Publications by authors named "Brianne A Kent"

31 Publications

Daytime Exposure to Short Wavelength-Enriched Light Improves Cognitive Performance in Sleep-Restricted College-Aged Adults.

Front Neurol 2021 22;12:624217. Epub 2021 Feb 22.

Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women's Hospital, Boston, MA, United States.

We tested the effect of daytime indoor light exposure with varying melanopic strength on cognitive performance in college-aged students who maintained an enforced nightly sleep opportunity of 7 h (i.e., nightly sleep duration no longer than 7 h) for 1 week immediately preceding the day of light exposure. Participants ( = 39; mean age ± SD = 24.5 ± 3.2 years; 21 F) were randomized to an 8 h daytime exposure to one of four white light conditions of equal photopic illuminance (~50 lux at eye level in the vertical plane) but different melanopic illuminance [24-45 melanopic-EDI lux (melEDI)] generated by varying correlated color temperatures [3000K (low-melEDI) or 5000K (high-melEDI)] and spectra [conventional or daylight-like]. Accuracy on a 2-min addition task was 5% better in the daylight-like high-melEDI condition (highest melEDI) compared to the conventional low-melEDI condition (lowest melEDI; < 0.01). Performance speed on the motor sequence learning task was 3.2 times faster ( < 0.05) during the daylight-like high-melEDI condition compared to the conventional low-melEDI. Subjective sleepiness was 1.5 times lower in the conventional high-melEDI condition compared to the conventional low-melEDI condition, but levels were similar between conventional low- and daylight-like high-melEDI conditions. These results demonstrate that exposure to high-melanopic (short wavelength-enriched) white light improves processing speed, working memory, and procedural learning on a motor sequence task in modestly sleep restricted young adults, and have important implications for optimizing lighting conditions in schools, colleges, and other built environments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fneur.2021.624217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937889PMC
February 2021

Sleep and its regulation: An emerging pathogenic and treatment frontier in Alzheimer's disease.

Prog Neurobiol 2021 Feb 30;197:101902. Epub 2020 Aug 30.

Division of Neurology, University of British Columbia, Vancouver, Canada.

A majority of patients with Alzheimer's disease (AD) experience some form of sleep disruption, including nocturnal sleep fragmentation, increased daytime napping, decreased slow-wave sleep (SWS, stage N3), and decreased rapid-eye-movement sleep (REM). Clinical studies are investigating whether such sleep disturbances are a consequence of the underlying disease, and whether they also contribute to the clinical and pathological manifestations of AD. Emerging research has provided a direct link between several of these sleep disruptions and AD pathophysiology, suggesting that treating sleep disorders in this population may target basic mechanisms of the disease. Here, we provide a comprehensive review of sleep disturbances associated with the spectrum of AD, ranging from the preclinical stages through dementia. We discuss how sleep interacts with AD pathophysiology and, critically, whether sleep impairments can be targeted to modify the disease course in a subgroup of affected AD patients. Ultimately, larger studies that fully utilize new diagnostic and experimental tools will be required to better define the most relevant sleep disturbance to target in AD, the interventions that best modulate this target symptom, and whether successful early intervention can modify AD risk and prevent dementia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pneurobio.2020.101902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855222PMC
February 2021

Calorie restriction activates new adult born olfactory-bulb neurones in a ghrelin-dependent manner but acyl-ghrelin does not enhance subventricular zone neurogenesis.

J Neuroendocrinol 2019 07 24;31(7):e12755. Epub 2019 Jun 24.

Molecular Neurobiology, Institute of Life Sciences, School of Medicine, Swansea University, Swansea, UK.

The ageing and degenerating brain show deficits in neural stem/progenitor cell (NSPC) plasticity that are accompanied by impairments in olfactory discrimination. Emerging evidence suggests that the gut hormone ghrelin plays an important role in protecting neurones, promoting synaptic plasticity and increasing hippocampal neurogenesis in the adult brain. In the present study, we investigated the role of ghrelin with respect to modulating adult subventricular zone (SVZ) NSPCs that give rise to new olfactory bulb (OB) neurones. We characterised the expression of the ghrelin receptor, growth hormone secretagogue receptor (GHSR), using an immunohistochemical approach in GHSR-eGFP reporter mice to show that GHSR is expressed in several regions, including the OB but not in the SVZ of the lateral ventricle. These data suggest that acyl-ghrelin does not mediate a direct effect on NSPC in the SVZ. Consistent with these findings, treatment with acyl-ghrelin or genetic silencing of GHSR did not alter NSPC proliferation within the SVZ. Similarly, using a bromodeoxyuridine pulse-chase approach, we show that peripheral treatment of adult rats with acyl-ghrelin did not increase the number of new adult-born neurones in the granule cell layer of the OB. These data demonstrate that acyl-ghrelin does not increase adult OB neurogenesis. Finally, we investigated whether elevating ghrelin indirectly, via calorie restriction (CR), regulated the activity of new adult-born cells in the OB. Overnight CR induced c-Fos expression in new adult-born OB cells but not in developmentally born cells, whereas neuronal activity was absent following re-feeding. These effects were not present in ghrelin mice, suggesting that adult-born cells are uniquely sensitive to changes in ghrelin mediated by fasting and re-feeding. In summary, ghrelin does not promote neurogenesis in the SVZ and OB; however, new adult-born OB cells are activated by CR in a ghrelin-dependent manner.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jne.12755DOI Listing
July 2019

Delayed daily activity and reduced NREM slow-wave power in the APPswe/PS1dE9 mouse model of Alzheimer's disease.

Neurobiol Aging 2019 06 14;78:74-86. Epub 2019 Feb 14.

