Neuroplasticity and brain change

The hippocampus, neurotrophic factors and depression: possible implications for the pharmacotherapy of depression.: Depression is a prevalent, highly debilitating mental disorder affecting up to 15% of the population at least once in their lifetime, with huge costs for society. Neurobiological mechanisms of depression are still not well known, although there is consensus about interplay between genetic and environmental factors. Antidepressant medications are frequently used in depression, but at least 50% of patients are poor responders, even to more recently discovered medications. Furthermore, clinical res

Orexins/hypocretins control bistability of hippocampal long-term synaptic plasticity through co-activation of multiple kinases.: Aim: Orexins/hypocretins (OX/Hcrt) are hypothalamic neuropeptides linking sleep-wakefulness, appetite and neuroendocrine control. Their role and mechanisms of action on higher brain functions, such as learning and memory, are not clear. Methods: We used field recordings of excitatory post-synaptic potentials (fEPSP) in acute mouse brain slice preparations to study the effects of orexins and pharmacological inhibitors of multiple kinases on long-term synaptic plasticity in the hippocampus. Result

Exergaming and older adult cognition: a cluster randomized clinical trial.: Background: Dementia cases may reach 100 million by 2050. Interventions are sought to curb or prevent cognitive decline. Exercise yields cognitive benefits, but few older adults exercise. Virtual reality-enhanced exercise or "exergames" may elicit greater participation. Purpose: To test the following hypotheses: (1) stationary cycling with virtual reality tours ("cybercycle") will enhance executive function and clinical status more than traditional exercise; (2) exercise effort will explain impr

Serotonin affects transcranial direct current-induced neuroplasticity in humans.: Background: Modulation of the serotonergic system affects long-term potentiation (LTP) and long-term depression (LTD), the likely neurophysiologic derivates of learning and memory formation, in animals and slice preparations. Serotonin-dependent modulation of plasticity has been proposed as an underlying mechanism for depression. However, direct knowledge about the impact of serotonin on neuroplasticity in humans is missing. Here we explore the impact of the serotonin reuptake blocker citalopram

A systematic review and meta-analysis of clinical studies on major depression and BDNF levels: implications for the role of neuroplasticity in depression.: Several clinical studies on major depressive disorder (MDD) have shown that blood brain-derived neurotrophic factor (BDNF) - a factor used to index neuroplasticity - is associated with depression response; however, the results are mixed. The purpose of our study was to evaluate whether BDNF levels are correlated with improvement of depression. We performed a systematic review and meta-analysis of the literature, searching Medline, Cochrane Central, SciELO databases and reference lists from retri

Neuroplasticity - exercise-induced response of peripheral brain-derived neurotrophic factor: a systematic review of experimental studies in human subjects.: Exercise is known to induce a cascade of molecular and cellular processes that support brain plasticity. Brain-derived neurotrophic factor (BDNF) is an essential neurotrophin that is also intimately connected with central and peripheral molecular processes of energy metabolism and homeostasis, and could play a crucial role in these induced mechanisms. This review provides an overview of the current knowledge on the effects of acute exercise and/or training on BDNF in healthy subjects and in pers

Does puberty mark a transition in sensitive periods for plasticity in the associative neocortex?

Postnatal brain development is studded with sensitive periods during which experience dependent plasticity is enhanced. This enables rapid learning from environmental inputs and reorganization of cortical circuits that matches behavior with environmental contingencies. Significant headway has been achieved in characterizing and understanding sensitive period biology in primary sensory cortices, but relatively little is known about sensitive period biology in associative neocortex. One possible mediator is the onset of puberty, which marks the transition to adolescence, when animals shift their behavior toward gaining independence and exploring their social world. Puberty onset correlates with reduced behavioral plasticity in some domains and enhanced plasticity in others, and therefore may drive the transition from juvenile to adolescent brain function. Pubertal onset is also occurring e…

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Principles of plasticity in the developing brain.

The developing brain is especially sensitive to a wide range of experiences, showing a remarkable capacity for plastic changes that influence behavioural outcomes throughout the lifetime. We review the principles that regulate this plasticity in development and consider the factors that modulate the developing brain. These include early sensory, motor, and language experience, early stress, caregiver interactions, peer interactions, psychoactive drugs, diet, microbiome, and the immune system. Emphasis is given to changes in behaviour, epigenetics, and neuronal morphology. What this paper adds: A discussion of the surprising range of factors influencing brain development Life experiences interact resulting in a phenomenon called metaplasticity.

