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Abstract Background Here, we jointly summarise scientific evidence for genetic variation in resistance to infection with Mycobacterium bovis, the primary agent of bovine tuberculosis (TB), provided by two recent and separate studies of Holstein-Friesian dairy cow populations in Great Britain (GB) and Ireland. Methods The studies quantified genetic variation within archived data from field and abattoir surveillance control programmes within each country. These data included results from the single intradermal comparative tuberculin test (SICTT), abattoir inspection for TB lesions and laboratory confirmation of disease status. Threshold animal models were used to estimate variance components for responsiveness to the SICTT and abattoir confirmed M. bovis infection. The link functions between the observed 0/1 scale and the liability scale were the complementary log-log in the GB, and logit link function in the Irish population. Results and discussion The estimated heritability of susceptibility to TB, as judged by responsiveness to the SICTT, was 0.16 (0.012) and 0.14 (0.025) in the GB and Irish populations, respectively. For abattoir or laboratory confirmation of infection, estimates were 0.18 (0.044) and 0.18 (0.041) from the GB and the Irish populations, respectively. Conclusions Estimates were all significantly different from zero and indicate that exploitable variation exists among GB and Irish Holstein Friesian dairy cows for resistance to TB. Epidemiological analysis suggests that factors such as variation in exposure or imperfect sensitivity and specificity would have resulted in underestimation of the true values.

Abstract There have been considerable recent advancements in animal breeding and genetics relevant to disease control in cattle, which can now be utilised as part of an overall programme for improved cattle health. This review summarises the contribution of genetic makeup to differences in resistance to many diseases affecting cattle. Significant genetic variation in susceptibility to disease does exist among cattle suggesting that genetic selection for improved resistance to disease will be fruitful. Deficiencies in accurately recorded data on individual animal susceptibility to disease are, however, currently hindering the inclusion of health and disease resistance traits in national breeding goals. Developments in 'omics' technologies, such as genomic selection, may help overcome some of the limitations of traditional breeding programmes and will be especially beneficial in breeding for lowly heritable disease traits that only manifest themselves following exposure to pathogens or environmental stressors in adulthood. However, access to large databases of phenotypes on health and disease will still be necessary. This review clearly shows that genetics make a significant contribution to the overall health and resistance to disease in cattle. Therefore, breeding programmes for improved animal health and disease resistance should be seen as an integral part of any overall national disease control strategy.

Abstract Background Despite CDC recommendations regarding universal catch-up vaccination against human papillomavirus (HPV), only about ten percent of young adult women in the United States have been vaccinated. The purpose of this study was to better understand reasons for non-vaccination among insured 19-26 year-old women and to evaluate future vaccination intentions. Methods We used an administrative claims database from a large US managed care plan to identify women aged 19-26 for receipt of a mailed survey. From a sample of 1,375 women with no evidence of HPV vaccination from June 1, 2006 through April 30, 2007, 222 completed surveys were received, of which 185 were eligible for this analysis. The main outcome measures were unvaccinated women's attitudes and vaccine awareness, likelihood of future action regarding the vaccine, and reasons for inaction. Results Among the 185 non-vaccinees, 25.4% were married, 83.2% were white, and 89.2% had a college or higher level education. The vaccine was described as very important by 32.4% of subjects, and 30.1% had discussed the vaccine with a doctor and received a doctor's recommendation. Half or fewer of respondents were "very" or "extremely" likely to discuss the vaccine with their doctor (50.0%), do additional research on the vaccine (42.6%), ask a doctor to get the vaccine (37.5%), or make an appointment to get the vaccine (27.8%), while 48.0% were "somewhat", "very", or "extremely" likely to do nothing to get the vaccine. Among the latter, reasons for taking no action included being married or in a monogamous relationship (54.9%), belief that the vaccine is too new (35.4%), not having enough information about the vaccine (31.7%), concerns about side effects (24.4%), and uncertainty about insurance coverage (24.4%). Conclusions Educational interventions may be needed to enhance HPV vaccination rates among 19-26 year-old women, particularly regarding information about vaccine safety, vaccine efficacy, insurance coverage, and the value of vaccination to women in monogamous relationships.

Abstract Background Colorectal cancer screening rates are low among disadvantaged patients; few studies have explored barriers to screening in community health centers. The purpose of this study was to describe barriers to/facilitators of colorectal cancer screening among diverse patients served by community health centers. Methods We identified twenty-three outpatients who were eligible for colorectal cancer screening and their 10 primary care physicians. Using in-depth semi-structured interviews, we asked patients to describe factors influencing their screening decisions. For each unscreened patient, we asked his or her physician to describe barriers to screening. We conducted patient interviews in English (n = 8), Spanish (n = 2), Portuguese (n = 5), Portuguese Creole (n = 1), and Haitian Creole (n = 7). We audiotaped and transcribed the interviews, and then identified major themes in the interviews. Results Four themes emerged: 1) Unscreened patients cited lack of trust in doctors as a barrier to screening whereas few physicians identified this barrier; 2) Unscreened patients identified lack of symptoms as the reason they had not been screened; 3) A doctor's recommendation, or lack thereof, significantly influenced patients' decisions to be screened; 4) Patients, but not their physicians, cited fatalistic views about cancer as a barrier. Conversely, physicians identified competing priorities, such as psychosocial stressors or comorbid medical illness, as barriers to screening. In this culturally diverse group of patients seen at community health centers, similar barriers to screening were reported by patients of different backgrounds, but physicians perceived other factors as more important. Conclusion Further study of these barriers is warranted.

A decline in hippocampal function has long been associated with the progression of cognitive impairments in patients with Alzheimer's disease (AD). The disruption of hippocampal synaptic plasticity [primarily the reduction of long-term potentiation LTP] by excess production of soluble beta-amyloid (Aβ) has long been accepted as the mechanism by which AD pathology impairs memory, at least during the early stages of AD pathogenesis. However, the premise that hippocampal LTP underpins the formation of associative, long-term memories has been challenged. Here, we consider evidence that this canonical view of LTP needs to be refined. Similarly, the view that the hippocampus simply supports memory ignores the wealth of data showing that the hippocampus is functionally heterogeneous along its septo-temporal axis. The ventral (but not the dorsal) hippocampus plays a major role in modulating emotional reactions to conflict. Here, we suggest that hippocampal LTP is not involved in forming long-term associative memories, but instead contributes to the disambiguation of overlapping memories in situations of conflict and associative interference. This conceptualisation of hippocampal synaptic plasticity may help explain how early-stage AD pathology may impact both memory and anxiety., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Aging and metabolic syndrome are associated with neurodegenerative pathologies including Alzheimer's disease (AD) and there is growing interest in the prophylactic potential of probiotic bacteria in this area. In this study, we assessed the neuroprotective potential of the Lab4P probiotic consortium in both age and metabolically challenged 3xTg-AD mice and in human SH-SY5Y cell culture models of neurodegeneration. In mice, supplementation prevented disease-associated deteriorations in novel object recognition, hippocampal neurone spine density (particularly thin spines) and mRNA expression in hippocampal tissue implying an anti-inflammatory impact of the probiotic, more notably in the metabolically challenged setting. In differentiated human SH-SY5Y neurones challenged with β-Amyloid, probiotic metabolites elicited a neuroprotective capability. Taken together, the results highlight Lab4P as a potential neuroprotective agent and provide compelling support for additional studies in animal models of other neurodegenerative conditions and human studies.

