Glucose metabolism,hippocampal subfields and cognition in first-episode and never-treated schizophrenia

BackgroundPrevious studies have indicated that glucose metabolism and altered hippocampal structure and function play a pivotal role in cognitive deficits in schizophrenia (SZ). This study was designed to explore the inter-relationship between glucose metabolism, hippocampal subfield volume, and cognitive function in the antipsychotics-naive first episode (ANFE) SZ patients.MethodsWe chose the fasting insulin, glucose, and insulin resistance (HOMA-IR) index as biomarkers of glucose metabolism. Cognitive function was assessed by the MATRICS Consensus Cognitive Battery (MCCB). The hippocampal subfield volume, glucose metabolism biomarkers, and cognitive function were evaluated in 43 ANFE SZ and 29 healthy controls (HCs).ResultsCompared with HCs, SZ patients had higher fasting blood glucose and insulin levels and HOMA-IR (all p < 0.05). Correlation analysis revealed that category fluency performance was positively associated with fasting glucose level. Fasting insulin or HOMA-IR was positively associated with the hippocampal subfield volume in patients (all p<0.05). Moreover, the spatial span index score was associated with the volume of the right presubiculum, subiculum, and right hippocampal tail. In addition, multiple regression analysis found that the interaction effects of insulin × right fimbria or insulin × left fimbria were independent predictors of the MCCB total score.ConclusionsOur findings suggest that abnormal glucose metabolism and cognitive decline occur in the early stage of SZ. The interaction between abnormal glucose metabolism and hippocampal subfields was associated with cognitive functions in SZ.     

Reelin supplementation enhances cognitive ability, synaptic plasticity, and dendritic spine density

Apolipoprotein receptors belong to an evolutionarily conserved surface receptor family that has intimate roles in the modulation of synaptic plasticity and is necessary for proper hippocampal-dependent memory formation. The known lipoprotein receptor ligand Reelin is important for normal synaptic plasticity, dendritic morphology, and cognitive function; however, the in vivo effect of enhanced Reelin signaling on cognitive function and synaptic plasticity in wild-type mice is unknown. The present studies test the hypothesis that in vivo enhancement of Reelin signaling can alter synaptic plasticity and ultimately influence processes of learning and memory. Purified recombinant Reelin was injected bilaterally into the ventricles of wild-type mice. We demonstrate that a single in vivo injection of Reelin increased activation of adaptor protein Disabled-1 and cAMP-response element binding protein after 15 min. These changes correlated with increased dendritic spine density, increased hippocampal CA1 long-term potentiation (LTP), and enhanced performance in associative and spatial learning and memory. The present study suggests that an acute elevation of in vivo Reelin can have long-term effects on synaptic function and cognitive ability in wild-type mice.     

Hippocampal memory processes are modulated by insulin and high-fat-induced insulin resistance

Insulin regulates glucose uptake and storage in peripheral tissues, and has been shown to act within the hypothalamus to acutely regulate food intake and metabolism. The machinery for transduction of insulin signaling is also present in other brain areas, particularly in the hippocampus, but a physiological role for brain insulin outside the hypothalamus has not been established. Recent studies suggest that insulin may be able to modulate cognitive functions including memory. Here we report that local delivery of insulin to the rat hippocampus enhances spatial memory, in a PI-3-kinase dependent manner, and that intrahippocampal insulin also increases local glycolytic metabolism. Selective blockade of endogenous intrahippocampal insulin signaling impairs memory performance. Further, a rodent model of type 2 diabetes mellitus produced by a high-fat diet impairs basal cognitive function and attenuates both cognitive and metabolic responses to hippocampal insulin administration. Our data demonstrate that insulin is required for optimal hippocampal memory processing. Insulin resistance within the telencephalon may underlie the cognitive deficits commonly reported to accompany type 2 diabetes.     

