism contributing to age-related cognitive impairments observed in humans.

Deepened sleep makes hippocampal spatial memory more persistent

Ample evidence has indicated a beneficial role of sleep, and particularly of slow wave sleep (SWS) in memory consolidation. However, how basic features of sleep, its depth and duration, contribute to this process remained elusive. Here, we investigated spatial object-place recognition (OPR) memory in rats, to systematically dissociate effects of sleep depth and duration on the formation of recent and remote hippocampus-dependent memory. Encoding of the spatial configuration was followed by an experimental post-encoding period of either 2 or 4 h, during which the rats had either “regular sleep”, “deeper sleep”, or were kept awake. A deeper sleep was achieved by an extended habituation of the rats to the sleep environment. Retrieval was tested either immediately after the 2-hour post-encoding period (recent memory test) or 1 week later (remote memory test). Deeper sleep expressed itself in a selective increase in the time spent in SWS, and in numbers of slow oscillations, spindles, and hippocampal ripples during SWS, whereas preREM and REM sleep were not affected. At the recent test, OPR memory was preserved only after sleep, but independent of its depth. At the remote test, however, OPR memory was preserved only after deeper sleep, whereas the wake and the regularly sleeping rats did not show remote OPR memory, even with the longer 4-h post-encoding period. Our results indicate that, rather than a longer duration, deeper sleep, i.e., a longer time in SWS together with enhanced oscillatory signatures of mnemonic processing during this sleep stage, occurring within a 2-hour window after encoding, is the factor that makes hippocampus-dependent memory more persistent.

A2A R inhibition in alleviating spatial recognition memory impairment after TBI is associated with improvement in autophagic flux in RSC.

Spatial recognition memory impairment is an important complication after traumatic brain injury (TBI). We previously found that spatial recognition memory impairment can be alleviated in adenosine A2A receptor knockout (A2AR KO) mice after TBI, but the mechanism remains unclear. In the current study, we used manganese‐enhanced magnetic resonance imaging and the Y‐maze test to determine whether the electrical activity of neurons in the retrosplenial cortex (RSC) was reduced and spatial recognition memory was impaired in wild‐type (WT) mice after moderate TBI. Furthermore, spatial recognition memory was damaged by optogenetically inhibiting the electrical activity of RSC neurons in WT mice. Additionally, the electrical activity of RSC neurons was significantly increased and spatial recognition memory impairment was reduced in A2AR KO mice after moderate TBI. Specific inhibition of A2AR in the ipsilateral RSC alleviated the impairment in spatial recognition memory in WT mice. In addition, A2AR KO improved autophagic flux in the ipsilateral RSC after injury. In primary cultured neurons, activation of A2AR reduced lysosomal‐associated membrane protein 1 and cathepsin D (CTSD) levels, increased phosphorylated protein kinase A and phosphorylated extracellular signal‐regulated kinase 2 levels, reduced transcription factor EB (TFEB) nuclear localization and impaired autophagic flux. These results suggest that the impairment of spatial recognition memory after TBI may be associated with impaired autophagic flux in the RSC and that A2AR activation may reduce lysosomal biogenesis through the PKA/ERK2/TFEB pathway to impair autophagic flux.

The neurobehavioral effects of the designer drug naphyrone - an experimental investigation with pharmacokinetics and concentration/effect relationship in mice.

The recreational use of naphyrone, a potent synthetic cathinone with a pyrovalerone structure, has raised questions about possible deleterious neurobehavioral consequences. To investigate naphyrone-induced neurobehavioral effects and alterations in brain monoamines using two patterns of abuse, i.e., single and repeated (binge) use. We studied naphyrone dose/induced locomotor activity relationship at 3, 10, 30, and 100mg/kg in mice. We investigated the effects of single (30mg/kg; acute injection) versus repeated (30mg/kg ×3/day for 3days; binge injection) intraperitoneal naphyrone administration on locomotor activity, anxiety-like behavior, spatial recognition memory, anhedonia, behavioral despair, and social interaction. We measured post-mortem prefrontal cortex levels of monoamines and modeled naphyrone pharmacokinetics and concentration/locomotor effect relationship. Both naphyrone administration patterns induced time-dependent increases in locomotor activity (p < 0.001 and p < 0.0001, respectively) and social interaction (p < 0.05 and p < 0.001, respectively) but did not alter spatial recognition memory or anhedonia. Acute naphyrone injection induced anxiety-like behavior (p < 0.01) and reduced resignation (p < 0.01) whereas binge administration induced non-anxiety-like behavior (p < 0.05) and did not alter behavioral despair. Both patterns increased the prefrontal cortex dopamine (p < 0.0001) and norepinephrine (p < 0.05 and p < 0.01, respectively) but not serotonin content. Naphyrone pharmacokinetics followed a two-compartment model with an overall elimination half-life of 0.3h. The naphyrone concentration/locomotor effect relationship was described by an additive Emax model with an EC50 of 672μg/L. Single naphyrone administration increases locomotor activity according to a direct concentration/effect relationship. The neurobehavioral effects after binge differs from those after single administration and are not explained by drug accumulation given the relatively fast elimination.

