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

Ceasing exercise induces depression-like, anxiety-like, and impaired cognitive-like behaviours and altered hippocampal gene expression.

Background: Regular exercise can reduce depression-, anxiety-, and impaired cognitive-like behaviours, and upregulate hippocampal genes associated with neuroplasticity. However, the effects of ceasing exercise on depression-, anxiety-, and cognitive-like behaviours, and hippocampal gene expression remain unknown. Methods: 12-week-old C57BL/6 mice (n = 12-16/group) were randomised to six months of exercise (exercise (EXC)), four months of exercise then two months of no exercise (exercise-cessation (EC)), or no-exercise control (CONT) until aged nine months. Depression-, anxiety-, and cognitive-like behaviours were tested with the forced swim test, open field and elevated zero maze, Y-maze, and Barnes maze. The expression of 75 hippocampal genes were investigated by high-throughput quantitative polymerase chain reaction (qPCR). Results: Exercise cessation increased depression- and anxiety-…

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Maternal insulin resistance multigenerationally impairs synaptic plasticity and memory via gametic mechanisms.

Metabolic diseases harm brain health and cognitive functions, but whether maternal metabolic unbalance may affect brain plasticity of next generations is still unclear. Here, we demonstrate that maternal high fat diet (HFD)-dependent insulin resistance multigenerationally impairs synaptic plasticity, learning and memory. HFD downregulates BDNF and insulin signaling in maternal tissues and epigenetically inhibits BDNF expression in both germline and hippocampus of progeny. Notably, exposure of the HFD offspring to novel enriched environment restores Bdnf epigenetic activation in the male germline and counteracts the transmission of cognitive impairment to the next generations. BDNF administration to HFD-fed mothers or preserved insulin sensitivity in HFD-fed p66Shc KO mice also prevents the intergenerational transmission of brain damage to the progeny. Collectively, our data suggest that …

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Social Isolation Stress Induces Anxious-Depressive-Like Behavior and Alterations of Neuroplasticity-Related Genes in Adult Male Mice.

Stress is a major risk factor in the onset of several neuropsychiatric disorders including anxiety and depression. Although several studies have shown that social isolation stress during postweaning period induces behavioral and brain molecular changes, the effects of social isolation on behavior during adulthood have been less characterized. Aim of this work was to investigate the relationship between the behavioral alterations and brain molecular changes induced by chronic social isolation stress in adult male mice. Plasma corticosterone levels and adrenal glands weight were also analyzed. Socially isolated (SI) mice showed higher locomotor activity, spent less time in the open field center, and displayed higher immobility time in the tail suspension test compared to group-housed (GH) mice. SI mice exhibited reduced plasma corticosterone levels and reduced difference between right and …

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Strain differences in stress responsivity are associated with divergent amygdala gene expression and glutamate-mediated neuronal excitability.

Stress is a major risk factor for numerous neuropsychiatric diseases. However, susceptibility to stress and the qualitative nature of stress effects on behavior differ markedly among individuals. This is partly because of the moderating influence of genetic factors. Inbred mouse strains provide a relatively stable and restricted range of genetic and environmental variability that is valuable for disentangling gene-stress interactions. Here, we screened a panel of inbred strains for anxiety- and depression-related phenotypes at baseline (trait) and after exposure to repeated restraint. Two strains, DBA/2J and C57BL/6J, differed in trait and restraint-induced anxiety-related behavior (dark/light exploration, elevated plus maze). Gene expression analysis of amygdala, medial prefrontal cortex, and hippocampus revealed divergent expression in DBA/2J and C57BL/6J both at baseline and after rep…

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Toll-like receptor 3 inhibits memory retention and constrains adult hippocampal neurogenesis.