Upregulation of hippocampal TrkB and synaptotagmin is involved in treadmill exercise-enhanced aversive memory in mice

Cognitive functions usually involve various synaptic proteins and neurotrophic factors in the hippocampus. However, whether treadmill exercise can improve learning and memory by upregulating some of these molecules remain unraveled. To address this question, male BALB/c mice were divided into control and exercise groups, the latter group went through 4 weeks of treadmill exercise training. At the end of exercise training period, they were either tested for passive avoidance (PA) performance or sacrificed for quantifying the hippocampal levels of brain-derived neurotrophic factor (BDNF), tropomyosin-related kinase B (TrkB, the BDNF receptor), synaptotagmin (a Ca²⁺-dependent synaptic vesicle protein), and SNAP-25 (a presynaptic vesicular fusion protein). Our results showed that treadmill exercise training (1) increased the retention latency without affecting the fear acquisition in the PA test, (2) transiently increased the hippocampal BDNF level at 1, 2, and 4 h after the completion of exercise training, and (3) persistently increased the hippocampal protein levels of full-length TrkB, phosphorylated TrkB and synaptotagmin, but not truncated TrkB or SNAP-25. Moreover, the protein expression level of full-length TrkB or synaptotagmin was positively correlated with PA performance in mice. Finally, inhibition of TrkB signaling by K252a abolished the exercise-facilitated PA performance and upregulation of TrkB and synaptotagmin. Taken together, these data suggest that the upregulation of TrkB and synaptotagmin in the hippocampus contributes to the exercise-facilitated aversive memory.     

Emotional and cognitive information processing: relations to behavioral performance and hippocampal long-term potentiation in vivo during a spatial water maze training in rats

Emotionality as well as cognitive abilities contribute to the acquisition and retrieval of memories as well as to the consolidation of long-term potentiation (LTP), a cellular model of memory formation. However, little is known about the timescale and relative contribution of these processes. Therefore, we tested the effects of weak water maze training, containing both emotional and cognitive demands, on LTP in the hippocampal dentate gyrus. The population spike amplitude (PSA)-LTP was prolonged in all rats irrespective of whether they memorized the platform position or not, whereas the field excitatory postsynaptic potential (fEPSP)-LTP was impaired in good learners and enhanced in poor learners. We then dissociated the behavioral performance of rats during the water maze task by principal component analysis and by means of stress hormone concentrations into underlying "emotional" and "cognitive" factors. PSA-LTP was associated with "emotional" and fEPSP-LTP with "cognitive" behavior. PSA-LTP was depotentiated after the blockade of corticosterone binding mineralocorticoid receptors (MRs) in trained animals, while fEPSP-LTP was unaffected. These results suggest that synaptic processing and encoding of emotional information in the hippocampal dentate gyrus is realized fast and further information transfer is detectable by the reinforcement of PSA-LTP, whereas that of cognitive memories is long lasting.     

Phase-dependent synaptic changes in the hippocampal CA1 field underlying extinction processes in freely moving rats

Recent studies focus on the functional significance of a novel form of synaptic plasticity, low-frequency stimulation (LFS)-induced synaptic potentiation in the hippocampal CA1 area. In the present study, we elucidated dynamic changes in synaptic function in the CA1 field during extinction processes associated with context-dependent fear memory in freely moving rats, with a focus on LFS-induced synaptic plasticity. Synaptic transmission in the CA1 field was transiently depressed during each extinction trial, but synaptic efficacy was gradually enhanced by repeated extinction trials, accompanied by decreases in freezing. On the day following the extinction training, synaptic transmission did not show further changes during extinction retrieval, suggesting that the hippocampal synaptic transmission that underlies extinction processes changes in a phase-dependent manner. The synaptic potentiation produced by extinction training was mimicked by synaptic changes induced by LFS (0.5 Hz) in the group that previously received footshock conditioning. Furthermore, the expression of freezing during re-exposure to footshock box was significantly reduced in the LFS application group in a manner similar to the extinction group. These results suggest that LFS-induced synaptic plasticity may be associated with the extinction processes that underlie context-dependent fear memory. This hypothesis was supported by the fact that synaptic potentiation induced by extinction training did not occur in a juvenile stress model that exhibited extinction deficits. Given the similarity between these electrophysiological and behavioral data, LFS-induced synaptic plasticity may be related to extinction learning, with some aspects of neuronal oscillations, during the acquisition and/or consolidation of extinction memory.     

