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Alzheimer's disease (AD) is the primary cause of dementia in the elderly. The cause of the disease is still unknown, but amyloid plaques and neurofibrillary tangles in the brain are thought to play a role. However, transgenic mouse models expressing these neuropathological features do not show severe or consistent cognitive impairments. There is accumulating evidence that diabetes increases the risk for developing AD. We tested the hypothesis that experimentally induced diabetes would exacerbate cognitive symptoms in a mouse model of AD. Diabetes was induced in 12-month old 3xTg mice using streptozotocin (STZ; 90mg/kg, i.p., on two successive days). Hyperglycemia was verified by sampling blood glucose levels. Three months after injection (at 15 months of age), the mice were behaviorally tested in the Morris water maze and contextual fear conditioning. Subsequently, the hippocampal region was examined using immunohistochemistry (6E10 antibody for amyloid) and immunoblotting (AT8 antibody for phosphorylated tau). No differences were found in learning or memory between the vehicle-treated control and STZ-treated groups. A significant increase in the number of amyloid-positive plaques was observed in the subiculum of STZ-treated mice; very few plaques were seen in other hippocampal regions in either group. No differences in AT8 load were observed. These results reinforce that amyloid plaques, per se, are not sufficient to cause memory impairments. Further, while diabetes can enhance this aspect of brain pathology, the combination of disrupted glucose metabolism and the transgenes is still not sufficient to cause the severe cognitive impairments associated with clinical AD., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The water maze task is widely used to evaluate spatial learning and memory in rodents. The basic paradigm requires an animal to swim in a pool until it finds a hidden escape platform. The animals learn to find the platform using extra-maze cues and, after several training trials, are able to swim directly to it from any starting location. Memory for the platform location is assessed by examining swimming behavior with the platform removed from the maze, while sensory, motor and motivational aspects of the task can be examined by making the platform visible to the animals. Described in this unit is the use of the water maze to identify rats with age-related spatial learning and memory impairments. The efficacy of potential pharmacological treatments for alleviating these deficits is then evaluated. This assay provides a means for studying the neurobiology of spatial learning and memory, and to identify potential pharmacotherapies for treating memory-impaired humans. While the use of aged rats is described in this unit, the protocol can also be employed for compound screening with other rodent models that have spatial learning and memory impairments, such as transgenic mouse models of Alzheimer's disease.

Rationale: Inhibition of cyclic AMP (cAMP)-specific phosphodiesterase (PDE4) enhances memory in rodents. MEM1018 and MEM1091 are newly developed PDE4 inhibitors that had not been evaluated as yet for their effects on working and reference memory., Objective: Experiments were carried out to determine whether these two drugs alter memory and if these effects are associated with changes in intracellular cAMP in the brain., Methods: The effects of MEM1018 and MEM1091 on memory deficits induced by the N-methyl-D-: aspartate (NMDA) receptor antagonist MK-801 were determined in the eight-arm radial maze and step-through inhibitory avoidance tasks in rats. Their effects on cAMP concentrations in primary cultures of rat cerebral cortical neurons and their potency for inhibiting recombinant PDE4 subtypes were examined., Results: In the radial-arm maze, MEM1018 and MEM1091 (0.1-2.5 mg/kg, IP) enhanced working and reference memory impaired by MK-801 (0.1 mg/kg). In addition, both drugs antagonized the amnesic effect of MK-801 on passive avoidance behavior. Overall, the behavioral effects of MEM1018 and MEM1091 were similar to the prototypic PDE4 inhibitor rolipram (0.1 mg/kg). Consistent with this, and similar to the effects of rolipram, both MEM1018 (10-30 microM) and MEM1091 (10 microM) enhanced the ability of NMDA (30 microM) to increase cAMP concentrations in rat cerebral cortical neurons, in vitro. MEM1018 and MEM1091 showed greater relative selectivity for PDE4D than rolipram, although the general profiles of the three compounds were similar., Conclusions: The novel PDE4 inhibitors MEM1018 and MEM1091 enhance memory in a manner generally similar to rolipram. PDE4D may be the primary target for the PDE4 inhibitors in the mediation of memory.

