Performance In Morris Water Maze Task Research Articles

Chronic α-Synuclein Accumulation in Rat Hippocampus Induces Lewy Bodies Formation and Specific Cognitive Impairments.

Occurrence of Lewy bodies (LBs)/Lewy neurites (LNs) containing misfolded fibrillar α-synuclein (α-syn) is one of the pathologic hallmarks of memory impairment-linked synucleinopathies, such as Parkinson’s disease (PD) and dementia with LBs (DLB). While it has been shown that brainstem LBs may contribute to motor symptoms, the neuropathological substrates for cognitive symptoms are still elusive. Here, recombinant mouse α-syn fibrils were bilaterally injected in the hippocampus of female Sprague Dawley rats, which underwent behavioral testing for sensorimotor and spatial learning and memory abilities. No sensorimotor deficits affecting Morris water maze task performance were observed, nor was any reference memory disturbances detectable in injected animals. By contrast, significant impairments in working memory performance became evident at 12 months postinjection. These deficits were associated to a time-dependent increase in the levels of phosphorylated α-syn at Ser129 and in the stereologically estimated numbers of proteinase K (PK)-resistant α-syn aggregates within the hippocampus. Interestingly, pathologic α-syn aggregates were found in the entorhinal cortex and, by 12 months postinjection, also in the vertical limb of the diagonal band and the piriform cortices. No pathologic α-syn deposits were found within the substantia nigra (SN), the ventral tegmental area (VTA), or the striatum, nor was any loss of dopaminergic, noradrenergic, or cholinergic neurons detected in α-syn-injected animals, compared with controls. This would suggest that the behavioral impairments seen in the α-syn-injected animals might be determined by the long-term α-syn neuropathology, rather than by neurodegeneration per se, thus leading to the onset of working memory deficits.

Effects of maternal exposure to nonylphenol on learning and memory in offspring involve inhibition of BDNF-PI3K/Akt signaling

Nonylphenol (NP), a global environmental pollutant, has been found to result in impairments of neurodevelopment. However, effects of maternal exposure to NP on learning and memory and the potential mechanisms are largely unexplored. Thus, we treated dams with NP during gestation and lactation to study its effect on learning and memory in offspring. Morris water maze (MWM) task and the electrophysiological recording in the hippocampus were conducted in pups. We also investigated the activation of BDNF-PI3K/Akt signaling and the expression of its target protein PSD-95 in offspring hippocampus, which are curial for the synaptic plasticity and learning and memory. The results showed that maternal exposure to NP led to poor performance in MWM task and especially impairments of long-term potentiation (LTP), although the termination of NP exposure was at the end of lactation. Meanwhile, maternal exposure to NP also decreased the activation of BDNF-PI3K/Akt signaling and the protein level of PSD-95. Taken together, our results support the hypothesis that maternal exposure to NP during gestation and lactation causes damages to learning and memory. In addition, suppressed activation of the BDNF-PI3K/Akt signaling may contribute to these impairments caused by maternal exposure to NP.

Extracellular calcium influx through L-type calcium channels, intracellular calcium currents and extracellular signal-regulated kinase signaling are involved in the abscisic acid-induced precognitive and anti-anxiety effects

Abscisic acid (ABA), a critical phytohormone, is also produced in animal tissues. It has been reported that ABA has pro-cognitive and anti-anxiety effects in rats. However, its detailed mechanism has not yet been clarified. Here, the possible roles of extracellular and intracellular calcium store and ERK signaling were evaluated in pro-cognitive and anti-anxiety effects of ABA. Morris water maze (MWM) and plus maze tests were used to evaluate the learning and memory and anxiety-like behavior, respectively, in rats. The inhibitors of L- (nifedipine) and T-type (amiloride) calcium channels and endoplasmic reticulum Ca2+-ATPase (thapsigargin) were centrally (i.c.v.) injected 15 min before ABA. Hippocampal and prefrontal lobe levels of phosphorylated extracellular signal-regulated Kinase (p-ERK) were assessed by immunoblotting. The data showed that ABA has promoting effect on rat’s performance in MWM task and induced anti-anxiety effect. In addition, nifedipine and thapsigargin significantly prevented while, amiloride had no effect on the mentioned effects of ABA. Furthermore, p-ERK levels were significantly increased in ABA-treated rats which were inhibited by nifedipine and thapsigargin pretreatment. It seems that the extracellular calcium influx through L-type calcium channels, intracellular calcium storage and ERK signaling are involved, at least in part, in the pro-cognitive and anti-anxiety effects of ABA.

The effects of GABAA and NMDA receptors in the shell–accumbens on spatial memory of METH-treated rats

