The effect of probiotic supplementation on sleep, depression-like behaviour, and central glucose and lactate metabolism in male and female pubertal mice exposed to chronic sleep disruption.

The prevalence of depression significantly increases during puberty and adolescence. Puberty is the period during which sexual maturity is attained, while adolescence persists beyond puberty and includes physiological, social, emotional, and cognitive maturation. A stressor that has been shown previously to induce depression is chronic sleep disruption. Probiotics can prevent stress-induced depression. However, it was unclear whether probiotics could prevent depression following chronic sleep disruption and what mechanism may be involved. Therefore, we investigated whether pubertal probiotic treatment could prevent depression-like behavior in mice following chronic sleep disruption. We also examined whether probiotic treatment could improve sleep quality, and increase serotonin, tryptophan, glucose, and L-lactate concentrations in chronically sleep-disrupted mice. We hypothesized that probiotic treatment would prevent depression-like behavior, improve sleep quality, and increase serotonin, tryptophan, glucose, and L-lactate concentrations in sleep-disrupted mice. Male and female mice (N=120) received cannula and electroencephalogram (EEG) electrode implants at postnatal day (PND) 26. Mice received Lacidofil® or Cerebiome® probiotics (PND 33-51) and were sleep-disrupted for the first 4 hours of the light phase (sleep period) (PND 40-51). Hippocampal L-lactate and glucose concentrations and sleep were measured over a 24-h period (PND 48-49). Depression-like behaviour was evaluated using tail suspension (PND 49) and forced swim tests (PND 50). Chronic sleep disruption increased depression-like behaviour and NREM duration in the dark phase, and reduced all metabolites and neuromodulating biomolecules measured within the brain. However, mice treated with probiotics did not display depression-like behaviour or decreased hippocampal L-lactate following chronic sleep disruption. Cerebiome prevented decreases to prefrontal serotonin and hippocampal glucose concentrations, while Lacidofil increased NREM duration in the latter half of the light phase. The current study not only replicates previous findings linking chronic sleep disruption to depression, but also demonstrates that pubertal probiotic treatment can mitigate the effects of chronic sleep disruption on depression-like behaviour and on the neural mechanisms underlying depression in a strain-dependent manner.

16p11.2 haploinsufficiency reduces mitochondrial biogenesis in brain endothelial cells and alters brain metabolism in adult mice.

Neurovascular abnormalities in mouse models of 16p11.2 deletion autism syndrome are reminiscent of alterations reported in murine models of glucose transporter deficiency, including reduced brain angiogenesis and behavioral alterations. Yet, whether cerebrovascular alterations in 16p11.2df/+ mice affect brain metabolism is unknown. Here, we report that anesthetized 16p11.2df/+ mice display elevated brain glucose uptake, a phenomenon recapitulated in mice with endothelial-specific 16p11.2 haplodeficiency. Awake 16p11.2df/+ mice display attenuated relative fluctuations of extracellular brain glucose following systemic glucose administration. Targeted metabolomics on cerebral cortex extracts reveals enhanced metabolic responses to systemic glucose in 16p11.2df/+ mice that also display reduced mitochondria number in brain endothelial cells. This is not associated with changes in mitochondria fusion or fission proteins, but 16p11.2df/+ brain endothelial cells lack the splice variant NT-PGC-1α, suggesting defective mitochondrial biogenesis. We propose that altered brain metabolism in 16p11.2df/+ mice is compensatory to endothelial dysfunction, shedding light on previously unknown adaptative responses.

Environmental enrichment alters LPS-induced changes in BDNF and PSD-95 expressions during puberty.