Djavad Mowafaghian Centre for Brain Health, Department of Medicine, Division of Neurology, University of British Columbia, Vancouver, Canada. Electronic address:

Alzheimer's disease (AD) is associated with disrupted circadian rhythms and sleep, which are thought to reflect an impairment of internal circadian timekeeping that contribute to clinical symptoms and disease progression. To evaluate these hypotheses, a suitable preclinical model of AD is needed. We performed a comprehensive assessment of circadian rhythms and sleep in the APP/PS1 (APP/PS1) mouse model using long-term in vivo electroencephalogram (EEG) monitoring and behavioral assays from 5 to 22 months of age. APP/PS1 mice were crossed with a PERIOD2::LUCIFERASE (PER2::LUC) mouse model to evaluate synchrony among peripheral circadian oscillators. The APP/PS1 mice exhibited a mild but persistent phase delay of nocturnal activity onset in 12:12h light:dark conditions, as well as a shift toward higher frequencies in the EEG power spectra compared to littermate controls. Our results suggest that APP/PS1 mice may not be the optimal preclinical model for studying the specific circadian changes associated with AD but that quantitative EEG may offer a sensitive measure of AD-associated changes in sleep quality that can be modeled in APP/PS1 mice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neurobiolaging.2019.01.010DOI Listing
June 2019

Midday meals do not impair mouse memory.

Sci Rep 2018 11 19;8(1):17013. Epub 2018 Nov 19.

Department of Psychology, Simon Fraser University, Burnaby, Canada.

Nocturnal mice fed in the middle of the light period exhibit food anticipatory rhythms of behavior and physiology under control of food-entrainable circadian clocks in the brain and body. This is presumed to be adaptive by aligning behavior and physiology with predictable mealtimes. This assumption is challenged by a report that daytime feeding schedules impair cognitive processes important for survival, including object memory and contextual fear conditioning assessed at two times of day. To further evaluate these effects, mice were restricted to a 6 h daily meal in the middle of the light or dark period and object memory was tested at four times of day. Object memory was not impaired by daytime feeding, and did not exhibit circadian variation in either group. To determine whether impairment might depend on methodology, experimental procedures used previously to detect impairment were followed. Daytime feeding induced food anticipatory rhythms and shifted hippocampal clock genes, but again did not impair object memory. Spontaneous alternation and contextual fear conditioning were also not impaired. Hippocampal memory function appears more robust to time of day and daytime feeding schedules than previously reported; day-fed mice can remember what they have seen, where they have been, and where it is dangerous.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-018-35427-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6242856PMC
November 2018

NMDA receptors and BDNF are necessary for discrimination of overlapping spatial and non-spatial memories in perirhinal cortex and hippocampus.

Neurobiol Learn Mem 2018 11 30;155:337-343. Epub 2018 Aug 30.

Laboratory of Memory Research and Molecular Cognition, Consejo Nacional de Investigaciones Científicas y Técnicas - Fundación INECO - Universidad Favaloro, Buenos Aires, Argentina. Electronic address:

Successful memory involves not only remembering information over time but also keeping memories distinct and less confusable. Discrimination of overlapping representations has been investigated in the dentate gyrus (DG) of the hippocampus and largely in the perirhinal cortex (Prh). In particular, the DG was shown to be important for discrimination of overlapping spatial memories and Prh was shown to be important for discrimination of overlapping object memories. In the present study, we used both a DG-dependent and a Prh-dependent task and manipulated the load of similarity between either spatial or object stimuli during information encoding. We showed that N-methyl-D-aspartate-type glutamate receptors (NMDAr) and BDNF participate of the same cellular network during consolidation of both overlapping object and spatial memories in the Prh and DG, respectively. This argues in favor of conserved cellular mechanisms across regions despite anatomical differences.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nlm.2018.08.019DOI Listing
November 2018

Sleep and EEG Power Spectral Analysis in Three Transgenic Mouse Models of Alzheimer's Disease: APP/PS1, 3xTgAD, and Tg2576.

J Alzheimers Dis 2018 ;64(4):1325-1336

Division of Neurology and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, Canada.

Background: Sleep disturbances have long been associated with Alzheimer's disease (AD), and there is a growing interest in how these disturbances might impact AD pathophysiology. Despite this growing interest, surprisingly little is known about how sleep architecture and the broader neuronal network are affected in widely used transgenic mouse models of AD.

Objective: We analyzed sleep and electroencephalography (EEG) power in three transgenic mouse models of AD, using identical and commercially available hardware and analytical software. The goal was to assess the suitability of these mouse lines to model sleep and the broader neuronal network dysfunction measured by EEG in AD.

Methods: Tg2576, APP/PS1, and 3xTgAD transgenic AD mice were studied using in vivo EEG recordings for sleep/wake time and power spectral analysis.

Results: Both the APP/PS1 model at 8- 10 months and the Tg2576 model at 12 months of age exhibited stage-dependent decreases in theta and delta power, and shifts in the power spectra toward higher frequencies. Stage-dependent power spectral analyses showed no changes in the 3xTgAD model at 18 months of age. The percentage of time spent awake, in non-rapid eye movement sleep (NREM), or in rapid-eye-movement sleep (REM) was not different between genotypes in any of the transgenic lines.

Conclusion: Our findings are consistent with data from several other transgenic AD models as well as certain studies in patients with mild cognitive impairment. Further studies will be needed to better understand the correlation between EEG spectra and AD pathophysiology, both in AD models and the human condition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JAD-180260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6176720PMC
July 2019

Whole-Exome Sequencing of an Exceptional Longevity Cohort.