Toll-like receptors (TLRs) are innate immune receptors that have recently emerged as regulators of neuronal survival and developmental neuroplasticity. Adult TLR3-deficient mice exhibited enhanced hippocampus-dependent working memory in the Morris water maze, novel object recognition, and contextual fear-conditioning tasks. In contrast, TLR3-deficient mice demonstrated impaired amygdala-related behavior and anxiety in the cued fear-conditioning, open field, and elevated plus maze tasks. Further, TLR3-deficient mice exhibited increased hippocampal CA1 and dentate gyrus volumes, increased hippocampal neurogenesis, and elevated levels of the AMPA receptor subunit GluR1 in the CA1 region of the hippocampus. In addition, levels of activated forms of the kinase ERK and the transcription factor CREB were elevated in the hippocampus of TLR3-deficient mice, suggesting that constitutive TLR3 signa…

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Towards an understanding of psychedelic-induced neuroplasticity.

Classic psychedelics, such as LSD, psilocybin, and the DMT-containing beverage ayahuasca, show some potential to treat depression, anxiety, and addiction. Importantly, clinical improvements can last for months or years after treatment. It has been theorized that these long-term improvements arise because psychedelics rapidly and lastingly stimulate neuroplasticity. The focus of this review is on answering specific questions about the effects of psychedelics on neuroplasticity. Firstly, we review the evidence that psychedelics promote neuroplasticity and examine the cellular and molecular mechanisms behind the effects of different psychedelics on different aspects of neuroplasticity, including dendritogenesis, synaptogenesis, neurogenesis, and expression of plasticity-related genes (e.g., brain-derived neurotrophic factor and immediate early genes). We then examine where in the brain psyc…

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Mechanisms of neuroplasticity linking early adversity to depression: developmental considerations.

Early exposure to psychosocial adversity is among the most potent predictors of depression. Because depression commonly emerges prior to adulthood, we must consider the fundamental principles of developmental neuroscience when examining how experiences of childhood adversity, including abuse and neglect, can lead to depression. Considering that both the environment and the brain are highly dynamic across the period spanning gestation through adolescence, the purpose of this review is to discuss and integrate stress-based models of depression that center developmental processes. We offer a general framework for understanding how psychosocial adversity in early life disrupts or calibrates the biobehavioral systems implicated in depression. Specifically, we propose that the sources and nature of the environmental input shaping the brain, and the mechanisms of neuroplasticity involved, chang…

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Neuroplasticity as a convergent mechanism of ketamine and classical psychedelics.

The emerging therapeutic efficacy of ketamine and classical psychedelics for depression has inspired tremendous interest in the underlying neurobiological mechanisms. We review preclinical and clinical evidence supporting neuroplasticity as a convergent downstream mechanism of action for these novel fast-acting antidepressants. Through their primary glutamate or serotonin receptor targets, ketamine and psychedelics [psilocybin, lysergic acid diethylamide (LSD), and N,N-dimethyltryptamine (DMT)] induce synaptic, structural, and functional changes, particularly in pyramidal neurons in the prefrontal cortex. These include increased glutamate release, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) activation, brain-derived neurotrophic factor (BDNF) and mammalian target of rapamycin (mTOR)-mediated signaling, expression of synaptic proteins, and synaptogenesis. Such in…

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Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms.

Mounting evidence suggests safety and efficacy of psychedelic compounds as potential novel therapeutics in psychiatry. Ketamine has been approved by the Food and Drug Administration in a new class of antidepressants, and 3,4-methylenedioxymethamphetamine (MDMA) is undergoing phase III clinical trials for post-traumatic stress disorder. Psilocybin and lysergic acid diethylamide (LSD) are being investigated in several phase II and phase I clinical trials. Hence, the concept of psychedelics as therapeutics may be incorporated into modern society. Here, we discuss the main known neurobiological therapeutic mechanisms of psychedelics, which are thought to be mediated by the effects of these compounds on the serotonergic (via 5-HT2A and 5-HT1A receptors) and glutamatergic [via N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors] systems. We foc…

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Dopamine: The Neuromodulator of Long-Term Synaptic Plasticity, Reward and Movement Control.