Puberty is a critical period of cortical reorganization and increased synaptogenesis. Healthy cortical reorganization and synaptic growth require sufficient environmental stimuli and minimalized stress exposure during pubertal development. Exposure to impoverished environments or immune challenges impact cortical reorganization and reduce the expression of proteins associated with neuronal plasticity (BDNF) and synaptogenesis (PSD-95). Environmentally enriched (EE) housing includes improved social-, physical-, and cognitive stimulation. We hypothesized that enriched housing environment would mitigate pubertal stress-induced decreases in BDNF and PSD-95 expressions. Three-week-old male and female CD-1 mice (n = 10 per group) were housed for three weeks in either EE, social or deprived housing conditions. At 6 weeks of age, mice were treated with either lipopolysaccharide (LPS) or saline eight hours prior to tissue collection. Male and female EE mice displayed greater BDNF and PSD-95 expressions in the medial prefrontal cortex and hippocampus compared to socially housed and deprived housed mice. LPS treatment decreased BDNF expression in all the brain regions examined in EE mice, except for the CA3 region of the hippocampus, where EE housing successfully mitigated the pubertal LPS-induced decrease in BDNF expression. Interestingly, LPS-treated mice housed in deprived conditions displayed unexpected increases in BDNF and PSD-95 expressions throughout the medial prefrontal cortex and hippocampus. Both enriched and deprived housing conditions moderate how an immune challenge influences BDNF and PSD-95 expressions in a region-specific manner. These findings also emphasize the vulnerability of brain plasticity during puberty to various environmental factors.

Voluntary Behavior and Training Conditions Modulate in vivo Extracellular Glucose and Lactate in the Mouse Primary Motor Cortex.

Learning or performing new behaviors requires significant neuronal signaling and is metabolically demanding. The metabolic cost of performing a behavior is mitigated by exposure and practice which result in diminished signaling and metabolic requirements. We examined the impact of novel and habituated wheel running, as well as effortful behaviors on the modulation of extracellular glucose and lactate using biosensors inserted in the primary motor cortex of mice. We found that motor behaviors produce increases in extracellular lactate and decreases in extracellular glucose in the primary motor cortex. These effects were modulated by experience, novelty and intensity of the behavior. The increase in extracellular lactate appears to be strongly associated with novelty of a behavior as well as the difficulty of performing a behavior. Our observations are consistent with the view that a main function of aerobic glycolysis is not to fuel the current neuronal activity but to sustain new bio-infrastructure as learning changes neural networks, chiefly through the shuttling of glucose derived carbons into the pentose phosphate pathway for the biosynthesis of nucleotides.

Chronic sleep disruption induces depression-like behavior in adolescent male and female mice and sensitization of the hypothalamic-pituitary-adrenal axis in adolescent female mice.

Depression is a prevalent mood disorder responsible for reduced quality of life for over 264 million people. Depression commonly develops during adolescence and becomes twice as prevalent in females than in males. However, the mechanisms underlying adolescent depression onset and sex differences in the prevalence rate remain unclear. Adolescent exposure to stress and subsequent sensitization of the hypothalamic-pituitary-adrenal (HPA) axis contributes to mood disorder development, and females are particularly vulnerable to HPA sensitization. Repeated exposure to stressors common to adolescent development, like sleep disruption, could partially be responsible for adolescent female susceptibility to depression. To address this possibility, 80 adolescent and adult CD-1 mice (Male, n = 40; Female, n = 40) were manually sleep disrupted for the first four hours of each rest cycle or allowed normal rest for eight consecutive days. Depression-like behavior was assessed with the forced swim test. 5-HT1A and glucocorticoid receptor expression and concurrent cellular activation via glucocorticoid receptor/c-Fos colocalization were examined in various brain regions to assess cellular correlates of depression and HPA-axis activation. Both adolescent male and female mice displayed significantly greater depression-like behavior and prelimbic c-Fos expression after chronic sleep disruption than non-sleep disrupted adolescent and sleep disrupted adult counterparts. However, sleep disrupted adolescent females demonstrated greater dorsal raphe 5-HT1A expression than sleep disrupted adolescent males. Adolescent females and males had decreased medial prefrontal 5-HT1A expression after chronic sleep disruption, but only adolescent females expressed decreased hippocampal 5-HT1A expression compared to controls. Chronic sleep disruption significantly increased corticosterone release, glucocorticoid expression in the CA1, and activation of glucocorticoid immunoreactive cells in the prelimbic cortex of adolescent females but not in adolescent males. These findings suggest that chronic sleep disruption during adolescence could give rise to depressive symptoms in male and female adolescents through differing signaling mechanisms.

Brain and muscle adaptation to high-fat diets and exercise: Metabolic transporters, enzymes and substrates in the rat cortex and muscle.