Voluntary exercise ameliorates cognitive deficits in morphine dependent rats: the role of hippocampal brain-derived neurotrophic factor

Chronic exposure to opiates impairs spatial learning and memory. Given the well-known beneficial effects of voluntary exercise on cognitive functions, we investigated whether voluntary exercise would ameliorate the cognitive deficits that are induced by morphine dependence. If an effect of exercise was observed, we aimed to investigate the possible role of hippocampal brain-derived neurotrophic factor (BDNF) in the exercise-induced enhancement of learning and memory in morphine-dependent rats. The rats were injected with bi-daily doses (10mg/kg, at 12h intervals) of morphine over a period of 10 days of voluntary exercise. Following these injections, a water maze task was performed twice a day for five consecutive days, followed by a probe trial 2 days later. A specific BDNF inhibitor (TrkB-IgG chimera) was used to block the hippocampal BDNF action during the 10 days of voluntary exercise. We found that voluntary exercise blocked the ability of chronic morphine to impair spatial memory retention. A blockade of the BDNF action blunted the exercise-induced improvement of spatial memory in the dependent rats. Moreover, the voluntary exercise diminished the severity of the rats' dependency on morphine. This study demonstrates that voluntary exercise ameliorates, via a TrkB-mediated mechanism, the cognitive deficits that are induced by chronic morphine. Thus, voluntary exercise might be a potential method to ameliorate some of the deleterious behavioral consequences of the abuse of morphine and other opiates.     

Glucose treatment reduces memory deficits in young adult rats fed high-fat diets

Feeding rats high-fat diets for 3 months produces a widespread cognitive deficit that affects performance on a wide range of learning and memory tasks. The present study tested the hypothesis that this effect is related to a fat-induced impairment in glucose metabolism. Following 3 months of dietary intervention (20% by weight fat diets, composed primarily of either beef tallow or soybean oil versus standard laboratory chow), male Long-Evans rats were tested on a variable interval delayed alternation (VIDA) task that measures learning and memory functions that differentially involve specific brain regions. Relative to rats fed chow, rats consuming the high-fat diets were impaired on all aspects of VIDA performance. Following baseline testing, rats were maintained on their respective diets and the effect of glucose administration (100 mg/kg BW; i.p.) was examined. For the next 6 days, animals alternately received injections of saline or glucose 30 min prior to VIDA testing. Glucose treatment improved performance, with the effect being most pronounced at the longer intertrial intervals where task performance is sensitive to hippocampal impairment. Importantly, the beneficial effect of glucose were confined to those animals consuming the high-fat diets and were not observed in rats fed chow. These results demonstrate that glucose administration can overcome those deficits associated with hippocampal function in rats fed high-fat diets and are consistent with the hypothesis that high-fat diets, in part, mediate their effect through the development of insulin resistance and glucose intolerance.     

New insights into the regulation of synaptic plasticity from an unexpected place: Hippocampal area CA2

The search for molecules that restrict synaptic plasticity in the brain has focused primarily on sensory systems during early postnatal development, as critical periods for inducing plasticity in sensory regions are easily defined. The recent discovery that Schaffer collateral inputs to hippocampal area CA2 do not readily support canonical activity-dependent long-term potentiation (LTP) serves as a reminder that the capacity for synaptic modification is also regulated anatomically across different brain regions. Hippocampal CA2 shares features with other similarly "LTP-resistant" brain areas in that many of the genes linked to synaptic function and the associated proteins known to restrict synaptic plasticity are expressed there. Add to this a rich complement of receptors and signaling molecules permissive for induction of atypical forms of synaptic potentiation, and area CA2 becomes an ideal model system for studying specific modulators of brain plasticity. Additionally, recent evidence suggests that hippocampal CA2 is instrumental for certain forms of learning, memory, and social behavior, but the links between CA2-enriched molecules and putative CA2-dependent behaviors are only just beginning to be made. In this review, we offer a detailed look at what is currently known about the synaptic plasticity in this important, yet largely overlooked component of the hippocampus and consider how the study of CA2 may provide clues to understanding the molecular signals critical to the modulation of synaptic function in different brain regions and across different stages of development.     