Dopamine (DA) is a key neurotransmitter involved in multiple physiological functions including motor control, modulation of affective and emotional states, reward mechanisms, reinforcement of behavior, and selected higher cognitive functions. Dysfunction in dopaminergic transmission is recognized as a core alteration in several devastating neurological and psychiatric disorders, including Parkinson's disease (PD), schizophrenia, bipolar disorder, attention deficit hyperactivity disorder (ADHD) and addiction. Here we will discuss the current insights on the role of DA in motor control and reward learning mechanisms and its involvement in the modulation of synaptic dynamics through different pathways. In particular, we will consider the role of DA as neuromodulator of two forms of synaptic plasticity, known as long-term potentiation (LTP) and long-term depression (LTD) in several cortical …

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Revisiting the Stress Concept: Implications for Affective Disorders.

Over the last 50 years, the concept of stress has evolved significantly, and our understanding of the underlying neurobiology has expanded dramatically. Rather than consider stress biology to be relevant only under unusual and threatening conditions, we conceive of it as an ongoing, adaptive process of assessing the environment, coping with it, and enabling the individual to anticipate and deal with future challenges. Though much remains to be discovered, the fundamental neurocircuitry that underlies these processes has been broadly delineated, key molecular players have been identified, and the impact of this system on neuroplasticity has been well established. More recently, we have come to appreciate the critical interaction between the brain and the rest of the body as it pertains to stress responsiveness. Importantly, this system can become overloaded due to ongoing environmental de…

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The translational landscape in spinal cord injury: focus on neuroplasticity and regeneration.

Over the past decade, we have witnessed a flourishing of novel strategies to enhance neuroplasticity and promote axon regeneration following spinal cord injury, and results from preclinical studies suggest that some of these strategies have the potential for clinical translation. Spinal cord injury leads to the disruption of neural circuitry and connectivity, resulting in permanent neurological disability. Recovery of function relies on augmenting neuroplasticity to potentiate sprouting and regeneration of spared and injured axons, to increase the strength of residual connections and to promote the formation of new connections and circuits. Neuroplasticity can be fostered by exploiting four main biological properties: neuronal intrinsic signalling, the neuronal extrinsic environment, the capacity to reconnect the severed spinal cord via neural stem cell grafts, and modulation of neuronal…

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Spinal cord repair: advances in biology and technology.

Individuals with spinal cord injury (SCI) can face decades with permanent disabilities. Advances in clinical management have decreased morbidity and improved outcomes, but no randomized clinical trial has demonstrated the efficacy of a repair strategy for improving recovery from SCI. Here, we summarize recent advances in biological and engineering strategies to augment neuroplasticity and/or functional recovery in animal models of SCI that are pushing toward clinical translation.

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Astrocyte function from information processing to cognition and cognitive impairment.

Astrocytes serve important roles that affect recruitment and function of neurons at the local and network levels. Here we review the contributions of astrocyte signaling to synaptic plasticity, neuronal network oscillations, and memory function. The roles played by astrocytes are not fully understood, but astrocytes seem to contribute to memory consolidation and seem to mediate the effects of vigilance and arousal on memory performance. Understanding the role of astrocytes in cognitive processes may also advance our understanding of how these processes go awry in pathological conditions. Indeed, abnormal astrocytic signaling can cause or contribute to synaptic and network imbalances, leading to cognitive impairment. We discuss evidence for this from animal models of Alzheimer's disease and multiple sclerosis and from animal studies of sleep deprivation and drug abuse and addiction. Under…

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Intermittent metabolic switching, neuroplasticity and brain health.

During evolution, individuals whose brains and bodies functioned well in a fasted state were successful in acquiring food, enabling their survival and reproduction. With fasting and extended exercise, liver glycogen stores are depleted and ketones are produced from adipose-cell-derived fatty acids. This metabolic switch in cellular fuel source is accompanied by cellular and molecular adaptations of neural networks in the brain that enhance their functionality and bolster their resistance to stress, injury and disease. Here, we consider how intermittent metabolic switching, repeating cycles of a metabolic challenge that induces ketosis (fasting and/or exercise) followed by a recovery period (eating, resting and sleeping), may optimize brain function and resilience throughout the lifespan, with a focus on the neuronal circuits involved in cognition and mood. Such metabolic switching impact…

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The balance of sleep: Role of the vestibular sensory system.