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Dopamine reward prediction error coding.

Reward prediction errors consist of the differences between received and predicted rewards. They are crucial for basic forms of learning about rewards and make us strive for more rewards-an evolutionary beneficial trait. Most dopamine neurons in the midbrain of humans, monkeys, and rodents signal a reward prediction error; they are activated by more reward than predicted (positive prediction error), remain at baseline activity for fully predicted rewards, and show depressed activity with less reward than predicted (negative prediction error). The dopamine signal increases nonlinearly with reward value and codes formal economic utility. Drugs of addiction generate, hijack, and amplify the dopamine reward signal and induce exaggerated, uncontrolled dopamine effects on neuronal plasticity. The striatum, amygdala, and frontal cortex also show reward prediction error coding, but only in subpo…

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The Neuro-Environmental Loop of Plasticity: A Cross-Species Analysis of Parental Effects on Emotion Circuitry Development Following Typical and Adverse Caregiving.

Early experiences critically shape the structure and function of the brain. Perturbations in typical/species-expected early experiences are known to have profound neural effects, especially in regions important for emotional responding. Parental care is one species-expected stimulus that plays a fundamental role in the development of emotion neurocircuitry. Emerging evidence across species suggests that phasic variation in parental presence during the sensitive period of childhood affects the recruitment of emotional networks on a moment-to-moment basis. In addition, it appears that increasing independence from caregivers cues the termination of the sensitive period for environmental input into emotion network development. In this review, we examine how early parental care, the central nervous system, and behavior come together to form a 'neuro-environmental loop,' contributing to the fo…

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The over-pruning hypothesis of autism.

This article outlines the over-pruning hypothesis of autism. The hypothesis originates in a neurocomputational model of the regressive sub-type (Thomas, Knowland & Karmiloff-Smith, 2011a, 2011b). Here we develop a more general version of the over-pruning hypothesis to address heterogeneity in the timing of manifestation of ASD, including new computer simulations which reconcile the different observed developmental trajectories (early onset, late onset, regression) via a single underlying atypical mechanism; and which show how unaffected siblings of individuals with ASD may differ from controls either by inheriting a milder version of the pathological mechanism or by co-inheriting the risk factors without the pathological mechanism. The proposed atypical mechanism involves overly aggressive synaptic pruning in infancy and early childhood, an exaggeration of a normal phase of brain develop…

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Major depressive disorder.

Major depressive disorder (MDD) is a debilitating disease that is characterized by depressed mood, diminished interests, impaired cognitive function and vegetative symptoms, such as disturbed sleep or appetite. MDD occurs about twice as often in women than it does in men and affects one in six adults in their lifetime. The aetiology of MDD is multifactorial and its heritability is estimated to be approximately 35%. In addition, environmental factors, such as sexual, physical or emotional abuse during childhood, are strongly associated with the risk of developing MDD. No established mechanism can explain all aspects of the disease. However, MDD is associated with alterations in regional brain volumes, particularly the hippocampus, and with functional changes in brain circuits, such as the cognitive control network and the affective-salience network. Furthermore, disturbances in the main n…

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Mechanisms of stress in the brain.

The brain is the central organ involved in perceiving and adapting to social and physical stressors via multiple interacting mediators, from the cell surface to the cytoskeleton to epigenetic regulation and nongenomic mechanisms. A key result of stress is structural remodeling of neural architecture, which may be a sign of successful adaptation, whereas persistence of these changes when stress ends indicates failed resilience. Excitatory amino acids and glucocorticoids have key roles in these processes, along with a growing list of extra- and intracellular mediators that includes endocannabinoids and brain-derived neurotrophic factor (BDNF). The result is a continually changing pattern of gene expression mediated by epigenetic mechanisms involving histone modifications and CpG methylation and hydroxymethylation as well as by the activity of retrotransposons that may alter genomic stabili…

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Role of social factors on cell death, cerebral plasticity and recovery after stroke.

Stroke is a serious global health care problem. It is now is the fourth leading cause of death and the primary cause of adult disability in the United States. Substantial evidence from both experimental and clinical studies has demonstrated that social isolation (SI) can increase stroke incidence and impair recovery. Epidemiological studies demonstrate that an increasing number of patients are living alone, and as the aging population increases, loneliness will only increase in prevalence. SI is increasingly identified as an independent risk factor for all-cause mortality. In contrast, individuals with high levels of social support exhibit more rapid and extensive functional and cognitive recovery after a wide variety of pathological insults, including stroke. Clinical data suggests that SI is an important risk factor for increased mortality and delayed functional recovery following isch…

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Neuroimmune mechanisms of stress: sex differences, developmental plasticity, and implications for pharmacotherapy of stress-related disease.

