Sources and targets of reactive oxygen species in synaptic plasticity and memory

Increasing evidence suggests that reactive oxygen species (ROS), such as superoxide and hydrogen peroxide, act as necessary signaling molecules in processes underlying cognition. Moreover, ROS have been shown to be necessary in molecular process underlying signal transduction, synaptic plasticity, and memory formation. Research from several laboratories suggests that NADPH oxidase is an important source of superoxide in the brain. Evidence is presented here to show that ROS are in fact important signaling molecules involved in synaptic plasticity and memory formation. Moreover, evidence that the NADPH oxidase complex is a key regulator of ROS generation in synaptic plasticity and memory formation is discussed. Understanding redox signaling in the brain, including the sources and molecular targets of ROS, are important for a full understanding of the signaling pathways that underlie synaptic plasticity and memory. Knowledge of ROS function in the brain also is critical for understanding aging and neurodegenerative diseases of the brain given that several of these disorders, including Alzheimer's disease and Parkinson disease, may be exacerbated by the unregulated generation of ROS.     

Docosahexaenoic acid dietary supplementation enhances the effects of exercise on synaptic plasticity and cognition

Omega-3 fatty acids (i.e. docosahexaenoic acid; DHA), similar to exercise, improve cognitive function, promote neuroplasticity, and protect against neurological lesion. In this study, we investigated a possible synergistic action between DHA dietary supplementation and voluntary exercise on modulating synaptic plasticity and cognition. Rats received DHA dietary supplementation (1.25% DHA) with or without voluntary exercise for 12 days. We found that the DHA-enriched diet significantly increased spatial learning ability, and these effects were enhanced by exercise. The DHA-enriched diet increased levels of pro-brain-derived neurotrophic factor (BDNF) and mature BDNF, whereas the additional application of exercise boosted the levels of both. Furthermore, the levels of the activated forms of CREB and synapsin I were incremented by the DHA-enriched diet with greater elevation by the concurrent application of exercise. While the DHA diet reduced hippocampal oxidized protein levels, a combination of a DHA diet and exercise resulted in a greater reduction rate. The levels of activated forms of hippocampal Akt and CaMKII were increased by the DHA-enriched diet, and with even greater elevation by a combination of diet and exercise. Akt and CaMKII signaling are crucial step by which BDNF exerts its action on synaptic plasticity and learning and memory. These results indicate that the DHA diet enhanced the effects of exercise on cognition and BDNF-related synaptic plasticity, a capacity that may be used to promote mental health and reduce risk of neurological disorders.     

Cognitive reserve and the neurobiology of cognitive aging

A hypothetical construct of "cognitive reserve" is widely used to explain how, in the face of neurodegenerative changes that are similar in nature and extent, individuals vary considerably in the severity of cognitive aging and clinical dementia. Intelligence, education and occupational level are believed to be major active components of cognitive reserve. Here, we summarize the main features of cognitive aging and their neuropathological correlates. We describe the neurobiology of cognitive aging and conclude that perturbations of neural health attributable to oxidative stress and inflammatory processes alone are insufficient to distinguish cognitive aging from Alzheimer's disease. We introduce the concept of cognitive reserve and illustrate its utility in explaining individual differences in cognitive aging. Structural and functional brain imaging studies suggest plausible neural substrates of cognitive reserve, probably involving processes that support neuroplasticity in the aging brain. The cognitive reserve hypothesis conforms with reported associations between early and mid life lifestyle choices, early education, lifelong dietary habit, leisure pursuits and the retention of late life mental ability.     

Non-coding RNA regulation of synaptic plasticity and memory: Implications for aging

Advancing age is associated with the loss of cognitive ability and vulnerability to debilitating mental diseases. Although much is known about the development of cognitive processes in the brain, the study of the molecular mechanisms governing memory decline with aging is still in its infancy. Recently, it has become apparent that most of the human genome is transcribed into non-coding RNAs (ncRNAs) rather than protein-coding mRNAs. Multiple types of ncRNAs are enriched in the central nervous system, and this large group of molecules may regulate the molecular complexity of the brain, its neurons, and synapses. Here, we review the current knowledge on the role of ncRNAs in synaptic plasticity, learning, and memory in the broader context of the aging brain and associated memory loss. We also discuss future directions to study the role of ncRNAs in the aging process.     