Premature synaptic mitochondrial dysfunction in the hippocampus during aging contributes to memory loss

Aging is a process characterized by cognitive impairment and mitochondrial dysfunction. In neurons, these organelles are classified as synaptic and non-synaptic mitochondria depending on their localization. Interestingly, synaptic mitochondria from the cerebral cortex accumulate more damage and are more sensitive to swelling than non-synaptic mitochondria. The hippocampus is fundamental for learning and memory, synaptic processes with high energy demand. However, it is unknown if functional differences are found in synaptic and non-synaptic hippocampal mitochondria; and whether this could contribute to memory loss during aging. In this study, we used 3, 6, 12 and 18 month-old (mo) mice to evaluate hippocampal memory and the function of both synaptic and non-synaptic mitochondria. Our results indicate that recognition memory is impaired from 12mo, whereas spatial memory is impaired at 18mo. This was accompanied by a differential function of synaptic and non-synaptic mitochondria. Interestingly, we observed premature dysfunction of synaptic mitochondria at 12mo, indicated by increased ROS generation, reduced ATP production and higher sensitivity to calcium overload, an effect that is not observed in non-synaptic mitochondria. In addition, at 18mo both mitochondrial populations showed bioenergetic defects, but synaptic mitochondria were prone to swelling than non-synaptic mitochondria. Finally, we treated 2, 11, and 17mo mice with MitoQ or Curcumin (Cc) for 5 weeks, to determine if the prevention of synaptic mitochondrial dysfunction could attenuate memory loss. Our results indicate that reducing synaptic mitochondrial dysfunction is sufficient to decrease age-associated cognitive impairment. In conclusion, our results indicate that age-related alterations in ATP produced by synaptic mitochondria are correlated with decreases in spatial and object recognition memory and propose that the maintenance of functional synaptic mitochondria is critical to prevent memory loss during aging.

Neutralizing CXCL13 attenuates neuropsychiatric manifestations in lupus-prone mice

Abstract The pathogenesis of neuropsychiatric systemic lupus erythematosus (NPSLE) remains unclear, despite the large number of lupus patients affected by neuropsychiatric manifestations. We recently showed that MRL/lpr mice, a classic SLE mouse model with neuropsychiatric symptoms, develop tertiary lymphoid structures (TLS) (a.k.a. ectopic germinal centers). TLS structurally and functionally resemble lymph nodes and form at the site of chronic inflammation to create more localized and specialized immune responses, which may promote a local immune response against self-antigen and thus contribute to the pathogenesis. Since CXCL13 is a key chemokine that drives lymphoid formation, we injected female MRL/lpr mice intraperitoneally with an anti-CXCL13 antibody, an IgG isotype control antibody, or PBS three times weekly for 12 weeks starting at 6–8 weeks of age. Cognitive dysfunction and affective deficits were assessed at the end of treatment. Anti-CXCL13 mAb treated MRL/lpr mice showed significant improvement in spatial memory, recognition memory, and depression-like behavior as compared to the two control groups (p=0.034, p=0.013, and p=0.0087, respectively). Furthermore, mice receiving the antibody by intracerebroventricular delivery showed similar results (p=0.055, p=0.20, and p=0.018, respectively). There were, however, no apparent differences in indicators of systemic disease, including autoantibody titers. Our results suggest that TLS play an important role in the pathophysiology of affective deficits and cognitive dysfunction, and that CXCL13 neutralization may be a potential therapeutic strategy to target NPSLE.

