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251 to 275 of 677Stress, serotonin, and hippocampal neurogenesis in relation to depression and antidepressant effects.
Chronic stressful life events are risk factors for developing major depression, the pathophysiology of which is strongly linked to impairments in serotonin (5-HT) neurotransmission. Exposure to chronic unpredictable stress (CUS) has been found to induce depressive-like behaviours, including passive behavioural coping and anhedonia in animal models, along with many other affective, cognitive, and behavioural symptoms. The heterogeneity of these symptoms represents the plurality of corticolimbic structures involved in mood regulation that are adversely affected in the disorder. Chronic stress has also been shown to negatively regulate adult hippocampal neurogenesis, a phenomenon that is involved in antidepressant effects and regulates subsequent stress responses. Although there exists an enormous body of data on stress-induced alterations of 5-HT activity, there has not been extensive expl…
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Training your brain: Do mental and physical (MAP) training enhance cognition through the process of neurogenesis in the hippocampus?
New neurons are produced each day in the hippocampus through the process of neurogenesis. Both mental and physical training can modify this process by increasing the number of new cells that mature into functional neurons in the adult brain. However, the mechanisms whereby these increases occur are not necessarily the same. Physical activity, especially aerobic exercise greatly increases the number of new neurons that are produced in the hippocampal formation. In contrast, mental training via skill learning increases the numbers that survive, particularly when the training goals are challenging. Both manipulations can increase cognitive performance in the future, some of which are reportedly mediated by the presence of new neurons in the adult hippocampus. Based on these data, we suggest that a combination of mental and physical training, referred to here as MAP training, is more benefic…
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Neurogenesis and generalization: a new approach to stratify and treat anxiety disorders.
Although an influence of adult neurogenesis in mediating some of the effects of antidepressants has received considerable attention in recent years, much less is known about how alterations in this form of plasticity may contribute to psychiatric disorders such as anxiety and depression. One way to begin to address this question is to link the functions of adult-born hippocampal neurons with specific endophenotypes of these disorders. Recent studies have implicated adult-born hippocampal neurons in pattern separation, a process by which similar experiences or events are transformed into discrete, non-overlapping representations. Here we propose that impaired pattern separation underlies the overgeneralization often seen in anxiety disorders, specifically post-traumatic stress disorder and panic disorder, and therefore represents an endophenotype for these disorders. The development of ne…
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The neurogenesis hypothesis of affective and anxiety disorders: are we mistaking the scaffolding for the building?
Hypotheses are scaffoldings erected in front of a building and then dismantled when the building is finished. They are indispensable for the workman; but you mustn't mistake the scaffolding for the building. Johann Wolfgang von Goethe. The neurogenesis hypothesis of affective disorders - in its simplest form - postulates that the generation of neurons in the postnatal hippocampal dentate gyrus is involved in the etiology and treatment efficacy of major depressive disorder (MDD). The hypothesis was established in the 1990s but was built on a broad foundation of earlier research on the hippocampus, serotonin and MDD. It has gone through several growth phases fueled by discoveries both correlative and causative in nature. Recently, the hypothesis has also been broadened to also include potential relevance for anxiety disorders, like post-traumatic stress disorder (PTSD). As any hypothesis s…
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The role of dietary polyphenols on adult hippocampal neurogenesis: molecular mechanisms and behavioural effects on depression and anxiety.
Although it has been long believed that new neurons were only generated during development, there is now growing evidence indicating that at least two regions in the brain are capable of continuously generating functional neurons: the subventricular zone and the dentate gyrus of the hippocampus. Adult hippocampal neurogenesis (AHN) is a widely observed phenomenon verified in different adult mammalian species including humans. Factors such as environmental enrichment, voluntary exercise, and diet have been linked to increased levels of AHN. Conversely, aging, stress, anxiety and depression have been suggested to hinder it. However, the mechanisms underlying these effects are still unclear and yet to be determined. In this paper, we discuss some recent findings addressing the effects of different dietary polyphenols on hippocampal cell proliferation and differentiation, models of anxiety, …
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Regulation of adult neurogenesis by stress, sleep disruption, exercise and inflammation: Implications for depression and antidepressant action.