Methamphetamine (METH) is a highly addictive and neurotoxic psychostimulant. Its use in humans is often associated with neurocognitive impairment and deficits in hippocampal plasticity. Striatal dopamine system is one of the main targets of METH. The dopamine neurons in the striatum directly or indirectly regulate the GABA and glutamatergic signaling in this region and thus their outputs. This is consistent with previous reports showing modification of neuronal activity in the striatum modulates the expression of hippocampal LTP and hippocampal-dependent memory tasks such as Morris water maze (MWM). Therefore, reversing or preventing METH-induced synaptic modifications via pharmacological manipulations of the shell–nucleus accumbens (shell–NAc) may introduce a viable therapeutic target to attenuate the METH-induced memory deficits. This study is designed to investigate the role of intra-shell NAc manipulation of GABAA and NMDA receptors and their interaction with METH on memory performance in MWM task. Pharmacological manipulations were performed in rats received METH or saline. We found systemic saline plus intra-shell NAc infusions of muscimol dose-dependently impaired performance, while bicuculline had no effect. Surprisingly, the intra-NAc infusions of 0.005μg/rat muscimol that has no effect on memory performance (ineffective dose) prevented METH-induced memory impairment. In the contrary, the intra-NAc infusions of bicuculline (0.2μg/rat) increased METH-induced memory impairment. However, pre-training intra-NAc infusions of D-AP5 dose-dependently impaired performance, while NMDA had no effect in rats received systemic saline (control group). The intra-NAc infusions with an ineffective dose of NMDA (0.1μg/rat) increased METH-induced memory impairment. Furthermore, intra-NAc infusions of D-AP5 with an ineffective dose (0.1μg/rat) prevented METH-induced memory impairment. Our result is consistent with the interpretation that METH-mediated learning deficit might be due to modification of hippocampus-VTA loop and that augmentation of GABAA receptor function in the shell–NAc may provide a new therapeutic target for alleviating METH-induced memory deficits.

Long-term mild exercise training enhances hippocampus-dependent memory in rats.

Although exercise training improves hippocampus-related cognition, the optimum exercise intensity is still disputed. Based on the lactate threshold (LT, approximately 20 m/min on treadmill) of rats, we have shown that 2 weeks of training with stress-free mild exercise (ME, <LT), but not intense exercise (IE, >LT), comprising exercise stress, promotes adult hippocampal neurogenesis (Okamoto et al., PNAS, 2012), a potential substrate for memory improvement. These results led us to postulate that long-term ME, but not IE, training leads to improved hippocampal function as assessed with a Morris water maze (MWM) task. To test this hypothesis, we investigated the changes in physiological stress levels and MWM task performance in rats assigned to 6 weeks of sedentary control (CONT), ME-training or IE-training conditions. Results showed that, compared to the other conditions, only IE causes general adaptive syndrome (GAS), including adrenal hypertrophy, thymic atrophy and hypercorticosteronemia. In the MWM, ME led to enhanced memory, but not learning, compared with CONT, while IE produced no change in either capacity, probably due to GAS. These findings support the hypothesis that 6 weeks of continuous ME training leads to enhanced hippocampus-related memory, which may have implications for both healthy adults and subjects with low physical capacity.

Effect of acetaminophen, a cyclooxygenase inhibitor, on Morris water maze task performance in mice

Although the mechanism of action of acetaminophen (AAP) is not fully understood, some studies suggest that AAP and phenacetin (PHE) are selective cyclooxygenase (COX)-3 inhibitors. To examine the participation of COX-3 in memory formation, water maze performance was studied in mice treated with AAP, PHE or other COX inhibitors. Mice received intraperitoneal injections of drugs immediately after each training session. Administration of high-dose AAP [302.3 mg/kg (IC50 for COX-2)] or PHE [179.2 mg/kg (IC50 for COX-2)] and of non-specific (indomethacin: 20 mg/kg) or specific COX-2 (NS-398: 10 mg/kg) inhibitor impaired the performance in hidden platform (HP) not visible platform (VP) tasks, whereas low-dose (15.1 mg/kg) AAP facilitated performance in HP and VP tasks. The facilitation of performance by low-dose AAP was reversed by co-administration with a 5-HT(1/2) receptor antagonist (methysergide: 0.47 mg/kg). The middle-dose [69.5 mg/kg (IC50 for COX-3)] of AAP, the PHE [17.9 mg/kg (IC50 for COX-3)] and a specific COX-1 inhibitor (piroxicam: 10-20 mg/kg) did not influence performance in either task. These results suggest that the memory impairment by high-dose AAP and PHE and facilitation of performance by low-dose AAP could involve endogenous COX-2 and serotonergic neuronal activity, but not COX-3, respectively.

Chronic intermittent ethanol exposure during adolescence reduces the effect of ethanol challenge on hippocampal allopregnanolone levels and Morris water maze task performance

Chronic intermittent ethanol exposure (CIEE) in adolescent rats has been shown to produce long-lasting hypnotic, metabolic, and functional tolerance. Recently, it has been hypothesized that allopregnanolone mediates some effects of ethanol, including ethanol-induced impairments in the performance of the Morris Water Maze Task (MWMT). The current studies explore the relationship between cortical and hippocampal allopregnanolone levels and ethanol-induced impairments in the MWMT following CIEE treatment in adolescent rats. Adolescent rats were administered 5.0 g/kg ethanol or saline every 48 h for a 20-day period beginning on postnatal day (P) 30. Training in the spatial version of the MWMT occurred on nontreatment days. Following completion of CIEE treatment and training, MWMT performance was tested 30 min after ethanol (2.0 g/kg) or saline challenge on P 50 and P 62. A separate group of rats were CIEE treated and received an ethanol (2.0 g/kg) or saline challenge on P 50 or 62, and were used for hippocampal and cortical allopregnanolone determination. CIEE during adolescence produced tolerance to both ethanol-induced impairments in the MWMT and ethanol-induced allopregnanolone levels in the hippocampus on P 50. However, when animals were tested at P 62, the reduction in ethanol-induced MWMT impairments found in CIEE rats was reversed and allopregnanolone levels from both saline or ethanol challenge were increased above levels found in control animals. Taken together, these results suggest that CIEE during adolescence produces tolerance to ethanol-induced impairments in MWMT and corresponding changes in ethanol-induced allopregnanolone levels in the hippocampus. Furthermore, cognitive tolerance is reversible and time dependent, but the reversal of cognitive tolerance is not correlated with normalization of hippocampal allopregnanolone levels.