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  1. For all you AI and Singularity geeks out there, I found this article entitled "How to Build a Mind?" really interesting and intuitive. It is about a new theory that attempts to integrate recent findings from both neuroscience and deep learning. It explains how the hippocampus encodes recent episodic memories of life events, and then plays them back while we sleep in order to "train" the neocortex. This is very similar to the approach used by the folks at DeepMind to teach AlphaGo using a combination of supervised learning and reinforcement learning. In fact, Demis Hassabis, founder of DeepMind, was a co-author on the paper, along with neuroscientist Jay McClelland from Stanford - a former colleague and collaborator of mine during the earlier days of artificial neural networks while we were both at CMU, along with neural net pioneer Geoff Hinton, who is also now at Google. In fact, most of the smartest people I've ever worked with (literally, at least 10 people I can think of off the top of my head) now work at Google... Which reminds me, earlier today I watched a really good video (embedded below) by Demis about DeepMind, AlphaGo and the future of AI. Demis describes in very accessible detail (starting at 28:15) the way AlphaGo works, and how it was trained (by playing against itself millions of times) to beat Lee Se-Dol, one of the world's top human Go players. I predict that DeepMind's approach to the development of artificial general intelligence may actually work, and come to fruition in the next couple decades. That will really make things interesting. I usually shy away from offering investment advice, but for those of you who haven't but can afford to, I recommend investing at least a little of your retirement savings in Google as an insurance policy against technological unemployment. When and if a Google AI steals all the jobs, you'll be glad you did... --Dean https://www.youtube.com/watch?v=f71RwCksAmI
  2. Hang in, there aging calorie restricters. Help may be on the way (eventually, alas): http://tinyurl.com/zy5hnj8 ("DNA-editing breakthrough could fix 'broken genes' in the brain, delay ageing and cure incurable diseases" -- Independent [uK])
  3. All, Over on the loneliness thread we've discussed how loneliness (or perhaps even simply living alone) can increase mortality (PMID 21834390). And as Zeta pointed out in this post about this article, loneliness can aggravate chronic viral infections, which in turn are associated with more rapid cognitive decline, as discussed in this post about PMID 26710257. So besides practicing CR, which at least in some of us seems to promote psychological resilience and a sense of "calm abiding", what can we do to avoid the apparent negative effects (esp. inflammation) resulting from loneliness, and stress/anxiety in general? This new study [1] (popular press article) from CMU1 researchers, and some of the papers it cites (see below) suggest a solution, namely mindfulness meditation, a practice I find quite helpful, as discussed here. Study [1] was a randomized control trial comparing the effects of 3-days of mindfulness training vs. relaxation training in 35 stressed and unemployed job seekers. Using FMRI brain imaging, they found that mindfulness training (vs. relaxation training) positively influenced activity in both the default mode network (the network of areas in the brain that becomes active when we aren't engaged in deliberate thought - e.g. when ruminating) and in the left dorsolateral prefrontal cortex, a brain area involved in executive function. But most importantly for this topic, they found that four months after the intervention, those in the mindfulness meditation group had reduced levels of an important marker of inflammation, interleukin-6, relative to the relaxation training group. This effect was independent of whether during the intervening 4 months the subjects found a job or not, which half of the subjects in each group in fact did. Some of the interesting commentary on the research expressed by the authors in the popular press article : The researchers concluded that the changes in functional brain connectivity resulting from the mindfulness program seemed to help the brain manage stress (a known inflammation trigger), and therefore is responsible for the reduced levels of inflammation. Why does it seem to be more beneficial than mere relaxation for managing stress? [Lead researcher] Creswell suggests that mindfulness may have a more lasting impact. "Mindfulness meditation teaches participants how to be more open and attentive to their experiences, even difficult ones," Creswell