Neurotrophic regulation of the development and function of the neuromuscular synapses

Recent studies have established that one of the major functions of neurotrophic factors is to regulate synaptic development and plasticity. This owes a great deal to the studies using the neuromuscular junction (NMJ) as a model system. In this review, we summarize the effects of various neurotrophic factors on the development and function of the neuromuscular synapses. We describe experiments addressing the role of neurotrophins, as well as that of other factors (GFLs, TGF-betas, and Wnts). The synaptic effects of neurotrophic factors are divided into two categories: acute effects on synaptic transmission and plasticity occurring within seconds or minutes after cells are exposed to a particular factor, and long-term regulation of synaptic structure and function that takes days to accomplish. We consider the presynaptic effects on the release of the neurotransmitter ACh, as well as the postsynaptic effects on the clustering of ACh receptors. Further studies of the mechanisms underlying these regulatory effects will help us better understand how neurotrophic factors can achieve diverse and synapse-specific modulation in the brain.     

Repeated stress and structural plasticity in the brain

Although adrenal steroid receptors are distributed widely throughout the central nervous system, specific limbic and cortical regions targeted by stress hormones play a key role in integrating behavioral and physiological responses during stress and adaptation to subsequent stressors. When the stressor is of a sufficient magnitude or prolonged, it may result in abnormal changes in brain plasticity that, paradoxically, may impair the ability of the brain to appropriately regulate and respond to subsequent stressors. Here we review how repeated stress produces alterations in brain plasticity in animal models, and discuss its relevance to behavioral changes associated with these regions. Interestingly, prolonged stress produces opposing effects on structural plasticity, notably dendritic atrophy and excitatory synapse loss in the hippocampus and prefrontal cortex, and growth of dendrites and spines in the amygdala. The granule cells of the dentate gyrus are also significantly affected through a decrease in the rate neurogenesis following prolonged stress. How functional impairments in these brain regions play a role in stress-related mental illnesses is discussed in this context. Finally, we discuss the cumulative impact of stress-induced structural plasticity in aging.     

A ketogenic diet reduces long-term potentiation in the dentate gyrus of freely behaving rats

Ketogenic diets are very low in carbohydrates and can reduce epileptic seizures significantly. This dietary therapy is particularly effective in pediatric and drug-resistant epilepsy. Hypothesized anticonvulsant mechanisms of ketogenic diets focus on increased inhibition and/or decreased excitability/excitation. Either of these consequences might not only reduce seizures, but also could affect normal brain function and synaptic plasticity. Here, we characterized effects of a ketogenic diet on hippocampal long-term potentiation, a widely studied form of synaptic plasticity. Adult male rats were placed on a control or ketogenic diet for 3 wk before recording. To maintain the most physiological conditions possible, we assessed synaptic transmission and plasticity using chronic in vivo recordings in freely behaving animals. Rats underwent stereotaxic surgery to chronically implant a recording electrode in the hippocampal dentate gyrus and a stimulating electrode in the perforant path; they recovered for 1 wk. After habituation and stable baseline recording, 5-Hz theta-burst stimulation was delivered to induce long-term potentiation. All animals showed successful plasticity, demonstrating that potentiation was not blocked by the ketogenic diet. Compared with rats fed a control diet, rats fed a ketogenic diet demonstrated significantly diminished long-term potentiation. This decreased potentiation lasted for at least 48 h. Reduced potentiation in ketogenic diet-fed rats is consistent with a general increase in neuronal inhibition (or decrease in excitability) and decreased seizure susceptibility. A better understanding of the effects of ketogenic diets on synaptic plasticity and learning is important, as diet-based therapy is often prescribed to children with epilepsy.     

