The existence of left-right hemispheric differences has been suggested not only in humans but also in rodents. In recent studies, left-right anatomical and functional differences of the rodent hippocampus have been revealed. However, there is only one report investigating the left-right difference for short-term memory (STM), and the left-right difference for long-term memory (LTM) is not consistent among previous studies. Therefore, we examined the effects of unilateral hippocampal lesion and stimulation on the formation of STM and LTM in rats. Our results showed that the right, but not the left, hippocampal lesion impaired STM performance, evaluated by the alternation rate in the spontaneous alternation test and the novel-arm choice rate in the novelty preference test. In addition, electrical stimulation of the left, but not the right, hippocampus immediately before the tests impaired STM performance. On the other hand, the left, but not the right, hippocampal lesion impaired the LTM performance, evaluated by the discrimination index in the object recognition test. In addition, the stimulation of the left, but not the right, hippocampus impaired LTM performance. These results suggest that both the left and right hippocampi are involved in STM formation, and the right hippocampus has a facilitating role while the left hippocampus has a suppressing role for STM. On the other hand, LTM may be driven correctly only by the left hippocampus with appropriate level of neural activity. The left and right hippocampi of rodents may work in different mechanisms depending on the demand for STM and LTM.

There is evidence that exposure to stressors in adolescence leads to lasting deficits on hippocampal-dependent tasks, but whether medial prefrontal cortical function is also impaired is unknown. We previously found that rats exposed to social instability stress in adolescence (SS; daily 1h isolation and subsequent change of cage partner between postnatal days 30 and 45) had impaired memory performance on a Spatial Object Location test and in memory for fear conditioning context, tasks that depend on the integrity of the hippocampus. Here we investigated whether impaired performance would be evident after adolescent SS in male rats on a different test of hippocampal function, spatial learning and memory in the Morris water maze (MWM) and on a working memory task for which performance depends on the integrity of the medial prefrontal cortex, the Delayed Alternation task (DAT). During MWM testing, SS rats showed greater improvements in performance across trials within days compared to control (CTL) rats, but showed less retention of learning between days (48 h) compared to CTL rats. Similarly, SS rats had impaired long-term memory in the Spatial Object Location test after a long delay (240 min), but not after shorter delays (15 or 60 min) compared to CTL rats. No group differences were observed on the DAT, which assessed working memory across brief delays (5-90 s). Thus, deficits in memory performance after chronic social stress in adolescence may be limited to long-term memory.

To investigate the involvement of oxytocin in their short-term lasting olfactory memory performance, adult female Wistar rats (n = 12) were tested for their juvenile discrimination abilities. As measured by their exploratory behavior towards juveniles, the adult rats were able to discriminate between a previously exposed juvenile and a novel one as long as the interval between the two exposures was less than 180 min. This ability was maintained across all days of the estrous cycle and was unaffected by intracerebroventricular administration of synthetic oxytocin (1 ng/5 microl Ringer's solution) or Ringer's solution immediately after the first exposure. However, treatment with the oxytocin receptor antagonist des-Gly-NH2 d(CH2)5[Tyr(Me)2Thr4]OVT interfered with the ability to establish this kind of olfactory memory although the vasopressin V1 receptor antagonist d(CH2)5Tyr(Me)AVP (100 ng/5 microl each) via the same route did not. This suggests that within a narrow range of concentrations endogenous oxytocin, but not vasopressin, is critically involved in short-term olfactory memory for juvenile conspecifics in female rats. These data are discussed in the light of sexual dimorphic brain development.

Environmental enrichment (EE) has been used to investigate behavioral changes and neuroplasticity in brain in normal and pathological conditions. Besides, the EE has been used to understand the neurobehavioral systems involved in learning experiences, visual inputs, defensive responses, social interactions and memory. However, the required exposure duration to remove aversive memories remains lacking. Therefore, the purpose of the present study was to investigate the time-course effect of EE exposure on the extinction of aversive memory. Young adult male Wistar rats were exposed to two different EE protocols: short-term environmental enrichment (EE2 - animal kept under enriched conditions for two weeks) and long-term environmental enrichment (EE4 - animal kept under enriched conditions for four weeks). The contextual fear conditioning test was used to assess aversive memory. The both EE protocols provide changes in Zif-268 immunoreactivity in mesocorticolimbic areas such as CA1 and central amygdala; however, only short-term EE reduces the ZIF-268 immunoreactivity in VTA. Besides, both EE protocols also provide an increase in TH immunoreactivity in VTA and nucleus accumbens, but only the short-term EE modifies the TH immunoreactivity in CA1 and infralimbic region of the prefrontal cortex. The time-course effect of EE interferes differently on the extinction of aversive memory, being two weeks of exposure with EE sufficient to cause improvement in coping during aversive situations, favoring the extinction of conditioned fear memory.

