Improved Recognition Memory Research Articles

Errorful learning improves recognition memory for new vocabulary for people living with memory and dysexecutive impairment following brain injury

ABSTRACT A widely accepted view is that errorless learning is essential for supporting new learning in people with anterograde amnesia, but findings are mixed for those with a broader range of memory impairments. People at a chronic stage of recovery from brain injury (BI) with impaired memory and executive function (N = 26) were compared with adults in a comparison group without any known risks to brain function (N = 25). Learning techniques were compared using a “Generate-and-correct” and “Read-only” condition when learning novel word pairs. At test, both groups scored above chance and showed benefits of Generate-and-correct (errorful learning). Poor learners in the BI group were classified from “flat” learning slopes extracted from an independent word-pair learning task. Critically, poor learners showed no benefit, but also no decrement to learning, using the Generate-and-correct method. No group was harmed by errorful learning; all, except the poorest learners, benefitted from errorful learning. This study indicates, that in some rehabilitation settings, encouraging clients to guess the meaning of unfamiliar material (e.g., from cards, magazines, newspapers) and then correct their errors, could have benefits for recognition memory. Determining when and how errorful learning benefits learning is a key aim for future research.

Beneficial effects of physical exercise and an orally active mGluR2/3 antagonist pro-drug on neurogenesis and behavior in an Alzheimer's amyloidosis model.

Modulation of physical activity represents an important intervention that may delay, slow, or prevent mild cognitive impairment (MCI) or dementia due to Alzheimer's disease (AD). One mechanism proposed to underlie the beneficial effect of physical exercise (PE) involves the apparent stimulation of adult hippocampal neurogenesis (AHN). BCI-838 is a pro-drug whose active metabolite BCI-632 is a negative allosteric modulator at group II metabotropic glutamate receptors (mGluR2/3). We previously demonstrated that administration of BCI-838 to a mouse model of brain accumulation of oligomeric AβE22Q (APP E693Q = "Dutch APP") reduced learning behavior impairment and anxiety, both of which are associated with the phenotype of Dutch APP mice. 3-month-old mice were administered BCI-838 and/or physical exercise for 1 month and then tested in novel object recognition, neurogenesis, and RNAseq. Here we show that (i) administration of BCI-838 and a combination of BCI-838 and PE enhanced AHN in a 4-month old mouse model of AD amyloid pathology (APP KM670/671NL /PSEN1 Δexon9= APP/PS1), (ii) administration of BCI-838 alone or with PE led to stimulation of AHN and improvement in recognition memory, (iii) the hippocampal dentate gyrus transcriptome of APP/PS1 mice following BCI-838 treatment showed up-regulation of brain-derived neurotrophic factor (BDNF), PIK3C2A of the PI3K-mTOR pathway, and metabotropic glutamate receptors, and down-regulation of EIF5A involved in modulation of mTOR activity by ketamine, and (iv) validation by qPCR of an association between increased BDNF levels and BCI-838 treatment. Our study points to BCI-838 as a safe and orally active compound capable of mimicking the beneficial effect of PE on AHN and recognition memory in a mouse model of AD amyloid pathology.

Phytochemical Extract from Carica papaya Leaves and Punica granatum Seeds as Therapy Against Cognitive Impairment in a Murine Model.

Mild cognitive impairment (MCI) is defined as inter-stage between normal cognitive aging and major neurocognitive disorder (MND). This state of decay is a crucial factor in treatment to prevent the progression to MND. In this study, our group developed a virtual screening process to evaluate 2568 phytochemical compounds against 5 key proteins associated with MCI and MND. As a result, two potential candidates were identified: carpaine, found in Carica papaya leaves, and punicalagin, present in Punica granatum. A model of cognitive impairment (CI) was developed in 10-month-old male Sprague Dawley rats by administering aluminum chloride (AlCl3) at a dose of 100mg/kg/day for 30days. After AlCl3administration period, one of the groups receivedcarpaine and punicalagin in a phytochemical extract (PE) by oral gavage for 30days. Novel object recognition test (NOR) was assessed at three different time points (T1 - before CI, T2 - after CI, and T3 - after PE treatment). Glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) were identified in the hippocampus of rats at the end of the study period. After administration of AlCl3, a reduction in discrimination index vs control rats (CI = 0.012 ± 0.08 vs Control = 0.076 ± 0.03), was observed. After phytochemical extract treatment, a significant increase in discrimination index values was observed in the PE group 0.4643 ± 0.13 vs CI group 0.012 ± 0.08. Additionally, the evaluation of immunohistochemistry showed an increase in GFAP positivity in the hippocampus of the CI groups, while a slight decrease was observed in the PE group. This work addressed a comprehensive methodology that utilized in silico tools to identify phytochemical compounds (carpaine and punicalagin) as potential candidates for affecting key proteins in CI. The phytochemical extract containing carpaine and punicalagin resulted in a trend in the decrease of GFAP expression in the hippocampus and improved recognition memory in rats with CI induced by age and AlCl3 administration.