An imbalance in the circulatory and organ-specific renin-angiotensin system (RAS) pathways is associated with age-related dysfunction and disease including cardiovascular burden and more recently Alzheimer's disease (AD). It is currently unclear whether an age-associated imbalance in components of the RAS within the brain precedes the onset of AD or whether a RAS imbalance is associated with the onset of disease pathology and cognitive decline. Angiotensin-converting enzyme-1 (ACE-1) and -2 (ACE-2) protein (ELISA) and enzyme activity (FRET assay), markers of the classical and counter-regulatory RAS axis respectively, and Ang-II and Ang-(1-7) peptide levels (ELISA), were measured in the left cortex across four transgenic AD mouse models of amyloid pathology (5xFAD - 2, 6, and 12 months of age; Apd9 - 3-4, 12, and 18 months of age; Tg2576 - 3-4 and 24 months of age; and PDAPP - 3-4, 7, 11, 15, and 18 months of age) and littermate wild-type (WT) controls. ACE-1 level, and enzyme activity, was unaltered in relation to age in WT mice and across all four models. In contrast, ACE-2 level and enzyme activity, was reduced and Ang-II increased with ageing in both WT animals and disease models. The changes in ACE-2 and Ang-II in AD models mirrored WT mice, except for the 5xFAD model, when the reduction in ACE-2 (and elevated Ang-II) was observed at a younger age. These data indicate an age-related dysregulation of brain RAS is likely to be driven by a reduction in ACE-2. The reduction in ACE-2 occurs at a young age, coinciding with early pathological changes and the initial deposition of Aβ, and preceding neuronal loss and cognitive decline, in the transgenic AD models. However, the age-related loss was mirrored in WT mice suggesting that the change was independent of pathological Aβ deposition., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Brain degenerative disorders such as Alzheimer's disease (AD) can be exacerbated by aberrant metabolism. Supplementation with probiotic bacteria is emerging as a promising preventative strategy for both neurodegeneration and metabolic syndrome. In this study, we assess the impact of the Lab4b probiotic consortium on (i) cognitive and pathological markers of AD progression and (ii) metabolic status in 3xTg-AD mice subjected to metabolic challenge with a high fat diet. The group receiving the probiotic performed better in the novel object recognition test and displayed higher hippocampal neuronal spine density than the control group at the end of the 12 weeks intervention period. These changes were accompanied by differences in localised (brain) and systemic anti-inflammatory responses that favoured the Probiotic group together with the prevention of diet induced weight gain and hypercholesterolaemia and the modulation of liver function. Compositional differences between the faecal microbiotas of the study groups included a lower Firmicutes:Bacteroidetes ratio and less numbers of viable yeast in the Probiotic group compared to the Control. The results illustrate the potential of the Lab4b probiotic as a neuroprotective agent and encourage further studies with human participants., Competing Interests: TW, GM, JK-S, AJ, DM, ST, DJ, and SP were employed by the Cultech Ltd. The funder had the following involvement in the study: the design of the study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Webberley, Masetti, Bevan, Kerry-Smith, Jack, Michael, Thomas, Glymenaki, Li, McDonald, John, Morgan, Marchesi, Good, Plummer and Hughes.)

Neuronal dendritic and synaptic pruning are early features of neurodegenerative diseases, including Alzheimer's disease. In addition to brain pathology, amyloid plaque deposition, microglial activation, and cell loss occur in the retinas of human patients and animal models of Alzheimer's disease. Retinal ganglion cells, the output neurons of the retina, are vulnerable to damage in neurodegenerative diseases and are a potential opportunity for non-invasive clinical diagnosis and monitoring of Alzheimer's progression. However, the extent of retinal involvement in Alzheimer's models and how well this reflects brain pathology is unclear. Here we have quantified changes in retinal ganglion cells dendritic structure and hippocampal dendritic spines in three well-studied Alzheimer's mouse models, Tg2576, 3xTg-AD and APP NL-G-F . Dendritic complexity of DiOlistically labelled retinal ganglion cells from retinal explants was reduced in all three models in an age-, gender-, and receptive field-dependent manner. DiOlistically labelled hippocampal slices showed spine loss in CA1 apical dendrites in all three Alzheimer's models, mirroring the early stages of neurodegeneration as seen in the retina. Morphological classification showed that loss of thin spines predominated in all. The demonstration that retinal ganglion cells dendritic field reduction occurs in parallel with hippocampal dendritic spine loss in all three Alzheimer's models provide compelling support for the use of retinal neurodegeneration. As retinal dendritic changes are within the optical range of current clinical imaging systems (for example optical coherence tomography), our study makes a case for imaging the retina as a non-invasive way to diagnose disease and monitor progression in Alzheimer's disease.

Objectives: High risks of falls have been reported in older adults with chronic pain but chronic pain similarly affects adults of all ages. This cross-sectional study aimed to determine the prevalence of falls and associated risk factors in adults of all ages living with chronic pain., Materials and Methods: Patient-reported data were analyzed from 591 adults with chronic pain enrolled in a local pain clinic between November 2017 and April 2019. Sociodemographic, history of falls, and biopsychosocial measures of pain were examined to identify and describe adults with chronic pain who fell in the previous year. Factors associated with falls were examined using logistic regression., Results: A total of 268 (45%) reported at least 1 fall in the previous year (fallers) where 194 (33%) fell in the previous 3 months, and 185 (31%) had multiple falls. The prevalence of falls in the previous year was over 37% across age groups. Overall, fallers were older, had greater pain severity and interference, lower physical function and pain self-efficacy, greater depression, more reported neuropathic pain, and had more pain sites compared with nonfallers. Number of pain sites reported (odds ratio=1.12; 95% confidence interval, 1.02-1.22) and lower physical function (odds ratio=0.96; 95% confidence interval, 0.94-0.99) were independently associated with falls., Discussion: A high prevalence of falls was found independent of age for adults with chronic pain. Although the risk of falls may increase with age, lower physical function and more pain sites are better indicators for falls. A better understanding of circumstances and consequences of falls in all adults with chronic pain is warranted.