said. "By contrast, relaxation approaches are good in the moment for making the body feel relaxed, but ... [they're] harder to translate when you are dealing with difficult stressors in your daily life." In the full text of the paper, the authors point to a number of other recent studies [2-5] that have found mindfulness meditation reduces both stress and inflammatory markers in the elderly, people experiencing job stress, as well as cancer patients and caregivers. Study [2] by this same group of researchers is particularly germane for this topic, since it investigated the effects of mindfulness meditation on feelings of loneliness and inflammation in elderly subjects. People who did 8 weeks of once-per-week mindfulness classes reported reduced loneliness and exhibited a decrease in pro-inflammatory gene expression relative to a control group from the waiting list for the mindfulness training. I resonated with this quote from the introduction of [2]: “Usually we regard loneliness as an enemy. Heartache is not something we choose to invite in. It's restless and pregnant and hot with the desire to escape and find something or someone to keep us company. When we can rest in the middle [through meditation practice], we begin to have a nonthreatening relationship with loneliness, a relaxing and cooling loneliness that completely turns our usual fearful patterns upside down” -- Pema Chodron (2000), Buddhist nun and teacher These were small studies and not without some shortcomings - e.g. the mindfulness training classes themselves might have reduced loneliness in [2]. But they are nonetheless suggestive evidence that practicing mindfulness meditation can help one deal with the negative effects of loneliness and stress in general. --Dean ----------- 1CMU is my alma mater and is located in Pittsburgh. Those Pittsburgh scientists are really churning out interesting research! -------------- [1] Biological Psychiatry, http://dx.doi.org/10.1016/j.biopsych.2016.01.008 Alterations in resting state functional connectivity link mindfulness meditation with reduced interleukin-6: a randomized controlled trial, J. David Creswell PhD, Adrienne A. Taren MD, Emily K. Lindsay MA, Carol M. Greco PhD, Peter J. Gianaros PhD, April Fairgrieve BS, Anna L. Marsland PhD, Kirk Warren Brown PhD, Baldwin M. Way PhD, Rhonda K. Rosen LCSW, Jennifer L. Ferris MA Full text: http://dx.doi.org.sci-hub.io/10.1016/j.biopsych.2016.01.008 Abstract Background Mindfulness meditation training interventions have been shown to improve markers of health, but the underlying neurobiological mechanisms are not known. Building on initial cross-sectional research showing that mindfulness meditation may increase default mode network (DMN) resting state functional connectivity (rsFC) with regions important in top-down executive control (dorsolateral prefrontal cortex, dlPFC), here we test whether mindfulness meditation training increases DMN-dlPFC rsFC, and whether these rsFC alterations prospectively explain improvements in interleukin-6 (IL-6) in a randomized controlled trial. Method Stressed job-seeking unemployed community adults (N=35) were randomized to either a 3-day intensive residential mindfulness meditation or relaxation training program. Participants completed a five-minute resting state scan before and after the intervention program. Participants also provided blood samples at pre-intervention and at 4-month follow-up, which were assayed for circulating IL-6, a biomarker of systemic inflammation. Results We tested for alterations in DMN rsFC using a posterior cingulate cortex (PCC) seed-based analysis, and found that mindfulness meditation training, and not relaxation training, increased PCC rsFC with left dlPFC (p<.05, corrected). These pre-post training alterations in PCC-dlPFC rsFC statistically mediated mindfulness meditation training improvements in IL-6 at 4-month follow-up. Specifically, these alterations in rsFC statistically explained 30% of the overall mindfulness meditation training effects on IL-6 at follow-up. Conclusions These findings provide the first evidence that mindfulness meditation training functionally couples the DMN with a region known to be important in top-down executive control at rest (left dlPFC), which in turn is associated with improvements in a marker of inflammatory disease risk. Trial Registration The RCT is registered on clinicaltrials.gov (#NCT01628809) Key words: mindfulness meditation, functional connectivity, IL-6, unemployment, fMRI, stress ---------------- [2] Brain Behav Immun. 