The gut microbiome:implications for neurogenesis and neurological diseases

There is an increasing recognition of the strong links between the gut microbiome and the brain,and there is persuasive evidence that the gut microbiome plays a role in a variety of physiological processes in the central nervous system.This review summarizes findings that gut microbial composition alterations are linked to hippocampal neurogenesis,as well as the possible mechanisms of action;the existing literature suggests that microbiota influence neurogenic processes,which can result in neurological disorders.We consider this evidence from the perspectives of neuroinflammation,microbial-derived metabolites,neurotrophins,and neurotransmitters.Based on the existing research,we propose that the administration of probiotics can normalize the gut microbiome.This could therefore also represent a promising treatment strategy to counteract neurological impairment.     

Dysregulation of neurogenesis by neuroinflammation:key differences in neurodevelopmental and neurological disorders

Embryonic neurogenesis is the process of generating neurons, the functional units of the brain. Because of its sensitivity to adverse intrauterine environment such as infection, dysregulation of this process has emerged as a key mechanism underlying many neurodevelopmental disorders such as autism spectrum disorders (ASD). Adult neurogenesis, although is restricted to a few neurogenic niches, plays pivotal roles in brain plasticity and repair. Increasing evidence suggests that impairments in adult neurogenesis are in-volved in major neurodegenerative disorders such as Alzheimer's disease. A hallmark feature of these brain disorders is neuroinflammation, which can either promote or inhibit neurogenesis depending upon the context of brain microenvironment. In this review paper, we present evidence from both experimental and human studies to show a complex picture of relationship between these two events, and discussed potential factors contributing to different or even opposing actions of neuroinflammation on neurogenesis in neuro-developmental and neurological disorders.     

Adult neurogenesis and neuroplasticity

After cerebral strokes and traumatic brain injuries (TBIs), there is a striking amount of neurological recovery in the following months and years, despite often-permanent structural damage. Though the mechanisms underlying such recovery are not fully understood, properties of plasticity of the central nervous system (CNS), such as the reorganization of the pre-existing network and axonal sprouting have been implicated in the recovery. With the recent evidences that neurogenesis occurs in the adult brain, and neural stem cells (NSCs) reside in the adult CNS, the involvement of newly generated neuronal cells in the recovery following injury to the CNS remains to be established. Neurogenesis is increased bilaterally in the dentate gyrus (DG) and the subventicular zone (SVZ) after cerebral strokes and TBIs, and new neuronal cells are generated at the sites of injury, where they replace some of the degenerated nerve cells. Newly generated neuronal cells at the sites of injury may represent an attempt by the CNS to regenerate itself after injury, whereas the increased neurogenesis in the DG and SVZ would also contribute to the CNS plasticity. Thus, injury-induced neurogenesis may contribute to the recovery and plasticity of the CNS.     

Adult brain neurogenesis and depression

The waning and waxing of neurogenesis in brain areas such as the dentate gyrus is proposed as a key factor in the descent into and recovery from clinical depression, respectively. A decrease in neurogenesis could occur due to genetic factors, stress (especially because of the involvement of adrenal corticoids), and/or a decline in serotonergic neurotransmission. An increase in neurogenesis could be brought about by several factors, but especially those that activate the serotonin 5-HT(1A) receptor. The possible interaction of immune system factors, especially the proinflammatory cytokines, with adult brain neurogenesis is discussed.     

成年海马神经再生与抑郁

重症抑郁是一种严重的精神障碍,其终生患病率超过15%,主要的行为变化是情绪低落、消极观念、无助、活力和注意力下降,自杀比例约15%,是全球第四大致残因素[1].     

Adult hippocampal neurogenesis and aging

The demographic changes in the foreseeable future stress the need for research on successful cognitive aging. Advancing age constitutes a primary risk factor for disease of the central nervous system most notably neurodegenerative disorders. The hippocampus is one of the brain regions that is prominently affected by neurodegeneration and functional decline even in what is still considered “normal aging”. Plasticity is the basis for how the brain adapts to changes over time. The discovery of adult hippocampal neurogenesis has added a whole new dimension to research on structural plasticity in the adult and aging hippocampus. In this article, we briefly summarize and discuss recent findings on the regulation of adult neurogenesis with relevance to aging. Aging is an important co-variable for many regulatory mechanisms affecting adult neurogenesis but so far, only few studies have specifically addressed this interaction. We hypothesize that adult neurogenesis contributes to a neural reserve, i.e. the maintained potential for structural plasticity that allows compensation in situations of functional losses with aging. As such we propose that adult neurogenesis might contribute to the structural correlates of successful aging.     