In an exploratory, block-randomised, parallel, double-blind, single-centre, placebo-controlled superiority study (ISRCTN12562026, funded by Cultech Ltd), 220 Bulgarian participants (30 to 65 years old) with BMI 25-34.9 kg/m 2 received Lab4P probiotic (50 billion/day) or a matched placebo for 6 months. Participants maintained their normal diet and lifestyle. Primary outcomes were changes in body weight, BMI, waist circumference (WC), waist-to-height ratio (WtHR), blood pressure and plasma lipids. Secondary outcomes were changes in plasma C-reactive protein (CRP), the diversity of the faecal microbiota, quality of life (QoL) assessments and the incidence of upper respiratory tract infection (URTI). Significant between group decreases in body weight (1.3 kg, p < 0.0001), BMI (0.045 kg/m 2 , p < 0.0001), WC (0.94 cm, p < 0.0001) and WtHR (0.006, p < 0.0001) were in favour of the probiotic. Stratification identified greater body weight reductions in overweight subjects (1.88%, p < 0.0001) and in females (1.62%, p = 0.0005). Greatest weight losses were among probiotic hypercholesterolaemic participants (-2.5%, p < 0.0001) alongside a significant between group reduction in small dense LDL-cholesterol (0.2 mmol/L, p = 0.0241). Improvements in QoL and the incidence rate ratio of URTI (0.60, p < 0.0001) were recorded for the probiotic group. No adverse events were recorded. Six months supplementation with Lab4P probiotic resulted in significant weight reduction and improved small dense low-density lipoprotein-cholesterol (sdLDL-C) profiles, QoL and URTI incidence outcomes in overweight/obese individuals.

Mid-life hypertension and cerebrovascular dysfunction are associated with increased risk of later life dementia, including Alzheimer's disease (AD). The classical renin-angiotensin system (cRAS), a physiological regulator of blood pressure, functions independently within the brain and is overactive in AD. cRAS-targeting anti-hypertensive drugs are associated with reduced incidence of AD, delayed onset of cognitive decline, and reduced levels of Aβ and tau in both animal models and human pathological studies. cRAS activity is moderated by a downstream regulatory RAS pathway (rRAS), which is underactive in AD and is strongly associated with pathological hallmarks in human AD, and cognitive decline in animal models of CNS disease. We now show that enhancement of brain ACE2 activity, a major effector of rRAS, by intraperitoneal administration of diminazene aceturate (DIZE), an established activator of ACE2, lowered hippocampal Aβ and restored cognition in mid-aged (13-14-month-old) symptomatic Tg2576 mice. We confirmed that the protective effects of DIZE were directly mediated through ACE2 and were associated with reduced hippocampal soluble Aβ 42 and IL1-β levels. DIZE restored hippocampal MasR levels in conjunction with increased NMDA NR2B and downstream ERK signalling expression in hippocampal synaptosomes from Tg2576 mice. Chronic (10 weeks) administration of DIZE to pre-symptomatic 9-10-month-old Tg2576 mice, and acute (10 days) treatment in cognitively impaired 12-13-month-old mice, prevented the development of cognitive impairment. Together these data demonstrate that ACE2 enhancement protects against and reverses amyloid-related hippocampal pathology and cognitive impairment in a preclinical model of AD.

Neurodegeneration has been linked to changes in the gut microbiota and this study compares the neuroprotective capability of two bacterial consortia, known as Lab4 and Lab4b, using the established SH-SY5Y neuronal cell model. Firstly, varying total antioxidant capacities (TAC) were identified in the intact cells from each consortia and their secreted metabolites, referred to as conditioned media (CM). 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and Crystal Violet (CV) assays of cell viability revealed that Lab4 CM and Lab4b CM could induce similar levels of proliferation in SH-SY5Y cells and, despite divergent TAC, possessed a comparable ability to protect undifferentiated and retinoic acid-differentiated cells from the cytotoxic actions of rotenone and undifferentiated cells from the cytotoxic actions of 1-methyl-4-phenylpyridinium iodide (MPP+). Lab4 CM and Lab4b CM also had the ability to attenuate rotenone-induced apoptosis and necrosis with Lab4b inducing the greater effect. Both consortia showed an analogous ability to attenuate intracellular reactive oxygen species accumulation in SH-SY5Y cells although the differential upregulation of genes encoding glutathione reductase and superoxide dismutase by Lab4 CM and Lab4b CM, respectively, implicates the involvement of consortia-specific antioxidative mechanisms of action. This study implicates Lab4 and Lab4b as potential neuroprotective agents and justifies their inclusion in further in vivo studies.

β-Amyloid (Aβ) accumulation is an early event of Alzheimer's disease (AD) pathogenesis. Inhibition of Aβ production by β-secretase (BACE) has been proposed as a potential therapeutic strategy for AD. However, BACE inhibitors lack specificity and have had limited clinical benefit. To better study the consequences of reducing BACE metabolism, specifically of APP, we used an antibody, 2B3, that binds to APP at the BACE cleavage site, inhibiting Aβ production. 2B3 was administered either directly into the lateral ventricles or by intraperitoneal injection to (platelet-derived growth factor promoter hAPP717V (PDAPP) mice and WT mice. 2B3 reduced soluble Aβ40 and βCTF (β-amyloid derived C-terminal fragment) and improved memory for object-in-place associations and working memory in a foraging task in PDAPP mice. 2B3 also normalized the phosphorylation of the N-methyl-D-aspartate receptor NR2B subunit and subsequent extracellular signal-regulated kinase signaling. The importance of this NR2B pathway for OiP memory was confirmed by administering the NR2B antagonist, Ro25-6981, to 18-month-old WT. In contrast, 2B3 impaired associative recognition memory in young WT mice. These data provide novel insights into the mechanism by which selective modulation of APP metabolism by BACE influences synaptic and cognitive processes in both normal mice and aged APP transgenic mice., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Three experiments examined the ability of mice to forage efficiently for liquid rewards in pots located in an open field arena. Search behaviour was unconstrained other than by the walls of the arena. All mice acquired the task within 4 days of training, with one trial per day. Experiment 1 tested the hypothesis that hippocampal lesions would disrupt foraging behaviour using extramaze cues. Mice with hippocampal lesions showed normal latency to initiate foraging and to complete the task relative to sham-operated mice. However, lesioned mice showed increased perseverative responding (sensitization) to recently rewarded locations, increased total working memory errors and an increased propensity to search near previously rewarded locations. In Experiment 2, the extramaze cues were obscured and each pot was identified by a unique pattern. Under these conditions, mice with hippocampal lesions showed comparable working memory errors to control mice. However, lesioned mice continued to display increased perseverative responding and altered search strategies. Experiment 3 tested the hypothesis that age-related accumulation of amyloid would disrupt foraging behaviour in transgenic PDAPP mice expressing the V717F amyloid precursor protein (APP) mutation. Consistent with previous findings, PDAPP mice showed both age-dependent and age-independent behavioural changes. More specifically, 14-16 month-old PDAPP mice showed a deficit in perseverative responding and working memory errors. In contrast, changes in search behaviour, such as systematic circling, were present throughout development. The latter indicates that APP overexpression contributed to some features of the PDAPP behavioural phenotype, whereas working memory and flexible responding was sensitive to ageing and β-amyloid burden. In conclusion, the present study provided novel insight into the role of the hippocampus and the effects of APP overexpression on memory and search behaviour in an open-field foraging task., (Copyright © 2018 Elsevier Inc. All rights reserved.)