J Gerontol A Biol Sci Med Sci 2019 08;74(9):1386-1390

Program in Cellular Neuroscience, Neurodegeneration and Repair (CNNR), Yale University School of Medicine, New Haven, Connecticut.

Centenarians represent a unique cohort to study the genetic basis for longevity and factors determining the risk of neurodegenerative disorders, including Alzheimer's disease (AD). The estimated genetic contribution to longevity is highest in centenarians and super-cententenarians, but few genetic variants have been shown to clearly impact this phenotype. While the genetic risk for AD and other dementias is now well understood, the frequency of known dementia risk variants in centenarians is not fully characterized. To address these questions, we performed whole-exome sequencing on 100 individuals of 98-108 years age in search of genes with large effect sizes towards the exceptional aging phenotype. Overall, we were unable to identify a rare protein-altering variant or individual genes with an increased burden of rare variants associated with exceptional longevity. Gene burden analysis revealed three genes of nominal statistical significance associated with extreme aging, including LYST, MDN1, and RBMXL1. Several genes with variants conferring an increased risk for AD and other dementias were identified, including TREM2, EPHA1, ABCA7, PLD3, MAPT, and NOTCH3. Larger centenarian studies will be required to further elucidate the genetic basis for longevity, and factors conferring protection against age-dependent neurodegenerative syndromes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/gerona/gly098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6696723PMC
August 2019

Longitudinal evaluation of Tau-P301L transgenic mice reveals no cognitive impairments at 17 months of age.

Brain Behav 2018 01 18;8(1):e00896. Epub 2017 Dec 18.

Department of Psychology and MRC & Wellcome Trust Behavioural and Clinical Neuroscience Institute University of Cambridge Cambridge UK.

Introduction: Tau is a microtubule-associated binding protein implicated in neurodegenerative tauopathies, including frontotemporal dementia (FTD) and Alzheimer's disease (AD). These diseases result in the intracellular accumulation of hyperphosphorylated tau in the form of neurofibrillary tangles, the presence of which is associated with cognitive deficits.

Methods: We conducted a longitudinal behavioral study to provide a profile of the TgTau(P301L)23027 transgenic mouse in multiple cognitive domains across multiple ages. P301L is the tau mutation most frequently observed in patients with frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) and this mouse model recapitulates the progressive development of glial and neurofibrillary tangles, and associated cerebral atrophy observed in patients. We examined frontal cortex-dependent executive function and attention with the touchscreen 5-choice serial reaction time test (5-CSRTT) and assessed the function of temporal cortical structures using novel object recognition (OR).

Results: Despite using sensitive tasks, there were no apparent changes in executive function, attention, or recognition memory in the transgenic mice from 5 to 17 months of age.

Conclusions: This study represents the first comprehensive longitudinal analysis of cognition in the TgTau mouse model and suggests that this model is not ideal for studying early attention and recognition memory impairments associated with tauopathy. However, spatial and object recognition memory impairments were observed during follow-up assessments when the mice were 18 and 21 months, respectively. These impairments are consistent with previous publications, and with a dementia-like phenotype in these mice when aged.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/brb3.896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5853624PMC
January 2018

Molecular Mechanisms in Perirhinal Cortex Selectively Necessary for Discrimination of Overlapping Memories, but Independent of Memory Persistence.

eNeuro 2017 Sep-Oct;4(5). Epub 2017 Oct 18.

Laboratory of Memory Research and Molecular Cognition, Institute for Cell Biology and Neuroscience CONICET and University of Buenos Aires Medical School, Buenos Aires, Argentina.

Successful memory involves not only remembering over time but also keeping memories distinct. The ability to separate similar experiences into distinct memories is a main feature of episodic memory. Discrimination of overlapping representations has been investigated in the dentate gyrus of the hippocampus (DG), but little is known about this process in other regions such as the perirhinal cortex (Prh). We found in male rats that perirhinal brain-derived neurotrophic factor (BDNF) is required for separable storage of overlapping, but not distinct, object representations, which is identical to its role in the DG for spatial representations. Also, activity-regulated cytoskeletal-associated protein (Arc) is required for disambiguation of object memories, as measured by infusion of antisense oligonucleotides. This is the first time Arc has been implicated in the discrimination of objects with overlapping features. Although molecular mechanisms for object memory have been shown previously in Prh, these have been dependent on delay, suggesting a role specifically in memory duration. BDNF and Arc involvement were independent of delay-the same demand for memory persistence was present in all conditions-but only when discrimination of similar objects was required were these mechanisms recruited and necessary. Finally, we show that BDNF and Arc participate in the same pathway during consolidation of overlapping object memories. We provide novel evidence regarding the proteins involved in disambiguation of object memories outside the DG and suggest that, despite the anatomical differences, similar mechanisms underlie this process in the DG and Prh that are engaged depending on the similarity of the stimuli.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1523/ENEURO.0293-17.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5659266PMC
June 2018

Central and peripheral circadian clocks and their role in Alzheimer's disease.

Dis Model Mech 2017 10;10(10):1187-1199

Neuroscience, Innovative Medicines and Early Development, AstraZeneca, Granta Park, Cambridge, CB21 6GH, UK

Molecular and cellular oscillations constitute an internal clock that tracks the time of day and permits organisms to optimize their behaviour and metabolism to suit the daily demands they face. The workings of this internal clock become impaired with age. In this review, we discuss whether such age-related impairments in the circadian clock interact with age-related neurodegenerative disorders, such as Alzheimer's disease. Findings from mouse and fly models of Alzheimer's disease have accelerated our understanding of the interaction between neurodegeneration and circadian biology. These models show that neurodegeneration likely impairs circadian rhythms either by damaging the central clock or by blocking its communication with other brain areas and with peripheral tissues. The consequent sleep and metabolic deficits could enhance the susceptibility of the brain to further degenerative processes. Thus, circadian dysfunction might be both a cause and an effect of neurodegeneration. We also discuss the primary role of light in the entrainment of the central clock and describe important, alternative time signals, such as food, that play a role in entraining central and peripheral circadian clocks. Finally, we propose how these recent insights could inform efforts to develop novel therapeutic approaches to re-entrain arrhythmic individuals with neurodegenerative disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1242/dmm.030627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5665458PMC
October 2017

Sleep and hippocampal neurogenesis: Implications for Alzheimer's disease.