2012 Oct;26(7):1095-101. doi: 10.1016/j.bbi.2012.07.006. Epub 2012 Jul 20. Mindfulness-Based Stress Reduction training reduces loneliness and pro-inflammatory gene expression in older adults: a small randomized controlled trial. Creswell JD1, Irwin MR, Burklund LJ, Lieberman MD, Arevalo JM, Ma J, Breen EC, Cole SW. Free full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3635809/ Abstract Lonely older adults have increased expression of pro-inflammatory genes as well as increased risk for morbidity and mortality. Previous behavioral treatments have attempted to reduce loneliness and its concomitant health risks, but have had limited success. The present study tested whether the 8-week Mindfulness-Based Stress Reduction (MBSR) program (compared to a Wait-List control group) reduces loneliness and downregulates loneliness-related pro-inflammatory gene expression in older adults (N = 40). Consistent with study predictions, mixed effect linear models indicated that the MBSR program reduced loneliness, compared to small increases in loneliness in the control group (treatment condition × time interaction: F(1,35) = 7.86, p = .008). Moreover, at baseline, there was an association between reported loneliness and upregulated pro-inflammatory NF-κB-related gene expression in circulating leukocytes, and MBSR downregulated this NF-κB-associated gene expression profile at post-treatment. Finally, there was a trend for MBSR to reduce C Reactive Protein (treatment condition × time interaction: (F(1,33) = 3.39, p = .075). This work provides an initial indication that MBSR may be a novel treatment approach for reducing loneliness and related pro-inflammatory gene expression in older adults. PMID: 22820409 ---------- [3] Malarkey WB, Jarjoura D, Klatt M (2013): Workplace based mindfulness practice and inflammation: A randomized trial. Brain Behav Immun. 27: 145–154. --------- [4] Rosenkranz MA, Davidson RJ, MacCoon DG, Sheridan JF, Kalin NH, Lutz A (2013): A comparison of mindfulness-based stress reduction and an active control in modulation of neurogenic inflammation. Brain Behav Immun. 27C: 174–184. -------------- [5] Lengacher CA, Kip KE, Barta MK, Post-White J, Jacobsen P, Groer M, et al. (2012): A Pilot Study Evaluating the Effect of Mindfulness-Based Stress Reduction on Psychological Status, Physical Status, Salivary Cortisol, and Interleukin-6 Among Advanced-Stage Cancer Patients and Their Caregivers. J Holist Nurs. 30: 170–185.
  4. All, As we've discussed elsewhere, the formation of amyloid-beta plaques are known to be an important step in the progression of Alzheimer's disease. Exercise is known to help reduce amyloid plaque buildup, as discussed here. I think the fermented food natto may be beneficial for amyloid clearance as well, but that is more controversial. Sleep is known to be a time when the brain "cleans house", psychologically in terms of memory consolidation and synapse decay, but also literally, through the glymphatic transport system, which flushes toxins from the brain, including beta-amyloid plaques [2]: Clearance [of toxic proteins including beta-amyloid] during sleep is as much as two-fold faster than during waking hours. This new study [1] (popular press article), found that at least in rats, sleep posture influences the rate of glymphatic transport and toxin clearance. In particular, rats that were made to sleep on their (right) side while sleeping had better flow of their glymphatic fluid than rats who were either sitting up or lying on the back although beta-amyloid clearance wasn't much different between the two prone positions. And of course, rat brain morphology and circulatory system is quite a bit different from people, but the authors nevertheless speculate that sleeping on your side may be advantageous for brain health relative to sleeping on your back (or stomach). They didn't compare sleeping on the left vs right side in these rats, but in people it looks like sleeping on one's left side appears to be better for digestion / acid reflux than sleeping on one's right side. --Dean ----- [1] J Neurosci. 2015 Aug 5;35(31):11034-44. doi: 10.1523/JNEUROSCI.1625-15.2015. The Effect of Body Posture on Brain Glymphatic Transport. Lee H(1), Xie L(2), Yu M(3), Kang H(2), Feng T(4), Deane R(2), Logan J(5), Nedergaard M(2), Benveniste H(6). full text: http://www.jneurosci.org.sci-hub.io/content/35/31/11034.long The glymphatic pathway expedites clearance of waste, including soluble amyloid β (Aβ) from the brain. Transport through this pathway is controlled by the brain's arousal level because, during sleep or anesthesia, the brain's interstitial space volume expands (compared with wakefulness), resulting in faster waste removal. Humans, as well as animals, exhibit different body postures during sleep, which may