A major risk factor for the development of Alzheimer's disease (AD) is increasing age, but the reason behind this association has not been identified. It is thought that the changes in endocytosis seen in AD patients are causal for this condition. Thus, we hypothesized that the increased risk of developing AD associated with ageing may be because of changes in endocytosis. We investigated using Western blotting whether the expression of endocytic proteins involved in clathrin-mediated and clathrin-independent endocytosis are altered by increasing age in a mouse model of amyloid pathology. We used mice transgenic for human amyloid precursor protein containing the V717I London mutation. We compared the London mutation mice with age-matched wild-type (WT) controls at three ages, 3, 9 and 18 months, representing different stages in the development of pathology in this model. Having verified that the London mutation mice overexpressed amyloid precursor protein and β-amyloid, we found that the expression of the smallest isoform of PICALM, a key protein involved in the regulation of clathrin-coated pit formation, was significantly increased in WT mice, but decreased in the London mutation mice with age. PICALM levels in WT 18-month mice and clathrin levels in WT 9-month mice were significantly higher than those in the London mutation mice of the same ages. The expression of caveolin-1, involved in clathrin-independent endocytosis, was significantly increased with age in all mice. Our results suggest that endocytic processes could be altered by the ageing process and such changes could partly explain the association between ageing and AD.

Ageing is associated with changes in the gut microbiome that may contribute to age-related changes in cognition. Previous work has shown that dietary supplements with multi-species live microorganisms can influence brain function, including induction of hippocampal synaptic plasticity and production of brain derived neurotrophic factor, in both young and aged rodents. However, the effect of such dietary supplements on memory processes has been less well documented, particularly in the context of aging. The main aim of the present study was to examine the impact of a long-term dietary supplement with a multi-species live Lactobacillus and Bifidobacteria mixture (Lactobacillus acidophilus CUL60, L. acidophilus CUL21, Bifidobacterium bifidum CUL20 and B. lactis CUL34) on tests of memory and behavioural flexibility in 15-17-month-old male rats. Following behavioural testing, the hippocampus and prefrontal cortex was extracted and analysed ex vivo using 1 H nuclear magnetic resonance ( 1 H NMR) spectroscopy to examine brain metabolites. The results showed a small beneficial effect of the dietary supplement on watermaze spatial navigation and robust improvements in long-term object recognition memory and short-term memory for object-in-place associations. Short-term object novelty and object temporal order memory was not influenced by the dietary supplement in aging rats. 1 H NMR analysis revealed diet-related regional-specific changes in brain metabolites; which indicated changes in several pathways contributing to modulation of neural signaling. These data suggest that chronic dietary supplement with multi-species live microorganisms can alter brain metabolites in aging rats and have beneficial effects on memory., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The conditions under which the hippocampus contributes to learning about spatio-temporal configural patterns are not fully established. The aim of Experiments 1-4 was to investigate the impact of hippocampal lesions on learning about where or when a reinforcer would be delivered. In each experiment, the rats received exposure to an identical set of patterns (i.e., spotted+morning, checked+morning, spotted+afternoon and checked+afternoon); and the contexts (Experiment 1), times of day (Experiment 2), or their configuration (Experiments 3 and 4) signalled whether or not a reinforcer would be delivered. The fact that hippocampal damage did not disrupt the formation of simple or configural associations involving spatio-temporal patterns is surprising, and suggests that the contribution of the hippocampus is restricted to mediated learning (or updating) involving spatio-temporal configurations., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The present study examined memory function in Tc1 mice, a transchromosomic model of Down syndrome (DS). Tc1 mice demonstrated an unusual delay-dependent deficit in recognition memory. More specifically, Tc1 mice showed intact immediate (30sec), impaired short-term (10-min) and intact long-term (24-h) memory for objects. A similar pattern was observed for olfactory stimuli, confirming the generality of the pattern across sensory modalities. The specificity of the behavioural deficits in Tc1 mice was confirmed using APP overexpressing mice that showed the opposite pattern of object memory deficits. In contrast to object memory, Tc1 mice showed no deficit in either immediate or long-term memory for object-in-place information. Similarly, Tc1 mice showed no deficit in short-term memory for object-location information. The latter result indicates that Tc1 mice were able to detect and react to spatial novelty at the same delay interval that was sensitive to an object novelty recognition impairment. These results demonstrate (1) that novelty detection per se and (2) the encoding of visuo-spatial information was not disrupted in adult Tc1 mice. The authors conclude that the task specific nature of the short-term recognition memory deficit suggests that the trisomy of genes on human chromosome 21 in Tc1 mice impacts on (perirhinal) cortical systems supporting short-term object and olfactory recognition memory., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Although episodic memory deficits are the most conspicuous cognitive change in patients with Alzheimer's disease (AD), patients also display alterations in emotional expression, including anxiety and impaired conditioned fear behaviours. The neural circuitry underlying emotional learning is known to involve the amygdala and hippocampus, although the precise impact of amyloid pathology on the interaction between these brain regions remains unclear. Recent evidence suggests that Tg2576 mice, which express a human amyloid precursor protein (APP) mutation associated with early-onset AD, demonstrate normal acquisition of conditioned freezing to auditory and contextual stimuli paired with footshock. However, examination of the expression of c-Fos revealed altered neural network activity in transgenic mice. In the present study we examined the effects of the APP mutation on the expression of c-Fos following the retrieval of emotional memories. To this end, stimulus-induced cellular activity was measured by analysing expression of the immediate-early gene c-Fos after the retrieval of auditory or contextual fear memories. To characterize regional interdependencies of c-Fos expression, structural equation modelling was used to compare patterns of neural network activity. Consistent with previous findings, Tg2576 mice displayed reduced freezing elicited by the auditory stimulus but not by the conditioning context. Interestingly, the analysis of c-Fos expression revealed that the APPswe mutation disrupted dentate gyrus and amygdala function, as well as altering the influence of these regions on the neural network dynamics activated during context memory retrieval. These results provide novel insight into the influence of excess amyloid production on neural network activity during memory retrieval., (© 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Current therapies for Alzheimer's disease only treat the symptoms of the disease. We have previously developed a novel monoclonal antibody, 2B3, which binds to the β-secretase cleavage site in amyloid precursor protein (APP) and reduces the production of amyloid-β (Aβ) in human cell lines. To determine whether the antibody was likely to be effective in mouse models of amyloid pathology in vivo, we investigated whether 2B3 could also bind to APP in mouse primary cortical neurones. Primary cortical neurones were produced from E15.5-17.5 C57Bl/6 wild-type and transgenic APP/V717I (London mutation) embryos. The percentage of the neuronal population was determined by immunocytochemistry. Cells were treated with 10 μg/ml 2B3 or an irrelevant IgG for 48 h and Aβ40 levels determined by ELISA. The population of cells was found to contain over 75% neurones and 2B3 bound effectively to these cells. No differences in Aβ40 were detected between wild-type and transgenic cells. Importantly, 2B3 significantly inhibited the production of Aβ40 by 75.15±1.37% of the media control, whereas an irrelevant IgG only significantly reduced Aβ40 levels by 23.35±5.55% of the media control. The reduction in Aβ40 produced by 2B3 was significantly greater than that caused by the IgG. These data indicate that 2B3 binds to APP in mouse neurones and can inhibit Aβ40, similar to our previous findings. The antibody is probably therefore acting by steric hindrance of β-secretase and these data suggest that it will be effective in mice in vivo and could be an alternative potential therapy for Alzheimer's disease.