Clinical neurophysiology of aging brain: from normal aging to neurodegeneration

Physiological brain aging is characterized by a loss of synaptic contacts and neuronal apoptosis that provokes age-dependant decline of sensory processing, motor performance, and cognitive function. Neural redundancy and plastic remodelling of brain networking, also secondary to mental and physical training, promotes maintenance of brain activity in healthy elderly for everyday life and fully productive affective and intellectual capabilities. However, age is the main risk factor for neurodegenerative disorders such as Alzheimer's disease (AD) that impact on cognition. Oscillatory electromagnetic brain activity is a hallmark of neuronal network function in various brain regions. Modern neurophysiological techniques including electroencephalography (EEG), event-related potential (ERP), magnetoencephalography (MEG), and transcranial magnetic stimulation (TMS) can accurately index normal and abnormal brain aging to facilitate non-invasive analysis of cortico–cortical connectivity and neuronal synchronization of firing and coherence of rhythmic oscillations at various frequencies. The present review provides a perspective of these issues by assaying different neurophysiological methods and integrating the results with functional brain imaging findings. It is concluded that discrimination between physiological and pathological brain aging clearly emerges at the group level, with applications at the individual level also suggested. Integrated approaches utilizing neurophysiological techniques together with biological markers and structural and functional imaging are promising for large-scale, low-cost and non-invasive evaluation of at-risk populations. Practical implications of the methods are emphasized.     

Synaptic plasticity in early aging

Studies of how aging affects brain plasticity have largely focused on old animals. However, deterioration of memory begins well in advance of old age in animals, including humans; the present review is concerned with the possibility that changes in synaptic plasticity, as found in the long-term potentiation (LTP) effect, are responsible for this. Recent results indicate that impairments to LTP are in fact present by early middle age in rats but only in certain dendritic domains. The search for the origins of these early aging effects necessarily involves ongoing analyses of how LTP is induced, expressed, and stabilized. Such work points to the conclusion that cellular mechanisms responsible for LTP are redundant and modulated both positively and negatively by factors released during induction of potentiation. Tests for causes of the localized failure of LTP during early aging suggest that the problem lies in excessive activity of a negative modulator. The view of LTP as having redundant and modulated substrates also suggests a number of approaches for reversing age-related losses. Particular attention will be given to the idea that induction of brain-derived neurotrophic factor, an extremely potent positive modulator, can be used to provide long periods of normal plasticity with very brief pharmacological interventions. The review concludes with a consideration of how the selective, regional deficits in LTP found in early middle age might be related to the global phenomenon of brain aging.     

Clinical neurophysiology of aging brain: From normal aging to neurodegeneration

Physiological brain aging is characterized by a loss of synaptic contacts and neuronal apoptosis that provokes age-dependant decline of sensory processing, motor performance, and cognitive function. Neural redundancy and plastic remodelling of brain networking, also secondary to mental and physical training, promotes maintenance of brain activity in healthy elderly for everyday life and fully productive affective and intellectual capabilities. However, age is the main risk factor for neurodegenerative disorders such as Alzheimer's disease (AD) that impact on cognition. Oscillatory electromagnetic brain activity is a hallmark of neuronal network function in various brain regions. Modern neurophysiological techniques including electroencephalography (EEG), event-related potential (ERP), magnetoencephalography (MEG), and transcranial magnetic stimulation (TMS) can accurately index normal and abnormal brain aging to facilitate non-invasive analysis of cortico–cortical connectivity and neuronal synchronization of firing and coherence of rhythmic oscillations at various frequencies. The present review provides a perspective of these issues by assaying different neurophysiological methods and integrating the results with functional brain imaging findings. It is concluded that discrimination between physiological and pathological brain aging clearly emerges at the group level, with applications at the individual level also suggested. Integrated approaches utilizing neurophysiological techniques together with biological markers and structural and functional imaging are promising for large-scale, low-cost and non-invasive evaluation of at-risk populations. Practical implications of the methods are emphasized.     

Opposing effects of positive and negative stress on hippocampal plasticity over the lifespan

Early developmental experience shapes neuronal circuits and influences the trajectory of cognitive aging. Just as adversity early in life can accelerate age-related synaptic impairments, enhancement of neuronal metabolism and function in the developing brain could potentially protect neurons against the synaptic consequences of aging. In this regard, metabolic enhancements following exercise directly oppose the deleterious consequences of adverse stress. In this review, we examine the relationship between exercise and other forms of stress over the lifespan. Exercise is a specialized form of stress in that it is predictable and voluntary, while other forms of psychological and physiological stress are unpredictable and uncontrollable, with distinct consequences for behavior and synaptic plasticity. Themes emerging from the literature surrounding the opposing effects of adversity and exercise include epigenetic mechanisms that converge on the regulation of neurotrophic factor expression and neurogenesis. These data suggest that exercise-induced neuroprotection and neuronal endangerment following adversity may both be transferable across generations, in a manner that has the potential to impact neuroplasticity over the lifespan.     