also affect waste removal. Therefore, not only the level of consciousness, but also body posture, might affect CSF-interstitial fluid (ISF) exchange efficiency. We used dynamic-contrast-enhanced MRI and kinetic modeling to quantify CSF-ISF exchange rates in anesthetized rodents' brains in supine, prone, or lateral positions. To validate the MRI data and to assess specifically the influence of body posture on clearance of Aβ, we used fluorescence microscopy and radioactive tracers, respectively. The analysis showed that glymphatic transport was most efficient in the lateral position compared with the supine or prone positions. In the prone position, in which the rat's head was in the most upright position (mimicking posture during the awake state), transport was characterized by "retention" of the tracer, slower clearance, and more CSF efflux along larger caliber cervical vessels. The optical imaging and radiotracer studies confirmed that glymphatic transport and Aβ clearance were superior in the lateral and supine positions. We propose that the most popular sleep posture (lateral) has evolved to optimize waste removal during sleep and that posture must be considered in diagnostic imaging procedures developed in the future to assess CSF-ISF transport in humans. SIGNIFICANCE STATEMENT: The rodent brain removes waste better during sleep or anesthesia compared with the awake state. Animals exhibit different body posture during the awake and sleep states, which might affect the brain's waste removal efficiency. We investigated the influence of body posture on brainwide transport of inert tracers of anesthetized rodents. The major finding of our study was that waste, including Aβ, removal was most efficient in the lateral position (compared with the prone position), which mimics the natural resting/sleeping position of rodents. Although our finding awaits testing in humans, we speculate that the lateral position during sleep has advantage with regard to the removal of waste products including Aβ, because clinical studies have shown that sleep drives Aβ clearance from the brain. Copyright © 2015 the authors 0270-6474/15/3511034-11$15.00/0. PMCID: PMC4524974 [Available on 2016-02-05] PMID: 26245965 ------- [2] Rejuvenation Res. 2013 Dec;16(6):518-23. doi: 10.1089/rej.2013.1530. Sleep facilitates clearance of metabolites from the brain: glymphatic function in aging and neurodegenerative diseases. Mendelsohn AR(1), Larrick JW. Author information: (1)Panorama Research Institute and Regenerative Sciences Institute , Sunnyvale, California. Decline of cognition and increasing risk of neurodegenerative diseases are major problems associated with aging in humans. Of particular importance is how the brain removes potentially toxic biomolecules that accumulate with normal neuronal function. Recently, a biomolecule clearance system using convective flow between the cerebrospinal fluid (CSF) and interstitial fluid (ISF) to remove toxic metabolites in the brain was described. Xie and colleagues now report that in mice the clearance activity of this so-called "glymphatic system" is strongly stimulated by sleep and is associated with an increase in interstitial volume, possibly by shrinkage of astroglial cells. Moreover, anesthesia and attenuation of adrenergic signaling can activate the glymphatic system to clear potentially toxic proteins known to contribute to the pathology of Alzheimer disease (AD) such as beta-amyloid (Abeta). Clearance during sleep is as much as two-fold faster than during waking hours. These results support a new hypothesis to answer the age-old question of why sleep is necessary. Glymphatic dysfunction may pay a hitherto unsuspected role in the pathogenesis of neurodegenerative diseases as well as maintenance of cognition. Furthermore, clinical studies suggest that quality and duration of sleep may be predictive of the onset of AD, and that quality sleep may significantly reduce the risk of AD for apolipoprotein E (ApoE) ɛ4 carriers, who have significantly greater chances of developing AD. Further characterization of the glymphatic system in humans may lead to new therapies and methods of prevention of neurodegenerative diseases. A public health initiative to ensure adequate sleep among middle-aged and older people may prove useful in preventing AD, especially in apolipoprotein E (ApoE) ɛ4 carriers. PMID: 24199995