Previous research demonstrates that disruption of forebrain dopamine systems impairs the use of high-order information to guide goal-directed performance, and that this deficit may be related to impaired use of task-setting cues in patients with schizophrenia. Such deficits can be interrogated through conflict resolution, which has been demonstrated to be sensitive to prefrontal integrity in rodents. We sought to examine the effects of acute systemic d-amphetamine administration on the contextual control of response conflict in rats, and whether deficits were reversed through pre-treatment with clozapine or the D₁/D₂ antagonist α-flupenthixol. Acute d-amphetamine (1.5 mg/kg) disrupted the utilisation of contextual cues; therefore rats were impaired during presentation of stimulus compounds that require conflict resolution. Evidence suggested that this effect was attenuated through pre-treatment with the atypical antipsychotic clozapine (5.0 mg/kg), but not the typical antipsychotic α-flupenthixol (0.25 mg/kg), at doses previously shown to attenuate d-amphetamine-induced cognitive deficits. These studies therefore demonstrate a potentially viable model of disrupted executive function such as that seen in schizophrenia.

Animal models are making an increasing contribution to our understanding of the psychology and brain mechanisms underlying behavioral inhibition and impulsivity. The aim here was to develop, for the first time, a mouse analog of the stop-signal reaction time task with high translational validity in order to be able to exploit this species in genetic and molecular investigations of impulsive behaviors. Cohorts of mice were trained to nose-poke to presentations of visual stimuli. Control of responding was manipulated by altering the onset of an auditory 'stop-signal' during the go response. The anticipated systematic changes in action cancellation were observed as stopping was made more difficult by placing the stop-signal closer to the execution of the action. Excitotoxic lesions of medial prefrontal cortex resulted in impaired stopping, while the clinically effective drugs methylphenidate and atomoxetine enhanced stopping abilities. The specific 5-HT2C receptor antagonist SB242084 also led to enhanced response control in this task. We conclude that stop-signal reaction time task performance can be successfully modeled in mice and is sensitive to prefrontal cortex dysfunction and drug treatments in a qualitatively similar manner to humans and previous rat models. Additionally, using this model we show novel and highly discrete effects of 5-HT2C receptor antagonism that suggest manipulation of 5-HT2C receptor function may be of use in correcting maladaptive impulsive behaviors and provide further evidence for dissociable contributions of serotonergic transmission to response control.

Frontotemporal lobe dementia (FTD) is a heterogeneous range of disorders, a subset of which arise from fully penetrant, autosomal dominant point mutations in the gene coding for the microtubule associated protein tau. These genetic tauopathies are associated with complex behavioural/cognitive disturbances, including compromised executive function. In the present study, we modelled the effects of the FTD with Parkinsonism linked to chromosome 17 (FTDP-17) tauV337M mutation (known as the Seattle Family A mutation) expressed in mice on executive processes using a novel murine analogue of the Stroop task. Employing biconditional discrimination procedures, Experiment 1 showed that normal mice, but not mice with excitotoxic lesions of the medial prefrontal cortex, were able to use context cues to resolve response conflict generated by incongruent stimulus compounds. In contrast to predictions, response conflict resolution was not disrupted by the tauV337M mutation (Experiment 2). However, while context appropriate actions were goal-directed in wild-type mice, performance of tauV337M mice was not goal-directed (Experiment 3). The results indicate that the tauV337M mutation in mice disrupts, selectively, a subset of processes related to executive function., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Retinal ganglion cells (RGCs) may be regarded as a target biomarker in Alzheimer's disease (AD). We therefore explored the possibility that RGC degeneration, rather than cell loss, is an early marker of neuronal degeneration in a murine model of AD. RGC dendritic morphology and dendritic spine densities of CA1 hippocampal pyramidal neurons were quantified in 14-month-old transgenic mice expressing the APP(SWE) (amyloid precusor protein-Swedish mutation) mutation (Tg2576). The dendritic integrity of RGCs was found to be significantly reduced in the absence of significant RGC loss in Tg2576 mice compared with age-matched wild-type controls. In hippocampal CA1 pyramidal neurons, we observed dendritic spines to be present at a lower frequency from the same animals, but this did not reach significance. Synaptic and mitochondrial protein expression markers (PSD95 [postsynaptic density protein 95], synaptophysin, and Mfn2 [mitofusin 2]) showed no significant changes in RGC synaptic densities but a highly significant change in mitochondrial morphology with a marked reduction in the integrity of the mitochondrial cristae. Our findings suggest that, in a well-characterized mouse model of AD, RGC dendritic atrophy precedes cell loss, and this change may be because of accumulations of amyloid-β. Because RGC dendrites are confined to the inner plexiform layer of the retina, imaging techniques that focus on this layer, rather than the loss of RGCs, may provide a sensitive biomarker for monitoring neural damage in AD., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Three experiments examined the encoding specificity of associations using sensory preconditioning procedures in rats. In Experiment 1a, after exposure to two compounds (AX and BY), X (but not Y) was either followed by shock after a trace interval (Group Trace) or immediately followed by shock (Group Immediate). AX elicited less activity than BX (i.e., more fear) in Group Trace, but equivalent activity levels in Group Immediate. These results, replicated using a within-subjects design in Experiment 1b, indicate that the presence of A (on AX trials) generates fear because it associatively evokes X's memory into the same state as it was associated with the shock during (trace) conditioning. In Experiment 2, after exposure to AX and BY, X (but not Y) was immediately followed by shock. As in Experiment 1a, presentations of AX and BX elicited equivalent levels of fear, but there was more fear in the trace period after AX than in the trace period after BX. This finding suggests that during aversive conditioning, the associatively provoked memory of A was part of the conditioned complex, and that the trace of AX was more likely to activate this memory than was the trace of BX.

Rats were trained in 2 experiments to find a submerged platform that was situated in 1 of 2 of the 4 corners of a rectangular pool with a curved long wall. Different landmarks occupied 2 of the corners on every trial, and the platform was always situated near a landmark. For the place group in each experiment, the location of the platform was indicated by the shape of the pool and stimuli outside the pool (place cues), but not the landmarks within the pool. For the landmark groups, the landmarks, not the place cues, indicated where the platform could be found. During Stage 2, 2 of the place cues were relevant, and 2 of the landmarks were irrelevant, for a new discrimination. The place cues better controlled searching for the platform in the place group than in the landmark group when the place cues had initially been relevant by signaling the presence (Experiment 1) or the absence (Experiment 2) of the platform. The results show that animals pay more attention to relevant than irrelevant cues.