The last decade has witnessed profound growth in studies examining the role of fundamental neuroimmune processes as key mechanisms that might form a natural bridge between normal physiology and pathological outcomes. Rooted in core concepts from psychoneuroimmunology, this review utilizes a succinct, exemplar-driven approach of several model systems that contribute significantly to our knowledge of the mechanisms by which neuroimmune processes interact with stress physiology. Specifically, we review recent evidence showing that (i) stress challenges produce time-dependent and stressor-specific patterns of cytokine/chemokine expression in the CNS; (ii) inflammation-related genes exhibit unique expression profiles in males and females depending upon individual, cooperative or antagonistic interactions between steroid hormone receptors (estrogen and glucocorticoid receptors); (iii) adverse …

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Neurobiological mechanisms underlying relapse to cocaine use: contributions of CRF and noradrenergic systems and regulation by glucocorticoids.

Considering its pervasive and uncontrollable influence in drug addicts, understanding the neurobiological processes through which stress contributes to drug use is a critical goal for addiction researchers and will likely be important for the development of effective medications aimed at relapse prevention. In this paper, we review work from our laboratory and others focused on determining the neurobiological mechanisms that underlie and contribute to stress-induced relapse of cocaine use with an emphasis on the actions of corticotropin-releasing factor in the ventral tegmental area (VTA) and a key pathway from the bed nucleus of the stria terminalis to the VTA that is regulated by norepinephrine and beta adrenergic receptors. Additionally, we discuss work suggesting that the influence of stress in cocaine addiction changes and intensifies with repeated cocaine use in an intake-dependent…

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Examining neural plasticity and cognitive benefit through the unique lens of musical training.

Training programs aimed to alleviate or improve auditory-cognitive abilities have either experienced mixed success or remain to be fully validated. The limited benefits of such regimens are largely attributable to our weak understanding of (i) how (and which) interventions provide the most robust and long lasting improvements to cognitive and perceptual abilities and (ii) how the neural mechanisms which underlie such abilities are positively modified by certain activities and experience. Recent studies indicate that music training provides robust, long-lasting biological benefits to auditory function. Importantly, the behavioral advantages conferred by musical experience extend beyond simple enhancements to perceptual abilities and even impact non-auditory functions necessary for higher-order aspects of cognition (e.g., working memory, intelligence). Collectively, preliminary findings in…

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Toward a biosignature for suicide.

Objective: Suicide, a major cause of death worldwide, has distinct biological underpinnings. The authors review and synthesize the research literature on biomarkers of suicide, with the aim of using the findings of these studies to develop a coherent model for the biological diathesis for suicide. Method: The authors examined studies covering a large range of neurobiological systems implicated in suicide. They provide succinct descriptions of each system to provide a context for interpreting the meaning of findings in suicide. Results: Several lines of evidence implicate dysregulation in stress response systems, especially the hypothalamic-pituitary-adrenal axis, as a diathesis for suicide. Additional findings related to neuroinflammatory indices, glutamatergic function, and neuronal plasticity at the cellular and circuitry level may reflect downstream effects of such dysregulation. Whet…

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Environmental enrichment and brain repair: harnessing the therapeutic effects of cognitive stimulation and physical activity to enhance experience-dependent plasticity.

Environmental enrichment (EE) increases levels of novelty and complexity, inducing enhanced sensory, cognitive and motor stimulation. In wild-type rodents, EE has been found to have a range of effects, such as enhancing experience-dependent cellular plasticity and cognitive performance, relative to standard-housed controls. Whilst environmental enrichment is of course a relative term, dependent on the nature of control environmental conditions, epidemiological studies suggest that EE has direct clinical relevance to a range of neurological and psychiatric disorders. EE has been demonstrated to induce beneficial effects in animal models of a wide variety of brain disorders. The first evidence of beneficial effects of EE in a genetically targeted animal model was generated using Huntington's disease transgenic mice. Subsequent studies found that EE was also therapeutic in mouse models of A…

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Targeting plasticity with vagus nerve stimulation to treat neurological disease.