  5. James highlighted this interesting study [1] in his latest weekly CR research update (thanks James!). It focused on the impact in mice of CR on learning, memory, brain metabolism and brain structural integrity, all of which get messed up by 'normal' aging. Mice were started on CR at 14 weeks of age (quite young), and then tested when young or old, in comparison with AL fed mice using a battery of tests. I'm always skeptical of learning and memory tests in rodents, like the radial water maze test employed in this study, because it is hard to tease apart the effects of the better physical health of the CR animals relative to AL-fed controls, vs. better cognitive health in CR vs. AL animals. But FWIW, the old CR animals in this study did retain memory of the water maze solution better than old AL-fed controls, and comparable to young mice. The CR animals also seemed to shift from burning glucose in the brain to burning ketones, when the authors suggest is helpful for brain preservation. But I thought the most interesting part of the paper were the measurements performed to evaluate the impact of CR on the structure of the brain during aging, and in particular white matter integrity. They measured structural integrity of an important brain structure, the corpus callosum (CC) which connects the two hemispheres of the brain together, using state-of-the-art magnetic resonance diffusion tensor imaging (MR-DTI) - a technology widely employed in the human connectome project, but which I didn't realize could be applied to rodents. I can just imagine the little magnetic donuts they are sticking these mice in... Anyway, they found that the structural integrity of the CC (i.e. the connectivity between the two hemispheres) drops significantly (p < 0.0001) with age in the AL-fed mice. But it was almost entirely preserved in the old CR mice relative to either young AL or young CR mice. The graph on the right of this figure (Fig. 4 from the paper) shows this preservation: Figure 4: Caloric restriction preserved white matter structural integrity. (A) The region showing corpus callosum (CC) on MRI diffusion-weighted images. (B)The quantitative measurements of fractional anisotropy (FA) in CC. Data are presented as Mean ± SEM. ***p < 0.001 and ****p < 0.0001. So that is encouraging. Rather than turning our brains to mush, CR appears to preserve the integrity of important brain structures, at least in rodents and if started at an early age... --Dean ------------ [1] Front Aging Neurosci. 2015 Nov 13;7:213. Early Shifts of Brain Metabolism by Caloric Restriction Preserve White Matter Integrity and Long-Term Memory in Aging Mice. Guo J(1), Bakshi V(1), Lin AL(2). Free full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4643125/ Preservation of brain integrity with age is highly associated with lifespan determination. Caloric restriction (CR) has been shown to increase longevity and healthspan in various species; however, its effects on preserving living brain functions in aging remain largely unexplored. In the study, we used multimodal, non-invasive neuroimaging (PET/MRI/MRS) to determine in vivo brain glucose metabolism, energy metabolites, and white matter structural integrity in young and old mice fed with either control or 40% CR diet. In addition, we determined the animals' memory and learning ability with behavioral assessments. Blood glucose, blood ketone bodies, and body weight were also measured. We found distinct patterns between normal aging and CR aging on brain functions - normal aging showed reductions in brain glucose metabolism, white matter integrity, and long-term memory, resembling human brain aging. CR aging, in contrast, displayed an early shift from glucose to ketone bodies metabolism, which was associated with preservations of brain energy production, white matter integrity, and long-term memory in aging mice. Among all the mice, we found a positive correlation between blood glucose level and body weight, but an inverse association between blood glucose level and lifespan. Our findings suggest that CR could slow down brain aging, in part due to the early shift of energy metabolism caused by lower caloric intake, and we were able to identify the age-dependent effects of CR non-invasively using neuroimaging. These results provide a rationale for CR-induced sustenance of brain health with extended longevity. PMCID: PMC4643125 PMID: 26617514