The neural circuitry underlying emotional learning and memory is known to involve both the amygdala and hippocampus. Both of these structures undergo anatomical and functional changes during the course of Alzheimer's disease. The present study used expression of the immediate early gene c-Fos to examine the effect of amyloid-induced synaptic pathology on neural activity in the hippocampus and amygdala immediately following Pavlovian fear conditioning. Tg2576 mice underwent cued fear conditioning and the regional interdependencies of c-Fos expression in the hippocampus and the amygdala were assessed using structural equation modelling. Tg2576 mice displayed normal acquisition of conditioned freezing to a punctate auditory cue paired with shock. However, the analysis of c-Fos expression indicated abnormal regional activity in the hippocampal dentate gyrus of Tg2576 mice. Structural equation modelling also supported the view that activity within the amygdala was independent of hippocampal activity in Tg2576 mice (unlike control mice) and regional interaction between the dentate gyrus and CA3 region was disrupted. The results provide novel insight into the effects of excess amyloid production on brain region interdependencies underpinning emotional learning., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Amyloid-β (Aβ) is cleaved from amyloid precursor protein (APP) predominantly after APP has trafficked through the secretory pathway and then become re-internalised by endocytosis. Clathrin-mediated and, more recently, clathrin-independent endocytosis have both been implicated in this process. Furthermore, endocytic abnormalities have been identified in cases of Alzheimer's disease (AD), however, the relevance of these changes to the aetiology of the disease remains unclear. We therefore examined the expression of proteins related to these endocytic processes in the cortex of Tg2576 mice that overexpress the Swedish mutation in APP, and consequently overexpress Aβ, to determine if there were any changes in their associated pathways. We identified significant increases in the levels of clathrin, dynamin and PICALM, all proteins intimately involved with the clathrin-mediated endocytic pathway, in the transgenic animals. However, levels of proteins associated with flotillin or caveolin-mediated endocytic pathways remained unchanged. These results emphasise the importance of clathrin-mediated endocytosis in the aetiology of AD and reinforce the results of the recent GWAS studies that identified genes for clathrin-mediated endocytosis as susceptibility genes for AD. Such studies in transgenic mice will allow us to learn more about the role of clathrin-mediated endocytosis in AD., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The GluR1 subunit of the AMPA receptor is required for hippocampal-dependent memory formation, emotional learning and synaptic plasticity. Recent work has shown that GluR1-independent synaptic plasticity is mediated by nitric oxide. Nitric oxide activity is influenced by estrogen. It is unknown whether this gender-dependent effect conveys a gender dimorphic requirement of GluR1 for learning. This hypothesis was tested in two behavioral paradigms. In Experiment 1, the retention of contextual fear conditioning was impaired in male but not female GluR1 knockout mice. In Experiment 2, GluR1 knockout mice made significantly more arm entry errors during acquisition of a radial-arm watermaze task. This deficit was independent of gender. These results indicate that some forms of learning are gender dimorphic in GluR1 knockout mice. The results are discussed with reference to task and gender-specific interactions between GluR1 receptor intracellular signalling pathways., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Instrumental performance in rats with hippocampal lesions is insensitive to the degradation of action-outcome contingencies, but sensitive to the effects of selective devaluation by satiation. One interpretation of this dissociation is that damage to the hippocampus impairs the formation of context-outcome associations upon which the effect of contingency degradation, but not selective satiation, relies. Here, we provide a direct assessment of this interpretation, and showed that conditioned responding to contexts did not show sensitivity to selective satiation (Experiment 1), and confirmed that instrumental performance was sensitive to selective satiation (Experiment 2) following hippocampal cell loss., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The onset of Alzheimer's disease (AD) is often accompanied by changes in emotion, motivation, and goal-directed behavior. The production of beta-amyloid is thought to be a major and early contributor to the pathogenesis of AD. The present study tested the hypothesis that amyloid pathology present in the amygdala, frontal cortex, and hippocampus of Tg2576 mice would disrupt the development of instrumental- and/or Pavlovian-outcome associations. The results showed that both instrumental- and Pavlovian-conditioned behaviors were sensitive to outcome devaluation (Experiments 1 & 2) and that Pavlovian cues influenced goal-directed actions associated with the same outcome (Experiment 2) in Tg2576 mice. In contrast, context mediated Pavlovian-conditioned behaviors in aged (Experiment 3a) but not young (Experiment 3b) Tg2576 mice were insensitive to outcome devaluation. Aged Tg2576, nevertheless, successfully acquired a simple context discrimination at the same rate as control mice. We conclude that amyloid pathology in aged Tg2576 mice may specifically disrupt context-outcome associations supported by the hippocampus and/or its interaction with the amygdala.

A mouse model of amyloid pathology was used to first examine using a cross sectional design changes in retrosplenial cortex activity in transgenic mice aged 5, 11, 17, and 23 months. Attention focused on: (1) overt amyloid labeled with β-amyloid((1-42)) and Congo Red staining, (2) metabolic function assessed by the enzyme, cytochrome oxidase, and (3) neuronal activity as assessed indirectly by the immediate-early gene (IEG), c-Fos. Changes in cytochrome oxidase and c-Fos activity were observed in the retrosplenial cortex in Tg2576 mice as early as 5 months of age, long before evidence of plaque formation. Subsequent analyses concentrating on this early dysfunction revealed at 5 months pervasive, amyloid precursor protein (APP)-derived peptide accumulation in the retrosplenial cortex and selective afferents (anterior thalamus, hippocampus), which was associated with the observed c-Fos hyporeactivity. These findings indicate that retrosplenial cortex dysfunction occurs during early stages of amyloid production in Tg2576 mice and may contribute to cognitive dysfunction., (Copyright © 2011 IBRO. All rights reserved.)