There is evidence suggesting that the effects of diet and physical activity on physical and mental well-being are the result of altered metabolic profiles. Though the central and peripheral systems work in tandem, the interactions between peripheral and central changes that lead to these altered states of well-being remains elusive. We measured changes in the metabolic profile of brain (cortex) and muscle (soleus and plantaris) tissue in rats following 5-weeks of treadmill exercise and/or a high-fat diet to evaluate peripheral and central interactions as well as identify any common adaptive mechanisms. To characterize changes in metabolic profiles, we measured relative changes in key metabolic enzymes (COX IV, hexokinase, LDHB, PFK), substrates (BHB, FFA, glucose, lactate, insulin, glycogen, BDNF) and transporters (MCT1, MCT2, MCT4, GLUT1, GLUT3). In the cortex, there was an increase in MCT1 and a decrease in glycogen following the high-fat diet, suggesting an increased reliance on monocarboxylates. Muscle changes were dependent muscle type. Within the plantaris, a high-fat diet increased the oxidative capacity of the muscle likely supported by increased glycolysis, whereas exercise increased the oxidative capacity of the muscle likely supported via increased glycogen synthesis. There was no effect of diet on soleus measurements, but exercise increased its oxidative capacity likely fueled by endogenous and exogenous monocarboxylates. For both the plantaris and soleus, combining exercise training and high-fat diet mediated results, resulting in a middling effect. Together, these results indicate the variable adaptions of two main metabolic pathways: glycolysis and oxidative phosphorylation. The results also suggest a dynamic relationship between the brain and body.

The impact of lactic acid and medium chain triglyceride on blood glucose, lactate and diurnal motor activity: A re-examination of a treatment of major depression using lactic acid.

While investigating the effect of alternative energy substrates on extracellular brain glucose or lactate, Béland-Millar (2017) noted a reduction of physical activity after intraperitoneal administration of lactate and ketone bodies. These observations were similar to an older study that examined the impact of drinking a sodium lactate/lactic acid solution before sleep in hospitalized patients with major depression. Patients and control participants self-reported drowsiness, early sleep onset and better overall sleep after consumption. Some patients showed improved mood after several days of treatment. We re-evaluated the effects of the solution used (0.59 g/kg) as well as several smaller doses (0.47, 0.35, 0.24 and 0.12 g/kg) on blood lactate and glucose in CD-1 mice and on sleep onset associated activity reduction. Because of adverse effects with the lactate/lactic acid solution, we also examined the effects of a medium chain triglyceride (MCT) solution (10, 5, 2.5, and 1 ml/kg) on blood lactate and glucose. Oral gavage administration of lactic acid/lactate produced adverse effects particularly for the largest doses. However consumption of 10 and 5 ml/kg volumes of MCT oils significantly increased blood lactate concentration to levels comparable to Lowenbach's solution without piloerection indicative of adverse effects. To evaluate pre-sleep activity reduction produced by lactate, mice were intraperitoneally administered diluted sodium lactate (2.0 g/kg, 1.0 g/kg, 0.5 g/kg, 0.25 g/kg, or saline) for 6 days, 120 min before their sleep period and their running activity was measured. Larger lactate doses reduced pre-sleep running each day up to 60 min post injection. Smaller doses reduced running after a single treatment only. These results suggest that the modulation of blood lactate levels may be useful in treating sleep onset problems associated with depression.

Utility of the Hebb-Williams Maze Paradigm for Translational Research in Fragile X Syndrome: A Direct Comparison of Mice and Humans.

To generate meaningful information, translational research must employ paradigms that allow extrapolation from animal models to humans. However, few studies have evaluated translational paradigms on the basis of defined validation criteria. We outline three criteria for validating translational paradigms. We then evaluate the Hebb-Williams maze paradigm (Hebb and Williams, 1946; Rabinovitch and Rosvold, 1951) on the basis of these criteria using Fragile X syndrome (FXS) as model disease. We focused on this paradigm because it allows direct comparison of humans and animals on tasks that are behaviorally equivalent (criterion #1) and because it measures spatial information processing, a cognitive domain for which FXS individuals and mice show impairments as compared to controls (criterion #2). We directly compared the performance of affected humans and mice across different experimental conditions and measures of behavior to identify which conditions produce comparable patterns of results in both species. Species differences were negligible for Mazes 2, 4, and 5 irrespective of the presence of visual cues, suggesting that these mazes could be used to measure spatial learning in both species. With regards to performance on the first trial, which reflects visuo-spatial problem solving, Mazes 5 and 9 without visual cues produced the most consistent results. We conclude that the Hebb-Williams mazes paradigm has the potential to be utilized in translational research to measure comparable cognitive functions in FXS humans and animals (criterion #3).