Front Neuroendocrinol 2017 04 27;45:35-52. Epub 2017 Feb 27.

Department of Psychology, Simon Fraser University, Burnaby, Canada. Electronic address:

Alzheimer's disease (AD) is the most common cause of dementia and currently there are no effective disease-modifying treatments available. Hallmark symptoms of AD include impaired hippocampus-dependent episodic memory and disrupted sleep and circadian rhythms. The pathways connecting these symptoms are of particular interest because it is well established that sleep and circadian disruption can impair hippocampus-dependent learning and memory. In rodents, these procedures also markedly suppress adult hippocampal neurogenesis, a form of brain plasticity that is believed to play an important role in pattern separation, and thus episodic memory. A causal role for sleep disruptions in AD pathophysiology is suggested by evidence for sleep-dependent glymphatic clearance of metabolic waste products from the brain. This review explores a complementary hypothesis that sleep and circadian disruptions in AD contribute to cognitive decline by activating neuroendocrine and neuroinflammatory signaling pathways that suppress hippocampal neurogenesis. Evidence for this hypothesis underscores the promise of sleep, circadian rhythms, and neurogenesis as therapeutic targets for remediation of memory impairment in AD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.yfrne.2017.02.004DOI Listing
April 2017

Assessing the Cognitive Translational Potential of a Mouse Model of the 22q11.2 Microdeletion Syndrome.

Cereb Cortex 2016 10 9;26(10):3991-4003. Epub 2016 Aug 9.

Department of Psychology, University of Cambridge, Cambridge CB2 3EB, UK Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge CB2 3EB, UK.

A chromosomal microdeletion at the 22q11.2 locus is associated with extensive cognitive impairments, schizophrenia and other psychopathology in humans. Previous reports indicate that mouse models of the 22q11.2 microdeletion syndrome (22q11.2DS) may model the genetic basis of cognitive deficits relevant for neuropsychiatric disorders such as schizophrenia. To assess the models usefulness for drug discovery, a novel mouse (Df(h22q11)/+) was assessed in an extensive battery of cognitive assays by partners within the NEWMEDS collaboration (Innovative Medicines Initiative Grant Agreement No. 115008). This battery included classic and touchscreen-based paradigms with recognized sensitivity and multiple attempts at reproducing previously published findings in 22q11.2DS mouse models. This work represents one of the most comprehensive reports of cognitive functioning in a transgenic animal model. In accordance with previous reports, there were non-significant trends or marginal impairment in some tasks. However, the Df(h22q11)/+ mouse did not show comprehensive deficits; no robust impairment was observed following more than 17 experiments and 14 behavioral paradigms. Thus - within the current protocols - the 22q11.2DS mouse model fails to mimic the cognitive alterations observed in human 22q11.2 deletion carriers. We suggest that the 22q11.2DS model may induce liability for cognitive dysfunction with additional "hits" being required for phenotypic expression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cercor/bhw229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5028007PMC
October 2016

A mouse model of the 15q13.3 microdeletion syndrome shows prefrontal neurophysiological dysfunctions and attentional impairment.

Psychopharmacology (Berl) 2016 06 17;233(11):2151-2163. Epub 2016 Mar 17.

H. Lundbeck A/S, Synaptic Transmission, Neuroscience Research DK, Ottiliavej 9, Valby, 2500, Denmark.

Rationale: A microdeletion at locus 15q13.3 is associated with high incidence rates of psychopathology, including schizophrenia. A mouse model of the 15q13.3 microdeletion syndrome has been generated (Df[h15q13]/+) with translational utility for modelling schizophrenia-like pathology. Among other deficits, schizophrenia is characterised by dysfunctions in prefrontal cortical (PFC) inhibitory circuitry and attention.

Objectives: The objective of this study is to assess PFC-dependent functioning in the Df(h15q13)/+ mouse using electrophysiological, pharmacological, and behavioural assays.

Method: Experiments 1-2 investigated baseline firing and auditory-evoked responses of PFC interneurons and pyramidal neurons. Experiment 3 measured pyramidal firing in response to intra-PFC GABAA receptor antagonism. Experiments 4-6 assessed PFC-dependent attentional functioning through the touchscreen 5-choice serial reaction time task (5-CSRTT). Experiments 7-12 assessed reversal learning, paired-associate learning, extinction learning, progressive ratio, trial-unique non-match to sample, and object recognition.

Results: In experiments 1-3, the Df(h15q13)/+ mouse showed reduced baseline firing rate of fast-spiking interneurons and in the ability of the GABAA receptor antagonist gabazine to increase the firing rate of pyramidal neurons. In assays of auditory-evoked responses, PFC interneurons in the Df(h15q13)/+ mouse had reduced detection amplitudes and increased detection latencies, while pyramidal neurons showed increased detection latencies. In experiments 4-6, the Df(h15q13)/+ mouse showed a stimulus duration-dependent decrease in percent accuracy in the 5-CSRTT. The impairment was insensitive to treatment with the partial α7nAChR agonist EVP-6124. The Df(h15q13)/+ mouse showed no cognitive impairments in experiments 7-12.