  6. We've known for quite some time that exercise (and CR!) can help stave off the cognitive decline that is often associated with aging. Scientists are now beginning to understand the mechanism underlying this effect. Here is a popular press description: http://www.kurzweilai.net/long-term-aerobic-exercise-prevents-age-related-brain-deterioration of a new paper [1] that helps elucidate the physiological mechanism of brain health preservation via exercise. The authors experimented with mice. They found that with age the support cells in the brain (microglia, astrocytes, etc.) are lost or become dysfunctional, reducing blood flow to neurons, increasing inflammation, etc. This age-related decline and damage was prevented in the mice that exercised (~2 miles per day on a running wheel). But exercise didn't have any positive effect in mice that were completely APOE-deficient. It is interesting that the APOE gene is involved in the beneficial cognitive benefits of exercise, since variants in this gene (i.e. APOE4) are well known to be associated with increased risk of Alzheimer's disease. Exactly what this means for people with APOE gene variants like APOE4 isn't clear, at least to me. Would exercise be somewhat of a waste of time for these people, unable to preserve cognitive health, like in the APOE-deficient mice? Or would exercise be more important for APOE4 carriers, to get the most from their relatively-impaired APOE activity on the brain? --Dean ----------- [1] PLOS Biology, October 29, 2015; DOI: 10.1371/journal.pbio.1002279 (open access) APOE Stabilization by Exercise Prevents Aging Neurovascular Dysfunction and Complement Induction. Ileana Soto, Leah C. Graham, Hannah J. Richter, Stephen N. Simeone, Jake E. Radell, Weronika Grabowska, W. Keith Funkhouser, Megan C. Howell, Gareth R. Howell. Abstract Aging is the major risk factor for neurodegenerative diseases such as Alzheimer's disease, but little is known about the processes that lead to age-related decline of brain structures and function. Here we use RNA-seq in combination with high resolution histological analyses to show that aging leads to a significant deterioration of neurovascular structures including basement membrane reduction, pericyte loss, and astrocyte dysfunction. Neurovascular decline was sufficient to cause vascular leakage and correlated strongly with an increase in neuroinflammation including up-regulation of complement component C1QA in microglia/monocytes. Importantly, long-term aerobic exercise from midlife to old age prevented this age-related neurovascular decline, reduced C1QA+ microglia/monocytes, and increased synaptic plasticity and overall behavioral capabilities of aged mice. Concomitant with age-related neurovascular decline and complement activation, astrocytic Apoe dramatically decreased in aged mice, a decrease that was prevented by exercise. Given the role of APOE in maintaining the neurovascular unit and as an anti-inflammatory molecule, this suggests a possible link between astrocytic Apoe, age-related neurovascular dysfunction and microglia/monocyte activation. To test this, Apoe-deficient mice were exercised from midlife to old age and in contrast to wild-type (Apoe-sufficient) mice, exercise had little to no effect on age-related neurovascular decline or microglia/monocyte activation in the absence of APOE. Collectively, our data shows that neurovascular structures decline with age, a process that we propose to be intimately linked to complement activation in microglia/monocytes. Exercise prevents these changes, but not in the absence of APOE, opening up new avenues for understanding the complex interactions between neurovascular and neuroinflammatory responses in aging and neurodegenerative diseases such as Alzheimer’s disease. Author Summary Aging is frequently accompanied with frailty and cognitive decline. In recent years, increasing evidence has linked physical inactivity with the development of dementias such as Alzheimer’s disease. In fact, it is recognized that exercise combats frailty and cognitive decline in older adults, but the biological mechanisms involved are not completely known. Understanding the biological changes that trigger cognitive deterioration during aging and the mechanisms by which exercise improves health and brain function is key to ensuring the quality of life of the elderly population and to reducing risk of dementias such as Alzheimer’s disease. Here, we show that the cerebrovascular system in mice significantly deteriorates with age, and the structure and function of the blood brain barrier is progressively compromised. These age-related neurovascular changes are accompanied by neuroinflammation and deficits in common and spontaneous behaviors in mice. We found, however, that exercise from middle to older age preserves the cerebrovascular health, prevents behavioral deficits and reduces the age-related neuroinflammation in the cortex and hippocampus in aged mice. Mice deficient in Apoe, a gene associated with longevity and Alzheimer’s disease, are resistant to the beneficial effects of exercise, suggesting a possible mediating role for APOE in the maintenance and function of the neurovascular system during aging.
