Long-term Object Recognition Memory Research Articles

Dysregulating mTORC1-4E-BP2 signaling in GABAergic interneurons impairs hippocampus-dependent learning and memory.

Memory formation is contingent on molecular and structural changes in neurons in response to learning stimuli-a process known as neuronal plasticity. The initiation step of mRNA translation is a gatekeeper of long-term memory by controlling the production of plasticity-related proteins in the brain. The mechanistic target of rapamycin complex 1 (mTORC1) controls mRNA translation, mainly through phosphorylation of the eukaryotic initiation factor 4E (eIF4E)-binding proteins (4E-BPs) and ribosomal protein S6 kinases (S6Ks). mTORC1 signaling decreases throughout brain development, starting from the early postnatal period. Here, we discovered that in mice, the age-dependent decrease in mTORC1 signaling occurs selectively in excitatory but not inhibitory neurons. Using a gene conditional knockout (cKO) strategy, we demonstrate that either up- or downregulating the mTORC1-4E-BP2 axis in GAD65 inhibitory interneurons, but not excitatory neurons, results in long-term object recognition and object location memory deficits. Our data indicate that the mTORC1 pathway in inhibitory but not excitatory neurons plays a key role in memory formation.

Dnmt3a1 regulates hippocampus-dependent memory via the downstream target Nrp1

Epigenetic factors are well-established players in memory formation. Specifically, DNA methylation is necessary for the formation of long-term memory in multiple brain regions including the hippocampus. Despite the demonstrated role of DNA methyltransferases (Dnmts) in memory formation, it is unclear whether individual Dnmts have unique or redundant functions in long-term memory formation. Furthermore, the downstream processes controlled by Dnmts during memory consolidation have not been investigated. In this study, we demonstrated that Dnmt3a1, the predominant Dnmt in the adult brain, is required for long-term spatial object recognition and contextual fear memory. Using RNA sequencing, we identified an activity-regulated Dnmt3a1-dependent genomic program in which several genes were associated with functional and structural plasticity. Furthermore, we found that some of the identified genes are selectively dependent on Dnmt3a1, but not its isoform Dnmt3a2. Specifically, we identified Neuropilin 1 (Nrp1) as a downstream target of Dnmt3a1 and further demonstrated the involvement of Nrp1 in hippocampus-dependent memory formation. Importantly, we found that Dnmt3a1 regulates hippocampus-dependent memory via Nrp1. In contrast, Nrp1 overexpression did not rescue memory impairments triggered by reduced Dnmt3a2 levels. Taken together, our study uncovered a Dnmt3a-isoform-specific mechanism in memory formation, identified a novel regulator of memory, and further highlighted the complex and highly regulated functions of distinct epigenetic regulators in brain function.

A role of frontal association cortex in long-term object recognition memory of objects with complex features in rats.

Perirhinal cortex is a brain area that has been considered crucial for the object recognition memory (ORM). However, with the use of an ORM enhancer named RGS14414 as gain-in-function tool, we show here that frontal association cortex and not the Perirhinal cortex is essential for the ORM of objects with complex features that consisted of detailed drawing on the object surface (complex ORM). An expression of RGS14414, in rat brain frontal association cortex, induced the formation of long-term complex ORM, whereas the expression of the same memory enhancer in Perirhinal cortex failed to produce this effect. Instead, RGS14414 expression in Perirhinal cortex caused the formation of ORM of objects with simple features that consisted of the shape of object (simple ORM). Further, a selective elimination of frontal association cortex neurons by treatment with an immunotoxin Ox7-SAP completely abrogated the formation of complex ORM. Thus, our results suggest that frontal association cortex plays a key role in processing of a high-order recognition memory information in brain.

After-effects of repetitive transcranial magnetic stimulation with parameter dependence on long-term potentiation-like plasticity and object recognition memory in rats.