Suv39h1 Silencing Recovers Memory Decline in Scopolamine-Induced Amnesic Mouse Model.

Histone post-translational modifications play an important role in the regulation of long-term memory and modulation of expression of neuronal immediate early genes (IEGs). The lysine methyltransferase KMT1A/ Suv39h1 (a mammalian ortholog of the Drosophila melanogaster SU (VAR) 3-9) aids in the methylation of histone H3 at lysine 9. We previously reported that age-related memory decline is associated with an increase in Suv39h1 expression in the hippocampus of male mice. The scopolamine-induced amnesic mouse model is a well-known animal model of memory impairment. In the current study, we have made an attempt to find a link between the changes in the H3K9 trimethylation pattern and memory decline during scopolamine-induced amnesia. It was followed by checking the effect of siRNA-mediated silencing of hippocampal Suv39h1 on memory and expression of neuronal IEGs. Scopolamine treatment significantly increased global levels of H3K9me3 and Suv39h1 in the amnesic hippocampus. Suv39h1 silencing in amnesic mice reduced H3K9me3 levels at the neuronal IEGs (Arc and BDNF) promoter, increased the expression of Arc and BDNF in the hippocampus, and improved recognition memory. Thus, these findings suggest that the silencing of Suv39h1 alone or in combination with other epigenetic drugs might be effective for treating memory decline during amnesia.

Moderate-to-vigorous intensity cycling exercise immediately after visual learning enhances delayed recognition memory performance

A single bout of acute aerobic exercise has been shown to improve long-term memory, though it is unclear if exercise before learning or after learning is optimal for memory enhancement. Although some research has demonstrated that exercise before learning is ideal, investigations have consistently shown that acute arousal post-learning is a powerful memory enhancer. Therefore, the purpose of this investigation was to compare the effects of self-perceived hard cycling before or after learning on recognition memory for emotional and neutral images, and examine the relationship between central noradrenergic activity and memory performance. Seventy-two males and females (18–35 years of age) participated in this between-subjects study. Participants were randomly assigned to one of the following groups: exercise before learning, exercise after learning, and control. Participants in the exercise groups engaged in 20 min of cycling at a rating of perceived exertion (RPE) of 15 (“hard”) on the Borg RPE scale before or after viewing a series of 90 pleasant, unpleasant, and neutral images (30 each). Participants in the control group engaged in no exercise before or after image viewing. At several time points throughout the experiment, saliva was collected to measure salivary alpha amylase (sAA), a marker of central noradrenergic activity. One-week later, recognition memory was assessed where participants viewed 180 images (90 new) and had to identify which images were previously viewed. Participants in the exercise after learning group had significantly higher recognition memory compared to the control group, but this was not seen with exercise before learning. sAA was not correlated with memory in any group, though it did increase during exercise. These results demonstrate that acute self-perceived hard cycling post-learning, but not pre-learning, improves recognition memory, though this was unrelated to the exercise-induced increase in central noradrenergic activity as measured in saliva.

Mumefural Improves Recognition Memory and Alters ERK-CREB-BDNF Signaling in a Mouse Model of Chronic Cerebral Hypoperfusion.

