Short-term Object Recognition Memory Research Articles

A high-salt diet induces synaptic loss and memory impairment via gut microbiota and butyrate in mice.

High-salt diet (HSD)-fed mice display cognitive impairment and lower synaptic proteins via changed gut microbiota composition and short-chain fatty acids production. Gut microbiota from HSD-fed mice impairs memory and synapse in normal salt diet-fed mice. Butyrate treatment partially reverses memory impairment in HSD-fed mice. Above all, this study indicates the important role of the gut microbiome and butyrate production in synaptic loss and memory impairment.

L-Serine Influences Epigenetic Modifications to Improve Cognition and Behaviors in Growth Hormone-Releasing Hormone Knockout Mice.

Neurodegenerative diseases feature changes in cognition, and anxiety-like and autism-like behaviors, which are associated with epigenetic alterations such as DNA methylation and histone modifications. The amino acid L-serine has been shown to have beneficial effects on neurological symptoms. Here, we found that growth hormone-releasing hormone knockout (GHRH-KO) mice, a GH-deficiency mouse model characterized by extended lifespan and enhanced insulin sensitivity, showed a lower anxiety symptom and impairment of short-term object recognition memory and autism-like behaviors. Interestingly, L-serine administration exerted anxiolytic effects in mice and ameliorated the behavioral deficits in GHRH-KO. L-serine treatment upregulated histone epigenetic markers of H3K4me, H3K9ac, H3K14ac and H3K18ac in the hippocampus and H3K4me in the cerebral cortex in both GHRH-KO mice and wild type controls. L-serine-modulated epigenetic marker changes, in turn, were found to regulate mRNA expression of BDNF, grm3, foxp1, shank3, auts2 and marcksl1, which are involved in anxiety-, cognitive- and autism-like behaviors. Our study provides a novel insight into the beneficial effects of L-serine intervention on neuropsychological impairments.

Epigenetic Mechanisms Mediate Nicotine-Induced Reward and Behaviour in Zebrafish.

Nicotine induces long-term changes in the neural activity of the mesocorticolimbic reward pathway structures. The mechanisms involved in this process have not been fully characterized. The hypothesis discussed here proposed that epigenetic regulation participates in the installation of persistent adaptations and long-lasting synaptic plasticity generated by nicotine action on the mesolimbic dopamine neurons of zebrafish. The epigenetic mechanisms induced by nicotine entail histone and DNA chemical modifications, which have been described to lead to changes in gene expression. Among the enzymes that catalyze epigenetic chemical modifications, histone deacetylases (HDACs) remove acetyl groups from histones, thereby facilitating DNA relaxation and making DNA more accessible to gene transcription. DNA methylation, which is dependent on DNA methyltransferase (DNMTs) activity, inhibits gene expression by recruiting several methyl binding proteins that prevent RNA polymerase binding to DNA. In zebrafish, phenylbutyrate (PhB), an HDAC inhibitor, abolishes nicotine rewarding properties together with a series of typical reward-associated behaviors. Furthermore, PhB and nicotine alter long- and short-term object recognition memory in zebrafish, respectively. Regarding DNA methylation effects, a methyl group donor L-methionine (L-met) was found to dramatically reduce nicotine-induced conditioned place preference (CPP) in zebrafish. Simultaneous treatment with DNMT inhibitor 5-aza-2'-deoxycytidine (AZA) was found to reverse the L-met effect on nicotine-induced CPP as well as nicotine reward-specific effects on genetic expression in zebrafish. Therefore, pharmacological interventions that modulate epigenetic regulation of gene expression should be considered as a potential therapeutic method to treat nicotine addiction.

β-Glucan-Rich Extract of Gray Oyster Mushroom, Pleurotus pulmonarius, Improves Object Recognition Memory and Hippocampus Morphology in Mice Fed a High-Fat Diet.