To investigate the after-effects of 25-Hz repetitive transcranial magnetic stimulation (rTMS) at 60, 100, and 120% resting motor threshold (rMT) on long-term potentiation (LTP) in the rat hippocampus, to clarify the intensity dependence of rTMS, and to determine whether it simultaneously affects learning and memory ability. Five rats were randomly selected from 70 male Wistar rats, and evoked rMT potentials were recorded in response to magnetic stimulation. The remaining 65 rats were randomly assigned to five groups (n = 13), including sham rTMS, 1 Hz 100% rMT, and 25 Hz rTMS groups with 3 subgroups of 60% rMT, 100% rMT, and 120% rMT. Five rats in each group were anesthetized and induced by a priming TMS-test design for population spike (PS) response of the perforant path-dentate gyrus in the hippocampus; the remaining eight rats in each group were evaluated for object recognition memory in the novel object recognition (NOR) task after the different rTMS protocols. Forty-five percent (approximately 1.03 T) of the magnetic stimulator output was confirmed as rMT in the biceps femoris muscle. The PS ratio was ranked as follows: 25 Hz 100% rMT (267.78 ± 25.71%) > sham rTMS (182 ± 9.4%) >1 Hz 100% rMT (102.69 ± 6.64%) > 25 Hz 120% rMT (98 ± 11.3%) > 25 Hz 60% rMT (36 ± 8.5%). Significant differences were observed between the groups, except for the difference between the 25 Hz 120% rMT and the 1 Hz 100% rMT groups (p = 0.446). LTP was successfully induced over the 60-min recording period only in the sham rTMS and 25 Hz 100% rMT groups. Moreover, these two groups spent more time exploring a novel object than a familiar object during the NOR task (p < 0.001), suggesting long-term recognition memory retention. In the between-group analysis of the discrimination index, the following ranking was observed: 25 Hz 100% rMT (0.812 ± 0.158) > sham rTMS (0.653 ± 0.111) > 25 Hz 120% rMT (0.583 ± 0.216) >1 Hz 100% rMT (0.581 ± 0.145) > 25 Hz 60% rMT (0.532 ± 0.220). The after-effect of 25-Hz rTMS was dependent on stimulus intensity and provided an inverted (V-shaped) bidirectional modulation on hippocampal plasticity that involved two forms of metaplasticity. Furthermore, the effects on the recognition memory ability were positively correlated with those on LTP induction in the hippocampus in vivo.

Effects of melatonin on phosphorylation of memory-related proteins in the hippocampus and the perirhinal cortex in male mice.

We recently demonstrated that a single post-training administration of either melatonin, an MT1/MT2 melatonin receptor agonist ramelteon, or a brain melatonin metabolite N1-acetyl-5-methoxyquinuramine (AMK) enhanced object recognition memory. The present study aims to investigate the effects of melatonin, ramelteon, and AMK on relative phosphorylation levels of memory-related proteins in order to explore candidate signaling pathways associated with the receptor-mediated and nonreceptor-mediated memory-enhancing effects of melatonin. We first confirmed that post-training administration of either melatonin, ramelteon, or AMK at 1 mg/kg promoted long-term memory formation, using the novel object recognition task. Next, the effects of the same doses of these drugs on relative phosphorylation levels of the extracellular signal-regulated kinase (ERK) and calcium/calmodulin-dependent kinases (CaMKs) in the hippocampus and the perirhinal cortex (PRC) were examined by western blot analysis. In the hippocampus, treatment with ramelteon or AMK significantly increased and decreased phosphorylation levels of ERK and cAMP-response element binding protein (CREB) and those of CaMKIIα and β, respectively. In the PRC, phosphorylation levels of ERK and those of CaMKIIβ were significantly increased by both ramelteon and AMK and by ramelteon, respectively. Neither ramelteon nor AMK altered the phosphorylation levels of CaMKIV in either hippocampus or PRC. These results suggest that melatonin may be involved in promoting the formation of long-term object recognition memory in a similar, if not identical, manner by modulating the phosphorylation levels of memory-related proteins such as ERK, CaMKIIs, and CREB in both receptor-mediated and nonreceptor-mediated signaling pathways.

Kratom (M. speciosa) exposure during adolescence caused long-lasting cognitive behavioural deficits associated with perturbated brain metabolism pathways in adult rats