Fluctuations of extracellular glucose and lactate in the mouse primary visual cortex during visual stimulation.

We measured the extracellular glucose and lactate in the primary visual cortex in the CD-1 mouse using electrochemical electrodes. To gain some additional information on brain metabolism, we examined the impact of systemic injections of lactate and fructose on the brain extracellular glucose and lactate changes observed during visual stimulation. We found that simple stimulation using a flashlight produced a decrease in visual cortex extracellular glucose and an increase in extracellular lactate. Similar results were observed following visual stimulation with an animated movie without soundtrack or the presentation of a novel object. Specificity of these observations was confirmed by the absence of extracellular glucose and lactate changes when the mice were presented a second time with the same object. Previous experiments have shown that systemic injections of fructose and lactate lead to an increase in blood lactate but no change in blood glucose while they both increase brain extracellular glucose but they do not increase brain extracellular lactate. When mice were visually stimulated after they had received these injections, we found that lactate, and to a slightly lesser degree fructose, both reduced the amplitude of the changes in extracellular glucose and lactate that accompanied visual stimulation. Thus, neural activation leads to an increase in extracellular lactate and a decrease in extracellular glucose. Novelty, attentional resources and availability of metabolic fuels modulate these fluctuations. The observations are consistent with a modified view of brain metabolism that takes into account the blood and brain glucose availability.

Oligodendrocyte progenitor cells are paired with GABA neurons in the mouse dorsal cortex: Unbiased stereological analysis.

Oligodendrocyte progenitor cells (OPC) are glial cells that differentiate into myelinating oligodendrocytes during early stages of post-natal life. However, OPCs persist beyond developmental myelination and represent an important population of cycling cells in the gray and white matter of the adult brain. While adult OPCs form unique territories that are maintained through self-avoidance, some cortical OPCs appear to position their cell body very close to that of a neuron, forming what are known as OPC-neuron pairs. We used unbiased systematic stereological analysis of the NG2-CreERTM:EYFP reporter mouse to determine that close to 170,000 OPC-neuron pairs can be found in the dorsal portion of the adult neocortex, with approximately 40% of OPCs and 4% of neurons in pairs. Through stereological analysis, we also determined that reference memory training does not change the prevalence of OPC-neuron pairs or the proportion of OPCs and neurons that form them. GABAergic agent administration did not affect the proportion of OPCs and neurons that can be found in pairs. However, the GABAB-receptor agonist baclofen and the GABAA receptor antagonist picrotoxin significantly increased the estimated number of pairs when compared to the control group and the GABAB-receptor antagonist (i.e. saclofen) group. Density of OPC-neuron pairs was increased by the GABAA receptor antagonist picrotoxin. Finally, histological analysis of OPC-neuron pairs suggested that in the dorsal portion of the cortex, GABAergic interneurons represent the most common neuronal component of the pairs, and that calbindin, calretinin and parvalbumin GABAergic interneurons found in the cortex take part in these pairs. Using previous estimates of the number of GABAergic neurons in the rodent cortex, we estimate that roughly one in four GABAergic neurons are paired with an OPC.

Doublecortin in Oligodendrocyte Precursor Cells in the Adult Mouse Brain.

Key Points Oligodendrocyte precursor cells express doublecortin, a microtubule-associated protein.Oligodendrocyte precursor cells express doublecortin, but at a lower level of expression than in neuronal precursor.Doublecortin is not associated with a potential immature neuronal phenotype in Oligodendrocyte precursor cells. Oligodendrocyte precursor cells (OPC) are glial cells that differentiate into myelinating oligodendrocytes during embryogenesis and early stages of post-natal life. OPCs continue to divide throughout adulthood and some eventually differentiate into oligodendrocytes in response to demyelinating lesions. There is growing evidence that OPCs are also involved in activity-driven de novo myelination of previously unmyelinated axons and myelin remodeling in adulthood. Considering these roles in the adult brain, OPCs are likely mobile cells that can migrate on some distances before they differentiate into myelinating oligodendrocytes. A number of studies have noted that OPCs express doublecortin (DCX), a microtubule-associated protein expressed in neural precursor cells and in migrating immature neurons. Here we describe the distribution of DCX in OPCs. We found that almost all OPCs express DCX, but the level of expression appears to be much lower than what is found in neural precursor. We found that DCX is downregulated when OPCs start expressing mature oligodendrocyte markers and is absent in myelinating oligodendrocytes. DCX does not appear to signal an immature neuronal phenotype in OPCs in the adult mouse brain. Rather, it could be involved either in cell migration, or as a marker of an immature oligodendroglial cell phenotype.

