Rodent Models Of Memory Research Articles

Combinatorial therapeutic effect of Environmental Enrichment and a Poly‐herbal formulation against amyloid‐beta induced Alzheimer’s disease in rodents

AbstractBackgroundAlzheimer’s disease (AD), a common form of dementia currently has no single disease‐modifying drug to halt disease progression. Environmental enrichment (EE) has emerged as an effective therapeutic strategy against various brain disorders. Our previous studies have revealed that the phytoformulation BN was effective in improving cognition and working memory in rodent models induced with cholinergic deficits. BN also inhibited tau hyperphosphorylation, increased dendritic arborization, and modulated AKT and MAPK pathways. In the present study, we propose to evaluate the combinatorial effect of BN and EE against AD.MethodA rodent model of AD was created in Wistar rats through bilateral intra‐hippocampal injection of 100 µg/µL amyloid beta(1‐42). After ten days, the animals were randomly divided in to five groups (GII to GVI) and compared with normal animals (GI). The treatment regimen was commenced with GII acting as disease control, GIII receiving BN (844 mg/kg b.w), GIV receiving combined treatment of EE and BN, GV received only EE and GVI receiving the standard drug donepezil (4 mg/kg b.w.) for a period of 28 days. The cognition and spatial learning were assessed using behavioral studies. Gene and protein expression of key molecular targets were performed to gain insights into the molecular mechanism involved in the combination therapy. Amyloid plaque load was detected using thioflavin S, and dendritic morphology was studied using Golgi‐Cox staining. For EE, cages measuring 60×60×60 cm containing a running wheel, play tubes, ladder, balls, toys, and nesting material that are rearranged weekly, were used to study behavioral changes associated with cognitive stimulation.ResultWe found improved exploratory behaviour of the animals in EE when compared to their counterparts in normal cages. Other behavioral patterns like chewing, physical activity, sorting are significantly higher in animals subjected to the combination of EE and therapy when compared to animals treated in the conventional environment. The cognition and behavioral studies coupled with the histopathological results, gene and protein expression studies will help in establishing the molecular mechanism of the combination.ConclusionThe results from this study open up new therapeutic directions involving environmental factors and multi‐targeted therapeutic agents against AD.

Dietary Supplementation With Branched Chain Amino Acids to Improve Sleep in Veterans With Traumatic Brain Injury: A Randomized Double-Blind Placebo-Controlled Pilot and Feasibility Trial.

Study ObjectivesTraumatic brain injury (TBI) is associated with chronic sleep disturbances and cognitive impairment. Our prior preclinical work demonstrated dietary supplementation with branched chain amino acids (BCAA: leucine, isoleucine, and valine), precursors to de novo glutamate production, restored impairments in glutamate, orexin/hypocretin neurons, sleep, and memory in rodent models of TBI. This pilot study assessed the feasibility and preliminary efficacy of dietary supplementation with BCAA on sleep and cognition in Veterans with TBI.MethodsThirty-two Veterans with TBI were prospectively enrolled in a randomized, double-blinded, placebo-controlled trial comparing BCAA (30 g, b.i.d. for 21-days) with one of two placebo arms (microcrystalline cellulose or rice protein, both 30 g, b.i.d. for 21-days). Pre- and post-intervention outcomes included sleep measures (questionnaires, daily sleep/study diaries, and wrist actigraphy), neuropsychological testing, and blood-based biomarkers related to BCAA consumption.ResultsSix subjects withdrew from the study (2/group), leaving 26 remaining subjects who were highly adherent to the protocol (BCAA, 93%; rice protein, 96%; microcrystalline, 95%; actigraphy 87%). BCAA were well-tolerated with few side effects and no adverse events. BCAA significantly improved subjective insomnia symptoms and objective sleep latency and wake after sleep onset on actigraphy.ConclusionDietary supplementation with BCAA is a mechanism-based, promising intervention that shows feasibility, acceptability, and preliminary efficacy to treat insomnia and objective sleep disruption in Veterans with TBI. A larger scale randomized clinical trial is warranted to further evaluate the efficacy, dosing, and duration of BCAA effects on sleep and other related outcome measures in individuals with TBI.Clinical Trial Registration[http://clinicaltrials.gov/], identifier [NCT03990909].