Pathological neural activity in a variety of neurological disorders could be treated by directing plasticity to specifically renormalize aberrant neural circuits, thereby restoring normal function. Brief bursts of acetylcholine and norepinephrine can enhance the neural plasticity associated with coincident events. Vagus nerve stimulation (VNS) represents a safe and effective means to trigger the release of these neuromodulators with a high degree of temporal control. VNS-event pairing can generate highly specific and long-lasting plasticity in sensory and motor cortex. Based on the capacity to drive specific changes in neural circuitry, VNS paired with experience has been successful in effectively ameliorating animal models of chronic tinnitus, stroke, and posttraumatic stress disorder. Targeted plasticity therapy utilizing VNS is currently being translated to humans to treat chronic tin…

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About sleep's role in memory.

Over more than a century of research has established the fact that sleep benefits the retention of memory. In this review we aim to comprehensively cover the field of "sleep and memory" research by providing a historical perspective on concepts and a discussion of more recent key findings. Whereas initial theories posed a passive role for sleep enhancing memories by protecting them from interfering stimuli, current theories highlight an active role for sleep in which memories undergo a process of system consolidation during sleep. Whereas older research concentrated on the role of rapid-eye-movement (REM) sleep, recent work has revealed the importance of slow-wave sleep (SWS) for memory consolidation and also enlightened some of the underlying electrophysiological, neurochemical, and genetic mechanisms, as well as developmental aspects in these processes. Specifically, newer findings cha…

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Brain development during adolescence: neuroscientific insights into this developmental period.

Background: Adolescence is the phase of life between late childhood and adulthood. Typically, adolescents seek diversion, new experiences, and strong emotions, sometimes putting their health at serious risk. In Germany, for example, 62% of all deaths among persons aged 15 to 20 are due to traumatic injuries. Neuroscientific explanations have been proposed for typical adolescent behavior; with these explanations in mind, one can derive appropriate ways of dealing with adolescents. Method: We selectively review pertinent articles retrieved from the PubMed database about the structural and functional development of the brain in adolescence. Results: New findings in developmental psychology and neuroscience reveal that a fundamental reorganization of the brain takes place in adolescence. In postnatal brain development, the maximum density of gray matter is reached first in the primary sensor…

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Mediators of allostasis and systemic toxicity in bipolar disorder.

Bipolar disorder is associated with a high rate of medical and psychiatric comorbidities. This burden of illness, along with cognitive impairment, is seen particularly in late cases, after multiple episodes. These changes in clinical presentation that take place over time have been recently conceptualized as "neuroprogression". The concept of allostatic load is instrumental in understanding how the cumulative stress associated with psychiatric disorders translates into bodily wear and tear, thus providing an underlying explanation for illness progression. Allostatic load is engendered by several factors which interact in a nonlinear manner. Glucocorticoids are fundamental mediators; when chronically in excess, glucocorticoids initiate a series of bodily dysfunctions that may include cortisol-related mitochondrial dysfunction, oxidative stress, inflammation and decrease in the expression …

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Cognitive training for impaired neural systems in neuropsychiatric illness.

Neuropsychiatric illnesses are associated with dysfunction in distributed prefrontal neural systems that underlie perception, cognition, social interactions, emotion regulation, and motivation. The high degree of learning-dependent plasticity in these networks-combined with the availability of advanced computerized technology-suggests that we should be able to engineer very specific training programs that drive meaningful and enduring improvements in impaired neural systems relevant to neuropsychiatric illness. However, cognitive training approaches for mental and addictive disorders must take into account possible inherent limitations in the underlying brain 'learning machinery' due to pathophysiology, must grapple with the presence of complex overlearned maladaptive patterns of neural functioning, and must find a way to ally with developmental and psychosocial factors that influence re…

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System consolidation of memory during sleep.

Over the past two decades, research has accumulated compelling evidence that sleep supports the formation of long-term memory. The standard two-stage memory model that has been originally elaborated for declarative memory assumes that new memories are transiently encoded into a temporary store (represented by the hippocampus in the declarative memory system) before they are gradually transferred into a long-term store (mainly represented by the neocortex), or are forgotten. Based on this model, we propose that sleep, as an offline mode of brain processing, serves the 'active system consolidation' of memory, i.e. the process in which newly encoded memory representations become redistributed to other neuron networks serving as long-term store. System consolidation takes place during slow-wave sleep (SWS) rather than rapid eye movement (REM) sleep. The concept of active system consolidation…

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Memory maintenance by PKMζ--an evolutionary perspective.