Kratom (M. speciosa Korth) is an herbal plant native to Southeast Asia. The leaves have been widely used to alleviate pain and opioid withdrawal symptoms. However, the increasing trend of recreational use of kratom among youth is concerning because substance abuse may render the adolescent brain more susceptible to neuropathological processes, causing dramatic consequences that persist into adulthood. Therefore, the present study aimed to investigate the long-term effects of mitragynine, the main alkaloid and lyophilized kratom decoction (LKD) exposure during adolescence on cognitive behaviours and brain metabolite profiles in adult rats. Adolescent male Sprague-Dawley rats were given mitragynine (3, 10 or 30 mg/kg) or LKD orally for 15 consecutive days during postnatal days 31–45 (PND31–45). Behavioural testing was performed during adulthood (PND70–84) and the brains were subjected to metabolomic analysis. The results show that a high dose of mitragynine impaired long-term object recognition memory. Social behaviour and spatial learning were not affected, but both mitragynine and LKD impaired reference memory. Brain metabolomic study revealed several altered metabolic pathways that may be involved in the cognitive behavioural effects of LKD and mitragynine exposure. These pathways include arachidonic acid, taurine and hypotaurine, pantothenate and CoA biosynthesis, and tryptophan metabolism, while the N-isovalerylglycine was identified as the potential biomarker. In summary, adolescent kratom exposure can cause long-lasting cognitive behavioural deficits and alter brain metabolite profiles that are still evident in adulthood. This finding also indicates that the adolescent brain is vulnerable to the impact of early kratom use.

N-acetyl-5-methoxykynuramine enhance object location and working memory performances via modulating CaMKII, ERK and CREB phosphorylation.

Melatonin (MEL) has been reported to enhance cognitive performance. Recently, we have demonstrated that a MEL metabolite N-acetyl-5-methoxykynuramine (AMK) promoted the formation of long-term object recognition memory more potently than MEL. Here, we examined the effects of 1 mg/kg MEL and AMK on both object location memory and spatial working memory. We also investigated the effects of the same dose of these drugs on relative phosphorylation/activation levels of memory-related proteins in the hippocampus (HP), the perirhinal cortex (PRC) and the medial prefrontal cortex (mPFC). Object location memory and spatial working memory were assessed using the object location task and the Y-maze spontaneous alternation task, respectively. Relative phosphorylation/activation levels of memory-related proteins were assessed using western blot analysis. AMK, as well as MEL, enhanced object location memory and spatial working memory. AMK increased the phosphorylation of cAMP-response element-binding protein (CREB) in both the HP and the mPFC 2 h after the treatment. AMK also increased the phosphorylation of extracellular signal-regulated kinases (ERKs) but decreased that of Ca2+/calmodulin-dependent protein kinases II (CaMKIIs) in the PRC and the mPFC 30 min after the treatment. MEL increased CREB phosphorylation in the HP 2 h after the treatment, whereas no detectable changes in the other proteins examined were observed. These results suggested the possibility that AMK exerts stronger memory-enhancing effects than MEL by more remarkably altering the activation of memory-related proteins such as ERKs, CaMKIIs and CREB in broader brain regions, including the HP, mPFC and PRC, compared to MEL.

Isoform-specific effects of neuronal repression of the AMPK catalytic subunit on cognitive function in aged mice.

AMP-activated protein kinase (AMPK) functions as a molecular sensor that plays a critical role in maintaining cellular energy homeostasis. Dysregulation of the AMPK signaling has been linked to synaptic failure and cognitive impairments. Our recent study demonstrates abnormally increased AMPK activity in the hippocampus of aged mice. The kinase catalytic subunit of AMPK exists in two isoforms α1 and α2, and their specific roles in aging-related cognitive deficits are unknown. Taking advantage of the unique transgenic mice (AMPKα1/α2 cKO) recently developed by our group, we investigated how isoform-specific suppression of the neuronal AMPKα may contribute to the regulation of cognitive and synaptic function associated with aging. We found that aging-related impairment of long-term object recognition memory was improved with suppression of AMPKα1 but not AMPKα2 isoform. Moreover, aging-related spatial memory deficits were unaltered with suppression of either AMPKα isoform. Biochemical experiments showed that the phosphorylation levels of the eukaryotic initiation factor 2 α subunit (eIF2α) were specifically decreased in the hippocampus of the AMPKα1 cKO mice. We further performed large-scale unbiased proteomics analysis and revealed identities of proteins whose expression is differentially regulated with AMPKα isoform suppression. These novel findings may provide insights into the roles of AMPK signaling pathway in cognitive aging.