Innate Preferences Affect Results of Object Recognition Task in Wild Type and Alzheimer's Disease Mouse Models.

Background: Object recognition task (ORT) is a widely used behavioral paradigm to assess memory in rodent models, due to its easy technical execution, the lack of aversive stressful stimuli, and the possibility to repeat the test on the same animals. However, mouse exploration might be strongly influenced by a variety of variables.Objective: To study whether innate preferences influenced exploration in male and female wild type mice and the Alzheimer’s disease (AD) model 3xTg.Methods: We first evaluated how object characteristics (material, size, and shape) influence exploration levels, latency, and exploration modality. Based on these findings, we evaluated whether these innate preferences biased the results of ORT performed in wild type mice and AD models.Results: Assessment of Exploration levels, i.e., the time spent in exploring a certain object in respect to the total exploration time, revealed an innate preference for objects made in shiny materials, such as metal and glass. A preference for bigger objects characterized by higher affordance was also evident, especially in male mice. When performing ORT, exploration was highly influenced by these innate preferences. Indeed, both wild type and AD mice spent more time in exploring the metal object, regardless of its novelty. Furthermore, the use of objects with higher affordance such as the cube was a confounding factor leading to “false” results that distorted ORT interpretation.Conclusion: When designing exploration-based behavioral experiments aimed at assessing memory in healthy and AD mice, object characteristics should be carefully evaluated to improve scientific outcomes and minimize possible biases.

Suppression of hippocampal GABAergic transmission impairs memory in rodent models of Alzheimer's disease

Emerging evidence demonstrates the potential involvement of hippocampal GABAergic transmission in the process of memory acquisition and consolidation, while no consistent report is available to address the adaptation of hippocampal GABAergic transmission and its contribution to memory deficiency in the setting of Alzheimer's disease (AD). Brain-derived neurotrophic factor (BDNF) is a key molecule that regulates GABAergic transmission. In the brain, mature BDNF is generated from the proteolytic cleavage of proBDNF, while BDNF and proBDNF have differential effects on central GABAergic transmission. First, the present study reports a remarkable increase of proBDNF/BNDF ratio in the hippocampal CA1 area in rodent models of AD, indicating a potential impaired process of BDNF maturation from proBDNF cleavage. We report a suppressed hippocampal GABAergic strength, potentially resulting from the reduced expression of anion chloride co-transporter KCC2 and subsequent positive shift of GABAergic Cl-equilibrium potential (ECl-), which is attenuated by microinjection of BDNF with proBDNF inhibitor TAT-Pep5. We also show that normalization of proBDNF/BDNF signaling or GABAergic ECl-by intracerebroventricular (i.c.v.) administration of bumetanide remarkably improves the cognitive performance in Morris water maze test and fear conditioning test in rodent models of AD. These results demonstrate a critical role of hippocampal proBDNF/BDNF in regulating GABAergic transmission and contributing to memory dysfunction in rodent models of AD.

Evaluation of Chenopodium Quinoa Extract on Diazepam Induced Memory Impairment in Animal Models

Aim: The present study explored the pharmacological and insilico studies of ethanolic seed extract of Chenopodium quinoa.
 Materials and Methods: The screening of in vivo anti- amnesic activity of the ethanolic seed extract of Chenopodium quinoa was carried out using Actophotometer and Rotarod apparatus. The extract exhibited active constituents like myristic acid, palmitic acid, eicosadienoic acid, pentadecanoic acid, tocopherols, stigmasterol, β-sitosterol, quercetin, benzoic acid, kaempferol, arachidonic acid, benzofuran and 2-bromodecanoic acid. In silico approaches like docking studies (Mcule software) and Ramchandran plot (procheck), online softwares were used in the study to establish mechanism of action of active constituents present in the extract.
 Results: The extract treated groups at doses (200 mg/kg and 400 mg/kg, bd.wt) showed significant anti-amnesic activity. The basal activity score in actophotometer is as an indicator for impairment of learning and memory. Fall of time by rotarod is used to evaluate learning and memory in rodent models of CNS disorders as in case of amnesia. The results revealed that quercetin, kaempferol, myristic acid, palmitic acid, stigmasterol, lenolenic acid, pentadecanoic acid, tocopherols, arachidonic acid and standard donepezil have got highest glide scores against selected Protein Data Bank (PDB ID): 1EVE, 2FY4, 7CUM and 3EJ8. According to Ramachandran plot a good quality model would be expected to have over 90% in the most favoured region. Proteins like PDB ID: 1EVE, 2FY4, 7CUM and 3EJ8 showed almost 80-90% favoured region which clearly indicates that the selected proteins in the present study are of good quality.
 Conclusion: Our research unveiled that ethanolic seed extract of Chenopodium quinoa possessed significant anti- amnesic activity.