Long-term memory is believed to be maintained by persistent modifications of synaptic transmission within the neural circuits that mediate behavior. Thus, long-term potentiation (LTP) is widely studied as a potential physiological basis for the persistent enhancement of synaptic strength that might sustain memory. Whereas the molecular mechanisms that initially induce LTP have been extensively characterized, the mechanisms that persistently maintain the potentiation have not. Recently, however, a candidate molecular mechanism linking the maintenance of LTP and the storage of long-term memory has been identified. The persistent activity of the autonomously active, atypical protein kinase C (aPKC) isoform, PKMζ, is both necessary and sufficient for maintaining LTP. Furthermore, blocking PKMζ activity by pharmacological or dominant negative inhibitors disrupts previously stored long-term me…

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Neuronal effects following working memory training.

There is accumulating evidence that training working memory (WM) leads to beneficial effects in tasks that were not trained, but the mechanisms underlying this transfer remain elusive. Brain imaging can be a valuable method to gain insights into such mechanisms. Here, we discuss the impact of cognitive training on neural correlates with an emphasis on studies that implemented a WM intervention. We focus on changes in activation patterns, changes in resting state connectivity, changes in brain structure, and changes in the dopaminergic system. Our analysis of the existing literature reveals that there is currently no clear pattern of results that would single out a specific neural mechanism underlying training and transfer. We conclude that although brain imaging has provided us with information about the mechanisms of WM training, more research is needed to understand its neural impact.

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Plasticity of the human auditory cortex related to musical training.

During the last decades music neuroscience has become a rapidly growing field within the area of neuroscience. Music is particularly well suited for studying neuronal plasticity in the human brain because musical training is more complex and multimodal than most other daily life activities, and because prospective and professional musicians usually pursue the training with high and long-lasting commitment. Therefore, music has increasingly been used as a tool for the investigation of human cognition and its underlying brain mechanisms. Music relates to many brain functions like perception, action, cognition, emotion, learning and memory and therefore music is an ideal tool to investigate how the human brain is working and how different brain functions interact. Novel findings have been obtained in the field of induced cortical plasticity by musical training. The positive effects, which m…

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Combination strategies for repair, plasticity, and regeneration using regulation of gene expression during the chronic phase after spinal cord injury.

Although recovery after spinal cord injury (SCI) is rare in humans, recent literature indicates that some patients do recover sensorimotor function years after the trauma. This study seeks to elucidate the genetic underpinnings of SCI repair through the investigation of neurodegenerative and regenerative associated genes involved in the response to SCI during the chronic phase in adult rats. Intervention on the level of gene regulation focused on enhancing naturally attempting SCI regenerative genes has the potential to promote SCI repair. Our aim was to analyze gene expression characteristics of candidate genes involved in the neuro-degenerative and -regenerative processes following various animal models of SCI. We compiled data showing gene expression changes after SCI in adult rats and created a chronological time-line of candidate genes differentially expressed during the chronic pha…

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Development of anxiety: the role of threat appraisal and fear learning.

Anxious individuals exhibit threat biases at multiple levels of information processing. From a developmental perspective, abnormal safety learning in childhood may establish threat-related appraisal biases early, which may contribute to chronic disorders in adulthood. This review illustrates how the interface among attention, threat appraisal, and fear learning can generate novel insights for outcome prediction. This review summarizes data on amygdala function, as it relates to learning and attention, highlights the importance of examining threat appraisal, and introduces a novel imaging paradigm to investigate the neural correlates of threat appraisal and threat-sensitivity during extinction recall. This novel paradigm can be used to investigate key questions relevant to prognosis and treatment. Depression and Anxiety, 2011.© 2010 Wiley-Liss, Inc.

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Stress- and allostasis-induced brain plasticity.

The brain is the key organ of stress processes. It determines what individuals will experience as stressful, it orchestrates how individuals will cope with stressful experiences, and it changes both functionally and structurally as a result of stressful experiences. Within the brain, a distributed, dynamic, and plastic neural circuitry coordinates, monitors, and calibrates behavioral and physiological stress response systems to meet the demands imposed by particular stressors. These allodynamic processes can be adaptive in the short term (allostasis) and maladaptive in the long term (allostatic load). Critically, these processes involve bidirectional signaling between the brain and body. Consequently, allostasis and allostatic load can jointly affect vulnerability to brain-dependent and stress-related mental and physical health conditions. This review focuses on the role of brain plastic…

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