Genetically modified mice, lacking the GluA1 AMPA receptor subunit, are impaired on spatial working memory tasks, but display normal acquisition of spatial reference memory tasks. One explanation for this dissociation is that working memory, win-shift performance engages a GluA1-dependent, non-associative, short-term memory process through which animals choose relatively novel arms in preference to relatively familiar options. In contrast, spatial reference memory, as exemplified by the Morris water maze task, reflects a GluA1-independent, associative, long-term memory mechanism. These results can be accommodated by Wagner's dual-process model of memory in which short and long-term memory mechanisms exist in parallel and, under certain circumstances, compete with each other. According to our analysis, GluA1(-/-) mice lack short-term memory for recently experienced spatial stimuli. One consequence of this impairment is that these stimuli should remain surprising and thus be better able to form long-term associative representations. Consistent with this hypothesis, we have recently shown that long-term spatial memory for recently visited locations is enhanced in GluA1(-/-) mice, despite impairments in hippocampal synaptic plasticity. Taken together, these results support a role for GluA1-containing AMPA receptors in short-term habituation, and in modulating the intensity or perceived salience of stimuli.

gamma-Secretase cleaves amyloid precursor protein (APP) to generate amyloid-beta (Abeta) peptides, which aggregate in the brain in Alzheimer's disease (AD). gamma-Secretase also cleaves molecules that regulate osteoblast activity, such as Notch and ephrinB2. However, the role of APP in bone is unknown. In this study, the expression, cleavage, and function of APP were investigated during osteogenesis in vitro and in vivo. Expression of all gamma-secretase subunits was confirmed in human primary osteoprogenitors cells, and a significant increase in enzyme activity was observed during osteogenic differentiation using a specific fluorimetric assay. Application of selective inhibitors confirmed gamma-secretase-dependent cleavage of APP within osteogenic cells, and secretion of Abeta by mature osteoblasts was demonstrated with the use of a chemiluminescent immunoassay. Osteoprogenitors showed a selective and significant increase in adhesion to extracellular matrices containing aged Abeta plaques compared with nonaged Abeta peptide controls. Abeta on the endosteal and periosteal surfaces of adult rat ulnae were identified by immunohistochemistry. MicroCT analysis of vertebrae from an AD mouse model, Tg2576, identified a decrease in bone volume, surface area, and thickness compared with wild-type controls. These findings indicate that APP functions as a novel regulator of osteoblast activity and suggest that the mechanisms underlying the pathogenesis of AD may also influence bone.

The GluA1 AMPA receptor subunit is a key mediator of hippocampal synaptic plasticity and is especially important for a rapidly-induced, short-lasting form of potentiation. GluA1 gene deletion impairs hippocampus-dependent, spatial working memory, but spares hippocampus-dependent spatial reference memory. These findings may reflect the necessity of GluA1-dependent synaptic plasticity for short-term memory of recently visited places, but not for the ability to form long-term associations between a particular spatial location and an outcome. This hypothesis is in concordance with the theory that short-term and long-term memory depend on dissociable psychological processes. In this study we tested GluA1-/- mice on both short-term and long-term spatial memory using a simple novelty preference task. Mice were given a series of repeated exposures to a particular spatial location (the arm of a Y-maze) before their preference for a novel spatial location (the unvisited arm of the maze) over the familiar spatial location was assessed. GluA1-/- mice were impaired if the interval between the trials was short (1 min), but showed enhanced spatial memory if the interval between the trials was long (24 h). This enhancement was caused by the interval between the exposure trials rather than the interval prior to the test, thus demonstrating enhanced learning and not simply enhanced performance or expression of memory. This seemingly paradoxical enhancement of hippocampus-dependent spatial learning may be caused by GluA1 gene deletion reducing the detrimental effects of short-term memory on subsequent long-term learning. Thus, these results support a dual-process model of memory in which short-term and long-term memory are separate and sometimes competitive processes.

In 2 experiments we examined the ability of rats to form configural memories of what auditory stimulus (X or Y) was presented where (Context A or B) and when (morning or afternoon). In both experiments, rats received morning presentations of X in Context A and Y in Context B and afternoon presentations of X in B and Y in A. Subsequently, at midday the rats were exposed to trials where X was paired with footshock whereas Y was not. We then assessed the degree of contextual fear in A and B in the morning and the afternoon. In the morning, rats showed more fear in A than in B, and in the afternoon they showed more fear in B than in A. These results indicate that rats can form configural memories that represent what (X or Y) was presented, where (A or B), and when (morning or afternoon).

It is widely believed that synaptic plasticity may provide the neural mechanism that underlies certain kinds of learning and memory in the mammalian brain. The expression of long-term potentiation (LTP) in the hippocampus, an experimental model of synaptic plasticity, requires the GluR-A subunit of the AMPA subtype of glutamate receptor. Genetically modified mice lacking the GluR-A subunit show normal acquisition of the standard, fixed-location, hidden-platform watermaze task, a spatial reference memory task that requires the hippocampus. In contrast, these mice are dramatically impaired on hippocampus-dependent, spatial working memory tasks, in which the spatial response of the animal is dependent on information in short-term memory. Taken together, these results argue for two distinct and independent spatial information processing mechanisms: (i) a GluR-A-independent associative learning mechanism through which a particular spatial response is gradually or incrementally strengthened, and which presumably underlies the acquisition of the classic watermaze paradigm and (ii) a GluR-A-dependent, non-associative, short-term memory trace which determines performance on spatial working memory tasks. These results are discussed in terms of Wagner's SOP model (1981).

Aged Tg2576 mice show abnormalities in hippocampal morphology and physiology and display behavioral deficits in spatial navigation tasks consonant with a deficit in the functional properties of the hippocampus. However, the nature of the spatial representations disrupted by the "Swedish" mutation of the amyloid precursor protein (APPswe) is unclear. In an effort to characterize the memory deficits in Tg2576 mice, the spontaneous object exploration paradigm was used to interrogate spatial and object memory in mice. With object arrays of comparable size, 16-month-old Tg2576 mice showed a normal object familiarity/novelty effect but impaired memory for the location of objects when 2 objects exchanged locations (topological transformation; Experiment 1). In contrast, Tg2576 mice showed preferential exploration of familiar objects when they were moved to previously unoccupied locations (Experiment 2), irrespective of whether the transformation altered the metric properties of the object array (Experiments 3). These results suggest that Tg2576 mice are able to form representations of the identity of objects and a memory of the spatial organization of objects in an arena. In contrast, conjunctive memory for specific object-location associations is severely impaired in aged Tg2576 mice.

The authors assessed the hypothesis that deletion of the GluR-1 subtype of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor in mice disrupts the associative activation of a sensory-specific representation of an appetitive reward. In Experiment 1, mice received training on a Pavlovian-instrumental transfer task. In the test stage, conditioned stimulus (CS) presentations enhanced instrumental actions in both groups. However, this effect was specific to the action that shared the same outcome as the CS in wild-type (WT), but not GluR-1-super(-/-), mice. In Experiment 2, the mice were trained on a heterogeneous instrumental chain in which rewards were obtained for emitting 1 response (R1, that was distal to reward delivery), followed by a 2nd response (R2, that was proximal to reward delivery). A change in general motivational state (from hungry to sated) reduced the number of R2 responses in both groups. In contrast, an outcome-specific satiety treatment produced a selective decline in R1 responding only in WT mice. The results support the hypothesis that GluR-1 deletion impairs the associative activation of a representation of the sensory-specific incentive motivational properties of an appetitive reward.

Hippocampal damage impairs navigation with respect to information provided by the shape of an arena. Recent evidence has suggested that normal rats use local geometric information, as opposed to a global geometric representation, to navigate to a correct corner. One implication of this pattern of results is that hippocampal lesions may impair processing of 1 or more of the local geometric features of an environment. The authors therefore investigated the effects of hippocampal cell loss in rats on navigation to a hidden goal with respect to a variety of local cues in an environment with a distinctive shape. Rats with lesions of the hippocampus were impaired in discriminating a right-angled corner from its mirror image. However, they were able to use cues provided by an acute-angled corner (Experiment 1) or a local polarizing cue (Experiment 2). In contrast, lesioned rats were impaired in discriminating long versus short walls (Experiment 3). Results indicate that the hippocampus plays a role in disambiguating locations by processing (metric) information related to the distance between corners.