Banhasasim-Tang Ameliorates Spatial Memory by Suppressing Oxidative Stress through Regulation of ERK/p38 Signaling in Hippocampus of Mice.

Since ancient times, Banhasasim-tang (BHS) has been used to treat functional dyspepsia in East Asia. Here, we aimed to determine the protective action of BHS on hippocampal neurons against oxidative stress. We investigated the functional effect of BHS on a scopolamine-induced mouse model, and molecular analysis was performed in glutamate-induced HT22 cells. We observed that BHS administration ameliorated memory dysfunction in scopolamine-treated mice. BHS administration also increased neuronal survival and acetylcholine activity and phosphorylation of extracellular signal-regulated kinase (ERK) and cAMP response element-binding protein (CREB) in the hippocampus of mice. In hippocampal cells, BHS treatment rescued glutamate-induced cytotoxicity, apoptosis, and oxidative stress. We observed an increase of HO-1 and a decrease of Nrf2 protein expression in glutamate-induced oxidative stress; however, the expression level of these proteins was significantly rescued by BHS treatment. BHS treatment also regulated phosphorylation of p38, p53, ERK, and CREB. Therefore, our data indicated that BHS may reduce oxidative stress through regulation of ERK-CREB and p38-p53 signaling in the hippocampus, resulting in decreased neuronal damage and improved memory in rodent models of neurodegenerative disease.

Investigations on a polyherbal formulation for treatment of cognitive impairment in a cholinergic dysfunctional rodent model

Alzheimer's disease is a multifactorial neurodegenerative condition manifested through acute cognitive decline, amyloid plaque deposits and neurofibrillary tangles. Complete cure for this disease remains elusive as the conventional drugs address only a single molecular target while Alzheimer's disease involves a complex interplay of different sets of molecular targets and signaling networks. In this context, the possibility of employing multi-drug combinations to rescue neurons from the dysregulated metabolic changes is being actively investigated. The present work investigates a poly-herbal formulation, Brahmi Nei that has been traditionally used for anxiolytic disorders and immunomodulatory effects, for its efficiency in ameliorating cognitive decline through a combination of behavioral, biochemical, histopathological, gene and protein expression analyses. Our results reveal that the formulation shows excellent neuroregenerative properties, rescues neurons from inflammatory damage, reduces neuritic plaque deposits and improves working memory in rodent models with scopolamine-induced dementia. The microarray analysis shows that the formulation induces the expression of pro-survival pathways and positively modulates genes involved in memory consolidation, axonal growth and proliferation in a concentration-dependent manner with therapeutic concentrations restoring the normal conditions in the brain of the diseased animals. The neuritic spine morphology confirms the long-term memory potentiation through improved mushroom spine density, increased dendritic length and connectivity. Taken together, our study provides mechanistic evidence to prove that the traditional formulation can be a superior therapeutic strategy to treat cognitive decline when compared to the conventional mono-drug treatment.

Synaptic plasticity/dysplasticity, process memory and item memory in rodent models of mental dysfunction

Activity-dependent changes in the effective connection strength of synapses are a fundamental feature of a nervous system. This so-called synaptic plasticity is thought to underlie storage of information in memory and has been hypothesized to be crucial for the effects of cognitive behavioral therapy. Synaptic plasticity stores information in a neural network, creating a trace of neural activity from past experience. The plasticity can also change the behavior of the network so the network can differentially transform/compute information in future activations. We discuss these two related but separable functions of synaptic plasticity; one we call “item memory” as it represents and stores items of information in memory, the other we call “process memory” as it encodes and stores functions such as computations to modify network information processing capabilities. We review evidence of item and process memory operations in behavior and evidence that experience modifies the brain's functional networks. We discuss neurodevelopmental rodent models relevant for understanding mental illness and compare two models in which one model, neonatal ventral hippocampal lesion (NVHL) has beneficial adult outcomes after being exposed to an adolescent cognitive experience that is potentially similar to cognitive behavioral therapy. The other model, gestational day 17 methylazoxymethanol acetate (GD17-MAM), does not benefit from the same adolescent cognitive experience. We propose that process memory is altered by early cognitive experience in NVHL rats but not in GD17-MAM rats, and discuss how dysplasticity factors may contribute to the differential adult outcomes after early cognitive experience in the NVHL and MAM models.