Conclusion: The Df(h15q13)/+ mouse has multiple dysfunctions converging on disrupted PFC processing as measured by several independent assays of inhibitory transmission and attentional function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00213-016-4265-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4869740PMC
June 2016

Performance of transgenic TgTau-P301L mice in a 5-choice serial reaction time task (5-CSRTT) as a model of Alzheimer's disease.

Psychiatr Danub 2015 Sep;27 Suppl 1:S515-25

Alzheimer's disease is increasing to epidemic levels with an estimated 36 million people affected worldwide (Wimo 2010). The aetiology of the disease is not known, which is hindering the progression of the treatment. This study is a longitudinal investigation into the performance of TgTauP301L mice as an animal model of Alzheimer's disease on the computer automated touchscreen 5-choice serial reaction time task (5-CSRTT). TgTauP301L mice have a single tau mutation in the P301L gene and develop the tau pathology that represents the observed tauopathy in patients with Alzheimer's disease. The aim of the investigation is to observe if tau pathology in the TgTauP301L mice causes a cognitive impairment in attention and executive function and at what stage this can be identified by the 5-CSRTT task. This will establish if the animals can be used as a therapeutic model for pre-clinical drug trials and help to identify an early indicator and intervention point in patients with Alzheimer's disease. The animals have previously been studied at 5-months and no differences between performances of the TgTauP301L mice and wild type mice were found (unpublished data). This study measured the performance of the animals at 7-months which is when the tauopathy begins to develop in TgTauP301L mice (Murakami 2005). The results of this study showed that there was no deficit in the performance of the TgTauP301L compared to the wild type mice and there had been no change in the animals' performance compared to at 5-months. The animals will be retested at 12-months once the pathology has extensively spread to see if the tauopathy causes a deficit in performance.
View Article and Find Full Text PDF

Download full-text PDF

Source
September 2015

Adult hippocampal neurogenesis and its role in cognition.

Wiley Interdiscip Rev Cogn Sci 2014 Sep 12;5(5):573-587. Epub 2014 Aug 12.

Department of Psychology, University of Cambridge, Cambridge, UK.

Unlabelled: Adult hippocampal neurogenesis (AHN) has intrigued neuroscientists for decades. Several lines of evidence show that adult-born neurons in the hippocampus are functionally integrated and contribute to cognitive function, in particular learning and memory processes. Biological properties of immature hippocampal neurons indicate that these cells are more easily excitable compared with mature neurons, and demonstrate enhanced structural plasticity. The structure in which adult-born hippocampal neurons are situated-the dentate gyrus-is thought to contribute to hippocampus function by disambiguating similar input patterns, a process referred to as pattern separation. Several ideas about AHN function have been put forward; currently there is good evidence in favor of a role for AHN in pattern separation. This function of AHN may be understood within a 'representational-hierarchical' view of brain organization. WIREs Cogn Sci 2014, 5:573-587. doi: 10.1002/wcs.1304 For further resources related to this article, please visit the WIREs website.

Conflict Of Interest: The authors have declared no conflicts of interest for this article.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/wcs.1304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4568304PMC
September 2014

Erratum to: The role of the dorsal hippocampus in two versions of the touchscreen automated paired associates learning (PAL) task for mice.

Psychopharmacology (Berl) 2015 Dec;232(24):4537

Department of Psychology, MRC/Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Downing St, Cambridge, CB2 3EB, UK.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00213-015-4025-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4714024PMC
December 2015

The role of the dorsal hippocampus in two versions of the touchscreen automated paired associates learning (PAL) task for mice.

Psychopharmacology (Berl) 2015 Nov 13;232(21-22):3899-910. Epub 2015 May 13.

Department of Psychology, MRC/Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Downing St, Cambridge, CB2 3EB, UK.

Rationale: The CANTAB object-location paired-associate learning (PAL) test can detect cognitive deficits in schizophrenia and Alzheimer's disease. A rodent version of touch screen PAL (dPAL) has been developed, but the underlying neural mechanisms are not fully understood. Although there is evidence that inactivation of the hippocampus following training leads to impairments in rats, this has not been tested in mice. Furthermore, it is not known whether acquisition, as opposed to performance, of the rodent version depends on the hippocampus. This is critical as many mouse models may have hippocampal dysfunction prior to the onset of task training.

Objectives: The objectives of this study are to examine the effects of dorsal hippocampal (dHp) dysfunction on both performance and acquisition of mouse dPAL and to determine if hippocampal task sensitivity could be increased using a newly developed context-disambiguated PAL (cdPAL) paradigm.

Methods: In experiment 1, C57Bl/6 mice received post-acquisition dHp infusions of the GABA agonist muscimol. In experiment 2, C57Bl/6 mice received excitotoxic dHp lesions prior to dPAL/cdPAL acquisition.

Results: Post-acquisition muscimol dose-dependently impaired dPAL and cdPAL performance. Pre-acquisition dHp lesions had only mild effects on both PAL tasks. Behavioural challenges including addition of objects and degradation of the visual stimuli with noise did not reveal any further impairments.

Conclusions: dPAL and cdPAL performance is hippocampus-dependent in the mouse, but both tasks can be learned in the absence of a functional dHp.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00213-015-3949-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4600471PMC
November 2015

The orexigenic hormone acyl-ghrelin increases adult hippocampal neurogenesis and enhances pattern separation.

Psychoneuroendocrinology 2015 Jan 23;51:431-9. Epub 2014 Oct 23.