Adult hippocampal neurogenesis, a once unorthodox concept, has changed into one of the most rapidly growing fields in neuroscience. The present report results from the ECNP targeted expert meeting in 2007 during which cellular plasticity changes were addressed in the adult brain, focusing on neurogenesis and apoptosis in hippocampus and frontal cortex. We discuss recent studies investigating factors that regulate neurogenesis with special emphasis on effects of stress, sleep disruption, exercise and inflammation, a group of seemingly unrelated factors that share at least two unifying properties, namely that they all regulate adult hippocampal neurogenesis and have all been implicated in the pathophysiology of mood disorders. We conclude that although neurogenesis has been implicated in cognitive function and is stimulated by antidepressant drugs, its functional impact and contribution to…
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Moliner R, Girych M, Brunello CA, Kovaleva V, Biojone C, Enkavi G, Antenucci L, Kot EF, Goncharuk SA, Kaurinkoski K, Kuutti M, Fred SM, Elsilä LV, Sakson S, Cannarozzo C, Diniz CRAF, Seiffert N, Rubiolo A, Haapaniemi H, Meshi E, Nagaeva E, Öhman T, Róg T, Kankuri E, Vilar M, Varjosalo M, Korpi ER, Permi P, Mineev KS, Saarma M, Vattulainen I, Casarotto PC, Castrén E (2023)MEDLINE-indexed journal, not yet read by usNature neuroscience382 citations Psychedelics promote plasticity by directly binding to BDNF receptor TrkB.
Psychedelics produce fast and persistent antidepressant effects and induce neuroplasticity resembling the effects of clinically approved antidepressants. We recently reported that pharmacologically diverse antidepressants, including fluoxetine and ketamine, act by binding to TrkB, the receptor for BDNF. Here we show that lysergic acid diethylamide (LSD) and psilocin directly bind to TrkB with affinities 1,000-fold higher than those for other antidepressants, and that psychedelics and antidepressants bind to distinct but partially overlapping sites within the transmembrane domain of TrkB dimers. The effects of psychedelics on neurotrophic signaling, plasticity and antidepressant-like behavior in mice depend on TrkB binding and promotion of endogenous BDNF signaling but are independent of serotonin 2A receptor (5-HT2A) activation, whereas LSD-induced head twitching is dependent on 5-HT2A a…
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Sleep-dependent upscaled excitability, saturated neuroplasticity, and modulated cognition in the human brain.
Sleep strongly affects synaptic strength, making it critical for cognition, especially learning and memory formation. Whether and how sleep deprivation modulates human brain physiology and cognition is not well understood. Here we examined how overnight sleep deprivation vs overnight sufficient sleep affects (a) cortical excitability, measured by transcranial magnetic stimulation, (b) inducibility of long-term potentiation (LTP)- and long-term depression (LTD)-like plasticity via transcranial direct current stimulation (tDCS), and (c) learning, memory, and attention. The results suggest that sleep deprivation upscales cortical excitability due to enhanced glutamate-related cortical facilitation and decreases and/or reverses GABAergic cortical inhibition. Furthermore, tDCS-induced LTP-like plasticity (anodal) abolishes while the inhibitory LTD-like plasticity (cathodal) converts to excita…
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Dance training is superior to repetitive physical exercise in inducing brain plasticity in the elderly.
Animal research indicates that a combination of physical activity and sensory enrichment has the largest and the only sustaining effect on adult neuroplasticity. Dancing has been suggested as a human homologue to this combined intervention as it poses demands on both physical and cognitive functions. For the present exploratory study, we designed an especially challenging dance program in which our elderly participants constantly had to learn novel and increasingly difficult choreographies. This six-month-long program was compared to conventional fitness training matched for intensity. An extensive pre/post-assessment was performed on the 38 participants (63-80 y), covering general cognition, attention, memory, postural and cardio-respiratory performance, neurotrophic factors and-most crucially-structural MRI using an exploratory analysis. For analysis of MRI data, a new method of voxel-…
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MicroRNA cluster miR-17-92 Cluster in Exosomes Enhance Neuroplasticity and Functional Recovery After Stroke in Rats.
Background and purpose: Multipotent mesenchymal stromal cell (MSC) harvested exosomes are hypothesized as the major paracrine effectors of MSCs. In vitro, the miR-17-92 cluster promotes oligodendrogenesis, neurogenesis, and axonal outgrowth. We, therefore, investigated whether the miR-17-92 cluster-enriched exosomes harvested from MSCs transfected with an miR-17-92 cluster plasmid enhance neurological recovery compared with control MSC-derived exosomes.