Molecular and cellular studies of PTSD: Postmortem transcriptome analysis and novel therapeutic targets.

The neurobiology of fear memory and extinction has been the subject of extensive research efforts that have increased our understanding of the brain regions, circuitry, and the cellular and molecular determinants of fear memory processes. However, the inability to access and directly study the brains of PTSD patients has made it difficult to translate the rodent fear memory studies to understand the neurobiological underpinnings of PTSD. The formation of a PTSD brain repository has recently been undertaken to address this issue. This will allow for high throughput gene expression and proteome analysis that can be coupled with epigenetic and genomic approaches to characterize the molecular alterations underlying PTSD. Preliminary studies using next generation RNA sequencing have identified PTSD specific gene expression alterations in the prefrontal cortex (PFC). The approaches used for transcriptome analysis and early findings regarding two glucocorticoid regulated genes of interest, FKBP5 and SGK1 are discussed, and the consequences of altered SGK1 are presented. Altered SGK1 could contribute to synaptic alterations in PFC subregions that could contribute to loss of inhibitory control and extinction of fear memories. Based on these findings, we discuss new studies demonstrating that ketamine can increase synapse number in the PFC and enhance the extinction of fear memory in rodent models and improve symptoms in PTSD patients. Continued molecular and cellular characterization of postmortem brain tissue of PTSD subjects will further define the neurobiology of PTSD and identify novel targets for safe and more efficacious treatments.

IPlasticity: Induced juvenile-like plasticity in the adult brain as a mechanism of antidepressants.

The network hypothesis of depression proposes that mood disorders reflect problems in information processing within particular neural networks. Antidepressants (AD), including selective serotonin reuptake inhibitors (SSRI), function by gradually improving information processing within these networks. AD have been shown to induce a state of juvenile‐like plasticity comparable to that observed during developmental critical periods: Such critical‐period‐like plasticity allows brain networks to better adapt to extrinsic and intrinsic signals. We have coined this drug‐induced state of juvenile‐like plasticity ‘iPlasticity.’ A combination of iPlasticity induced by chronic SSRI treatment together with training, rehabilitation, or psychotherapy improves symptoms of neuropsychiatric disorders and issues underlying the developmentally or genetically malfunctioning networks. We have proposed that iPlasticity might be a critical component of AD action. We have demonstrated that iPlasticity occurs in the visual cortex, fear erasure network, extinction of aggression caused by social isolation, and spatial reversal memory in rodent models. Chronic SSRI treatment is known to promote neurogenesis and to cause dematuration of granule cells in the dentate gyrus and of interneurons, especially parvalbumin interneurons enwrapped by perineuronal nets in the prefrontal cortex, visual cortex, and amygdala. Brain‐derived neurotrophic factor (BDNF), via its receptor tropomyosin kinase receptor B, is involved in the processes of synaptic plasticity, including neurogenesis, neuronal differentiation, weight of synapses, and gene regulation of synaptic formation. BDNF can be activated by both chronic SSRI treatment and neuronal activity. Accordingly, the BDNF/tropomyosin kinase receptor B pathway is critical for iPlasticity, but further analyses will be needed to provide mechanical insight into the processes of iPlasticity.