Differences in relatives' and patients' illness perceptions in functional neurological symptom disorders compared with neurological diseases

ObjectiveThe illness perceptions of the relatives of patients with functional neurological symptom disorders (FNSDs) and their relation to the illness perceptions of the patients have been little studied. We aimed to compare illness perceptions of relatives of patients with FNSDs with those held by patients themselves. We used control pairs with neurological diseases (NDs) to examine the specificity of the findings to FNSDs.Material and methodsPatients with FNSDs (functional limb weakness and psychogenic nonepileptic seizures) and patients with NDs causing limb weakness and epilepsy, as well as their relatives, completed adapted versions of the Illness Perception Questionnaire — Revised (IPQ-R).ResultsWe included 112 pairs of patients with FNSDs and their relatives and 60 pairs of patients with NDs and their relatives. Relatives of patients with FNSDs were more likely to endorse psychological explanations and, in particular, stress as causal factors than patients with FNSDs (p < .001). Relatives of patients with FNSDs were also more pessimistic about the expected duration of the disorder and perceived a greater emotional impact compared with patients themselves (p < .001). However, the latter two differences between patients and relatives were also found in pairs of patients with NDs and their relatives.ConclusionThe main difference in illness perceptions between relatives and patients that appeared specific to FNSDs was a tendency for relatives to see psychological factors as more relevant compared with patients. Some other differences were observed between pairs of patients with FNSDs and their relatives, but the same differences were also seen in pairs of patients with NDs and their relatives. These other differences were, therefore, not specific to FNSDs. Discussion about possibly relevant psychological factors with patients suffering from FNSDs may be helped by including relatives.     

Adult neurogenesis and Parkinson's disease

Parkinson's disease is a neurodegenerative disorder characterized by a progressive neuronal loss affecting preferentially the dopaminergic neurons of the nigrostriatal projection. Transplantation of fetal dopaminergic precursor cells has provided the proof of principle that a cell replacement therapy can ameliorate clinical symptoms in affected patients. Recent years have provided evidence for the existence of neural stem cells with the potential to produce new neurons, particularly of a dopaminergic phenotype, in the adult mammalian brain. Such stem cells have been identified in so called neurogenic brain areas, where neurogenesis is constitutively ongoing, but also in primarily non-neurogenic areas, such as the midbrain and the striatum, where neurogenesis does not occur under normal physiological conditions. We review here presently published evidence to evaluate the concept that endogenous neural stem cells may have the potential to be instrumentalized for a non-invasive cell replacement therapy with autologous neurons to repair the damaged nigrostriatal dopaminergic projection in Parkinson's disease.     

Adult neurogenesis in Alzheimer's disease

Alzheimer's disease (AD) is the most common form of age-related dementia, characterized by progressive memory loss and cognitive disturbances. The hippocampus, where adult hippocampal neurogenesis (AHN), a relatively novel form of brain plasticity that refers to the birth of new neurons, occurs, is one of the first brain regions to be affected in AD patients. Recent studies showed that AHN persists throughout life in humans, but it drops sharply in AD patients. Next questions to consider would be whether AHN impairment is a contributing factor to learning and memory impairment in AD and whether restoring AHN could ameliorate or delay cognitive dysfunction. Here, we outline and discuss the current knowledge about the state of AHN in AD patients, AHN impairment as a potentially relevant mechanism underlying memory deficits in AD, therapeutic potential of activating AHN in AD, and the mechanisms of AHN impairment in AD.     

Affective disorders in neurological diseases: a case register-based study

OBJECTIVE: To investigate the temporal relationships between a range of neurological diseases and affective disorders. METHOD: Data derived from linkage of the Danish Psychiatric Central Register and the Danish National Hospital Register. Seven cohorts with neurological index diagnoses and two control group diagnoses were followed for up to 21 years. The incidences of affective disorders in the different groups were compared with the control groups, using competing risks to consider the risk of affective disorder and the risk of death in the same analysis. RESULTS: We found an increased incidence of affective disorders in dementia, Parkinson's disease, epilepsy, stroke and intracerebral haemorrhage compared with control groups. The association was found to be the strongest for dementia and Parkinson's disease. In hospitalized patients, with incident multiple sclerosis, the incidence of affective disorder was lower than the incidence in the control groups. CONCLUSION: In neurological diseases there seems to be an increased incidence of affective disorders. The elevated incidence was found to be particularly high for dementia and Parkinson's disease (neurodegenerative diseases).     

Cerebrospinal fluid arginine vasopressin in degenerative disorders and other neurological diseases.