Several studies suggest that EEG parameters, reflecting top-down processes in the brain, may predict cognitive performance, e.g. short-term memory (STM) capacity. According to Lisman and Idiart's model, STM capacity is predicted by theta and gamma EEG waves and their ratio. This model suggests that the more periods of gamma band waves fit into one period of theta band waves, the more information can be stored. We replicated the study by Kaminski et al. (2011), which recorded spontaneous EEG activity and measured verbal STM capacity with a modified digit span task from the Wechsler battery. Our study included more subjects and two EEG recording sessions. We discuss the possible limits of EEG correlates of STM capacity as EEG parameters were not stable across the two measurements and no correlation was found between the theta/gamma ratio and performance in the digit span task.

Malformation of cortical developments (MCDs) is currently an incurable disease and is associated with significant neuropsychological problems, such as intellectual disability, epilepsy, and anxiety disorders from a young age. Development of a suitable animal model and pathophysiological study is therefore necessary to better understand and treat MCDs from being an incurable disease. The Y-maze, open field, and fear conditioning studies were performed at postnatal days 40-44 to validate the behavioral phenotypes of the existing rat model of MCD with prenatal methylazoxymethanol exposure at their developmental period. The study results show that juvenile rats with MCD spent significantly less time inside the novel arms in Y-maze and less time in the peripheral zones of the open field. Additionally, the rats with MCDs showed attenuated freezing behavior to sound and light cues as well as to context after fear conditioning. This comprehensive behavioral analysis of rats with MCDs at the juvenile period indicate a lack of spatial memory, decreased anxiety, and learning disability in these rats, which is compatible with the human behavioral phenotype of MCDs and can be used as the behavioral biomarkers for future translational research.

Alzheimer's disease (AD) is a neurodegenerative condition associated with loss of memory function, depression and anxiety. The etiology of AD is poorly understood, but both cholesterol dyshomeostasis and dysregulation of the immune system are contributing factors. Current evidence is consistent with a detrimental effect of excess cholesterol on neuroinflammation, both in mouse models of memory loss and in dementia in humans. However, whether the impact of cholesterol on neuroinflammation occurs early and contributes to pathogenesis of the disease or simply reflects a pleiotropic impact at advanced stages of disease is unclear. To explore this question, we measured, in 9-13 week-old mice, cognitive status and changes in brain inflammatory mediators in response to a short-term high-cholesterol diet. We hypothesized that short-term exposure to excess dietary cholesterol would alter the early inflammatory responses associated with cognitive and/or behavioral impairment. We report that short-term exposure to a high-cholesterol diet led to decreased thigmotaxis and short-term spatial memory impairment without affecting long-term recognition memory. Furthermore, cognitive and behavioral phenotypes in these mice were associated with a reduction in interleukin-15 levels in the absence of changes in other inflammatory mediators. Our findings indicate that interleukin-15 may play a role in early stages of cognitive impairment secondary to hypercholesterolemia. Consequently, optimization of interleukin-15 signaling may be a viable effective cognitive therapy in the population susceptible to developing dementia due to risk factors associated with cholesterol dysregulation.