A role for CA3 in social recognition memory

Social recognition memory is crucial for survival across species, underlying the need to correctly identify conspecifics, mates and potential enemies. In humans the hippocampus is engaged in social and episodic memory, however the circuit mechanisms of social memory in rodent models has only recently come under scrutiny. Work in mice has established that the dorsal CA2 and ventral CA1 regions play critical roles, however a more comprehensive comparative analyses of the circuits and mechanisms required has not been reported. Here we employ conditional genetics to examine the differential contributions of the hippocampal subfields to social memory. We find that the deletion of NMDA receptor subunit 1 gene (NR1), which abolishes NMDA receptor synaptic plasticity, in CA3 pyramidal cells led to deficits in social memory; however, mice lacking the same gene in DG granule cells performed indistinguishable from controls. Further, we use conditional pharmacogenetic inhibition to demonstrate that activity in ventral, but not dorsal, CA3 is necessary for the encoding of a social memory. These findings demonstrated CA3 pyramidal cell plasticity and transmission contribute to the encoding of social stimuli and help further identify the distinct circuits underlying the role of the hippocampus in social memory.

Vascular Endothelial Growth Factor (VEGF) in Neurodevelopmental Disorders

Neurovascular dysfunction and the role of vascular endothelial growth factor (VEGF) have been explored in neurodevelopmental disorders including schizophrenia, bipolar disorder, major depressive and mood disorders, and autism. These disorders are correlated with hypoxia-ischemia insults during early life and are strongly associated with cognitive dysfunction. This review focuses on the hypoxia-regulated protein, VEGF, to discuss its crucial roles in brain development and function. These data implicate that alterations to VEGF signaling during early life can impair neural development, underlying the severe cognitive deficits observed in neurodevelopmental disorders. VEGF has been linked to neurological processes that influence learning and memory. VEGF is advancing towards being a novel biomarker and possible therapeutic for neurological disorders. Prenatal environmental enrichment positively impacted neurotrophic factors, brain structure, and memory in rodent models. Understanding the molecular mechanisms of VEGF in neurodevelopment will create intervention strategies for at-risk children born to adverse early-life events. By proactively working with those in a pliable neurodevelopmental state, we hope to ameliorate cognitive deficits to increase their chance to develop into high-functioning adults with disabilities.

Methyl jasmonate ameliorates memory deficits in mice exposed to passive avoidance paradigm

Passive avoidance task is a rodent model of memory in which the animal learnt to avoid an aversive stimulus precipitated by fear and it is always accompanied by inhibition of motor behavior. We have shown in our previous studies that methyl jasmonate (MJ), a bioactive compound isolated from Jasminum grandiflorum demonstrated memory enhancing effect in hippocampal-dependent memory tasks such as Y-maze and object recognition tests in mice. This present study was designed to investigate if MJ could ameliorate memory deficits associated majorly with the activation of the amygdala in response to an aversive stimulus in the passive avoidance paradigm. The present study also evaluated the effect of MJ on scopolamine (SC)- and lipopolysaccharide (LPS)-induced memory impairment in the passive avoidance paradigm. Mice were given intraperitoneal (i.p) injection of MJ (10-40 mg/kg), donepezil, DP (1 mg/kg) or vehicle daily for 7 days before testing for memory using passive avoidance step-down apparatus. In the interaction studies, the effects of SC (3 mg/kg, i.p.) or LPS (250 µg/kg, i.p.) given alone or with MJ (10, 20, 40 mg/kg) or DP (1 mg/kg) for 7 consecutive days were also evaluated. SC and LPS were injected 30 min after MJ or DP administration. The time it took (step-down latency) the mouse to step down from the elevated vibrating platform onto the grids (electrified stainless steel bars on the floor of the cage), which indicates memory function was recorded. Our findings revealed that MJ (10-40 mg/kg, i.p.) ameliorated memory deficits induced by electric shock in the passive avoidance test. MJ (10-40 mg/kg, i.p.) also attenuated memory impairment induced by SC (3 mg/kg) or LPS (250 µg/kg) in mice subjected to the shock in the passive avoidance task. Taken together, this study provides additional behavioral data, which further supports the potential usefulness of MJ in conditions associated with memory decline.

Aryl Sulfonamide Inhibitors of Insulin-Regulated Aminopeptidase Enhance Spine Density in Primary Hippocampal Neuron Cultures.