Caloric restriction prevents aging-associated changes in spike-mediated Ca2+ accumulation and the slow afterhyperpolarization in hippocampal CA1 pyramidal neurons

In hippocampal pyramidal neurons from aged animals voltage-gated Ca2+ entry and the slow, post-burst afterhyperpolarization are enhanced. As a result, there is a decrease in neuronal excitability and, in turn, an alteration in synaptic plasticity. Restricting the caloric intake of a rodent is a well-known paradigm for increasing lifespan and ameliorating a number of neurodegenerative features of aging, including deficits in synaptic plasticity and cognition. Here we show in rat CA1 pyramidal neurons from aged animals (18-20 months old) that a restricted diet prevents the enhancement of dendritic spike-mediated Ca2+ accumulation. In contrast, no significant changes in the rates of Ca2+ recovery were observed suggesting that Ca2+ clearance mechanisms are not affected by aging or caloric restriction. Lastly, we found that caloric restriction also prevented the aging-associated increase in the slow, post-burst afterhyperpolarization. Our results suggest that caloric restriction-sensitive changes in Ca2+ accumulation and membrane excitability may in part account for the protective effects of dietary restriction on synaptic plasticity and learning deficits in aged animals.     

Deregulated mitochondrial microRNAs in Alzheimer's disease: Focus on synapse and mitochondria

Alzheimer’s disease (AD) is the most common cause of dementia and is currently one of the biggest public health concerns in the world. Mitochondrial dysfunction in neurons is one of the major hallmarks of AD. Emerging evidence suggests that mitochondrial miRNAs potentially play important roles in the mitochondrial dysfunctions, focusing on synapse in AD progression. In this meta-analysis paper, a comprehensive literature review was conducted to identify and discuss the (1) role of mitochondrial miRNAs that regulate mitochondrial and synaptic functions; (2) the role of various factors such as mitochondrial dynamics, biogenesis, calcium signaling, biological sex, and aging on synapse and mitochondrial function; (3) how synapse damage and mitochondrial dysfunctions contribute to AD; (4) the structure and function of synapse and mitochondria in the disease process; (5) latest research developments in synapse and mitochondria in healthy and disease states; and (6) therapeutic strategies that improve synaptic and mitochondrial functions in AD. Specifically, we discussed how differences in the expression of mitochondrial miRNAs affect ATP production, oxidative stress, mitophagy, bioenergetics, mitochondrial dynamics, synaptic activity, synaptic plasticity, neurotransmission, and synaptotoxicity in neurons observed during AD. However, more research is needed to confirm the locations and roles of individual mitochondrial miRNAs in the development of AD.     

‘Tagging’ along memories in aging: Synaptic tagging and capture mechanisms in the aged hippocampus

Aging is accompanied by a general decline in the physiological functions of the body with the deteriorating organ systems. Brain is no exception to this and deficits in cognitive functions are quite common in advanced aging. Though a variety of age-related alterations are observed in the structure and function throughout the brain, certain regions show selective vulnerability. Medial temporal lobe, especially the hippocampus, is one such preferentially vulnerable region and is a crucial structure involved in the learning and long-term memory functions. Hippocampal synaptic plasticity, such as long-term potentiation (LTP) and depression (LTD), are candidate cellular correlates of learning and memory and alterations in these properties have been well documented in aging. A related phenomenon called synaptic tagging and capture (STC) has been proposed as a mechanism for cellular memory consolidation and to account for temporal association of memories. Mounting evidences from behavioral settings suggest that STC could be a physiological phenomenon. In this article, we review the recent data concerning STC and provide a framework for how alterations in STC-related mechanisms could contribute to the age-associated memory impairments. The enormity of impairment in learning and memory functions demands an understanding of age-associated memory deficits at the fundamental level given its impact in the everyday tasks, thereby in the quality of life. Such an understanding is also crucial for designing interventions and preventive measures for successful brain aging.     