Cognitive impairment resulting from chronic cerebral hypoperfusion (CCH) is known as vascular dementia (VaD) and is associated with cerebral atrophy and cholinergic deficiencies. Mumefural (MF), a bioactive compound found in a heated fruit of Prunus mume Sieb. et Zucc, was recently found to improve cognitive impairment in a rat CCH model. However, additional evidence is necessary to validate the efficacy of MF administration for treating VaD. Therefore, we evaluated MF effects in a mouse CCH model using unilateral common carotid artery occlusion (UCCAO). Mice were subjected to UCCAO or sham surgery and orally treated with MF daily for 8 weeks. Behavioral tests were used to investigate cognitive function and locomotor activity. Changes in body and brain weights were measured, and levels of hippocampal proteins (brain-derived neurotrophic factor (BDNF), extracellular signal-regulated kinase (ERK), cyclic AMP-response element-binding protein (CREB), and acetylcholinesterase (AChE)) were assessed. Additionally, proteomic analysis was conducted to examine the alterations in protein profiles induced by MF treatment. Our study showed that MF administration significantly improved cognitive deficits. Brain atrophy was attenuated and MF treatment reversed the increase in AChE levels. Furthermore, MF significantly upregulated p-ERK/ERK, p-CREB/CREB, and BDNF levels after UCCAO. Thus, MF treatment ameliorates CCH-induced cognitive impairment by regulating ERK/CREB/BDNF signaling, suggesting that MF is a therapeutic candidate for treating CCH.

Memory impairment in the D2.mdx mouse model of Duchenne muscular dystrophy is prevented by the adiponectin receptor agonist ALY688.

What is the central question of this study? Can adiponectin receptor agonism improve recognition memory in a mouse model of Duchenne muscular dystrophy? What is the main finding and its importance? Short-term treatment with the new adiponectin receptor agonist ALY688 improves recognition memory in D2.mdx mice. This finding suggests that further investigation into adiponectin receptor agonism is warranted, given that there remains an unmet need for clinical approaches to treat this cognitive dysfunction in people with Duchenne muscular dystrophy. Memory impairments have been well documented in people with Duchenne muscular dystrophy (DMD). However, the underlying mechanisms are poorly understood, and there is an unmet need to develop new therapies to treat this condition. Using a novel object recognition test, we show that recognition memory impairments in D2.mdx mice are completely prevented by daily treatment with the new adiponectin receptor agonist ALY688 from day 7 to 28 of age. In comparison to age-matched wild-type mice, untreated D2.mdx mice demonstrated lower hippocampal mitochondrial respiration (carbohydrate substrate), greater serum interleukin-6 cytokine content and greater hippocampal total tau and Raptor protein contents. Each of these measures was partly or fully preserved after treatment with ALY688. Collectively, these results indicate that adiponectin receptor agonism improves recognition memory in young D2.mdx mice.

Exercise training and BDNF injections alter APP processing enzymes and improve cognition.

Exercise reduces cognitive aging, neurodegeneration, and Alzheimer's disease (AD) risk. Acute exercise reduces the activity of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), the rate limiting enzyme in the production of Aβ. However, mechanisms mediating these effects remain largely unknown. Work has implicated brain-derived neurotrophic factor (BDNF) in the processing of amyloid precursor protein (APP). BDNF is an exercise-induced neurotrophin known for its role in synaptic plasticity, neurite growth, and neuronal survival. Previously, our lab has shown using an ex vivo model that treatment of the prefrontal cortex with BDNF reduced BACE1 activity, highlighting a BDNF to BACE1 link. The purpose of this research was to examine whether BDNF treatments resulted in similar biochemical adaptations to APP processing as exercise training. Male C57BL6/J mice were assigned into one of four groups (n=12/group): 1) control; 2) exercise training (progressive treadmill training 5 days/week); 3) BDNF (0.5 mg/kg body mass subcutaneous injection 5 days/week); or 4) endurance training and BDNF, for an 8-week intervention. Recognition memory was measured with a novel object recognition test. Serum, the prefrontal cortex, and hippocampus were collected. BDNF improved recognition memory to a similar extent as endurance training. BDNF and exercise decreased BACE1 activity and increased ADAM10 activity in the prefrontal cortex, indicating a shift in APP processing. Our novel results indicate that BDNF exerts similar beneficial effects on cognition and APP processing as exercise. Future evidence-based preventative or therapeutic interventions that increase BDNF and reduce BACE1 will be valuable for populations at risk of AD.

The Effects of Acute Resistance Exercise on Memory, Processing Speed, and Mood State After a Cognitive Challenge.