Restrictive diets (RD) can influence the inflammatory phenotype of dams and their offspring. Thus, this study aimed to evaluate the effects of caloric restriction on the neuroinflammatory profile in the hippocampus and the short-term recognition memory of male offspring from RD-fed dams. Mice dams received standard diet ad libitum (CONT) or restrictive diet (RD; 30% reduction of CONT consumption) during pregnancy and lactation. Male pups were weaned at 21 days and randomly divided into two groups that received CONT or RD; groups were named according to maternal/offspring diets: CONT/CONT, CONT/RD, RD/CONT, and RD/RD. At 90 days old, short-term memory was assessed by the object recognition test (ORT); the inflammatory state of the hippocampus was analyzed by gene expression of sirtuin-1 (Sirt1) and inflammasome Nlrp3; and by protein expression of toll-like receptor-4 (TLR-4) and zonula occludens-1 (ZO-1). Our results showed an improvement in short-term memory in RD-fed offspring. The expression of Sirt1 was higher in RD/CONT compared to CONT/CONT and decreased in RD/RD compared to CONT/RD. Nlrp3 gene expression showed an offspring effect, being decreased in RD-fed mice. TLR-4 expression was higher in RD/CONT compared to CONT/CONT, similarly to ZO-1 expression. However, ZO-1 also showed a maternal diet effect and increased expression in the offspring of RD dams. Our findings demonstrate that caloric restriction improved short-term recognition memory. However, a restrictive diet should be applied with caution; depending on the offspring's diet, it may not benefit the neuroinflammatory phenotype or cognition.

Chronic high-energy diets are known to induce obesity and impair memory; these changes have been associated with inflammation in brain areas crucial for memory. In this study, we investigated whether inflammation could also be related to diet-induced memory deficits, prior to obesity. We exposed rats to chow, chow supplemented with a 10% sucrose solution (Sugar) or a diet high in fat and sugar (Caf+Sugar) and assessed hippocampal-dependent and perirhinal-dependent memory at 1 week. Both high-energy diet groups displayed similar, selective hippocampal-dependent memory deficits despite the Caf+Sugar rats consuming 4-5 times more energy, and weighing significantly more than the other groups. Extreme weight gain and excessive energy intake are therefore not necessary for deficits in memory. Weight gain across the diet period however, was correlated with the memory deficits, even in the Chow rats. The Sugar rats had elevated expression of a number of inflammatory genes in the hippocampus and WAT compared to Chow and Caf+Sugar rats but not in the perirhinal cortex or hypothalamus. Blood glucose concentrations were also elevated in the Sugar rats, and were correlated with the hippocampal inflammatory markers. Together, these results indicate that liquid sugar can rapidly elevate markers of central and peripheral inflammation, in association with hyperglycemia, and this may be related to the memory deficits in the Sugar rats.

Excessive consumption of high-fat fructose diet (HFFD) is associated with the development of systemic insulin resistance (InsRes) and further progression into type-2 diabetes (T2DM). InsRes induced hippocampal insulin signaling has serious consequence on hampered sensorimotor, cognitive performance and long term potentiation accompained to neuronal cell death in hippocampus. However, short-term HFFD/Streptozotocin (STZ) mediated hippocampal InsRes and related neurobehavioral alterations in adoloscents have not been reported. Therefore, we investigated a one-week HFFD model to augment the state of InsRes along with a single sub-diabetogenic dose of STZ (45 mg/kg i.p) to produce a hampered hippocampal insulin signaling associated with frank hyperglycemia and other biochemical and neurobehavioral alterations in young rats. To achieve this, male wistar rats of age (8-10 weeks) and weight 80-120 g were divided into two main groups: (1) fed with commercial standard normal fat diet (NFD: 6.5% kcal fat) and (2) fed an in-house prepared high-fat diet [HFFD: 58% kcal fat] and 20% high-fructose corn syrup in the distilled water. Our results showed an increase in calorie intake, water intake, body weight and blood glucose levels. Further, an increase in fasting serum insulin and Homeostasis Model Assessment-index (HOMA-I) and oral glucose tolerance test (OGTT) was observed. Whereas, we observed a decrease in hippocampal insulin signaling and translocation of glucose transporter type 4 (GLUT4) to neuronal membrane. Further, HFFD/STZ mediated oxidative stress, lipid peroxidation (LPO), decreased antioxidant levels, Brain-derived neurotrophic factor (BDNF) levels and further activation of increase caspase-3 was observed. These battery of events indicate biochemical alterations in hippocampus resulting in cognition and memory deficit.