Methods: Rats subjected to 2 hours of transient middle cerebral artery occlusion were intravenously administered miR-17-92 cluster-enriched exosomes, control MSC exosomes, or liposomes and were euthanized 28 days post-middle cerebral artery occlusion. Histochemistry, immunohistochemistry, and Golgi-Cox staining were used to assess dendritic, axonal, synaptic, and myelin remodeling. Expression of phosphatase and tensin homolog and activati…
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Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants.
Depression is a common, devastating illness. Current pharmacotherapies help many patients, but high rates of a partial response or no response, and the delayed onset of the effects of antidepressant therapies, leave many patients inadequately treated. However, new insights into the neurobiology of stress and human mood disorders have shed light on mechanisms underlying the vulnerability of individuals to depression and have pointed to novel antidepressants. Environmental events and other risk factors contribute to depression through converging molecular and cellular mechanisms that disrupt neuronal function and morphology, resulting in dysfunction of the circuitry that is essential for mood regulation and cognitive function. Although current antidepressants, such as serotonin-reuptake inhibitors, produce subtle changes that take effect in weeks or months, it has recently been shown that …
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Reversal of the Detrimental Effects of Post-Stroke Social Isolation by Pair-Housing is Mediated by Activation of BDNF-MAPK/ERK in Aged Mice.
Social isolation (SI) increases stroke-related mortality and morbidity in clinical populations. The detrimental effects of SI have been successfully modeled in the laboratory using young animals. Mechanistically, the negative effects of SI in young animals are primarily mediated by an enhanced inflammatory response to injury and a reduction in neurotrophic factors. However, the response to brain injury differs considerably in the aged. Given that SI is more prevalent in aged populations, we hypothesized that isolation, even when initiated after stroke, would delay recovery in aged mice. We found that aged isolated male mice had significantly increased infarct volume, neurological deficits, and serum IL-6 levels three days after stroke compared to pair housed (PH) mice. Using RT(2) Profiler PCR Array and real-time quantitative PCR we found several important synaptic plasticity genes were …
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Probiotic gut effect prevents the chronic psychological stress-induced brain activity abnormality in mice.
Background: A probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 combination, Probio'Stick(®) ) displays anxiolytic-like activity and reduces apoptosis in the lymbic system in animal models of depression. Based on the hypothesis that modulation of gut microbiota by this probiotic formulation has beneficial effects on brain activity in stress conditions, we report a set of probiotic-evoked physiological, cellular, and molecular events in the brain of Probio'Stick(®) pretreated mice submitted to chronic psychological stress.
Methods: Water avoidance stress (WAS) was applied or not (sham). Hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS) responses to the chronic stress were assessed through plasma corticosterone and catecholamine measurements. Specific markers for neuronal activity, neurogenesis, and synaptic plasticity were us…
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Altered dendritic spine plasticity in cocaine-withdrawn rats.
Chronic cocaine treatment is associated with changes in dendritic spines in the nucleus accumbens, but it is unknown whether this neuroplasticity alters the effect of a subsequent cocaine injection on spine morphology and protein content. Three weeks after daily cocaine or saline administration, neurons in the accumbens were filled with the lipophilic dye, DiI. Although daily cocaine pretreatment did not alter spine density compared with daily saline, there was a shift from smaller to larger diameter spines. During the first 2 h after an acute cocaine challenge, a bidirectional change in spine head diameter and increase in spine density was measured in daily cocaine-pretreated animals. In contrast, no change in spine diameter or density was elicited by a cocaine challenge in daily saline animals during the first 2 h after injection. However, spine density was elevated at 6 h after a coca…
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Chronic stress increases pituitary adenylate cyclase-activating peptide (PACAP) and brain-derived neurotrophic factor (BDNF) mRNA expression in the bed nucleus of the stria terminalis (BNST): roles for PACAP in anxiety-like behavior.
Exposure to chronic stress has been argued to produce maladaptive anxiety-like behavioral states, and many of the brain regions associated with stressor responding also mediate anxiety-like behavior. Pituitary adenylate cyclase activating polypeptide (PACAP) and its specific G protein-coupled PAC(1) receptor have been associated with many of these stress- and anxiety-associated brain regions, and signaling via this peptidergic system may facilitate the neuroplasticity associated with pathological affective states. Here we investigated whether chronic stress increased transcript expression for PACAP, PAC(1) receptor, brain-derived neurotrophic factor (BDNF), and tyrosine receptor kinase B (TrkB) in several nuclei. In rats exposed to a 7 days chronic variate stress paradigm, chronic stress enhanced baseline startle responding induced by handling and exposure to bright lights. Following chr…
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Motor cortex plasticity induced by paired associative stimulation is enhanced in physically active individuals.