Venezia, AC, Barney, P, Spagnoli, D, Greco-Hiranaka, C, Piepmeier, AT, Smith, JC, and Weiss, LR. The effects of acute resistance exercise on memory, processing speed, and mood state after a cognitive challenge. J Strength Cond Res 37(9): 1738-1745, 2023-Acute moderate-to-vigorous-intensity aerobic exercise has been shown to improve learning and memory, but the effectiveness of acute high-intensity resistance exercise for improving memory is not fully understood. Like acute aerobic exercise, acute resistance exercise increases arousal and circulating catecholamines, mechanisms suggested to mediate the memory-enhancing effects of acute exercise. Furthermore, although acute exercise has been shown to benefit mood state, it is unknown if high-intensity resistance exercise positively influences mood state after a cognitive challenge. In this within-subjects design, subjects (18- to 25-year-old men) completed an approximately 40-minute session of resistance exercise or seated rest. Immediately after, the Automated Neuropsychological Assessment Metrics (ANAM) Code Substitution (CS)-Learning, CS-Immediate Recognition, and CS-Delayed Recognition tasks were completed, followed by the ANAM Mood Scale. There were no significant effects of exercise on recognition memory; however, CS-Learning (attention and processing speed) was better after resistance exercise ( p = 0.03). After the cognitive challenge, restlessness ( p < 0.001), vigor ( p = 0.03), and depression ( p = 0.047) scores were higher after resistance exercise compared with rest; however, after false discovery rate correction, only restlessness remained significantly different between sessions ( q = 0.002), whereas vigor ( q = 0.09) and depression ( q = 0.09) did not. These results suggest that an acute bout of resistance exercise improves attention and processing speed, although it does not improve recognition memory and has mixed effects on mood state in college-aged men.

A Novel Ketone-Supplemented Diet Improves Recognition Memory and Hippocampal Mitochondrial Efficiency in Healthy Adult Mice.

Mitochondrial dysfunction and cognitive impairment are common symptoms in many neurologic and psychiatric disorders, as well as nonpathological aging. Ketones have been suggested as therapeutic for their efficacy in epilepsy and other brain pathologies such as Alzheimer's disease and major depressive disorder. However, their effects on cognitive function in healthy individuals is less established. Here, we explored the mitochondrial and performative outcomes of a novel eight-week ketone-supplemented ketogenic (KETO) diet in healthy adult male and female mice. In a novel object recognition test, KETO mice spent more time with the novel, compared to familiar, object, indicating an improvement in recognition memory. High-resolution respirometry on permeabilized hippocampal tissue returned significant reductions in mitochondrial O2 consumption. No changes in ATP production were observed, yielding a significantly higher ATP:O2 ratio, a measure of mitochondrial efficiency. Together, these findings demonstrate the KETO diet improves hippocampal mitochondrial efficiency. They add to a growing body of evidence that suggests ketones and ketogenic diets are neuroprotective and metabolically and cognitively relevant, even in healthy adults. They also suggest that ketogenic lifestyle changes may be effective strategies for protecting against cognitive decline associated with aging and disease.

The extent and specificity of visual exploration determines the formation of recollected memories in complex scenes.

Our visual memories of complex scenes often appear as robust, detailed records of the past. Several studies have demonstrated that active exploration with eye movements improves recognition memory for scenes, but it is unclear whether this improvement is due to stronger feelings of familiarity or more detailed recollection. We related the extent and specificity of fixation patterns at encoding and retrieval to different recognition decisions in an incidental memory paradigm. After incidental encoding of 240 real-world scene photographs, participants (N = 44) answered a surprise memory test by reporting whether an image was new, remembered (indicating recollection), or just known to be old (indicating familiarity). To assess the specificity of their visual memories, we devised a novel report procedure in which participants selected the scene region that they specifically recollected, that appeared most familiar, or that was particularly new to them. At encoding, when considering the entire scene,subsequently recollected compared to familiar or forgotten scenes showed a larger number of fixations that were more broadly distributed, suggesting that more extensive visual exploration determines stronger and more detailed memories. However, when considering only the memory-relevant image areas, fixations were more dense and more clustered for subsequently recollected compared to subsequently familiar scenes. At retrieval, the extent of visual exploration was more restricted for recollected compared to new or forgotten scenes, with a smaller number of fixations. Importantly, fixation density and clustering was greater in memory-relevant areas for recollected versus familiar or falsely recognized images. Our findings suggest that more extensive visual exploration across the entire scene, with a subset of more focal and dense fixations in specific image areas, leads to increased potential for recollecting specific image aspects.

Instructing Use of an Effective Strategy Improves Recognition Memory in Healthy Adults.