Department of Psychology, University of Cambridge, UK; Behavioural and Clinical Neuroscience Institute, University of Cambridge, UK. Electronic address:

An important link exists between intact metabolic processes and normal cognitive functioning; however, the underlying mechanisms remain unknown. There is accumulating evidence that the gut hormone ghrelin, an orexigenic peptide that is elevated during calorie restriction (CR) and known primarily for stimulating growth hormone release, has important extra-hypothalamic functions, such as enhancing synaptic plasticity and hippocampal neurogenesis. The present study was designed to evaluate the long-term effects of elevating acyl-ghrelin levels, albeit within the physiological range, on the number of new adult born neurons in the dentate gyrus (DG) and performance on the Spontaneous Location Recognition (SLR) task, previously shown to be DG-dependent and sensitive to manipulations of plasticity mechanisms and cell proliferation. The results revealed that peripheral treatment of rats with acyl-ghrelin enhanced both adult hippocampal neurogenesis and performance on SLR when measured 8-10 days after the end of acyl-ghrelin treatment. Our data show that systemic administration of physiological levels of acyl-ghrelin can produce long-lasting improvements in spatial memory that persist following the end of treatment. As ghrelin is potentially involved in regulating the relationship between metabolic and cognitive dysfunction in ageing and neurodegenerative disease, elucidating the underlying mechanisms holds promise for identifying novel therapeutic targets and modifiable lifestyle factors that may have beneficial effects on the brain.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.psyneuen.2014.10.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4275579PMC
January 2015

Synchronizing an aging brain: can entraining circadian clocks by food slow Alzheimer's disease?

Authors:
Brianne A Kent

Front Aging Neurosci 2014 1;6:234. Epub 2014 Sep 1.

Department of Psychology, University of Cambridge Cambridge, UK.

Alzheimer's disease (AD) is a global epidemic. Unfortunately, we are still without effective treatments or a cure for this disease, which is having devastating consequences for patients, their families, and societies around the world. Until effective treatments are developed, promoting overall health may hold potential for delaying the onset or preventing neurodegenerative diseases such as AD. In particular, chronobiological concepts may provide a useful framework for identifying the earliest signs of age-related disease as well as inexpensive and noninvasive methods for promoting health. It is well reported that AD is associated with disrupted circadian functioning to a greater extent than normal aging. However, it is unclear if the central circadian clock (i.e., the suprachiasmatic nucleus) is dysfunctioning, or whether the synchrony between the central and peripheral clocks that control behavior and metabolic processes are becoming uncoupled. Desynchrony of rhythms can negatively affect health, increasing morbidity and mortality in both animal models and humans. If the uncoupling of rhythms is contributing to AD progression or exacerbating symptoms, then it may be possible to draw from the food-entrainment literature to identify mechanisms for re-synchronizing rhythms to improve overall health and reduce the severity of symptoms. The following review will briefly summarize the circadian system, its potential role in AD, and propose using a feeding-related neuropeptide, such as ghrelin, to synchronize uncoupled rhythms. Synchronizing rhythms may be an inexpensive way to promote healthy aging and delay the onset of neurodegenerative disease such as AD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnagi.2014.00234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4150207PMC
September 2014

Brain-derived neurotrophic factor interacts with adult-born immature cells in the dentate gyrus during consolidation of overlapping memories.

Hippocampus 2014 Aug 23;24(8):905-11. Epub 2014 May 23.

Department of Psychology, University of Cambridge, Cambridge, United Kingdom; MRC and Wellcome Trust Behavioural and Clinical Neuroscience Institute, Translational and Cognitive Neuroscience Laboratory, University of Cambridge, Cambridge, United Kingdom.

Successful memory involves not only remembering information over time but also keeping memories distinct and less confusable. The computational process for making representations of similar input patterns more distinct from each other has been referred to as "pattern separation." Although adult-born immature neurons have been implicated in this memory feature, the precise role of these neurons and associated molecules in the processing of overlapping memories is unknown. Recently, we found that brain-derived neurotrophic factor (BDNF) in the dentate gyrus is required for the encoding/consolidation of overlapping memories. In this study, we provide evidence that consolidation of these "pattern-separated" memories requires the action of BDNF on immature neurons specifically.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hipo.22304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4312906PMC
August 2014

BDNF in the dentate gyrus is required for consolidation of "pattern-separated" memories.

Cell Rep 2013 Nov 24;5(3):759-68. Epub 2013 Oct 24.

Department of Psychology and MRC and Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge 23EB, UK. Electronic address:

Successful memory involves not only remembering information over time, but also keeping memories distinct and less confusable. The computational process for making representations for similar input patterns more distinct from each other has been referred to as "pattern separation." In this work, we developed a set of behavioral conditions that allowed us to manipulate the load for pattern separation at different stages of memory. Thus, we provide experimental evidence that a brain-derived neurotrophic factor (BDNF)-dependent pattern separation process occurs during the encoding/storage/consolidation, but not the retrieval stage of memory processing. We also found that a spontaneous increase in BDNF in the dentate gyrus of the hippocampus is associated with exposure to landmarks delineating similar, but not dissimilar, spatial locations, suggesting that BDNF is expressed on an "as-needed" basis for pattern separation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2013.09.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898274PMC
November 2013

The touchscreen operant platform for assessing executive function in rats and mice.

Nat Protoc 2013 Oct 19;8(10):1985-2005. Epub 2013 Sep 19.

Department of Psychology, University of Cambridge, Cambridge, UK.