Unbiased stereological analysis of the fate of oligodendrocyte progenitor cells in the adult mouse brain and effect of reference memory training.

Oligodendrocyte progenitor cells (OPCs) are glial cells that differentiate into myelinating oligodendrocytes during early stages of post-natal life. However, OPCs persist beyond developmental myelination and represent an important population of cycling cells in the gray and white matter of the adult brain. Here, we used unbiased systematic stereological analysis to determine the total number of OPCs in the neocortex and corpus callosum of the adult mouse. We found that the ratio of OPCs to neurons is of 1:10 in the adult neocortex. Likewise, the ratio of OPCs to oligodendrocytes is of 1:1 in the cortex and 1:7 in the corpus callosum. We also used BrdU labeling and the NG2-CreER™:EYFP reporter mouse to determine the proportion of proliferating adult OPCs and their fate. We show that OPCs continue to differentiate into oligodendrocytes in adulthood, with white matter OPCs being more likely to differentiate into an oligodendrocyte phenotype than gray matter OPCs. The differentiation of OPCs into an oligodendrocyte phenotype can occur either directly from a spontaneous differentiation by an OPC or following OPC cell division. We also provide evidence for the neuronal differentiation of adult OPCs in the cortical gray matter. Although activity-dependent neural network activity has been hypothesized to serve as a modulator of OPC proliferation and differentiation, we found that reference memory training did not affect the proportion of proliferating and differentiated OPCs in the adult mouse brain.

Effects of Systemic Metabolic Fuels on Glucose and Lactate Levels in the Brain Extracellular Compartment of the Mouse.

Classic neuroenergetic research has emphasized the role of glucose, its transport and its metabolism in sustaining normal neural function leading to the textbook statement that it is the necessary and sole metabolic fuel of the mammalian brain. New evidence, including the Astrocyte-to-Neuron Lactate Shuttle hypothesis, suggests that the brain can use other metabolic substrates. To further study that possibility, we examined the effect of intraperitoneally administered metabolic fuels (glucose, fructose, lactate, pyruvate, ß-hydroxybutyrate, and galactose), and insulin, on blood, and extracellular brain levels of glucose and lactate in the adult male CD1 mouse. Primary motor cortex extracellular levels of glucose and lactate were monitored in freely moving mice with the use of electrochemical electrodes. Blood concentration of these same metabolites were obtained by tail vein sampling and measured with glucose and lactate meters. Blood and extracellular fluctuations of glucose and lactate were monitored for a 2-h period. We found that the systemic injections of glucose, fructose, lactate, pyruvate, and ß-hydroxybutyrate increased blood lactate levels. Apart for a small transitory rise in brain extracellular lactate levels, the main effect of the systemic injection of glucose, fructose, lactate, pyruvate, and ß-hydroxybutyrate was an increase in brain extracellular glucose levels. Systemic galactose injections produced a small rise in blood glucose and lactate but almost no change in brain extracellular lactate and glucose. Systemic insulin injections led to a decrease in blood glucose and a small rise in blood lactate; however brain extracellular glucose and lactate monotonically decreased at the same rate. Our results support the concept that the brain is able to use alternative fuels and the current experiments suggest some of the mechanisms involved.

A TgCRND8 Mouse Model of Alzheimer's Disease Exhibits Sexual Dimorphisms in Behavioral Indices of Cognitive Reserve.