Age-related memory decrements correlate with metacognitive declines, including knowledge and deployment of effective mnemonic encoding strategies. However, whether imparting such strategy suffices for mitigating memory differences is unclear. In a longitudinal study of 276 healthy adults aged 18-79 years, we tested associative and working memory, and assessed beliefs regarding mnemonic strategies. Testing was repeated every 2 years, 5 times. Starting with the third occasion, we instructed participants to use an effective mnemonic strategy (sentence generation). Using continuous-time dynamic modeling, we assessed changes in the item and associative recognition, intervention effects, and their relations with age, sex, meta-memory beliefs, working memory, and metabolic health. Younger age, better working memory, and stronger belief in effective mnemonic strategies predicted better recognition, whereas instructional intervention attenuated associative memory deficits, with some persistence over time. The present findings show merely imparting effective strategies holds promise for mitigating age-related associative memory deficits.

Prenatal alcohol exposure causes persistent microglial activation and age- and sex- specific effects on cognition and metabolic outcomes in an Alzheimer’s Disease mouse model

ABSTRACT Background: Prenatal alcohol exposure (PAE) causes behavioral deficits and increases risk of metabolic diseases. Alzheimer’s Disease (AD) is a neurodegenerative disease that has a higher risk in adults with metabolic diseases. Both present with persistent neuroinflammation. Objectives: We tested whether PAE exacerbates AD-related cognitive decline in a mouse model (3xTg-AD; presenilin/amyloid precursor protein/tau), and assessed associations among cognition, metabolic impairment, and microglial reactivity. Methods: Alcohol-exposed (ALC) pregnant 3xTg-AD mice received 3 g/kg alcohol from embryonic day 8.5–17.5. We evaluated recognition memory and associative memory (fear conditioning) in 8–10 males and females per group at 3 months of age (3mo), 7mo, and 11mo, then assessed glucose tolerance, body composition, and hippocampal microglial activation at 12mo. Results: ALC females had higher body weights than controls from 5mo (p < .0001). Controls showed improved recognition memory at 11mo compared with 3mo (p = .007); this was not seen in ALC mice. Older animals froze more during fear conditioning than younger, and ALC mice were hyper-responsive to the fear-related cue (p = .017). Fasting blood glucose was lower in ALC males and higher in ALC females than controls. Positive associations occurred between glucose and fear-related context (p = .04) and adiposity and fear-related cue (p = .0002) in ALC animals. Hippocampal microglial activation was higher in ALC than controls (p < .0001); this trended to correlate with recognition memory. Conclusions: ALC animals showed age-related cognitive impairments that did not interact with AD risk but did correlate with metabolic dysfunction and somewhat with microglial activation. Thus, metabolic disorders may be a therapeutic target for people with FASDs.

Pharmaceutical Potential of Casein-Derived Tripeptide Met-Lys-Pro: Improvement in Cognitive Impairments and Suppression of Inflammation in APP/PS1 Mice.

Background:Tripeptide Met-Lys-Pro (MKP), a component of casein hydrolysates, has effective angiotensin-converting enzyme (ACE) inhibitory activity. Brain angiotensin II enzyme activates the NADPH oxidase complex via angiotensin II receptor type 1 (AT1) and enhances oxidative stress injury. ACE inhibitors improved cognitive function in Alzheimer’s disease (AD) mouse models and previous clinical trials. Thus, although undetermined, MKP may be effective against pathological amyloid-β (Aβ) accumulation-induced cognitive impairment.Objective:The current study aimed to investigate the potential of MKP as a pharmaceutical against AD by examining MKP’s effect on cognitive function and molecular changes in the brain using double transgenic (APP/PS1) mice.Methods:Experimental procedures were conducted in APP/PS1 mice (n = 38) with a C57BL/6 background. A novel object recognition test was used to evaluate recognition memory. ELISA was used to measure insoluble Aβ40, Aβ42, and TNF-α levels in brain tissue. Immunohistochemical analysis allowed the assessment of glial cell activation in MKP-treated APP/PS1 mice.Results:The novel object recognition test revealed that MKP-treated APP/PS1 mice showed significant improvement in recognition memory. ELISA of brain tissue showed that MKP significantly reduced insoluble Aβ40, Aβ42, and TNF-α levels. Immunohistochemical analysis indicated the suppression of the marker for microglia and reactive astrocytes in MKP-treated APP/PS1 mice.Conclusion:Based on these results, we consider that MKP could ameliorate pathological Aβ accumulation-induced cognitive impairment in APP/PS1 mice. Furthermore, our findings suggest that MKP potentially contributes to preventing cognitive decline in AD.