Examining the Effects of Exercise on Pattern Separation and the Moderating Effects of Mood Symptoms

Aerobic exercise has broad cognitive benefits. One target of interest is enhanced memory. The present study explored pattern separation as a specific memory process that could be sensitive to acute and regular exercise and clinically significant for disorders (e.g., depression) characterized by cognitive-affective deficits and hippocampal impairment. In a within-subjects design, participants (N = 69) attended two visits during which they repeated a behavioral pattern separation task at rest and after an activity (cycling, stretching). Regular exercise habits, demographics, mood and anxiety symptoms, and recognition memory capacity were also measured. More regular exercise predicted better resting pattern separation, t(62) = 2.13, b = 1.74, p = .037. Age moderated this effect, t(61) = 2.35, b = .25, p = .02; exercise most strongly predicted performance among middle-age participants. There was no main effect of activity condition on post-activity performance, t(61) = .67, p = .51. However, with significant heterogeneity in reported mood symptoms and regular exercise habits, there was a three-way interaction between condition, regular exercise, and depression, t(55) = 2.08, b = .22, p = .04. Relative to stretching, cycling appears to have enhanced the benefit of regular exercise for pattern separation performance; however, this was evident among participants with mild to no symptoms of depression, but absent among participants with moderate to severe symptoms. Results have implications for how exercise might protect against declines in pattern separation. Future research should explore exercise’s potential as a prevention tool or early intervention for pattern separation and related clinical outcomes.     

Brain insulin signaling: a key component of cognitive processes and a potential basis for cognitive impairment in type 2 diabetes

Understanding of the role of insulin in the brain has gradually expanded, from initial conceptions of the brain as insulin-insensitive through identification of a role in regulation of feeding, to recent demonstration of insulin as a key component of hippocampal memory processes. Conversely, systemic insulin resistance such as that seen in type 2 diabetes is associated with a range of cognitive and neural deficits. Here we review the evidence for insulin as a cognitive and neural modulator, including potential effector mechanisms, and examine the impact that type 2 diabetes has on these mechanisms in order to identify likely bases for the cognitive impairments seen in type 2 diabetic patients.     

Reprint of: 'Brain insulin signaling: A key component of cognitive processes and a potential basis for cognitive impairment in type 2 diabetes'

Understanding of the role of insulin in the brain has gradually expanded, from initial conceptions of the brain as insulin-insensitive through identification of a role in regulation of feeding, to recent demonstration of insulin as a key component of hippocampal memory processes. Conversely, systemic insulin resistance such as that seen in type 2 diabetes is associated with a range of cognitive and neural deficits. Here we review the evidence for insulin as a cognitive and neural modulator, including potential effector mechanisms, and examine the impact that type 2 diabetes has on these mechanisms in order to identify likely bases for the cognitive impairments seen in type 2 diabetic patients.     

运动习惯与社区老年人认知功能的关系

为评估社区老年人运动习惯与认知功能的关系,在北京市通过分层、方便取样的方法选取60岁以上的老年人732名,采用自编调查表收集一般人口学资料及运动习惯情况（包括有无运动习惯,运动频率,运动持续时间）,使用简明精神状态评估量表（MMSE）和北京版蒙特利尔认知评估量表（MoCA-BJ）评估认知功能。结果发现：（1）运动组整体认知功能及视空间定向能力得分均高于无运动组;（2）有无运动习惯可正向预测整体认知功能及视空间定向能力得分;（3）运动持续10年及以上组整体认知功能得分高于运动持续10年以下组。结果表明：相对于无运动习惯的社区老年人,有运动习惯的社区老年人的整体认知功能及视空间定向能力更好;运动持续年数较长,对社区老年人的认知功能起到促进作用。     

Insulin receptor signaling in long-term memory consolidation following spatial learning

Evidence has shown that the insulin and insulin receptor (IR) play a role in cognitive function. However, the detailed mechanisms underlying insulin's action on learning and memory are not yet understood. Here we investigated changes in long-term memory-associated expression of the IR and downstream molecules in the rat hippocampus. After long-term memory consolidation following a water maze learning experience, gene expression of IR showed an up-regulation in the CA1, but a down-regulation in the CA3 region. These were correlated with a significant reduction in hippocampal IR protein levels. Learning-specific increases in levels of downstream molecules such as IRS-1 and Akt were detected in the synaptic membrane accompanied by decreases in Akt phosphorylation. Translocation of Shc protein to the synaptic membrane and activation of Erk1/2 were also observed after long-term memory formation. Despite the clear memory-correlated alterations in IR signaling pathways, insulin deficits in experimental diabetes mellitus (DM) rats induced by intraperitoneal injections of streptozotocin resulted in only minor memory impairments. This may be due to higher glucose levels in the DM brain, and to compensatory mechanisms from other signaling pathways such as the insulin-like growth factor-1 receptor (IGF-1R) system. Our results suggest that insulin/IR signaling plays a modulatory role in learning and memory processing, which may be compensated for by alternative pathways in the brain when an insulin deficit occurs.     