Effects of endogenous and exogenous N-acetyl-5-methoxy kynuramine on object recognition memory in male C3H mice

Prevention of dementia is important, because it is a leading cause of disability in elderly people. We previously reported that acute intraperitoneal treatment with N-acetyl-5-methoxy kynuramine (AMK), a melatonin (MEL) metabolite, enhanced long-term object recognition memory in ICR mice, a MEL deficient strain. Despite the presumable availability of AMK for dementia, its effects on cognitive performance have not been elucidated. It is unclear whether endogenous AMK is responsible for modulating long-term memory performance. To address this question, we assessed the effects of endogenous AMK on learning and memory using an object recognition test. C3H mice, a MEL-proficient strain, showed peak MEL levels at zeitgeber times (ZT) 19 and 22. Object recognition memory at ZT20 was superior to that at ZT8. Norharmane (NHM, 100 mg/kg), an indoleamine-2,3-dioxygenase (IDO) inhibitor, prevented the transformation of MEL to AMK, thereby suppressing AMK synthesis at ZT20. NHM (100 mg/kg) and another IDO inhibitor, 1-methyl-L-tryptophan (1-MT, 100 mg/kg), disrupted elevated cognitive performance at ZT20. These data imply that endogenous AMK may play a physiological role in the modulation of cognitive function. We also investigated the effects of pharmacological doses of MEL and AMK on object recognition memory in young C3H mice. MEL administration of 0.1 mg/kg, but not 0.01 mg/kg, enhanced object recognition memory, whereas 0.01 and 1 mg/kg AMK enhanced object recognition memory. Administration of 0.1 and 1 mg/kg AMK also enhanced object recognition memory in old C3H mice. These findings in MEL-proficient mice should be confirmed in other learning and memory tests before encouraging the clinical use of AMK.

Social recognition, short-term and long-term object recognition memory in CYP2C19 humanised transgenic mice

Social recognition, short-term and long-term object recognition memory in CYP2C19 humanised transgenic mice

Infusing zeta inhibitory peptide into the perirhinal cortex of rats abolishes long-term object recognition memory without affecting novel object location recognition.

Infusing the amnesic agent zeta inhibitory peptide (ZIP) into the dorsal hippocampus disrupts established long-term object location recognition memory without affecting object identity recognition, which likely depends on the perirhinal cortex. Here, we tested whether infusing ZIP into the perirhinal cortex can abolish long-term memory supporting object identity recognition, leaving long-term object location recognition memory intact. We infused ZIP into the perirhinal cortex of rats either 1 day or 6 days after exposing them to two identical objects in an open field arena. One day after ZIP infusion, that is, 2 or 7 days after object exposure, we either assessed whether the animals recognized that now one of the two objects was novel or whether they recognized that one of the two familiar objects was at a new location. Our results show for both retention intervals, infusions of ZIP into the perirhinal cortex impaired novel object recognition but spared novel object location recognition. Rats that received a scrambled version of ZIP had no deficit in either test at both retention intervals and expressed stronger novel object recognition compared to rats infused with ZIP. These findings support the view that object recognition depends on dissociable memory representations distributed across different brain areas, with perirhinal cortex maintaining long-term memory for what objects had been encountered, and hippocampus supporting memory for where these objects had been placed.

Two distinct ways to form long-term object recognition memory during sleep and wakefulness

Memory consolidation is promoted by sleep. However, there is also evidence for consolidation into long-term memory during wakefulness via processes that preferentially affect nonhippocampal representations. We compared, in rats, the effects of 2-h postencoding periods of sleep and wakefulness on the formation of long-term memory for objects and their associated environmental contexts. We employed a novel-object recognition (NOR) task, using object exploration and exploratory rearing as behavioral indicators of these memories. Remote recall testing (after 1 wk) confirmed significant long-term NOR memory under both conditions, with NOR memory after sleep predicted by the occurrence of EEG spindle-slow oscillation coupling. Rats in the sleep group decreased their exploratory rearing at recall testing, revealing successful recall of the environmental context. By contrast, rats that stayed awake after encoding showed equally high levels of rearing upon remote testing as during encoding, indicating that context memory was lost. Disruption of hippocampal function during the postencoding interval (by muscimol administration) suppressed long-term NOR memory together with context memory formation when animals slept, but enhanced NOR memory when they were awake during this interval. Testing remote recall in a context different from that during encoding impaired NOR memory in the sleep condition, while exploratory rearing was increased. By contrast, NOR memory in the wake rats was preserved and actually superior to that after sleep. Our findings indicate two distinct modes of long-term memory formation: Sleep consolidation is hippocampus dependent and implicates event-context binding, whereas wake consolidation is impaired by hippocampal activation and strengthens context-independent representations.