Temporal Expectation Improves Recognition Memory for Spatially Attended Objects.

Recent evidence suggests that temporal expectation is beneficial to memory formation. Rhythmic presentation of stimuli during encoding enhances subsequent recognition and is associated with distinct neural activity compared with when stimuli are presented in an arrhythmic manner. However, no prior study has examined how temporal expectation interacts with another important form of facilitation-spatial attention-to affect memory. This study systematically manipulated temporal expectation and spatial attention during encoding to examine their combined effect on behavioral recognition and associated ERPs. Participants performed eight experimental blocks consisting of an encoding phase and recognition test, with EEG recorded throughout. During encoding, pairs of objects and checkerboards were presented and participants were cued to attend to the left or right stream and detect targets as quickly as possible. In four blocks, stimulus presentation followed a rhythmic (constant, predictable) temporal structure, and in the other four blocks, stimulus onset was arrhythmic (random, unpredictable). An interaction between temporal expectation and spatial attention emerged, with greater recognition in the rhythmic than the arrhythmic condition for spatially attended items. Analysis of memory-specific ERP components uncovered effects of spatial attention. There were late positive component and FN400 old/new effects in the attended condition for both rhythmic and arrhythmic items, whereas in the unattended condition, there was an FN400 old/new effect and no late positive component effect. The study provides new evidence that memory improvement as a function of temporal expectation is dependent upon spatial attention.

I2-Imidazoline Ligand CR4056 Improves Memory, Increases ApoE Expression and Reduces BBB Leakage in 5xFAD Mice.

Recent evidence suggests that I2-imidazoline ligands have neuroprotective properties in animal models of neurodegeneration, such as Alzheimer’s disease (AD). We recently demonstrated that the I2-ligand BU224 reversed memory impairments in AD transgenic mice and this effect was not because of reductions in amyloid-β (Aβ) deposition. In this study, our aim was to determine the therapeutic potential of the powerful analgesic I2-imidazoline ligand CR4056 in the 5xFAD model of AD, since this ligand has been proven to be safely tolerated in humans. Sub-chronic oral administration of CR4056 (30 mg/kg for 10 days) led to an improvement in recognition memory in 6-month-old 5xFAD mice, but not in wild-type littermates, without affecting Aβ levels or deposition. Our results also revealed a change in the profile of microglia by CR4056, resulting in a suppression of pro-inflammatory activated microglia, but increased the density of astrocytes and the expression of ApoE, which is mainly produced by these glial cells. In addition, CR4056 restored fibrinogen extravasation, affecting the distribution of markers of astrocytic end feet in blood vessels. Therefore, these results suggest that CR4056 protects against Aβ-mediated neuroinflammation and vascular damage, and offers therapeutic potential at any stage of AD.

Interferon beta attenuates recognition memory impairment and improves brain glucose uptake in a rat model of Alzheimer's disease: Involvement of mitochondrial biogenesis and PI3K pathway

Interferon beta (IFNβ) is a cytokine with anti-apoptotic and anti-inflammatory properties, and its beneficial effects on Alzheimer's disease (AD) have been recently shown. The alterations in cerebral glucose uptake are closely linked to memory deficit and AD progression. The current study was designed to determine if IFNβ can improve recognition memory and brain glucose uptake in a rat model of AD. The lentiviruses expressing mutant human amyloid precursor protein were injected bilaterally to the rat hippocampus. From day 23 after virus injection, rats were intranasally treated with recombinant IFNβ protein (68,000 IU/rat) every other day until day 50. Recognition memory performance was evaluated by novel object recognition test on days 46–49. The 18F-2- fluoro-deoxy-d-glucose positron emission tomography (18F-FDG-PET) was used to determine changes in brain glucose metabolism on day 50. The expression of the PI3K/Akt pathway components, neurotrophins and mitochondrial biogenesis factors were also measured by qPCR in the hippocampus. Our results showed that IFNβ treatment improves recognition memory performance in parallel with increased glucose uptake and neuronal survival in the hippocampus of the AD rats. The neuroprotective effect of IFNβ could be attributed, at least partly, to activation of PI3K-Akt-mTOR signaling pathway, increased expression of NGF, and mitochondrial biogenesis. Taken together, our findings suggest the therapeutic potential of IFNβ for AD.