Dispersion in models of categorical perception

A signal detection theory model of auditory discrimination with a nonlinear mapping from stimulus continuum to perceptual continuum can account for the enhanced discrimination at the category boundary found in categorical perception. Properties of this transformation are specified by a unimodal “dispersion function”. Furthermore, it is shown that a system consisting of two acoustic feature detectors with an associated decision function is also a dispersive system, which models categorical perception of a stimulus continuum as well as boundary shifts under adaptation. The effect of detector adaptation on discrimination is discussed in view of three different types of decision variable and different types of detector noise.     

The consciousness continuum: from “qualia” to “free will”

The consciousness continuum is seen as extending from simple sensory experiences to complex subjective constructions resulting in the apparent exercise of conscious will. The phenomena between these two extremes include spontaneously occurring mental contents, unintended perceptual experiences, memory retrievals, and problem solving including feedback of conscious contents. Two factors describe this continuum: The presence or absence of intention (psychologically defined) and the complexity of the cognitive construction involved. Among other benefits, such an analysis is intended to provide an alternative to metaphysical and vague concepts such as qualia, free will, and intentionality.     

Enhanced cognitive activity--over and above social or physical activity--is required to protect Alzheimer's mice against cognitive impairment, reduce Abeta deposition, and increase synaptic immunoreactivity

Although social, physical, and cognitive activities have each been suggested to reduce the risk of Alzheimer's disease (AD), epidemiologic studies cannot determine which activity or combination of activities is most important. To address this question, mutant APP transgenic AD mice were reared long-term in one of four housing conditions (impoverished, social, social+physical, or complete enrichment) from 1(1/2) through 9 months of age. Thus, a stepwise layering of social, physical, and enhanced cognitive activity was created. Behavioral evaluation in a full battery of sensorimotor, anxiety, and cognitive tasks was carried out during the final 5 weeks of housing. Only AD mice raised in complete enrichment (i.e., enhanced cognitive activity) showed: (1) protection against cognitive impairment, (2) decreased brain beta-amyloid deposition, and (3) increased hippocampal synaptic immunoreactivity. The protection provided by enhanced cognitive activity spanned multiple cognitive domains (working memory, reference learning, and recognition/identification). Cognitive and neurohistologic benefits of complete enrichment occurred without any changes in blood cytokine or corticosterone levels, suggesting that enrichment-dependent mechanisms do not involve changes in the inflammatory response or stress levels, respectively. These results indicate that the enhanced cognitive activity of complete enrichment is required for cognitive and neurologic benefit to AD mice-physical and/or social activity are insufficient. Thus, our data suggest that humans who emphasize a high lifelong level of cognitive activity (over and above social and physical activities) will attain the maximal environmental protection against AD.     

Le vieillissement cognitif et l’hypothèse de l’exercice mental révisée

Although intuitively plausible, the evidence relevant to the mental exercise hypothesis is currently mixed. One of the main controversial issues concerning the investigation of this hypothesis has to do with how cognitive stimulation is assessed. The mental exercise hypothesis was here tested with a subjective and self-reported measure of cognitive stimulation. Overall, results have supported that a greater engagement in cognitively stimulating activities was associated with higher levels of cognitive functioning. However, the rate of cognitive decline with advancing age was not reduced for people who were more mentally active. Of great interest, the subjective measure of cognitive engagement have supported that cognitive demands assessed by participants on activities varied as a function of participants’ cognitive resources: lower cognitive resources were associated with lower perceived cognitive demands.     

Estrogen and Neural Plasticity

Converging clinical evidence suggests that postmenopausal estrogen therapy in women is associated with improved cognition and a reduced incidence of Alzheimer's disease. In experimental work, investigators have found estrogen to promote changes in synaptic plasticity within the nervous system. In this article, we review both the clinical and the experimental literature, and consider mechanisms of action of estrogen on neurons and synaptic plasticity, and how they might protect against the cognitive impairments of old age.