The zinc metallopeptidase insulin regulated aminopeptidase (IRAP), which is highly expressed in the hippocampus and other brain regions associated with cognitive function, has been identified as a high-affinity binding site of the hexapeptide angiotensin IV (Ang IV). This hexapeptide is thought to facilitate learning and memory by binding to the catalytic site of IRAP to inhibit its enzymatic activity. In support of this hypothesis, low molecular weight, nonpeptide specific inhibitors of IRAP have been shown to enhance memory in rodent models. Recently, it was demonstrated that linear and macrocyclic Ang IV-derived peptides can alter the shape and increase the number of dendritic spines in hippocampal cultures, properties associated with enhanced cognitive performance. After screening a library of 10 500 drug-like substances for their ability to inhibit IRAP, we identified a series of low molecular weight aryl sulfonamides, which exhibit no structural similarity to Ang IV, as moderately potent IRAP inhibitors. A structural and biological characterization of three of these aryl sulfonamides was performed. Their binding modes to human IRAP were explored by docking calculations combined with molecular dynamics simulations and binding affinity estimations using the linear interaction energy method. Two alternative binding modes emerged from this analysis, both of which correctly rank the ligands according to their experimental binding affinities for this series of compounds. Finally, we show that two of these drug-like IRAP inhibitors can alter dendritic spine morphology and increase spine density in primary cultures of hippocampal neurons.

Ghrelin modulates encoding-related brain function without enhancing memory formation in humans

Ghrelin regulates energy homeostasis in various species and enhances memory in rodent models. In humans, the role of ghrelin in cognitive processes has yet to be characterized. Here we show in a double-blind randomized crossover design that acute administration of ghrelin alters encoding-related brain activity, however does not enhance memory formation in humans. Twenty-one healthy young male participants had to memorize food- and non-food-related words presented on a background of a virtual navigational route while undergoing fMRI recordings. After acute ghrelin administration, we observed decreased post-encoding resting state fMRI connectivity between the caudate nucleus and the insula, amygdala, and orbitofrontal cortex. In addition, brain activity related to subsequent memory performance was modulated by ghrelin. On the next day, however, no differences were found in free word recall or cued location-word association recall between conditions; and ghrelin's effects on brain activity or functional connectivity were unrelated to memory performance. Further, ghrelin had no effect on a cognitive test battery comprising tests for working memory, fluid reasoning, creativity, mental speed, and attention. In conclusion, in contrast to studies with animal models, we did not find any evidence for the potential of ghrelin acting as a short-term cognitive enhancer in humans.

Spontaneous object recognition: a promising approach to the comparative study of memory.

Spontaneous recognition of a novel object is a popular measure of exploratory behavior, perception and recognition memory in rodent models. Because of its relative simplicity and speed of testing, the variety of stimuli that can be used, and its ecological validity across species, it is also an attractive task for comparative research. To date, variants of this test have been used with vertebrate and invertebrate species, but the methods have seldom been sufficiently standardized to allow cross-species comparison. Here, we review the methods necessary for the study of novel object recognition in mammalian and non-mammalian models, as well as the results of these experiments. Critical to the use of this test is an understanding of the organism’s initial response to a novel object, the modulation of exploration by context, and species differences in object perception and exploratory behaviors. We argue that with appropriate consideration of species differences in perception, object affordances, and natural exploratory behaviors, the spontaneous object recognition test can be a valid and versatile tool for translational research with non-mammalian models.

Sleep and circadian rhythm disruption and recognition memory in schizophrenia.

Schizophrenia patients often show irregularities in sleep and circadian rhythms and deficits in recognition memory. Similar phenotypes are seen in schizophrenia-relevant genetic mouse models, such as synaptosomal associated protein of 25 kDa (Snap-25) point mutant mice, vasoactive intestinal peptide receptor 2 (Vipr2) knockout mice, and neuregulin 1 (Nrg1)-deficient mice. Sleep and circadian abnormalities and impaired recognition memory may be causally related in both schizophrenia patients and schizophrenia-relevant mouse models, since sleep deprivation, abnormal photic input, and the manipulation of core clock genes (cryptochrome 1/2) can all disrupt object recognition memory in rodent models. The recognition deficits observed in patients and mouse models (both schizophrenia-related and -unrelated) are discussed here in terms of the dual-process theory of recognition, which postulates that there are two recognition mechanisms-recollection versus familiarity-that can be selectively impaired by brain lesions, neuropsychiatric conditions, and putatively, sleep and circadian rhythm disruption. However, based on this view, the findings from patient studies and studies using genetic mouse models (Nrg1 deficiency) seem to be inconsistent with each other. Schizophrenia patients are impaired at recollection (and to a lesser extent, familiarity judgments), but Nrg1-deficient mice are impaired at familiarity-based object recognition, raising concerns regarding the validity of using these genetically modified mice to model recognition phenotypes observed in patients. This issue can be resolved in future animal studies by examining performance in different variants of the spontaneous recognition task-the standard, perirhinal cortex-dependent, object recognition task versus the hippocampus-dependent object-place recognition task-in order to see which of the two recognition mechanisms is more disrupted.