Recent evidence indicates that regular physical activity enhances brain plasticity (i.e. the ability to reorganise neural connections) and improves neurocognitive function. However, the effect of regular physical activity on human motor cortex function is unknown. The purpose of this study was to examine motor cortex plasticity for a small hand muscle in highly active and sedentary individuals. Electromyographic recordings were obtained from the left abductor pollicis brevis (APB) muscle of 14 active and 14 sedentary subjects (aged 18-38 yrs). The extent of physical activity was assessed by questionnaire, where the physically active subjects performed >150 min per day moderate-to-vigorous aerobic activity on at least 5 days per week, whereas the sedentary group performed <20 min per day of physical activity on no more than 3 days per week. Transcranial magnetic stimulation (TMS) of the r…
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Dose-dependent inverted U-shaped effect of dopamine (D2-like) receptor activation on focal and nonfocal plasticity in humans.
The neuromodulator dopamine (DA) has multiple modes of action on neuroplasticity induction and modulation, depending on subreceptor specificity, concentration level, and the kind of stimulation-induced plasticity. To determine the dosage-dependent effects of D(2)-like receptor activation on nonfocal and focal neuroplasticity in the human motor cortex, different doses of ropinirole (0.125, 0.25, 0.5, and 1.0 mg), a D(2)/D(3) dopamine agonist, or placebo medication were combined with anodal and cathodal transcranial direct current stimulation (tDCS) protocols, which induce nonfocal plasticity, or paired associative stimulation (PAS, ISI of 10 or 25 ms), which generates focal plasticity, in healthy volunteers. D(2)-like receptor activation produced an inverted "U"-shaped dose-response curve on plasticity for facilitatory tDCS and PAS and for inhibitory tDCS. Here, high or low dosages of rop…
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Cognitive neuroscience of sleep.
Mechanism is at the heart of understanding, and this chapter addresses underlying brain mechanisms and pathways of cognition and the impact of sleep on these processes, especially those serving learning and memory. This chapter reviews the current understanding of the relationship between sleep/waking states and cognition from the perspective afforded by basic neurophysiological investigations. The extensive overlap between sleep mechanisms and the neurophysiology of learning and memory processes provide a foundation for theories of a functional link between the sleep and learning systems. Each of the sleep states, with its attendant alterations in neurophysiology, is associated with facilitation of important functional learning and memory processes. For rapid eye movement (REM) sleep, salient features such as PGO waves, theta synchrony, increased acetylcholine, reduced levels of monoami…
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REM sleep selectively prunes and maintains new synapses in development and learning.
The functions and underlying mechanisms of rapid eye movement (REM) sleep remain unclear. Here we show that REM sleep prunes newly formed postsynaptic dendritic spines of layer 5 pyramidal neurons in the mouse motor cortex during development and motor learning. This REM sleep-dependent elimination of new spines facilitates subsequent spine formation during development and when a new motor task is learned, indicating a role for REM sleep in pruning to balance the number of new spines formed over time. Moreover, REM sleep also strengthens and maintains newly formed spines, which are critical for neuronal circuit development and behavioral improvement after learning. We further show that dendritic calcium spikes arising during REM sleep are important for pruning and strengthening new spines. Together, these findings indicate that REM sleep has multifaceted functions in brain development, le…
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Chronic vagus nerve stimulation induces neuronal plasticity in the rat hippocampus.
Vagus nerve stimulation (VNS) is used to treat pharmacotherapy-resistant epilepsy and depression. However, the mechanisms underlying the therapeutic efficacy of VNS remain unclear. We examined the effects of VNS on hippocampal neuronal plasticity and behaviour in rats. Cell proliferation in the hippocampus of rats subjected to acute (3 h) or chronic (1 month) VNS was examined by injection of bromodeoxyuridine (BrdU) and immunohistochemistry. Expression of doublecortin (DCX) and brain-derived neurotrophic factor (BDNF) was evaluated by immunofluorescence staining. The dendritic morphology of DCX+ neurons was measured by Sholl analysis. Our results show that acute VNS induced an increase in the number of BrdU+ cells in the dentate gyrus that was apparent 24 h and 3 wk after treatment. It also induced long-lasting increases in the amount of DCX immunoreactivity and in the number of DCX+ neu…
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Sleep and homeostatic control of plasticity.