Curcumin is a natural polyphenol with evidence of antioxidant, anti-inflammatory and neuroprotective properties. Recent evidence also suggests that curcumin increases cognitive performance in animal models of dementia, and this effect would be related to its capacity to enhance adult neurogenesis. The aim of this study was to test the hypothesis that curcumin treatment would be able to preserve cognition by increasing neurogenesis and decreasing neuroinflammation in the model of dementia of Alzheimer's type induced by an intracerebroventricular injection of streptozotocin (ICV-STZ) in Wistar rats. The animals were injected with ICV-STZ or vehicle and curcumin treatments (25, 50 and 100mg/kg, gavage) were performed for 30days. Four weeks after surgery, STZ-lesioned animals exhibited impairments in short-term spatial memory (Object Location Test (OLT) and Y maze) and short-term recognition memory (Object Recognition Test - ORT), decreased cell proliferation and immature neurons (Ki-67- and doublecortin-positive cells, respectively) in the subventricular zone (SVZ) and dentate gyrus (DG) of hippocampus, and increased immunoreactivity for the glial markers GFAP and Iba-1 (neuroinflammation). Curcumin treatment in the doses of 50 and 100mg/kg prevented the deficits in recognition memory in the ORT, but not in spatial memory in the OLT and Y maze. Curcumin treatment exerted only slight improvements in neuroinflammation, resulting in no improvements in hippocampal and subventricular neurogenesis. These results suggest a positive effect of curcumin in object recognition memory which was not related to hippocampal neurogenesis.

The prefrontal cortex (PFC) plays critical roles in social cognition and emotional regulation in humans and rodents; however, its involvement in social recognition memory in mice remains unclear. Here, we examined the roles of the PFC in short-term and long-term social recognition memory, social motivation, and anxiety-related behavior in C57BL/6J male mice. Sham control and PFC-lesioned mice underwent four different behavioral tests. In the social recognition test, composed of three daily trials over 3 consecutive days, the control mice spent less time investigating the juvenile stimulus mouse both within each day and across days. By contrast, while social investigation behavior in PFC-lesioned mice decreased across the three trials within each day, it did not decrease over the 3-day testing period. These results indicate that the PFC has an important role in long-term, but not short-term, social recognition memory. The control and PFC-lesioned mice exhibited similar social motivation in the three-chamber test - both groups preferred the juvenile mouse to the empty cylinder and did not prefer the adult mouse. In addition, the PFC lesion had no impact on anxiety-related behavior or general activity in the light-dark transition test or the open field test. Our findings demonstrate that the PFC is essential for long-term social recognition memory and that it plays a critical role in higher-order social cognition.

Trisomy 21 or Down syndrome (DS) is the most common form of human aneuploid disorder. Increase in the copy number of human chromosome 21 genes leads to several alterations including mental retardation, heart and skeletal dysmorphologies with additional physiological defects. To better understand the genotype and phenotype relationships, several mouse models have been developed, including the transchromosomic Tc1 mouse, which carries an almost complete human chromosome 21, that displays several locomotor and cognitive alterations related to DS. In this report we explore the contribution of the genetic dosage of 47 mouse genes located in the most telomeric part of Hsa21, using a novel model, named Ms4Yah, carrying a deletion of the 2.2Mb Ctsb-Prmt2 genetic interval. We combine this deletion with the Tc1 Hsa21 in a rescue experiment. We could recapitulate most of the Tc1 phenotypes but we found no phenotypes induced by the Ms4Yah and no contribution to the Tc1-induced phenotypes even if we described new alteration in social preference but not in olfaction. Thus we conclude that the genes conserved between mouse and human, found in the most telomeric part of Hsa21, and trisomic in Tc1, are not contributing to the major Tc1 phenotypes, suggesting that the Cstb-Prmt2 region is not playing a major role in locomotor and cognitive deficits found in DS.

Glucocorticoids released as part of the physiological response to stress are known to affect cognitive function, presumably via effects on the hippocampus. Trace classical eyeblink conditioning is an associative learning task which depends on the hippocampus and has been used to examine the development of learning processes in young mammals. Previously, we demonstrated deficits in trace eyeblink conditioning associated with postnatal administration of the glucocorticoid corticosterone by creating a sustained elevation with methods such as subcutaneous timed-release pellets and osmotic mini-pumps which were active over several days. In the present study, we examined the effects of an oscillating pattern of corticosterone elevation on subsequent trace eyeblink conditioning. Twice daily corticosterone injections (high, low, or vehicle) were administered over a 3-day period, starting at postnatal day 15. Then, on postnatal day 28, animals underwent trace classical eyeblink conditioning to examine the possible influence of earlier corticosterone elevations on the development of learning and memory. Eyeblink conditioning was affected by corticosterone treatments, but only for males, and only very early in acquisition; Males receiving the high dose of corticosterone exhibited facilitation of learning relative to controls. These data demonstrate that oscillating corticosterone elevations produce opposite effects on this associative learning task than do sustained elevations.