Arginine vasopressin (AVP) was determined in plasma and lumbar CSF from 46 patients with Parkinson's disease, dementia, cerebrovascular disease, multiple sclerosis and other, mostly peripheral neurological disorders. The mean plasma concentration of AVP was 1.62 microU/ml, the CSF concentration 1.14 microU/ml and the gradient CSF/plasma 0.72. There was a good correlation between the plasma and the CSF values in most patients. No sex difference could be found. A slight decrease of the CSF values could be found with increasing age. Significantly higher CSF-AVP values were found in patients with cerebrovascular disease, whereas lower CSF values were found in patients with dementia and Parkinson's disease. However there were decreased CSF/plasma gradients in patients with dementia and Parkinson's disease to about 0.30 compared to 0.98 in patients with peripheral neurological disorders. Patients with multiple sclerosis had an increased IgG index indicating an intrathecal IgG production but there was no obvious correlation between this and the AVP concentrations in plasma and CSF, nor with the total CSF protein content, nor with the albumin and IgG concentrations in plasma and CSF.     

Adult neurogenesis in a moth brain

In both vertebrates and invertebrates, neurogenesis not only occurs during development but also persists throughout adult life. So far, adult neurogenesis has been detected in a few insect orders but not in Lepidoptera. In the moth, Agrotis ipsilon, the sensitivity of antennal lobe interneurons of males to sex pheromone is age- and juvenile hormone-dependent in accordance with changes in the behavioral response. As a first step to understand this neuronal plasticity, we tested the hypothesis that adult neurogenesis could occur in the moth brain using 5-bromo-2'-deoxyuridine injections on newly born and sexually mature moths. Our results show that persistent neurogenesis occurs in mushroom bodies of adult males and females of A. ipsilon. Two clusters of one to four neuroblasts in each brain hemisphere continue to divide in adult moths and give rise to small clusters of Kenyon cells in the cortex of the mushroom body calyces. Neurogenesis was observed in both newly born and sexually mature males. There was a clear increase in the number of newly born cells in brains as the time increased after the treatment that was performed soon after emergence. When treatments were performed in mature 3-day-old adults, neurogenesis was still detected in brains dissected 3 hours after treatment but was hardly visible 2 days later. Adult neurogenesis was also detected in the optic lobes but not in the antennal lobes. We hypothesize that the newly born neurons could play a role in the central nervous plasticity of olfactory processing in the adult moth A. ipsilon.     

Adult hippocampal neurogenesis and memory interference

Rats, subjected to low-dose irradiation that suppressed hippocampal neurogenesis, or a sham treatment, were administered a visual discrimination task under conditions of high, or low interference. Half of the rats engaged in running activity and the other half did not. In the non-runners, there was no effect of irradiation on learning, or remembering the discrimination response under low interference, but irradiation treatment increased their susceptibility to interference, resulting in loss of memory for the previously learned discrimination. Irradiated rats that engaged in running activity exhibited increased neuronal growth and protection from memory impairment. The results, which show that hippocampal cells generated in adulthood play a role in differentiating between conflicting, context-dependent memories, provide further evidence of the importance of neurogenesis in hippocampus-sensitive memory tasks. The results are consistent with computational models of hippocampal function that specify a central role for neurogenesis in the modulation of interfering influences during learning and memory.     

Adult neurogenesis from reprogrammed astrocytes

The details of adult neurogenesis,including environmental triggers,region specificity,and species homology remain an area of intense investigation.Slowing or halting age-related cognitive dysfunction,or restoring neurons lost to disease or injury represent just a fraction of potential therapeutic applications.New neurons can derive from stem cells,pluripotent neural progenitor cells,or non-neuronal glial cells,such as astrocytes.Astrocytes must be epigeneticallyreprogrammedto become neurons,which can occur both naturally in vivo,and via artificial exogenous treatments.While neural progenitor cells are localized to a few neurogenic zones in the adult brain,astrocytes populate almost every brain structure.In this review,we will summarize recent research into neurogenesis that arises from conversion of post-mitotic astrocytes,detail the genetic and epigenetic pathways that regulate this process,and discuss the possible clinical relevance in supplementing stem-cell neurogenic therapies.     