Obesity may cause behavioral alterations, while maternal obesity can contribute to metabolic disorders in subsequent generations. The effect of β-glucan-rich Pleurotus pulmonarius (βgPp) was investigated on mouse neurobehavior and hippocampus and its offspring's hippocampus development. Female ICR mice were fed with normal diet (ND), ND with βgPp, high-fat diet (HFD), or HFD with βgPp for 3 months followed by behavioral test and mating. Immunohistochemistry for the expression of neuronal nuclear protein (NeuN) and ionized calcium binding adaptor molecule-1 (Iba-1) in the hippocampus was carried out. βgPp significantly enhanced short-term object recognition memory in HFD-fed mice. βgPp also ameliorated the histological alterations and neuronal loss and increased Iba-1-positive microglia in the hippocampus regions of HFD-fed mice and their male offspring. These findings demonstrated that βgPp supplementation attenuated the effects of HFD on object recognition memory and the alterations on the hippocampal regions of maternal mice and their male offspring.

Prenatal LPS exposure increases hippocampus IL-10 and prevents short-term memory loss in the male adolescent offspring of high-fat diet fed dams

Lipopolysaccharide (LPS) tolerance can reduce the neuroinflammation caused by high fat maternal diets; however, there are no reports that have evaluated the effects of prenatal LPS exposure on the memories of the offspring of high-fat diet fed dams. This study evaluated the effects of prenatal LPS exposure on the inflammatory parameters and redox status in the brain, as well as the object recognition memory of adolescent offspring of Wistar rat dams that were treated with a high-fat diet during gestation and lactation. Female pregnant Wistar rats randomly received a standard diet (17.5% fat) or a high-fat diet (45.0% fat) during gestation and lactation. On gestation days 8, 10, and 12, half of the females in each group were intraperitoneally treated with LPS (0.1 mg.kg−1). After weaning, the male offspring were placed in cages in standard conditions, and at 6 weeks old, animals underwent the novel object recognition test (for short- and long-term memory). The offspring of the high-fat diet fed dams showed increased hippocampus IL-6 levels (21-days-old) and impaired short-term memories. These effects were avoided in the offspring of high-fat diet fed dams submitted to prenatal LPS exposure, which showed greater hippocampus IL-10 levels (at 21- and 50-days-old), increased antioxidant activity (50-days-old) in the hippocampus and prefrontal cortex, without memory impairments (short- and long-term memory). IL-6 has been consistently implicated in memory deficits and as an endogenous mechanism for limiting plasticity, while IL-10 regulates glial activation and has a strong association with improvements in cognitive function. Prenatal LPS exposure preventing the increase of IL-6 in the hippocampus and the impairment to short-term object recognition memory caused by the high-fat maternal diet.

Perineuronal Net Receptor PTPσ Regulates Retention of Memories.

Perineuronal nets (PNNs) have an important physiological role in the retention of learning by restricting cognitive flexibility. Their deposition peaks after developmental periods of intensive learning, usually in late childhood, and they help in long-term preservation of newly acquired skills and information. Modulation of PNN function by various techniques enhances plasticity and regulates the retention of memories, which may be beneficial when memory persistence entails negative symptoms such as post-traumatic stress disorder (PTSD). In this study, we investigated the role of PTPσ [receptor-type tyrosine-protein phosphatase S, a phosphatase that is activated by binding of chondroitin sulfate proteoglycans (CSPGs) from PNNs] in retention of memories using Novel Object Recognition and Fear Conditioning models. We observed that mice haploinsufficient for PTPRS gene (PTPσ+/–), although having improved short-term object recognition memory, display impaired long-term memory in both Novel Object Recognition and Fear Conditioning paradigm, as compared to WT littermates. However, PTPσ+/– mice did not show any differences in behavioral tests that do not heavily rely on cognitive flexibility, such as Elevated Plus Maze, Open Field, Marble Burying, and Forced Swimming Test. Since PTPσ has been shown to interact with and dephosphorylate TRKB, we investigated activation of this receptor and its downstream pathways in limbic areas known to be associated with memory. We found that phosphorylation of TRKB and PLCγ are increased in the hippocampus, prefrontal cortex, and amygdaloid complex of PTPσ+/– mice, but other TRKB-mediated signaling pathways are not affected. Our data suggest that PTPσ downregulation promotes TRKB phosphorylation in different brain areas, improves short-term memory performance but disrupts long-term memory retention in the tested animal models. Inhibition of PTPσ or disruption of PNN-PTPσ-TRKB complex might be a potential target for disorders where negative modulation of the acquired memories can be beneficial.