  7. CR is known to improve spatial learning and memory in rodents on tasks like the Morris water maze. But it is a matter of some controversy as to whether this improvement is due to beneficial effects of CR on memory/cognition, or whether the lean CR rodents can just swim better [2][3]. James Cain posted this new study [1] which speaks to this issue a bit. Researchers found that short-term CR in young rats resulted in beneficial changes in the microstructure of synapses in their hippocampus, part of the brain known to be important for spatial learning. So that is nice to see! --Dean ---------------- [1] Hippocampus. 2015 Sep 19. doi: 10.1002/hipo.22533. [Epub ahead of print] Food restriction modifies ultrastructure of hippocampal synapses. Babits R1, Szőke B, Sótonyi P1, Rácz B1. Abstract Consumption of high-energy diets may compromise health and may also impair cognition; these impairments have been linked to tasks that require hippocampal function. Conversely, food restriction has been shown to improve certain aspects of hippocampal function, including spatial memory and memory persistence. These diet-dependent functional changes raise the possibility that the synaptic structure underlying hippocampal function is also affected. To examine how short-term food restriction (FR) alters the synaptic structure of the hippocampus, we used quantitative electron microscopy to analyze the organization of neuropil in the CA1 stratum radiatum of the hippocampus in young rats, consequent to reduced food. While four weeks of FR did not modify the density, size, or shape of postsynaptic spines, the synapses established by these spines were altered, displaying increased mean length, and more frequent perforations of postsynaptic densities. That the number of perforated synapses (believed to be an indicator of synaptic enhancement) increased, and that the CA1 spine population had on average significantly longer PSDs suggests that synaptic efficacy of axospinous synapses also increased in the CA1. Taken together, our ultrastructural data reveal previously unrecognized structural changes at hippocampal synapses as a function of food restriction, supporting a link between metabolic balance and synaptic plasticity. This article is protected by copyright. All rights reserved. © 2015 Wiley Periodicals, Inc. KEYWORDS: CA1; dietary restriction; electron microscopy; memory; synaptic plasticity PMID: 26386363 -------------- [2] Physiol Behav. 2008 Feb 27;93(3):560-9. Epub 2007 Oct 30. Effects of chronic adult dietary restriction on spatial learning in the aged F344 x BN hybrid F1 rat. Fitting S(1), Booze RM, Gilbert CA, Mactutus CF. Author information: (1)Program in Behavioral Neuroscience, Department of Psychology, University of South Carolina, Columbia, SC 29208, USA. fitting@sc.edu <fitting@sc.edu> Dietary restriction (DR) has been shown to increase life span and reduce disease incidence across a variety of species. Recent research suggests that chronic adult DR may also alter age-related cognitive decline. The purpose of this study was twofold: (1) to examine the potential deficits in spatial learning ability in the aged F344 x BN hybrid F1 rat with specific attention to the contributory effects of motoric impairments and (2) to determine the influence of chronic adult DR on any such impairments. The Morris water maze (MWM) task was employed with a 1.8 m diameter tank, 10 cm2 escape platform, 28 degrees C water, and an automated collapsing central starting platform. Spatial learning impairments in the aged rats were evident on all dependent measures during training and the probe test. Motoric function, as reflected in measures of strength and locomotion demonstrated profound age-related performance impairments that were attenuated by chronic adult DR. The present data also replicate previous reports, indicating that DR attenuates the age-related impairments of performance in the MWM as indexed by the latency measure in acquisition, but critically was dissociated from any DR effect on measures of preference and, more critically, accuracy in the probe test. Collectively, the most parsimonious interpretation of DR effects on MWM performance would appear to be the preservation of motoric, and not cognitive, function. PMCID: PMC4041982 PMID: 18035382 ----------- [3] J Gerontol A Biol Sci Med Sci. 2009 Aug; 64A(8): 850–859. Published online 2009 May 6. doi: 10.1093/gerona/glp060 Influence of Calorie Restriction on Measures of Age-Related Cognitive Decline: Role of Increased Physical Activity Christy S. Carter,corresponding author1,2,3 Christiaan Leeuwenburgh,1 Michael Daniels,4 and Thomas C. Foster3 Abstract Controversy exists as to whether lifelong 40% calorie restriction (CR) enhances, has no effect on, or disrupts cognitive function during aging. Here, we report the effects of CR versus ad-lib feeding on cognitive function in male Brown Norway × Fisher344 rats across a range of ages (8–38 months), using two tasks that are differentially sensitive to age-related cognitive decline: object recognition and Morris water maze (MWM). All ages performed equally in object recognition, whereas, as a group, CR rats were impaired. In contrast, there was an age-related impairment in the MWM that was attenuated by CR as measured by time in proximity with and latency to reach the platform. Distance to the platform, a more sensitive measure, was not affected by CR. Finally, CR resulted in an overall increase in physical activity, one of several behavioral confounders to consider in the interpretation of cognitive outcomes in both tasks. PMCID: PMC2709546