1306-P: In Vivo Downregulation of Pancreatic Amylin in Diabetic Mice Improves Recognition Memory

Hypersecretion of amylin, a β-cell hormone that regulates satiation, is common in individuals with prediabetes and is associated with pancreatic amyloid deposition and type-2 diabetes. Evidence has emerged that increased circulating levels of amyloid-forming human amylin may potentially impair brain function. Because mouse amylin is non-amyloidogenic, we generated transgenic mice with conditional pancreatic expression of amyloid-forming human amylin to study how in vivo knockdown of human amylin expression influences brain function during the development of type-2 diabetes. Males and females were fed a high-fat diet starting at 3 months of age to induce amylin hypersecretion and glucose dysregulation. Males developed hyperglycemia at 5 months of age, whereas females showed glucose dysregulation 3-4 months later. At 5 months of age, human amylin-expressing male mice were randomly assigned to either amylin downregulation (by peritoneal tamoxifen injection) or control (maintained amylin expression) groups (n = 10/group) . Two months later, we assessed brain function with a novel object recognition test and performed comparative non-targeted metabolomics and global RNA-seq analyses of hippocampal tissue. Mice with downregulated human amylin showed enhanced recognition memory index (p &amp;lt; 0.001) and lower blood glucose levels (p &amp;lt; 0.001) compared to those that continued to express human amylin. This was associated with increased hippocampal levels of glycolysis metabolites, including lactic acid (p &amp;lt; 0.01) , glucose-6-phosphate (p = 0.06) , and fructose (p = 0.07) . Hippocampal gene-expression patterns between the two mouse groups revealed extensive compensatory changes in gene expression related to glucose metabolism. In conclusion, amylin downregulation in diabetic mice improves systemic glucose homeostasis and memory. Molecular processes associated with improved memory involve increased hippocampal glycolytic fluxes and compensatory gene expression. Disclosure V.Gopal viswanathan: None. M.Muehlbauer: None. J.R.Bain: Other Relationship; CardioEphEx, LLC. F.Despa: None. N.Verma: None. E.D.Winford: None. D.Kotiya: None. L.E.Radulescu: None. N.Leibold: None. K.C.Chen: None. S.Despa: None. D.A.Hill: None. Funding National Institutes of Health NS116058, AG057290, AG053999

Effects of a ketogenic diet on recognition memory and locomotor activity

Ketones are generally considered neuroprotective and may have therapeutic potential in conditions such as Alzheimer’s and other diseases in which cognition is impaired. The novel object recognition (NOR) assay is a widely‐used test of non‐spatial memory that relies, not on food reward or survival instincts, but on rodents’ innate predisposition to explore in the absence of external stimuli. Here we investigated whether a ketogenic diet (KD) enhances behavioral recognition memory. Adult‐to‐middle‐aged male and female mice were placed on a ketogenic diet supplemented with an exogenous ketone ester for eight weeks and memory was assessed in a two‐object novel object recognition test. We observed trends toward significant improvements in recognition memory (p=0.12) and velocity (p=0.066), and a significant increase in total distance traveled (p=0.047) in the KD mice compared to controls. These data suggest a KD induces beneficial locomotor adaptations, but cognitively, may be more relevant in conditions associated with more severe cognitive deficits.

Treadmill exercise improve recognition memory by TREM2 pathway to inhibit hippocampal microglial activation and neuroinflammation in Alzheimer's disease model

Alzheimer's disease-related cognition impairment is correlated with increased neuroinflammation. Studies show that physical exercises improve cognitive function and regulate neuroinflammation. However, no sufficient studies have been performed to directly observe the mechanism of exercise-related effects on microglia and neuroinflammation, in association with memory function under Alzheimer's disease. This study aims to explore the relationship of TREM2, microglia activation and neuroinflammation in the development of Alzheimer's disease, followed by investigating why physical exercises improve cognition in the Alzheimer's disease model by means of the adeno-associated virus (AAV) injection. We found that: 1) Recognition memory impairment in Aβ-induced Alzheimer's disease model was associated with the reduction in TREM2 which induced microglial activation and neuroinflammation; 2) Exercise activated the TREM2 pathway, which was necessary for inhibiting microglial activation and neuroinflammation, leading to improved recognition memory in the Alzheimer's disease model. Together, the improvement of AD-associated recognition memory by exercises is associated with up-regulation of the TREM2 pathway which promotes the phenotypic conversion of microglia and decreases the level of neuroinflammation.