The vestibular system encodes linear and angular head motion supporting numerous functions from gaze stabilization and postural control, to high-level cortical functions involving spatial cognition, including self-body perception, verticality perception, orientation, navigation and spatial memory. At the brainstem and mesencephalic levels, the vestibular organs also influence postural blood pressure regulation, bone density and muscle composition via specific vestibulo-sympathetic efferences and have been shown to act as a powerful synchronizer of circadian rhythms. Here, we review the evidence that sleep deprivation and sleep apnea syndrome alter vestibular-related oculo-motor and postural control, and that, in turn, vestibular pathologies induce sleep disturbances. We suggest that sleep-related neuroplasticity might serve the adaptation and compensation processes following vestibular l…

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Closed-loop brain training: the science of neurofeedback.

Neurofeedback is a psychophysiological procedure in which online feedback of neural activation is provided to the participant for the purpose of self-regulation. Learning control over specific neural substrates has been shown to change specific behaviours. As a progenitor of brain-machine interfaces, neurofeedback has provided a novel way to investigate brain function and neuroplasticity. In this Review, we examine the mechanisms underlying neurofeedback, which have started to be uncovered. We also discuss how neurofeedback is being used in novel experimental and clinical paradigms from a multidisciplinary perspective, encompassing neuroscientific, neuroengineering and learning-science viewpoints.

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Biomarkers of Suicide Attempt Behavior: Towards a Biological Model of Risk.

Purpose of review: The rising suicide rate in the USA will not be reversed without improved risk assessment and prevention practices. To date, the best method for clinicians to assess a patient's risk for suicide is screening for past suicide attempts in the patient and their family. However, neuroimaging, genomic, and biochemical studies have generated a body of findings that allow description of an initial heuristic biological model for suicidal behavior that may have predictive value. Recent findings: We review studies from the past 3 years examining potential biological predictors of suicide attempt behavior. We divide findings into two major categories: (1) structural and functional brain imaging findings and (2) biochemical and genomic findings encompassing several systems, including major neurotransmitters (serotonin, catecholamines, GABA, and glutamate), the hypothalamic pituitar…

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Rehabilitating the addicted brain with transcranial magnetic stimulation.

Substance use disorders (SUDs) are one of the leading causes of morbidity and mortality worldwide. In spite of considerable advances in understanding the neural underpinnings of SUDs, therapeutic options remain limited. Recent studies have highlighted the potential of transcranial magnetic stimulation (TMS) as an innovative, safe and cost-effective treatment for some SUDs. Repetitive TMS (rTMS) influences neural activity in the short and long term by mechanisms involving neuroplasticity both locally, under the stimulating coil, and at the network level, throughout the brain. The long-term neurophysiological changes induced by rTMS have the potential to affect behaviours relating to drug craving, intake and relapse. Here, we review TMS mechanisms and evidence that rTMS is opening new avenues in addiction treatments.

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Early Rehabilitation After Stroke: a Narrative Review.

Purpose of review: Despite current rehabilitative strategies, stroke remains a leading cause of disability in the USA. There is a window of enhanced neuroplasticity early after stroke, during which the brain's dynamic response to injury is heightened and rehabilitation might be particularly effective. This review summarizes the evidence of the existence of this plastic window, and the evidence regarding safety and efficacy of early rehabilitative strategies for several stroke domain-specific deficits. Recent findings: Overall, trials of rehabilitation in the first 2 weeks after stroke are scarce. In the realm of very early mobilization, one large and one small trial found potential harm from mobilizing patients within the first 24 h after stroke, and only one small trial found benefit in doing so. For the upper extremity, constraint-induced movement therapy appears to have benefit when s…

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Long-term effects of exercise and physical therapy in people with Parkinson disease.