Functional connectivity of anterior retrosplenial cortex in object recognition memory

Recognition memory can rely on three components: “what”, “where” and “when”. Recently we demonstrated that the anterior retrosplenial cortex (aRSC), like the perirhinal cortex (PRH) and unlike the hippocampus (HP), is required for consolidation of the “what” component. Here, we aimed at studying which brain structures interact with the aRSC to process object recognition (OR) memory in rats. We studied the interaction of six brain structures that are connected to the aRSC during OR memory processing: PRH, medial prefrontal cortex (mPFC), anteromedial thalamic nuclei (AM), medial entorhinal cortex (MEC), anterior cingulate cortex (ACC) and the dorsal HP (dHP). We previously described the role of the PRH and dHP, so we first studied the participation of the mPFC, AM, MEC and ACC in OR memory consolidation by bilateral microinfusions of the GABAA receptor agonist muscimol. We observed an impairment in OR long-term memory (LTM) when inactivating the mPFC, the AM and the MEC, but not the ACC. Then, we studied the functional connections by unilateral inactivation of the aRSC and each one of the six structures in the same (ipsilateral) or the opposite (contralateral) hemisphere. Our results showed an amnesic LTM effect in rats with ipsilateral inactivations of aRSC-PRH, aRSC-mPFC, aRSC-AM, or aRSC-MEC. On the other hand, we observed memory impairment when aRSC-ACC were inactivated in opposite hemispheres, and no effect when the aRSC-dHP connection was inactivated. Thus, our ipsilateral inactivation findings reveal that the aRSC and, at least one brain region required in OR LTM processing are essential to consolidate OR memory. In conclusion, our results show that several cortico-cortical and cortico-thalamic pathways are important for OR memory consolidation.

Persistent exercise fatigue and associative learning deficits in combination with transient glucose dyshomeostasis in a mouse model of Gulf War Illness

AimsTo characterize exercise fatigue, metabolic phenotype and cognitive and mood deficits correlated with brain neuroinflammatory and gut microbiome changes in a chronic Gulf War Illness (GWI) mouse model. The latter have been described in an accompanying paper [1]. Main methodsAdult male C57Bl/6N mice were exposed for 28 days (5 days/week) to pyridostigmine bromide: 6.5 mg/kg, b.i.d., P.O. (GW1) or 8.7 mg/kg, q.d., P.O. (GW2); topical permethrin (1.3 mg/kg in 100% DMSO) and N,N-diethyl-meta-toluamide (DEET 33% in 70% EtOH) and restraint stress (5 min). Exercise, metabolic and behavioral endpoints were compared to sham stress control (CON/S). Key findingsRelative to CON/S, GW2 presented persistent exercise intolerance (through post-treatment (PT) day 161), deficient associative learning/memory, and transient insulin insensitivity. In contrast to GW2, GW1 showed deficient long-term object recognition memory, milder associative learning/memory deficit, and behavioral despair. SignificanceOur findings demonstrate that GW chemicals dose-dependently determine the presentation of exercise fatigue and severity/type of cognitive/mood-deficient phenotypes that show persistence. Our comprehensive mouse model of GWI recapitulates the major multiple symptom domains characterizing GWI, including fatigue and cognitive impairment that can be used to more efficiently develop diagnostic tests and curative treatments for ill Gulf War veterans.

Major role of MT2 receptors in the beneficial effect of melatonin on long-term recognition memory in C57BL/6J male mice

Melatonin, a major signal of the circadian system, is also involved in brain functions such as learning and memory. Chronic melatonin treatment is known to improve memory performances, but the respective contribution of its central receptors, MT1 and MT2, is still unclear. Here, we used new single receptor deficient MT1-/- and MT2-/- mice to investigate the contribution of each receptor in the positive effect of chronic melatonin treatment on long-term recognition memory. The lack of MT2 receptor precluded memory-enhancing effect of melatonin in the object recognition task and to a lesser extent in the object location task, whereas the lack of MT1 receptor mitigated its effect in the object location task only. Our findings support a key role of MT2 in mediating melatonin's beneficial action on long-term object recognition memory, whereas MT1 may contribute to the effect on object location memory.

14-3-3ζ is crucial for the conversion of labile short-term object recognition memory into stable long-term memory.