This protocol details a subset of assays developed within the touchscreen platform to measure various aspects of executive function in rodents. Three main procedures are included: extinction, measuring the rate and extent of curtailing a response that was previously, but is no longer, associated with reward; reversal learning, measuring the rate and extent of switching a response toward a visual stimulus that was previously not, but has become, associated with reward (and away from a visual stimulus that was previously, but is no longer, rewarded); and the 5-choice serial reaction time (5-CSRT) task, gauging the ability to selectively detect and appropriately respond to briefly presented, spatially unpredictable visual stimuli. These protocols were designed to assess both complementary and overlapping constructs including selective and divided visual attention, inhibitory control, flexibility, impulsivity and compulsivity. The procedures comprise part of a wider touchscreen test battery assessing cognition in rodents with high potential for translation to human studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nprot.2013.123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4131754PMC
October 2013

The touchscreen operant platform for testing learning and memory in rats and mice.

Nat Protoc 2013 Oct 19;8(10):1961-84. Epub 2013 Sep 19.

Synome Ltd., Babraham Research Campus, Cambridge, UK.

An increasingly popular method of assessing cognitive functions in rodents is the automated touchscreen platform, on which a number of different cognitive tests can be run in a manner very similar to touchscreen methods currently used to test human subjects. This methodology is low stress (using appetitive rather than aversive reinforcement), has high translational potential and lends itself to a high degree of standardization and throughput. Applications include the study of cognition in rodent models of psychiatric and neurodegenerative diseases (e.g., Alzheimer's disease, schizophrenia, Huntington's disease, frontotemporal dementia), as well as the characterization of the role of select brain regions, neurotransmitter systems and genes in rodents. This protocol describes how to perform four touchscreen assays of learning and memory: visual discrimination, object-location paired-associates learning, visuomotor conditional learning and autoshaping. It is accompanied by two further protocols (also published in this issue) that use the touchscreen platform to assess executive function, working memory and pattern separation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nprot.2013.122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3914026PMC
October 2013

Muscarinic receptors in amygdala control trace fear conditioning.

PLoS One 2012 21;7(9):e45720. Epub 2012 Sep 21.

Department of Psychology, Yale University, New Haven, CT, USA.

Intelligent behavior requires transient memory, which entails the ability to retain information over short time periods. A newly-emerging hypothesis posits that endogenous persistent firing (EPF) is the neurophysiological foundation for aspects or types of transient memory. EPF is enabled by the activation of muscarinic acetylcholine receptors (mAChRs) and is triggered by suprathreshold stimulation. EPF occurs in several brain regions, including the lateral amygdala (LA). The present study examined the role of amygdalar mAChRs in trace fear conditioning, a paradigm that requires transient memory. If mAChR-dependent EPF selectively supports transient memory, then blocking amygdalar mAChRs should impair trace conditioning, while sparing delay and context conditioning, which presumably do not rely upon transient memory. To test the EPF hypothesis, LA was bilaterally infused, prior to trace or delay conditioning, with either a mAChR antagonist (scopolamine) or saline. Computerized video analysis quantified the amount of freezing elicited by the cue and by the training context. Scopolamine infusion profoundly reduced freezing in the trace conditioning group but had no significant effect on delay or context conditioning. This pattern of results was uniquely anticipated by the EPF hypothesis. The present findings are discussed in terms of a systems-level theory of how EPF in LA and several other brain regions might help support trace fear conditioning.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0045720PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3448705PMC
March 2013

Dual functions of perirhinal cortex in fear conditioning.

Hippocampus 2012 Oct 18;22(10):2068-79. Epub 2012 Aug 18.

Department of Experimental Psychology, University of Cambridge, Cambridge, CB2 3EB, United Kingdom.

The present review examines the role of perirhinal cortex (PRC) in Pavlovian fear conditioning. The focus is on rats, partly because so much is known, behaviorally and neurobiologically, about fear conditioning in these animals. In addition, the neuroanatomy and neurophysiology of rat PRC have been described in considerable detail at the cellular and systems levels. The evidence suggests that PRC can serve at least two types of mnemonic functions in Pavlovian fear conditioning. The first function, termed "stimulus unitization," refers to the ability to treat two or more separate items or stimulus elements as a single entity. Supporting evidence for this perceptual function comes from studies of context conditioning as well as delay conditioning to discontinuous auditory cues. In a delay paradigm, the conditional stimulus (CS) and unconditional stimulus (US) overlap temporally and co-terminate. The second PRC function entails a type of "transient memory." Supporting evidence comes from studies of trace cue conditioning, where there is a temporal gap or trace interval between the CS offset and the US onset. For learning to occur, there must be a transient CS representation during the trace interval. We advance a novel neurophysiological mechanism for this transient representation. These two hypothesized functions of PRC are consistent with inferences based on non-aversive forms of learning.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hipo.22058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3445704PMC
October 2012

Circadian clocks for all meal-times: anticipation of 2 daily meals in rats.

PLoS One 2012 15;7(2):e31772. Epub 2012 Feb 15.

Department of Psychology, Simon Fraser University, Burnaby, Canada.

Anticipation of a daily meal in rats has been conceptualized as a rest-activity rhythm driven by a food-entrained circadian oscillator separate from the pacemaker generating light-dark (LD) entrained rhythms. Rats can also anticipate two daily mealtimes, but whether this involves independently entrained oscillators, one 'continuously consulted' clock, cue-dependent non-circadian interval timing or a combination of processes, is unclear. Rats received two daily meals, beginning 3-h (meal 1) and 13-h (meal 2) after lights-on (LD 14:10). Anticipatory wheel running began 68±8 min prior to meal 1 and 101±9 min prior to meal 2 but neither the duration nor the variability of anticipation bout lengths exhibited the scalar property, a hallmark of interval timing. Meal omission tests in LD and constant dark (DD) did not alter the timing of either bout of anticipation, and anticipation of meal 2 was not altered by a 3-h advance of meal 1. Food anticipatory running in this 2-meal protocol thus does not exhibit properties of interval timing despite the availability of external time cues in LD. Across all days, the two bouts of anticipation were uncorrelated, a result more consistent with two independently entrained oscillators than a single consulted clock. Similar results were obtained for meals scheduled 3-h and 10-h after lights-on, and for a food-bin measure of anticipation. Most rats that showed weak or no anticipation to one or both meals exhibited elevated activity at mealtime during 1 or 2 day food deprivation tests in DD, suggesting covert operation of circadian timing in the absence of anticipatory behavior. A control experiment confirmed that daytime feeding did not shift LD-entrained rhythms, ruling out displaced nocturnal activity as an explanation for daytime activity. The results favor a multiple oscillator basis for 2-meal anticipatory rhythms and provide no evidence for involvement of cue-dependent interval timing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0031772PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3280322PMC
June 2012