Cognitive decline is sexually dimorphic in Alzheimer's disease (AD). Men show higher incidences of amnestic mild cognitive impairment yet women disproportionally phenoconvert to AD. It is hypothesized that men maintain greater cognitive reserve than women under comparable amyloid-ß (Aß) challenge. One behavioral aspect of cognitive reserve in mice is the capacity to cope with Aß-associated stereotypies by switching to increasingly effective navigational search strategies in the Morris water maze. To explore inherent sex differences in this paradigm, however, we require an AßPP mouse model wherein behavioral flexibility is impaired earlier in females than males despite equivalent Aß load. Here, we show that when F1 C57Bl/6×C3H/HeJ TgCRND8 mice are placed on C57Bl/6 background, N5 Tg males and females exhibit equivalent Aß pathologies at 2, 4, 6, and 8 months of age yet females display learning and memory deficits earlier than males. We further show that this N5 line does not carry the autosomal recessive pde6brd1 mutation that impairs visual acuity and that the estrous cycle is not disrupted on this genetic background. At 5.5 months of age, Tg males, but not females, compensate for Aß-associated stereotypic behaviors (i.e., hyperactive tight circling) by alternating navigational search strategies and adopting increasingly productive spatial search strategies. Females fail to overcome Aß-associated stereotypies and do not efficiently switch from systematic to spatial learning strategies. Together, these data identify a novel AßPP mouse model that can be used for preclinical testing of interventions targeting sexual dimorphisms in behavioral indices of cognitive reserve.

A simple histological technique to improve immunostaining when using DNA denaturation for BrdU labelling.

The typical immunohistochemistry technique used to reveal 5-bromo-2'-deoxyuridine (BrdU) incorporation requires denaturation of the DNA by heat and acid to permeabilize the cell nucleus. This treatment can damage tissue and reduce the antigenicity of several proteins, which then leads to weak immunostaining and/or false negatives. We show that an overnight post-fixation step following immunohistochemistry for antigens of interest protects immunostaining during the acid/heat denaturation treatment for subsequent BrdU staining. We used this technique to study the differentiation of recently divided oligodendrocyte progenitor cells in NG2CreER:EYFP reporter mice. We used a GFP anti-EYFP antibody to maximize visualization of the EYFP-containing oligodendrocyte progenitor cells, Olig1, and GST-pi to confirm the cell phenotype. Immunostaining for GFP, Olig1, and GST-pi is reduced by DNA denaturation. We found that incorporating a post-fixation step after double immunostaining for GFP/Olig1 and GFP/GST-pi prior to DNA denaturation prevented the fading and false negatives associated with this treatment. This simple addition to BrdU immunohistochemistry protocols extends the range of proteins that can be detected in combination with BrdU, along with the number of antibodies that can be used successfully in the study of cell proliferation.

Translating the impact of exercise on cognition: methodological issues in animal research.

Physical exercise and fitness have been proposed as potential factors that promote healthy cognitive aging. Some of the support for this hypothesis has come from animal research. Animal studies are also used to propose the physiological mechanisms underlying the cognitive performance improvement associated with exercise. In the present review and meta-analysis, we discuss several methodological problems that limit the contribution of animal studies to the understanding of the putative effects of exercise on cognitive aging. We suggest that the most likely measure to equate exercise intensity in rodent and humans may be oxygen consumption (VO2) because observed values are surprisingly similar in young and older rodents and humans. For practical reasons, several animal studies use young rodents kept in social isolation. We show that social isolation is associated with an enhanced impact of exercise on cognitive performance but not on some physiological measures thought to mediate the effect of exercise. Surprisingly, two months or more of exercise intervention appeared to be ineffective to promote cognitive performance compared to shorter durations. We argue that impact of exercise in socially isolated animals is explained by an alleviation of environmental impoverishment as much as an effect of physical exercise. It is possible that the introduction of exercise in rodents is partly mediated by environmental changes. It may explain why larger effects are observed for the shorter durations of exercise while much smaller effects are found after longer periods of exercise.

2-Methyl-6-(phenylethynyl) pyridine (MPEP) reverses maze learning and PSD-95 deficits in Fmr1 knock-out mice.