The consolidation of new memories into long-lasting memories is multistage process characterized by distinct temporal dynamics. However, our understanding on the initial stage of transformation of labile memory of recent experience into stable memory remains elusive. Here, with the use of rats and mice overexpressing a memory enhancer called regulator of G protein signaling 14 of 414 amino acids (RGS14414 ) as a tool, we show that the expression of RGS14414 in male rats' perirhinal cortex (PRh), which is a brain area crucial for object recognition memory (ORM), enhanced the ORM to the extent that it caused the conversion of labile short-term ORM (ST-ORM) expected to last for 40min into stable long-term ORM (LT-ORM) traceable after a delay of 24hr, and that the temporal window of 40 to 60min after object exposure not only was key for this conversion but also was the time frame when a surge in 14-3-3ζ protein was observed. A knockdown of 14-3-3ζ gene abrogated both the increase in 14-3-3ζ protein and the formation of LT-ORM. Furthermore, this 14-3-3ζ upregulation increased brain-derived growth factor (BDNF) levels in the time frame of 60min and 24hr and 14-3-3ζ knockdown decreased the BDNF levels, and a deletion of BDNF gene produced loss in mice ability to form LT-ORM. Thus, within 60min of object exposure, 14-3-3ζ facilitated the conversion of labile ORM into stable ORM, whereas beyond the 60min, it mediated the consolidation of the stable memory into long-lasting ORM by regulating BDNF signaling.

Amphetamine Modulation of Long-Term Object Recognition Memory in Rats: Influence of Stress.

Amphetamine is a potent psychostimulant that increases brain monoamine levels. Extensive evidence demonstrated that norepinephrine is crucially involved in the regulation of memory consolidation for stressful experiences. Here, we investigated amphetamine effects on the consolidation of long-term recognition memory in rats exposed to different intensities of forced swim stress immediately after training. Furthermore, we evaluated whether such effects are dependent on the activation of the peripheral adrenergic system. To this aim, male adult Sprague Dawley rats were subjected to an object recognition task and intraperitoneally administered soon after training with amphetamine (0.5 or 1 mg/kg), or its corresponding vehicle. Rats were thereafter exposed to a mild (1 min, 25 ± 1°C) or strong (5 min, 19 ± 1°C) forced swim stress procedure. Recognition memory retention was assessed 24-h after training. Our findings showed that amphetamine enhances the consolidation of memory in rats subjected to mild stress condition, while it impairs long-term memory performance in rats exposed to strong stress. These dichotomic effects is dependent on stress-induced activation of the peripheral adrenergic response.

Chemogenetic silencing of hippocampus and amygdala reveals a double dissociation in periadolescent obesogenic diet-induced memory alterations

In addition to numerous metabolic comorbidities, obesity is associated with several adverse neurobiological outcomes, especially learning and memory alterations. Obesity prevalence is rising dramatically in youth and is persisting in adulthood. This is especially worrying since adolescence is a crucial period for the maturation of certain brain regions playing a central role in memory processes such as the hippocampus and the amygdala. We previously showed that periadolescent, but not adult, exposure to obesogenic high-fat diet (HFD) had opposite effects on hippocampus- and amygdala-dependent memory, impairing the former and enhancing the latter. However, the causal role of these two brain regions in periadolescent HFD-induced memory alterations remains unclear. Here, we first showed that periadolescent HFD induced long-term, but not short-term, object recognition memory deficits, specifically when rats were exposed to a novel context. Using chemogenetic approaches to inhibit targeted brain regions, we then demonstrated that recognition memory deficits are dependent on the activity of the ventral hippocampus, but not the basolateral amygdala. On the contrary, the HFD- induced enhancement of conditioned odor aversion specifically requires amygdala activity. Taken together, these findings suggest that HFD consumption throughout adolescence impairs long-term object recognition memory through alterations of ventral hippocampal activity during memory acquisition. Moreover, these results further highlight the bidirectional effects of adolescent HFD on hippocampal and amygdala functions.

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 Reversal of Memory Deficits in an Alzheimer's Disease Model Using Physical and Cognitive Exercise.

Alzheimer’s disease (AD) is the leading cause of dementia in the world, accounting for 50–75% of cases. Currently, there is limited treatment for AD. The current pharmacological therapy minimizes symptom progression but does not reverse brain damage. Studies focused on nonpharmacological treatment for AD have been developed to act on brain plasticity and minimize the neurotoxicity caused by the amyloid-beta (Aβ) peptide. Using a neurotoxicity model induced by Aβ in rats, the present study shows that physical (PE) and cognitive exercise (CE) reverse recognition memory deficits (with a prominent effect of long-term object recognition memory), decrease hippocampal lipid peroxidation, restore the acetylcholinesterase activity altered by Aβ neurotoxicity, and seems to reverse, at least partially, hippocampal tissue disorganization.