Ketamine is a multimodal dissociative anesthetic and analgesic that is widely used after traumatic injury. We previously reported that an analgesic dose of intravenous (IV) ketamine infusion (10 mg/kg, 2-h) after fear conditioning enhanced short-term fear memory in rats. Here, we investigated the effects of the same dose of an IV ketamine infusion on plasma stress hormone levels and long-term fear memory in rats. Adult male Sprague-Dawley rats (9-week-old with an average weight of 308 g upon arrival) received a ketamine infusion (0 or 10 mg/kg, 2-h) immediately after auditory fear conditioning (three auditory tone and footshock [0.6 mA, 1-s] pairings) on Day 0. After the infusion, a blood sample was collected from a jugular vein catheter for corticosterone and progesterone assays, and each animal was tested on tail flick to measure thermal antinociception. One week later, animals were tested on fear extinction acquisition (Day 7), fear extinction retrieval (Day 8), and fear renewal (Day 9). The IV ketamine infusion, compared to the saline infusion, reduced locomotor activity (sedation), increased tail flick latency (antinociception), and elevated plasma corticosterone and progesterone levels. The ketamine infusion did not alter long-term fear memory extinction or fear renewal. However, elevated corticosterone and progesterone levels resulting from the ketamine infusion were correlated with sedation, antinociception, and long-term fear memory renewal. These results suggest that individual differences in sensitivity to acute ketamine may predict vulnerability to develop fear-related disorders.

The interconnectivity of the hippocampus, interpeduncular nucleus (IPN) and several brain structures which are involved in modulating hippocampal theta rhythm activity makes a complicated dynamic network of interconnected regions and highlights the role of IPN in the hippocampal dependent learning and memory. In the present study we aimed to address whether IPN is involved in the perforant path-dentate gyrus (PPDG) short term and long term synaptic plasticity in rats. To silent IPN transiently, lidocaine was injected through the implanted cannula above the IPN. To evaluate short term plasticity, paired pulses stimulation of PPDG synapses were used upon IPN temporary inactivation. Furthermore, long term plasticity was investigated by measuring the induction and maintenance of PPDG synapses long term potentiation (LTP) after high frequency stimulation (HFS) of the mentioned pathway following to IPN inactivation. The results showed that IPN reversible inactivation had no effect on short term plasticity of PPDG synapses. However, IPN inactivation before the PPDG high frequency stimulation could significantly suppress both the population spike (PS) and fEPSP-LTP induction compared to the saline group. Conversely, IPN inactivation had no significant effect on maintenance of both PS-LTP and fEPSP-LTP. All together our study suggests the contribution of IPN in the PPDG synaptic plasticity and excitability of DG granule cells which could be through direct and/or indirect pathways from IPN to the hippocampus.

Our previous study has shown that pentobarbital causes memory deficits and impairs hippocampal synaptic plasticity. The Tat-GluA23Y peptide (GluA23Y) prevents activity-dependent α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) endocytosis. It enables early-phase long-term potentiation (LTP) to proceed to late-phase LTP allowing short-term memory to convert to long-term memory. The purpose of this study is to explore the potential effects of GluA23Y on pentobarbital-induced memory deficits through behavioral and electrophysiological paradigms. We found that in vivo intrahippocampal infusion of GluA23Y (100μM, 1μl per hippocampus) 30min prior to pentobarbital administration (8mM, 1μl per hippocampus) significantly rescued the pentobarbital-induced deficit of memory retrieval in rats during the Morris water maze test. Pre-incubation of GluA23Y (10μM) partially rescued bath application of pentobarbital-induced synaptic transmission of the CA3-CA1 pathway in hippocampal slices. More importantly, GluA23Y selectively upregulated the synaptic GluA2 expression that was suppressed by pentobarbital. Together, these results suggest that inhibition of GluA2-containing AMPAR endocytosis by GluA23Y increases the pentobarbital-suppressed basal synaptic transmission by upregulating the synaptic GluA2, and then subsequently alleviates spatial memory deficits. Therefore, inhibition of AMPAR endocytosis may be a potential therapeutic way to treat memory disorders caused by anesthetics.

