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

This is the final published version. It was originally published by Frontiers in Frontiers in Aging Neuroscience here: http://journal.frontiersin.org/Journal/10.3389/fnagi.2014.00234/abstract.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.Othe

Disambiguating the Similar: Investigating Pattern Separation in Medial Temporal Lobe Structures Using Rodent Models

This dissertation investigates the mechanisms underlying pattern separation, using rodent models and behavioural tasks that assess the use of representations for similar stimuli. Pattern separation is a theoretical mechanism involving the transformation of inputs into output representations that are less correlated to each other. Because of this orthogonalizing process, similar experiences are stored as discrete non-overlapping representations. Studying pattern separation emphasizes the important but often overlooked fact that successful memory involves more than just remembering events over a period of time, but also differentiating between similar memories. Through a series of experiments this dissertation adds support to the literature that the dentate gyrus (DG) subregion of the hippocampus is important for pattern separation when encoding spatial and contextual inputs. Using the Spontaneous Location Recognition (SLR) task it is shown the brain-derived neurotrophic factor (BDNF) can improve performance by acting via N-methyl-D-aspartate (NMDA) glutamate receptors in the DG and adult-born hippocampal neurons. Manipulating the level of neurogenesis by inhibiting Wnt signalling or by administering acyl-ghrelin systemically is shown to impair and enhance performance on SLR, respectively. Using a novel exposure paradigm in combination with SLR, it is demonstrated for the first time that the relationship between pattern separation and neurogenesis may be reciprocal, such that inhibiting neurogenesis impairs pattern separation, enhancing neurogenesis improves pattern separation, and performing pattern separation enhances the production or survival of adult-born hippocampal neurons. Finally, it is shown that the $TgTau^{P301L}$ mouse model of dementia exhibits spatial and object recognition memory impairments once aged, recapitulating a dementia-like phenotype. Understanding the mechanisms that contribute to effective pattern separation may help elucidate the processes underlying the memory impairment experienced by AD patients. This dissertation concludes with a critical discussion about whether pattern separation can be studied using behavioural paradigms.Gates Cambridge; NSERC; St. John’s Colleg

PERFORMANCE OF TRANSGENIC TgTau-P301L MICE IN A 5-CHOICE SERIAL REACTION TIME TASK (5-CSRTT) AS A MODEL OF ALZHEIMER’S DISEASE

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

Adult hippocampal neurogenesis and its role in cognition.

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.The discovery of neurogenesis in the brain of adult mammals1-3 , including humans4 , received considerable attention as it challenged the prevailing dogma that the brain is ‘post-mitotic’ and as such is endowed with limited regenerative capacity. In the mammalian brain, adult neurogenesis is restricted to two regions: 1. the DG, at the border of the granule cell layer and hilus (the subgranular zone) where adult neurogenesis gives rise to the primary granule cells (GCs), and 2. the subventricular zone of the lateral ventricles; cells born here subsequently migrate to the olfactory bulb5-7 . Given the well-established role of the hippocampus in learning and memory8 , it was soon suggested that AHN may contribute to these functions in some way. This idea was supported by the finding that memory demand correlated with AHN in birds9 and that in rats AHN could be stimulated by learning a spatial task10. In this manuscript, we will review some of the biological properties of adult-born hippocampal neurons and provide an overview of the structure in which adult-born hippocampal neurons are situated, the dentate gyrus. This is followed by an overview of studies that have addressed a putative role of AHN in learning and memory function and a discussion of the ideas on how adult-born hippocampal neurons may contribute to hippocampus function.This is the author accepted manuscript. The final version is available from Wiley at http://onlinelibrary.wiley.com/doi/10.1002/wcs.1304/abstract

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

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.CHK received funding from the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI11C1183). CJH, LMS and TJB were funded by Medical Research Council/Wellcome Trust grant 089703/Z/09/Z. BAK was funded by a Gates-Cambridge Fellowship. LMS and TJB also received funding from the Innovative Medicine Initiative Joint Undertaking under grant agreement no 115008 of which resources are composed of EFPIA inkind contribution and financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013).This is the final published version. It first appeared from Springer at http://dx.doi.org/10.1007/s00213-015-3949-

Circadian Clocks for All Meal-Times: Anticipation of 2 Daily Meals in Rats

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

Midday Meals Do Not Impair Mouse Memory

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

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

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.The Biotechnology and Biological Sciences Research Council . Grant Number: BB/G019002/1 The Innovative Medicine Initiative Joint Undertaking . Grant Number: 115008 The European Union's Seventh Framework Programme . Grant Number: FP7/2007-2013 The James S. McDonnell Foundation, Mather's Foundation, NIMH, Ellison Foundation, NINDS, NIMH, NIA, JPB FoundationThis is the final published version, which can also be viewed online at: http://onlinelibrary.wiley.com/doi/10.1002/hipo.22304/ful

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

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.This work was supported by grants from the Medical Research Council (grant G0902250/94306), The Royal Society and the Biotechnology and Biological Sciences Research Council (grant BB/G019002/1).This is the final version. It was first published by Elsevier at http://www.sciencedirect.com/science/article/pii/S030645301400399

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

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