Sleep homeostasis is a complex neurobiologic phenomenon involving a number of molecular pathways, neurotransmitter release, synaptic activity, and factors modulating neural networks. Sleep plasticity allows for homeostatic optimization of neural networks and the replay-based consolidation of specific circuits, especially important for cognition, behavior, and information processing. Furthermore, research is currently moving from an essentially brain-focused to a more comprehensive view involving other systems, such as the immune system, hormonal status, and metabolic pathways. When dysfunctional, these systems contribute to sleep loss and fragmentation as well as to sleep need. In this chapter, the implications of neural plasticity and sleep homeostasis for the diagnosis and treatment of some major sleep disorders, such as insomnia and sleep deprivation, obstructive sleep apnea syndrome,…
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Inflammation in psychiatric disorders: what comes first?
Neuropsychiatric disorders (i.e., mood disorders and schizophrenia) and inflammation are closely intertwined, and possibly powering each other in a bidirectional loop. Depression facilitates inflammatory reactions and inflammation promotes depression and other neuropsychiatric disorders. Patients with neuropsychiatric disorders exhibit all cardinal features of inflammation, including increased circulating levels of inflammatory inducers, activated sensors, and inflammatory mediators targeting all tissues. Inflammation may contribute to the pathophysiology and clinical progression of these disorders. Of note, proinflammatory cytokines modulate mood behavior and cognition by reducing brain monoamine levels, activating neuroendocrine responses, promoting excitotoxicity (increased glutamate levels), and impairing brain plasticity. What are the sources of this chronic inflammation? Increasing…
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It matters what you practice: differential training effects on subjective experience, behavior, brain and body in the ReSource Project.
Mindfulness interventions have gained much attraction, also due to their promise to improve health and wellbeing. However, not enough attention is devoted to the differentiation between various mental practice types. Here, we summarize findings from the ReSource Project, a 9-month longitudinal mental training study comparing practices focusing on (a) present-moment attention and interoception, (b) socio-emotional processes such as compassion and loving kindness and (c) meta-cognitive processes and perspective-taking on self and others. We find evidence for differential training effects of these practice types on all levels of observation, ranging from distinct phenomenological fingerprints and structural brain plasticity to selective improvements in social cognition, altruism and peripheral physiology, including the cortisol response to psychosocial stress. We argue for a more differenti…
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Cryan JF, O'Riordan KJ, Cowan CSM, Sandhu KV, Bastiaanssen TFS, Boehme M, Codagnone MG, Cussotto S, Fulling C, Golubeva AV, Guzzetta KE, Jaggar M, Long-Smith CM, Lyte JM, Martin JA, Molinero-Perez A, Moloney G, Morelli E, Morillas E, O'Connor R, Cruz-Pereira JS, Peterson VL, Rea K, Ritz NL, Sherwin E, Spichak S, Teichman EM, van de Wouw M, Ventura-Silva AP, Wallace-Fitzsimons SE, Hyland N, Clarke G, Dinan TG (2019)reviewMEDLINE-indexed journal, not yet read by usPhysiological reviews3,652 citations The Microbiota-Gut-Brain Axis.
The importance of the gut-brain axis in maintaining homeostasis has long been appreciated. However, the past 15 yr have seen the emergence of the microbiota (the trillions of microorganisms within and on our bodies) as one of the key regulators of gut-brain function and has led to the appreciation of the importance of a distinct microbiota-gut-brain axis. This axis is gaining ever more traction in fields investigating the biological and physiological basis of psychiatric, neurodevelopmental, age-related, and neurodegenerative disorders. The microbiota and the brain communicate with each other via various routes including the immune system, tryptophan metabolism, the vagus nerve and the enteric nervous system, involving microbial metabolites such as short-chain fatty acids, branched chain amino acids, and peptidoglycans. Many factors can influence microbiota composition in early life, inc…
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Epigenetics and depression
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The risk for major depression is both genetically and environmentally determined. It has been proposed that epigenetic mechanisms could mediate the lasting increases in depression risk following exposure to adverse life events and provide a mechanistic framework within which genetic and environmental factors can be integrated. Epigenetics refers to processes affecting gene expression and translation that do not involve changes in the DNA sequence and include DNA methylation (DNAm) and microRNAs (miRNAs) as well as histone modifications. Here we review evidence for a role of epigenetics in the pathogenesis of depression from studies investigating DNAm, miRNAs, and histone modifications using different tissues and various experimental designs. From these studies, a model emerges where underlying genetic and environmental risk factors, and interactions between the two, could drive aberrant …
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