Antiamnesic Potential of &lt;i&gt;Coccinia indica&lt;/i&gt; (Linn.) Extract: A Mechanism Based Study

Coccinia indica Linn., a well explored traditional edible medicinal plant of North East region of India, is routinely used as folkloric medicine to treat neurological disorders associated with cognitive dysfunction. The objective of the study was to evaluate the antiamnesic activity of Coccinia indica fruit extract. Antiamnesic activity of Coccinia indica was studied in Elevated plus maze and Y-maze against scopolamine induced amnesia. Moreover, we studied the influence of Coccinia indica extract on whole brain acetyl cholinesterase enzyme. Ethanolic extracts of Coccinia indica (100, 200 and 400 mg/kg body weight) were administered to healthy adult Wistar rats for successive seven days and acquisition, retention and retrieval of spatial recognition memory was determined against scopolamine (1 mg/kg, i.p.) induced amnesia in-vivo. Further, whole brain acetylcholinesterase was estimated as per Elman’s method. Pre-treatment with Coccinia indica ethanolic extract significantly improved spatial learning and memory and decreased rat brain acetyl cholinesterase activity in a dose dependent manner and comparable with standard drug Donepezil. The results indicate that ethanolic extract of Coccinia indica might be a useful as natural source of antiamnesic drug to improve learning and memory deficit associated symptoms of dementia and Alzheimer’s patients.

The Effect of Modified Curcumin Compounds on the Numbers and Morphology of Microglia

Chronic neuroinflammation is a promising therapeutic target in many neurodegenerative and age‐related brain disorders. In this study, we investigated two highly bioavailable curcumin preparations, Longvida (LC) and Meriva (MC) for their anti‐inflammatory properties, using the GFAP‐IL6 mouse model. We hypothesized that the highly bioavailable curcumin, as a potent cytokine‐suppressive anti‐inflammatory drug, will decrease microglial and astroglial activation measured by cell number and morphology, and consequently improve motor and cognitive functions.MethodsGFAP‐IL6 and wild type mice were fed with LC and MC for 1 and 5 months, respectively. LC fed mice were tested on the elevated walking beam, Rotarod, Barnes maze and Novel object recognition tests before all the mice were sacrificed. Immunohistological staining for microglia and astrocytes were carried out and unbiased stereological analysis was completed for all groups on microglia(labelled by Iba‐1 and TSPO) and astrocytes numbers (GFAP) as well as the morphology of the cells were analyzed using the MBF Biosciences system (StereoInvestigator and Neurolucida 360).ResultsShort term MC oral administration lead to a dose‐dependent reduction in neuroinflammatory markers. Moreover, MC decreased the number of activated microglia and astroglia, as well as changed the microglial morphology from activated to resting state. Long term LC treatment led to a significant decrease in the number of microglia in the hippocampus and cerebellum and in turn, led to significant improvement of both motor and cognitive function. Both short‐ and long‐term consumption of modified curcumin preparations significantly downregulated microglial activation GFAP‐IL6 mice. Spatial memory and recognition memory improvements were also found in mice fed with LC in comparison to control counterparts. Our results promise potential therapeutic applications of both Longvida and Meriva curcumin against brain inflammation and associated cognitive and motor decline.Support or Funding InformationThe present study was supported by a project grant (#P00023016) by Indena S.P.A, Italy to GM and EG. F.U has been supported by a postgraduate scholarship by Western Sydney University.

Minocycline-induced microbiome alterations predict cafeteria diet-induced spatial recognition memory impairments in rats

Diets rich in sugar and saturated fat are associated with cognitive impairments in both humans and rodents with several potential mechanisms proposed. To test the involvement of diet-induced pro-inflammatory signaling, we exposed rats to a high-fat, high-sugar cafeteria diet, and administered the anti-inflammatory antibiotic minocycline. In the first experiment minocycline was coadministered across the diet, then in a second, independent cohort it was introduced following 4 weeks of cafeteria diet. Cafeteria diet impaired novel place recognition memory throughout the study. Minocycline not only prevented impairment in spatial recognition memory but also reversed impairment established in rats following 4 weeks cafeteria diet. Further, minocycline normalized diet-induced increases in hippocampal pro-inflammatory gene expression. No effects of minocycline were seen on adiposity or dietary intake across the experiments. Cafeteria diet and minocycline treatment significantly altered microbiome composition. The relative abundance of Desulfovibrio_OTU31, uniquely enriched in vehicle-treated cafeteria-fed rats, negatively and significantly correlated with spatial recognition memory. We developed a statistical model that accurately predicts spatial recognition memory based on Desulfovibrio_OTU31 relative abundance and fat mass. Thus, our results show that minocycline prevents and reverses a dietary-induced diet impairment in spatial recognition memory, and that spatial recognition performance is best predicted by changes in body composition and Desulfovibrio_OTU31, rather than changes in pro-inflammatory gene expression.