The progesterone-induced enhancement of object recognition memory consolidation involves activation of the extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin (mTOR) pathways in the dorsal hippocampus.

Horm Behav 2012 Apr 13;61(4):487-95. Epub 2012 Jan 13.

Department of Psychology, Yale University, New Haven, CT 06520, USA.

Although much recent work has elucidated the biochemical mechanisms underlying the modulation of memory by 17β-estradiol, little is known about the signaling events through which progesterone (P) regulates memory. We recently demonstrated that immediate post-training infusion of P into the dorsal hippocampus enhances object recognition memory consolidation in young ovariectomized female mice (Orr et al., 2009). The goal of the present study was to identify the biochemical alterations that might underlie this mnemonic enhancement. We hypothesized that the P-induced enhancement of object recognition would be dependent on activation of the ERK and mTOR pathways. In young ovariectomized mice, we found that bilateral dorsal hippocampal infusion of P significantly increased levels of phospho-p42 ERK and the mTOR substrate S6K in the dorsal hippocampus 5 min after infusion. Phospho-p42 ERK levels were downregulated 15 min after infusion and returned to baseline 30 min after infusion, suggesting a biphasic effect of P on ERK activation. Dorsal hippocampal ERK and mTOR activation were necessary for P to facilitate memory consolidation, as suggested by the fact that inhibitors of both pathways infused into the dorsal hippocampus immediately after training blocked the P-induced enhancement of object recognition. Collectively, these data provide the first demonstration that the ability of P to enhance memory consolidation depends on the rapid activation of cell signaling and protein synthesis pathways in the dorsal hippocampus.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.yhbeh.2012.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3401043PMC
April 2012

Evidence for time-of-day dependent effect of neurotoxic dorsomedial hypothalamic lesions on food anticipatory circadian rhythms in rats.

PLoS One 2011 2;6(9):e24187. Epub 2011 Sep 2.

Department of Psychology, Simon Fraser University, Burnaby, British Columbia, Canada.

The dorsomedial hypothalamus (DMH) is a site of circadian clock gene and immediate early gene expression inducible by daytime restricted feeding schedules that entrain food anticipatory circadian rhythms in rats and mice. The role of the DMH in the expression of anticipatory rhythms has been evaluated using different lesion methods. Partial lesions created with the neurotoxin ibotenic acid (IBO) have been reported to attenuate food anticipatory rhythms, while complete lesions made with radiofrequency current leave anticipatory rhythms largely intact. We tested a hypothesis that the DMH and fibers of passage spared by IBO lesions play a time-of-day dependent role in the expression of food anticipatory rhythms. Rats received intra-DMH microinjections of IBO and activity and body temperature (T(b)) rhythms were recorded by telemetry during ad-lib food access, total food deprivation and scheduled feeding, with food provided for 4-h/day for 20 days in the middle of the light period and then for 20 days late in the dark period. During ad-lib food access, rats with DMH lesions exhibited a lower amplitude and mean level of light-dark entrained activity and T(b) rhythms. During the daytime feeding schedule, all rats exhibited food anticipatory activity and T(b) rhythms that persisted during 2 days without food in constant dark. In some rats with partial or total DMH ablation, the magnitude of the anticipatory rhythm was weak relative to most intact rats. When mealtime was shifted to the late night, the magnitude of the food anticipatory activity rhythms in these cases was restored to levels characteristic of intact rats. These results confirm that rats can anticipate scheduled daytime or nighttime meals without the DMH. Improved anticipation at night suggests a modulatory role for the DMH in the expression of food anticipatory activity rhythms during the daily light period, when nocturnal rodents normally sleep.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0024187PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3166290PMC
December 2011

The impact of age-related ovarian hormone loss on cognitive and neural function.

Curr Top Behav Neurosci 2012 ;10:165-84

Department of Psychology, University of Wisconsin-Milwaukee, 2441 E. Hartford Ave, Milwaukee, WI 53211, USA.

On average, women now live one-third of their lives after menopause. Because menopause has been associated with an elevated risk of dementia, an increasing body of research has studied the effects of reproductive senescence on cognitive function. Compelling evidence from humans, nonhuman primates, and rodents suggests that ovarian sex-steroid hormones can have rapid and profound effects on memory, attention, and executive function, and on regions of the brain that mediate these processes, such as the hippocampus and prefrontal cortex. This chapter will provide an overview of studies in humans, nonhuman primates, and rodents that examine the effects of ovarian hormone loss and hormone replacement on cognitive functions mediated by the hippocampus and prefrontal cortex. For humans and each animal model, we outline the effects of aging on reproductive function, describe how ovarian hormones (primarily estrogens) modulate hippocampal and prefrontal physiology, and discuss the effects of both reproductive aging and hormone treatment on cognitive function. Although this review will show that much has been learned about the effects of reproductive senescence on cognition, many critical questions remain for future investigation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/7854_2011_122DOI Listing
January 2015