Sex differences in spatial memory have long been observed in humans, non-human primates and rodents, but the underlying cellular and molecular mechanisms responsible for these differences remain obscure. In the present study we found that adolescent male rats outperformed female rats in 7 d and 28 d retention probes, but not in learning trials and immediate probes, in the Morris water maze task. Male rats also had larger long-term potentiation (LTP) at hippocampal temproammonic-CA1 (TA-CA1) synapses, which have been implicated to play a key role in place field and memory consolidation, when protocols designed to elicit late-stage LTP (LLTP) were used. Interestingly, the ratio of evoked AMPA/NMDA currents was found to be smaller at TA-CA1 synapses in male rats compared to female rats. Protein biotinylation experiments showed that male rats expressed more surface GluN1 receptors in hippocampal CA1 stratum lacunosum-moleculare (SLM) than female rats, although GluA1 expression was also slightly higher in male rats. Taken together, our results suggest that differences in the expression of AMPA and NMDA receptors may affect LTP expression at TA-CA1 synapses in adolescent male and female rats, and thus possibly contribute to the observed sex difference in spatial memory. [ABSTRACT FROM AUTHOR]

Rationale: Inhibition of cyclic AMP (cAMP)-specific phosphodiesterase (PDE4) enhances memory in rodents. MEM1018 and MEM1091 are newly developed PDE4 inhibitors that had not been evaluated as yet for their effects on working and reference memory. Objective: Experiments were carried out to determine whether these two drugs alter memory and if these effects are associated with changes in intracellular cAMP in the brain. Methods: The effects of MEM1018 and MEM1091 on memory deficits induced by the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 were determined in the eight-arm radial maze and step-through inhibitory avoidance tasks in rats. Their effects on cAMP concentrations in primary cultures of rat cerebral cortical neurons and their potency for inhibiting recombinant PDE4 subtypes were examined. Results: In the radial-arm maze, MEM1018 and MEM1091 (0.1-2.5 mg/kg, IP) enhanced working and reference memory impaired by MK-801 (0.1 mg/kg). In addition, both drugs antagonized the amnesic effect of MK-801 on passive avoidance behavior. Overall, the behavioral effects of MEM1018 and MEM1091 were similar to the prototypic PDE4 inhibitor rolipram (0.1 mg/kg). Consistent with this, and similar to the effects of rolipram, both MEM1018 (10-30 µ M) and MEM1091 (10 µ M) enhanced the ability of NMDA (30 µ M) to increase cAMP concentrations in rat cerebral cortical neurons, in vitro. MEM1018 and MEM1091 showed greater relative selectivity for PDE4D than rolipram, although the general profiles of the three compounds were similar. Conclusions: The novel PDE4 inhibitors MEM1018 and MEM1091 enhance memory in a manner generally similar to rolipram. PDE4D may be the primary target for the PDE4 inhibitors in the mediation of memory. [ABSTRACT FROM AUTHOR]

• Deaf1 expression is involved in contextual fear and spatial memory. • Conditional deletion of Deaf1 decreases marble burying activity. • Dorsal hippocampal area is reduced in mice lacking Deaf1. Deleterious mutations within the DNA binding domain of the transcription factor deformed epidermal autoregulatory factor 1 (DEAF1) result in a phenotypic spectrum of neurodevelopmental disorders including intellectual disabilities and autism spectrum disorders. While whole animal deletion of Deaf1 in mice is lethal, mice with conditional disruption of the gene in neuronal precursor cells can display memory deficits and increased anxiety-like behavior. This study aimed to further characterize learning and memory alterations and assess changes in marble burying activity and hippocampal size in mice with conditional deletion of Deaf1. Mice lacking DEAF1 in the CNS (NKO) displayed reduced memory in both contextual fear conditioning and a 3-day massed trials Morris water maze paradigm. NKO mice had reduced marble burying activity in full cage marble burying tests. Using a half-cage marble test, NKO mice again buried fewer marbles and spent significantly more time on the side of the cage away from the marbles compared to control animals. The area of the dorsal hippocampus of NKO mice was decreased compared to control and animals with a single Deaf1 allele. These results continue to establish the importance of DEAF1 in cognitive behavior and provide new evidence that DEAF1 regulates hippocampal morphology. [ABSTRACT FROM AUTHOR]

Provides information on the evaluation of the relationship between rapid eye movement (REM) and memory consolidation. Need for scholarship and hypothesis testing; Mechanism through which REM deprivation affects consolidation; Background of studies on REM and learning in humans.