Parkinson disease (PD) is a progressive, neurodegenerative movement disorder with symptoms reflecting various impairments and functional limitations, such as postural instability, gait disturbance, immobility and falls. In addition to pharmacological and surgical management of PD, exercise and physical therapy interventions are also being actively researched. This Review provides an overview of the effects of PD on physical activity - including muscle weakness, reduced aerobic capacity, gait impairment, balance disorders and falls. Previously published reviews have discussed only the short-term benefits of exercises and physical therapy for people with PD. However, owing to the progressive nature of PD, the present Review focuses on the long-term effects of such interventions. We also discuss exercise-induced neuroplasticity, present data on the possible risks and adverse effects of exer…

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Central Nervous System Adaptation After Ligamentous Injury: a Summary of Theories, Evidence, and Clinical Interpretation.

The array of dysfunction occurring after ligamentous injury is tied to long-term clinical impairments in functional performance, joint stability, and health-related quality of life. To appropriately treat individuals, and in an attempt to avoid sequelae such as post-traumatic osteoarthritis, investigators have sought to better establish the etiology of the persistent dysfunction present in patients who have sustained joint ligament injuries to the lower extremities. Recent evidence has suggested that changes within the brain and central nervous system may underlie these functional deficits, with support arising from direct neurophysiologic measures of somatosensory dysfunction, motor system excitability, and plasticity of neural networks. As research begins to utilize these findings to develop targeted interventions to enhance patient outcomes, it is crucial for sports medicine professio…

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The Link between Depression and Chronic Pain: Neural Mechanisms in the Brain.

Chronic pain, as a stress state, is one of the critical factors for determining depression, and their coexistence tends to further aggravate the severity of both disorders. Unfortunately, their association remains unclear, which creates a bottleneck problem for managing chronic pain-induced depression. In recent years, studies have found considerable overlaps between pain- and depression-induced neuroplasticity changes and neurobiological mechanism changes. Such overlaps are vital to facilitating the occurrence and development of chronic pain and chronic pain-induced depression. In this review, we summarized the role of neuroplasticity in the occurrence and development of the two disorders in question and explored individualized application strategies of analgesic drugs and antidepressants that have different pharmacological effects in the treatment of chronic pain-induced depression. Th…

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Lifestyle Modulators of Neuroplasticity: How Physical Activity, Mental Engagement, and Diet Promote Cognitive Health during Aging.

The number of the elderly across the globe will approximate 2.1 billion by 2050. Juxtaposed against this burgeoning segment of the population is evidence that nonpathological aging is associated with an increased risk for cognitive decline in a variety of domains, changes that can cause mild disability even before the onset of dementia. Given that pharmacological treatments that mitigate dementia are still outstanding, alternative therapeutic options are being investigated increasingly. The results from translational studies have shown that modifiable lifestyle factors-including physical activity, cognitive engagement, and diet-are a key strategy for maintaining brain health during aging. Indeed, a multiplicity of studies has demonstrated relationships between lifestyle factors, brain structure and function, and cognitive function in aging adults. For example, physical activity and diet …

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Genomic and epigenomic mechanisms of glucocorticoids in the brain.

Following the discovery of glucocorticoid receptors in the hippocampus and other brain regions, research has focused on understanding the effects of glucocorticoids in the brain and their role in regulating emotion and cognition. Glucocorticoids are essential for adaptation to stressors (allostasis) and in maladaptation resulting from allostatic load and overload. Allostatic overload, which can occur during chronic stress, can reshape the hypothalamic-pituitary-adrenal axis through epigenetic modification of genes in the hippocampus, hypothalamus and other stress-responsive brain regions. Glucocorticoids exert their effects on the brain through genomic mechanisms that involve both glucocorticoid receptors and mineralocorticoid receptors directly binding to DNA, as well as by non-genomic mechanisms. Furthermore, glucocorticoids synergize both genomically and non-genomically with neurotran…

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