Reelin signaling in development,maintenance, and plasticity of neural networks

The developing brain is formed through an orchestrated pattern of neuronal migration, leading to the formation of heterogeneous functional regions in the adult. Several proteins and pathways have been identified as mediators of developmental neuronal migration and cell positioning. However, these pathways do not cease to be functionally relevant after the embryonic and early postnatal period; instead, they switch from guiding cells, to guiding synapses. The outcome of synaptic guidance determines the strength and plasticity of neuronal networks by creating a scalable functional architecture that is sculpted by cues from the internal and external environment. Reelin is a multifunctional signal that coordinates cortical and subcortical morphogenesis during development and regulates structural plasticity in adulthood and aging. Gain or loss of function in reelin or its receptors has the potential to influence synaptic strength and patterns of connectivity, with consequences for memory and cognition. The current review highlights similarities in the signaling cascades that modulate neuronal positioning during development, and synaptic plasticity in the adult, with a focus on reelin, a glycoprotein that is increasingly recognized for its dual role in the formation and maintenance of neural circuits.     

Modifiable lifestyle factors and cognitive reserve: A systematic review of current evidence

This systematic review aims to summarize cognitive reserve (CR) evaluation approaches and to examine the role of seven selected modifiable lifestyle factors (diet, smoking, alcohol consumption, physical activity, cognitive leisure activity, sleep, and meditation) in mitigating the impacts of age- or disease-related brain changes on cognition. Eighteen population-based English empirical studies were included. We summarize the study designs and identify three CR models that were broadly used in these studies, including a residual model assessing lifestyle factors in relation to unexplained variance in cognition after accounting for brain markers, a moderation model testing whether lifestyle factors moderate the relationship between brain status and cognition, and a controlling model examining the associations between lifestyle factors and cognition when controlling for brain measures. We also present the findings for the impact of each lifestyle factor. No studies examined diet, sleep, or meditation, and only two studies focused on smoking and alcohol consumption each. Overall, the studies suggest lifestyle activity factors (physical and cognitive leisure activities) may contribute to CR and attenuate the damaging impact of brain changes on cognition. Standardized measurements of lifestyle factors and CR are needed, and mechanisms underlying CR need to be further addressed as well.     

Aging, stress and the hippocampus

Functional loss often occurs in many body systems (e.g., endocrine, cognitive, motor) with the passage of years, but there is great individual variation in the degree of compromise shown. The current focus on brain aging will continue because demographic trends indicate that the average lifespan will show a continued increase. There is increasing emphasis on understanding how aging contributes to a decline in brain functions, cognition being a prime example. This is due in part to the fact that dementias and other losses in brain function that sometimes accompany aging cause an obvious decline in the quality of life and these deficits are of more concern as the number of elderly increase. Stress also is a ubiquitous aspect of life and there is now a greater interest in understanding the role of stress and the stress response in brain aging. The key role of the hippocampus and its related brain structures in cognition, as well as in the feedback control of the response to stress, have made this brain area a logical focus of investigation for those interested in the impact of stress on brain aging. Here, we describe how the hippocampus changes with age and we examine the idea that age-related changes in the secretion patterns of the hypothalamic-pituitary adrenal (HPA) axis can contribute to aging of this structure. We also examine the proposal that stress, perhaps due to compromised HPA axis function, can contribute to hippocampal aging through exposure to excessive levels of glucocorticoids. The aging hippocampus does not appear to suffer a generalized loss of cells or synapses, although atrophy of the structure may occur in humans. Thus, age-related cognitive impairments are likely related to other neurobiological alterations that could include changes in the signaling, information encoding, plasticity, electrophysiological or neurochemical properties of neurons or glia. Although excessive levels of glucocorticoids are able to interfere with cognition, as well as hippocampal neuronal integrity, and aging is sometimes accompanied by an increase in these steroids because of inadequate feedback control of the HPA axis, none of these are a foregone consequence of aging. The general preservation of cells and the plastic potential of the hippocampus provide a focus for the development of pharmacological, nutritive or lifestyle strategies to combat age-related declines in the hippocampus as well as other brain areas.