Fragile X Syndrome (FXS) is caused by the lack of expression of the fragile X mental retardation protein (FMRP), which results in intellectual disability and other debilitating symptoms including impairment of visual-spatial functioning. FXS is the only single-gene disorder that is highly co-morbid with autism spectrum disorder and can therefore provide insight into its pathophysiology. Lack of FMRP results in altered group I metabotropic glutamate receptor (mGluR) signaling, which is a target for putative treatments. The Hebb-Williams (H-W) mazes are a set of increasingly complex spatial navigation problems that depend on intact hippocampal and thus mGluR-5 functioning. In the present investigation, we examined whether an antagonist of mGluR-5 would reverse previously described behavioral deficits in fragile X mental retardation 1 knock-out (Fmr1 KO) mice. Mice were trained on a subset of the H-W mazes and then treated with either 20 mg/kg of an mGluR-5 antagonist, 2-Methyl-6-(phenylethynyl) pyridine (MPEP; n = 11) or an equivalent dose of saline (n = 11) prior to running test mazes. Latency and errors were dependent variables recorded during the test phase. Immediately after completing each test, marble-burying behavior was assessed, which confirmed that the drug treatment was pharmacologically active during maze learning. Although latency was not statistically different between the groups, MPEP treated Fmr1 KO mice made significantly fewer errors on mazes deemed more difficult suggesting a reversal of the behavioral deficit. MPEP treated mice were also less perseverative and impulsive when navigating mazes. Furthermore, MPEP treatment reversed post-synaptic density-95 (PSD-95) protein deficits in Fmr1 KO treated mice, whereas levels of a control protein (ß-tubulin) remained unchanged. These data further validate MPEP as a potentially beneficial treatment for FXS. Our findings also suggest that adapted H-W mazes may be a useful tool to document alterations in behavioral functioning following pharmacological intervention in FXS.

Voluntary Out-of-Body Experience: An fMRI Study.

The present single-case study examined functional brain imaging patterns in a participant that reported being able, at will, to produce somatosensory sensations that are experienced as her body moving outside the boundaries of her physical body all the while remaining aware of her unmoving physical body. We found that the brain functional changes associated with the reported extra-corporeal experience (ECE) were different than those observed in motor imagery. Activations were mainly left-sided and involved the left supplementary motor area and supramarginal and posterior superior temporal gyri, the last two overlapping with the temporal parietal junction that has been associated with out-of-body experiences. The cerebellum also showed activation that is consistent with the participant's report of the impression of movement during the ECE. There was also left middle and superior orbital frontal gyri activity, regions often associated with action monitoring. The results suggest that the ECE reported here represents an unusual type of kinesthetic imagery.

Visual-spatial learning impairments are associated with hippocampal PSD-95 protein dysregulation in a mouse model of fragile X syndrome.

Fragile X syndrome is the most common cause of inherited intellectual disability and is caused by the lack of fragile X mental retardation protein (FMRP) expression. In-vitro findings in mice and post-mortem autopsies in humans are characterized by dendritic spine abnormalities in the absence of Fmrp/FMRP. Biochemical and electrophysiological studies have identified postsynaptic density protein (PSD)-95 as having an established role in dendritic morphology as well as a molecular target of Fmrp. How Fmrp affects the expression of PSD-95 following behavioral learning is unknown. In the current study, wild type controls and Fmr1 knockout mice were trained in a subset of the Hebb-Williams (H-W) mazes. Dorsal hippocampal PSD-95 protein levels relative to a stable cytoskeleton protein (ß-tubulin) were measured. We report a significant upregulation of PSD-95 protein levels in wild type mice, whereas training-related protein increases were blunted in Fmr1 knockout mice. In addition, there was a significant negative correlation between mean total errors on the mazes and PSD-95 protein levels. The coefficient of determination indicated that the mean total errors on the H-W mazes accounted for 35% of the variance in PSD-95 protein levels. These novel findings suggest that reduced PSD-95-associated postsynaptic plasticity may contribute to the learning and memory deficits observed in human fragile X syndrome patients.

Older people's attitudes toward interactive voice response systems.

BACKGROUND: Interactive voice response (IVR) systems are computer programs that interact with people to provide a number of services from business to healthcare. The healthcare applications are particularly relevant to older adults because they are important consumers of medical services. However, research has found that older adults can experience significant difficulties with IVR and have more negative attitudes toward the technology. SUBJECTS AND METHODS: Seniors' attitudes appear to be related to their most recent experiences with IVR systems. The objective of this study was to examine attitudes toward four commercial or governmental IVR systems and how these attitudes relate to participants' ability to interact with the technology in a sample of 185 community-dwelling older (>65-year-old) adults. We also examined the effects of several demographic factors on both success and attitudes toward automated systems. RESULTS: We found a significant positive correlation between IVR success and attitudes toward IVR. However, a large subset of our sample gave high ratings despite experiencing significant difficulties with the systems. These participants tended to have lower full scale IQ. No gender differences emerged in terms of attitudes and ability to interact with IVR systems. CONCLUSIONS: Results also indicated that older adults in our sample viewed the IVR interaction as particularly demanding on attention and concentration abilities.