Chronic treatment with DCPCX, an adenosine A1 antagonist, worsens long-term memory

Alzheimer's disease is characterized by progressive cognitive disturbances and neurotransmitter dysfunction. Previous studies targeting the adrenergic A1 pathway suggest that this plays a role in cognitive impairment in Alzheimer's disease. Previous studies have reported that acute treatment with A1 antagonists appears to improve behavioral deficits in rodent models of memory and behavioral impairment. In this study, we addressed whether the chronic administration of 8-cyclopentyl-1,3-dipropylxanthine, a potent and selective adenosine A1 antagonist, could reverse the memory deficits found in aged APPswe/PS1dE9 mice. Chronic treatment did not improve memory in the APPswe/PS1dE9 mouse model and resulted in reduced exploratory behavior, suggestive of reduced anxiety, and a worsening of long-term memory in nontransgenic mice. These results have important implications for understanding the mechanisms of A1 receptor modulation as a target in Alzheimer's disease therapy.

Acute Inhibition of 11β-Hydroxysteroid Dehydrogenase Type-1 Improves Memory in Rodent Models of Cognition

Mounting evidence suggests excessive glucocorticoid activity may contribute to Alzheimer's disease (AD) and age-associated memory impairment. 11β-hydroxysteroid dehydrogenase type-1 (HSD1) regulates conversion of glucocorticoids from inactive to active forms. HSD1 knock-out mice have improved cognition, and the nonselective inhibitor carbenoxolone improved verbal memory in elderly men. Together, these data suggest that HSD1 inhibition may be a potential therapy for cognitive deficits, such as those associated with AD. To investigate this, we characterized two novel and selective HSD1 inhibitors, A-918446 and A-801195. Learning, memory consolidation, and recall were evaluated in mouse 24 h inhibitory avoidance. Inhibition of brain cortisol production and phosphorylation of cAMP response element-binding protein (CREB), a transcription factor involved in cognition, were also examined. Rats were tested in a short-term memory model, social recognition, and in a separate group cortical and hippocampal acetylcholine release was measured via in vivo microdialysis. Acute treatment with A-801195 (10-30 mg/kg) or A-918446 (3-30 mg/kg) inhibited cortisol production in the ex vivo assay by ∼ 35-90%. Acute treatment with A-918446 improved memory consolidation and recall in inhibitory avoidance and increased CREB phosphorylation in the cingulate cortex. Acute treatment with A-801195 significantly improved short-term memory in rat social recognition that was not likely due to alterations of the cholinergic system, as acetylcholine release was not increased in a separate set of rats. These studies suggest that selective HSD1 inhibitors work through a novel, noncholinergic mechanism to facilitate cognitive processing.

Galanin in Alzheimer's disease: neuroinhibitory or neuroprotective?

Galanin (GAL) and GAL receptors (GALRs) are overexpressed in degenerating brain regions associated with cognitive decline in Alzheimer's disease (AD). The functional consequences of GAL plasticity in AD are unclear. GAL inhibits cholinergic transmission in the hippocampus and impairs spatial memory in rodent models, suggesting GAL overexpression exacerbates cognitive impairment in AD. By contrast, gene expression profiling of individual cholinergic basal forebrain (CBF) neurons aspirated from AD tissue revealed that GAL hyperinnervation positively regulates mRNAs that promote CBF neuronal function and survival. GAL also exerts neuroprotective effects in rodent models of neurotoxicity. These data support the growing concept that GAL overexpression preserves CBF neuron function which in turn may slow the onset of AD symptoms. Further elucidation of GAL activity in selectively vulnerable brain regions will help gauge the therapeutic potential of GALR ligands for the treatment of AD.