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.

Gut microbiota from mice with cerebral ischemia-reperfusion injury affects the brain in healthy mice.

Gut microorganisms can profoundly influence brain function in the host and their behavior. Since altered brain functional connectivity (FC) has been implicated in various cerebrovascular disorders, including cerebral ischemia-reperfusion (I/R) injury, we hypothesized that gut microbiota in mice with cerebral I/R injury would affect brain FC when transplanted into germ-free mice. Metagenomic analysis of germ-free male C57BL/6J mice colonized with microbiota from mice with and without cerebral I/R injury showed a clear distinction in microbiota composition between mice colonized with control and I/R microbiota. The I/R microbiota-colonized mice showed decreased FC in the cingulate cortex, hippocampus, and thalamus, and exhibited increased anxiety as well as diminished spatial learning and memory and short-term object recognition memory. I/R microbiota-colonized mice also had significantly reduced dendritic spine density and synaptic protein levels and exhibited increased hippocampal inflammation. These results indicate that gut microbiota components from mice with cerebral I/R injury can alter animal behavior, brain functional connectivity, hippocampal neuronal plasticity, and neuroinflammation. Moreover, they increase our understanding of the mechanisms through which the gut microbiome contributes to the pathobiology of cerebrovascular diseases.

Estradiol effect on short-term object memory under hypocholinergic condition

Estrogens positively affect object recognition memory (ORM). However, whether this effect rely on acetylcholine is unknown. Here we investigated if 17β-estradiol (E2) would be able to recover ORM deficits in animals with decreased expression of the Vesicular Acetylcholine Transporter (VAChT KDHET). We found that E2 improved short-term ORM (STM) in VAChT KDHET male and in OVX female mutant mice. However, E2 did not recover long-term (LTM) ORM in both sexes. Next, we tested whether hippocampal ERs activation could also rescue STM in mutant mice. Our results showed that ERα seems to be both sufficient and necessary for STM consolidation in female VAChT KDHET. Differently, in male, both ERα and ERβ activation recovered STM. In addition, we tested whether mRNA level of estrogen receptors (ER) is also sensitive to VAChT expression. Female mutant mice showed lower levels of ER alpha (ERα) mRNA in the hippocampus, while no differences in male were observed. Together, our results showed that under hypocholinergic function, E2 improve short-term object recognition in both male and female. Furthermore, we showed that changes in VAChT expression might potentially modulate hippocampal ERα expression in a sex-dependent-manner.

Loop F of the GABAA receptor alpha subunit governs GABA potency

Gamma-amino butyric acid (GABA) is an abundant neurotransmitter in the CNS. GABAergic interneurons orchestrate pyramidal neurons in the cerebral cortex, and thus control learning and memory. Ionotropic receptors for GABA (GABAAR) are heteropentameric complexes of α, β and γ integral membrane-protein subunits forming Cl− -channels operated by GABA, which are vital for brain function and are important drug targets. However, knowledge on how GABAAR bind GABA is controversial. Structural biology versus functional modelling combined with site-directed mutagenesis suggest markedly different roles for loop F of the extracellular domain of the α-subunit when complexed with GABA. Here, we report that contrary to the results of structural studies, loop F of the α-subunit controls the potency of GABA on GABAAR. We examined the effect of replacing a short, variable segment of loop F of the GABAA α5-subunit with the corresponding segment of the α2-subunit (GABAA5_LF2) and vice versa (GABAA2-LF5). When compared with their respective wild-type counterparts, GABAA5_LF2 receptors displayed enhanced sensitivity towards GABA, whilst in GABAA2-LF5 sensitivity was diminished. Mice homozygous for the genetic knock-in of the GABAA5_LF2 subunit showed a marked deficit in long- but not short-term object recognition memory. Working memory in place learning, spontaneous alternation and the rewarded T-maze were all normal. The deficit in long-term recognition memory was reversed by an α5-GABAA negative allosteric modulator compound. The data show that loop F governs GABA potency in a receptor isoform-specific manner in vitro. Moreover, this mechanism of ligand recognition appears to be operative in vivo and impacts cognitive performance.