Intermittent cafeteria diet identifies fecal microbiome changes as a predictor of spatial recognition memory impairment in female rats

Excessive consumption of diets high in saturated fat and sugar impairs short-term spatial recognition memory in both humans and rodents. Several studies have identified associations between the observed behavioral phenotype and diet-induced changes in adiposity, hippocampal gene expression of inflammatory and blood–brain barrier-related markers, and gut microbiome composition. However, the causal role of such variables in producing cognitive impairments remains unclear. As intermittent cafeteria diet access produces an intermediate phenotype, we contrasted continuous and intermittent diet access to identify specific changes in hippocampal gene expression and microbial species that underlie the cognitive impairment observed in rats fed continuous cafeteria diet. Female adult rats were fed either regular chow, continuous cafeteria diet, or intermittent cafeteria diet cycles (4 days regular chow and 3 days cafeteria) for 7 weeks (12 rats per group). Any cafeteria diet exposure affected metabolic health, hippocampal gene expression, and gut microbiota, but only continuous access impaired short-term spatial recognition memory. Multiple regression identified an operational taxonomic unit, from species Muribaculum intestinale, as a significant predictor of performance in the novel place recognition task. Thus, contrasting intermittent and continuous cafeteria diet exposure allowed us to identify specific changes in microbial species abundance and growth as potential underlying mechanisms relevant to diet-induced cognitive impairment.

5-aminolevulinic acid inhibits oxidative stress and ameliorates autistic-like behaviors in prenatal valproic acid-exposed rats

Autism spectrum disorders (ASDs) constitute a neurodevelopmental disorder characterized by social deficits, repetitive behaviors, and learning disability. Oxidative stress and mitochondrial dysfunction are associated with ASD brain pathology. Here, we used oxidative stress in prenatal valproic acid (VPA)-exposed rats as an ASD model. After maternal VPA exposure (600 mg/kg, p.o.) on embryonic day (E) 12.5, temporal analyses of oxidative stress in the brain using an anti-4-hydroxy-2-nonenal antibody revealed that oxidative stress was increased in the hippocampus after birth. This was accompanied by aberrant enzymatic activity in the mitochondrial electron transport chain and reduced adenosine triphosphate (ATP) levels in the hippocampus. VPA-exposed rats exhibited impaired spatial reference and object recognition memory alongside impaired social behaviors and repetitive behaviors. ASD-like behaviors including learning and memory were rescued by chronic oral administration of 5-aminolevulinic acid (5-ALA; 30 mg/kg/day) and intranasal administration of oxytocin (OXT; 12 μg/kg/day), a neuropeptide that improves social behavior in ASD patients. 5-ALA but not OXT treatment ameliorated oxidative stress and mitochondrial dysfunction in the hippocampus of VPA-exposed rats. Fewer parvalbumin-positive interneurons were observed in VPA-exposed rats. Both 5-ALA and OXT treatments augmented the number of parvalbumin-positive interneurons. Collectively, our results indicate that oral 5-ALA administration ameliorated oxidative stress and mitochondrial dysfunction, suggesting that 5-ALA administration improves ASD-like neuropathology and behaviors via mechanisms different to those of OXT.

β-Sitosterol treatment attenuates cognitive deficits and prevents amyloid plaque deposition in amyloid protein precursor/presenilin 1 mice.

Alzheimer's disease (AD) is the most common neurodegenerative disorder causing dementia worldwide, and is mainly characterized by aggregated β-amyloid (Aβ). Increasing evidence has shown that plant extracts have the potential to delay AD development. The plant sterol β-Sitosterol has a potential role in inhibiting the production of platelet Aβ, suggesting that it may be useful for AD prevention. In the present study, we aimed to investigate the effect and mechanism of β-Sitosterol on deficits in learning and memory in amyloid protein precursor/presenilin 1 (APP/PS1) double transgenic mice. APP/PS1 mice were treated with β-Sitosterol for four weeks, from the age of seven months. Brain Aβ metabolism was evaluated using ELISA and Western blotting. We found that β-Sitosterol treatment can improve spatial learning and recognition memory ability, and reduce plaque load in APP/PS1 mice. β-Sitosterol treatment helped reverse dendritic spine loss in APP/PS1 mice and reversed the decreased hippocampal neuron miniature excitatory postsynaptic current frequency. Our research helps to explain and support the neuroprotective effect of β-Sitosterol, which may offer a novel pharmaceutical agent for the treatment of AD. Taken together, these findings suggest that β-Sitosterol ameliorates memory and learning impairment in APP/PS1 mice and possibly decreases Aβ deposition.