The AMPA receptor subunit glutamate receptor 1 (GluR1 or GluR-A) contributes to amygdala-dependent emotional learning. It remains unclear, however, to what extent different amygdala pathways depend on GluR1, or other AMPA receptor subunits, for proper synaptic transmission and plasticity, and whether GluR1-dependent long-term potentiation (LTP) is necessary for auditory and contextual fear conditioning. Here, we dissected the role of GluR1 and GluR3 (GluR-C) subunits in AMPA receptor-dependent amygdala LTP and fear conditioning using knock-out mice (GluR1-/- and GluR3-/-). We found that, whereas LTP at thalamic inputs to lateral amygdala (LA) projection neurons and at glutamatergic synapses in the basal amygdala was completely absent in GluR1-/- mice, both GluR1 and GluR3 contributed to LTP in the cortico-LA pathway. Because both auditory and contextual fear conditioning were selectively impaired in GluR1-/- but not GluR3-/- mice, we conclude that GluR1-dependent synaptic plasticity is the dominant form of LTP underlying the acquisition of auditory and contextual fear conditioning, and that plasticity in distinct amygdala pathways differentially contributes to aversive conditioning.

Genetically modified mice lacking the glutamate receptor A (GluR-A) subunit of the AMPA receptor (GluR-A-/- mice) display normal spatial reference memory but impaired spatial working memory (SWM). This study tested whether the SWM impairment in these mice could be explained by a greater sensitivity to within-session proactive interference. The SWM performance of GluR-A-/- and wild-type mice was assessed during nonmatching-to-place testing under conditions in which potential proactive interference from previous trials was reduced or eliminated. SWM was impaired in GluR-A-/- mice, both during testing with pseudotrial-unique arm presentations on the radial maze and when conducting each trial on a different 3-arm maze, each in a novel testing room. Experimentally naive GluR-A-/- mice also exhibited chance performance during a single trial of spontaneous alternation. This 1-trial spatial memory deficit was present irrespective of the delay between the sample information and the response choice (0 or 45 min) and the length of the sample phase (0.5 or 5 min). These results imply that the SWM deficit in GluR-A-/- mice is not due to increased susceptibility to proactive interference., (Copyright (c) 2007 APA, all rights reserved.)

An early clinical symptom of Alzheimer's disease is impaired episodic memory. However, the precise pathological event(s) that underpins this deficit remains unclear. In the present study, the authors examined whether wild-type mice and Tg2576 mice expressing an amyloid precursor protein (APP) mutation are able to form an integrated memory of the spatio-temporal context in which objects are presented. In Experiment 1, wild-type mice, but not Tg2576 mice that were 10-12 months old, explored objects presented in a novel location. In Experiment 2, wild-type mice explored an object that was presented both earlier in a sequence and in a different location relative to other objects that possessed only one of these properties (i.e., memory for "what," "where," and "when" items were presented). In contrast, the behavior of adult Tg2576 mice was influenced only by the temporal order in which objects were presented. These results demonstrate that wild-type, but not APP-mutant, mice are able to form an "episodic-like" memory of the spatio-temporal properties of objects and support the hypothesis that aberrant APP processing contributes to impairments in event memory., ((c) 2007 APA, all rights reserved)

Dual-process models of recognition memory in animals propose that recognition memory is supported by two independent processes that reflect the operation of distinct brain structures: a familiarity process that operates independently of the hippocampus and a context-dependent (episodic) memory process that is dependent on the hippocampus. A novel variant of an object recognition procedure was used to examine this proposal. Healthy rats showed a preference for exploring a novel object rather than a familiar object: a familiarity-dependent recognition effect. They also showed a preference for exploring a familiar object that was presented in a different spatiotemporal context rather than a familiar object that was presented either in a different spatial or temporal context: a context-dependent form of recognition that is sensitive to "what" object has been presented "where" and "when." Rats with excitotoxic hippocampal lesions showed the familiarity-dependent but not the context-dependent form of recognition. The results provide support for dual-process theories of recognition memory., (Copyright (c) 2007 APA, all rights reserved.)

Recent evidence suggests that estrogen may interact with the basal forebrain cholinergic system to influence learning. The authors examined whether the loss of estrogen following ovariectomy (Experiment 1) or the disruption to the estrogen cycle during aging (Experiment 2) impaired performance of the 5-choice serial reaction time task (5-CSRT)--a sustained and divided attention task sensitive to cholinergic challenges in rats. In Experiment 1, posttraining ovariectomy in young rats did not disrupt baseline performance but did impair performance when attention was challenged by variation in the intertrial interval (ITI) or in the intermittent presentation of a novel distracting auditory stimulus. Administration of 17-beta estradiol rescued these impairments. Through the use of a within-subjects design, Experiment 2 revealed that 17-beta estradiol did not influence the baseline performance of 21-month-old female rats trained on the 5-CSRT task from a young age but did improve performance when attention was challenged by varying the ITI or by presenting a distracting auditory cue. The results indicate that 17-beta estradiol administration can improve specific components of attention in young ovariectomized rats and gonadally intact aged female rats., (2006 APA, all rights reserved)

Objective: The aim of this article is to provide a review of studies using N-methyl-D-aspartate (NMDA) receptor antagonists to assess the hippocampal long-term potentiation (LTP)/learning hypothesis., Discussion: In particular, we will re-examine the validity of both (1) the original hippocampal LTP/spatial learning hypothesis of Morris and (2) the sensorimotor account put forward by Cain, among others, both from the point of view of the pharmacological studies on which they were based and with regard to recent studies with genetically modified mice. More specifically, we will review the pharmacological studies in the light of recent work on the glutamate receptor A (GluR-A or GluR1) L-alpha-amino-3-hydroxy-5-methyl-4-isoxazelopropionate (AMPA) receptor sub-unit knockout mouse. We will argue that neither the original hippocampal LTP/spatial learning hypothesis nor a sensorimotor account can adequately explain all of the available data. We argue instead that hippocampal synaptic plasticity, which requires NMDA receptors for its induction and GluR-A-containing AMPA receptors for its continued expression, contributes to a process whereby appropriate behavioural responses are selected rapidly on the basis of conditional information provided by the context. These contextual cues could include not only the spatial context (i.e. the 'where') and the temporal context (the 'when'), but also other aspects of context, such as internal state cues (hunger and fear state), and can be used to rapidly and flexibly alter valences of specific response options., Recommendations: We also suggest that there is a separate, distinct, NMDA/GluR-A-independent mechanism through which the context can gradually (incrementally or decrementally) alter the valence of a particular response option.