Methamphetamine (METH) is a strong psychostimulant drug which can essentially affect different brain regions. Hippocampus as one of main components of limbic system plays key roles in processing of short term, long term and spatial memory. Herein, we explored the changes in behavior, synaptic transmission and hippocampal volume along with gliosis following METH treatment. Besides, using genome-wide expression profiling, we applied a pathway-based approach to detect significantly dysregulated signaling pathways. In this regard, we found that METH administration interrupts spatial memory and long term potentiation (LTP). Additionally, stereological analysis revealed a significant alteration in hippocampal volume along with increased gliosis upon METH treatment. We also identified several signaling cascades chiefly related to synaptic transmission which were considerably interrupted in the hippocampus of METH-treated rats. Taken together, our data suggests a potential link between behavioral disruptions and dysregulated signaling pathways.

Deficits in olfaction are associated with neurodegenerative disorders such as Alzheimer's disease. A recent study reported that intranasal zinc sulfate (ZnSO4)-treated mice show olfaction and memory deficits. However, it remains unknown whether olfaction deficit-induced learning and memory impairment is associated with the cholinergic system in the brain. In this study, we evaluated olfactory function by the buried food find test, and learning and memory function by the Y-maze and passive avoidance tests in ZnSO4-treated mice. The expression of choline acetyltransferase (ChAT) protein in the olfactory bulb (OB), prefrontal cortex, hippocampus, and amygdala was assessed by western blotting. Moreover, we observed the effect of the acetylcholinesterase inhibitor physostigmine on ZnSO4-induced learning and memory deficits. We found that intranasal ZnSO4-treated mice exhibited olfactory dysfunction, while this change was recovered on day 14 after treatment. Both short-term and long-term learning and memory were impaired on days 4 and 7 after treatment with ZnSO4, whereas the former, but not the latter, was recovered on day 14 after treatment. A significant correlation was observed between olfactory function and short-term memory, but not long-term memory. Treatment with ZnSO4 decreased the ChAT level in the OB on day 4, and increased and decreased the ChAT levels in the OB and hippocampus on day 7, respectively. Physostigmine improved the ZnSO4-induced deficit in short-term, but not long-term, memory. Taken together, the present results suggest that short-term memory may be closely associated with olfactory function via the cholinergic system.

The present study investigated the effects of a single intravenous (i.v.) dose of Vitamin C (ascorbate, ASC) on spatial memory in APP/PSEN1 mice, an Alzheimer's disease model. First, we confirmed the uptake time course in ASC-depleted gulo (-/-) mice, which cannot synthesize ASC. Differential tissue uptake was seen based on ASC transporter distribution. Liver (SVCT1 and SVCT2) ASC was elevated at 30, 60 and 120 min post-treatment (125 mg/kg, i.v.), whereas spleen (SVCT2) ASC increased at 60 and 120 min. There was no detectable change in cortical (SVCT2 at choroid plexus, and neurons) ASC within the 2-h interval, although the cortex preferentially retained ASC. APP/PSEN1 and wild type (WT) mice at three ages (3, 9, or 20 months) were treated with ASC (125 mg/kg, i.v.) or saline 45 min before testing on the Modified Y-maze, a two-trial task of spatial memory. Memory declined with age and ASC treatment improved performance in 9-month-old APP/PSEN1 and WT mice. APP/PSEN1 mice displayed no behavioral impairment relative to WT controls. Although dopamine and metabolite DOPAC decreased in the nucleus accumbens with age, and improved spatial memory was correlated with increased dopamine in saline treated mice, acute ASC treatment did not alter monoamine levels in the nucleus accumbens. These data show that the Modified Y-maze is sensitive to age-related deficits, but not additional memory deficits due to amyloid pathology in APP/PSEN1 mice. They also suggest improvements in short-term spatial memory were not due to changes in the neuropathological features of AD or monoamine signaling.