Adult neurogenesis and depression: an introduction

The following essay provides a summary of a seminar given on the sixth of November, 2010 at the combined annual congress, held at Brussels of the Centro Studi Psichatrici Vrije Universiteit Brussel, Université Catholique de Louvain & the Bedfordshire Centre for Mental Health Research. The talk aimed to present a brief taster, assuming no prior knowledge, of adult neurogenesis, the formation of new nerve cells, in relation to the aetiology and treatment of depression. The talk begins with an introduction to the principles of adult neurogenesis: from initial investigations by Ramon y Cajal in the 19th century, resulting in a "static brain hypothesis", to their subsequent challenge almost one hundred years later. The potential functional implications emerging, especially in relation to depression, are explored. The fascinating effects of corticosteroids and antidepressants are used as examples to explore the possible roles of neurogenesis that have led some to propose a neurogenic theory of depression. Arguments against this theory are then presented. Finally, a consideration of future opinion: could neurogenesis be less important in the aetiology of depression, but involved in its treatment - a property of antidepressant action rather than a central final aetiological pathway. In this young branch of neuroscience controversy abounds: our understanding of the process itself, its relations and most importantly its implications are all in their infancy. This has allowed for some of the most interesting debate of recent years as to the neurological basis and treatment of affective disorders.     

Adult neurogenesis and the ischemic forebrain.

The recent identification of endogenous neural stem cells and persistent neuronal production in the adult brain suggests a previously unrecognized capacity for self-repair after brain injury. Neurogenesis not only continues in discrete regions of the adult mammalian brain, but new evidence also suggests that neural progenitors form new neurons that integrate into existing circuitry after certain forms of brain injury in the adult. Experimental stroke in adult rodents and primates increases neurogenesis in the persistent forebrain subventricular and hippocampal dentate gyrus germinative zones. Of greater relevance for regenerative potential, ischemic insults stimulate endogenous neural progenitors to migrate to areas of damage and form neurons in otherwise dormant forebrain regions, such as the neostriatum and hippocampal pyramidal cell layer, of the mature brain. This review summarizes the current understanding of adult neurogenesis and its regulation in vivo, and describes evidence for stroke-induced neurogenesis and neuronal replacement in the adult. Current strategies used to modify endogenous neurogenesis after ischemic brain injury also will be discussed, as well as future research directions with potential for achieving regeneration after stroke and other brain insults.     

Adult neurogenesis in serotonin transporter deficient mice

Summary Serotonin (5-HT) is a regulator of morphogenetic activities during early brain development and neurogenesis, including cell proliferation, migration, differentiation, and synaptogenesis. The 5-HT transporter (5-HTT, SLC6A4) mediates high-affinity reuptake of 5-HT into presynaptic terminals and thereby fine-tunes serotonergic neurotransmission. Inactivation of the 5-HTT gene in mice reduces 5-HT clearance resulting in persistently increased concentrations of synaptic 5-HT. In the present study, we investigated the effects of elevated 5-HT levels on adult neurogenesis in the hippocampus of 5-HTT deficient mice, including stem cell proliferation, survival, and differentiation. Using an in vivo approach, we showed an increase in proliferative capacity of hippocampal adult neural stem cells in aged 5-HTT knockout mice (∼14.5 months) compared to wildtype controls. In contrast, in vivo and additional in vitro analyses of younger adult 5-HTT knockout mice (∼7 weeks and ∼3.0 months) did not reveal significant changes in proliferation of neural stem cells or survival of newborn cells. We showed that the cellular fate of newly generated cells in 5-HTT knockout mice is not different with respect to the total number and percentage of neurons or glial cells from wildtype controls. Our findings indicate that elevated synaptic 5-HT concentration throughout early development and later life of 5-HTT deficient mice does not induce adult neurogenesis in adult mice, but that elevated 5-HT levels in aged mice influence stem cell proliferation. First two authors contributed equally to this work     

Acanthocytosis and neurological disorders

Acanthocytosis occurs because of ultrastructural abnormalities of the erythrocyte membranous skeleton resulting in reduced membrane fluidity. At least three hereditary neurological conditions are associated with it, although as yet the pathogenesis of the neurological features is unknown. In abetalipoproteinaemia, an autosomal recessive condition, vitamin E deficiency results in a progressive spinocerebellar syndrome associated with peripheral neuropathy and retinitis pigmentosa. Neuroacanthocytosis is also probably an autosomal recessive condition and is characterised by chorea, orofaciolingual dyskinesia, dysarthria, areflexia, seizures and dementia. McLeod syndrome is an X-linked recessive disorder usually presneting in males as a benign myopathy within areflexia, in association with a particular abnormality of expression of Kell blood group antigens. However, occasionally the neurological features are more severe and indistinguishable from those of neuroacanthocytosis. Recent advances in molecular genetics may assist better understanding of the disease mechanisms and the search for more effective treatment. Received: 19 June 2000 / Accepted: 28 July 2000