Hippocampal Protein Kinase C Signaling Mediates the Short-Term Memory Impairment Induced by Delta9-Tetrahydrocannabinol.

Cannabis affects cognitive performance through the activation of the endocannabinoid system, and the molecular mechanisms involved in this process are poorly understood. Using the novel object-recognition memory test in mice, we found that the main psychoactive component of cannabis, delta9-tetrahydrocannabinol (THC), alters short-term object-recognition memory specifically involving protein kinase C (PKC)-dependent signaling. Indeed, the systemic or intra-hippocampal pre-treatment with the PKC inhibitors prevented the short-term, but not the long-term, memory impairment induced by THC. In contrast, systemic pre-treatment with mammalian target of rapamycin complex 1 inhibitors, known to block the amnesic-like effects of THC on long-term memory, did not modify such a short-term cognitive deficit. Immunoblot analysis revealed a transient increase in PKC signaling activity in the hippocampus after THC treatment. Thus, THC administration induced the phosphorylation of a specific Ser residue in the hydrophobic-motif at the C-terminal tail of several PKC isoforms. This significant immunoreactive band that paralleled cognitive performance did not match in size with the major PKC isoforms expressed in the hippocampus except for PKCθ. Moreover, THC transiently enhanced the phosphorylation of the postsynaptic calmodulin-binding protein neurogranin in a PKC dependent manner. These data demonstrate that THC alters short-term object-recognition memory through hippocampal PKC/neurogranin signaling.

Divergent short- and long-term effects of acute stress in object recognition memory are mediated by endogenous opioid system activation

Acute stress induces short-term object recognition memory impairment and elicits endogenous opioid system activation. The aim of this study was thus to evaluate whether opiate system activation mediates the acute stress-induced object recognition memory changes. Adult male Wistar rats were trained in an object recognition task designed to test both short- and long-term memory. Subjects were randomly assigned to receive an intraperitoneal injection of saline, 1mg/kg naltrexone or 3mg/kg naltrexone, four and a half hours before the sample trial. Five minutes after the injection, half the subjects were submitted to movement restraint during four hours while the other half remained in their home cages. Non-stressed subjects receiving saline (control) performed adequately during the short-term memory test, while stressed subjects receiving saline displayed impaired performance. Naltrexone prevented such deleterious effect, in spite of the fact that it had no intrinsic effect on short-term object recognition memory. Stressed subjects receiving saline and non-stressed subjects receiving naltrexone performed adequately during the long-term memory test; however, control subjects as well as stressed subjects receiving a high dose of naltrexone performed poorly. Control subjects’ dissociated performance during both memory tests suggests that the short-term memory test induced a retroactive interference effect mediated through light opioid system activation; such effect was prevented either by low dose naltrexone administration or by strongly activating the opioid system through acute stress. Both short-term memory retrieval impairment and long-term memory improvement observed in stressed subjects may have been mediated through strong opioid system activation, since they were prevented by high dose naltrexone administration. Therefore, the activation of the opioid system plays a dual modulating role in object recognition memory.

Short-term object recognition memory in the rat: Nonmatching with trial-unique junk stimuli.

Short-term object recognition memory in the rat: Nonmatching with trial-unique junk stimuli.

Short-term object recognition memory in the rat: nonmatching with trial-unique junk stimuli.

A delayed nonmatching-to-sample task with trial-unique stimuli (DNMS), similar to that used to test object recognition memory in primates, was adapted for use with rats. For each trial of the DNMS task, two stimuli were randomly selected from a pool of 250 small "junk" objects; one member of the pair was designated as the sample. On the first part of a trial, the rat traversed an elevated runway and displaced the sample for food reward. After a 10-s delay, the rat again traversed the runway to choose between the previously presented sample and the second member of the pair. Reward on the choice trial followed selection of the new object. Scores on the first day of DNMS were significantly above chance, and animals could consistently perform at approximately 75% accuracy. Extending the delay to 30 or 120 s lowered choice accuracy, but performance was still above chance. The DNMS taks for rats, unlike most other memory tests for rodents, does not require memory for spatial location. The similarity to tests used with primates should allow for more direct comparison of results of memory research across species.