Stress-Related Dysfunction of Adult Hippocampal Neurogenesis—An Attempt for Understanding Resilience?

Newborn neurons in the adult hippocampus are regulated by many intrinsic and extrinsic cues. It is well accepted that elevated glucocorticoid levels lead to downregulation of adult neurogenesis, which this review discusses as one reason why psychiatric diseases, such as major depression, develop after long-term stress exposure. In reverse, adult neurogenesis has been suggested to protect against stress-induced major depression, and hence, could serve as a resilience mechanism. In this review, we will summarize current knowledge about the functional relation of adult neurogenesis and stress in health and disease. A special focus will lie on the mechanisms underlying the cascades of events from prolonged high glucocorticoid concentrations to reduced numbers of newborn neurons. In addition to neurotransmitter and neurotrophic factor dysregulation, these mechanisms include immunomodulatory pathways, as well as microbiota changes influencing the gut-brain axis. Finally, we discuss recent findings delineating the role of adult neurogenesis in stress resilience.

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Agrin-Lrp4-Ror2 signaling regulates adult hippocampal neurogenesis in mice

eLife ◽

10.7554/elife.45303 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 9

Author(s):

Hongsheng Zhang ◽

Anupama Sathyamurthy ◽

Fang Liu ◽

Lei Li ◽

Lei Zhang ◽

...

Keyword(s):

Adult Neurogenesis ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Orphan Receptor ◽

Brain Functions ◽

Density Lipoprotein Receptor ◽

Neural Stem Progenitor Cells ◽

Newborn Neurons

Adult neurogenesis in the hippocampus may represent a form of plasticity in brain functions including mood, learning and memory. However, mechanisms underlying neural stem/progenitor cells (NSPCs) proliferation are not well understood. We found that Agrin, a factor critical for neuromuscular junction formation, is elevated in the hippocampus of mice that are stimulated by enriched environment (EE). Genetic deletion of the Agrn gene in excitatory neurons decreases NSPCs proliferation and increases depressive-like behavior. Low-density lipoprotein receptor-related protein 4 (Lrp4), a receptor for Agrin, is expressed in hippocampal NSPCs and its mutation blocked basal as well as EE-induced NSPCs proliferation and maturation of newborn neurons. Finally, we show that Lrp4 interacts with and activates receptor tyrosine kinase-like orphan receptor 2 (Ror2); and Ror2 mutation impairs NSPCs proliferation. Together, these observations identify a role of Agrin-Lrp4-Ror2 signaling for adult neurogenesis, uncovering previously unexpected functions of Agrin and Lrp4 in the brain.

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Adult Hippocampal Neurogenesis in Parkinson’s Disease: Impact on Neuronal Survival and Plasticity

Neural Plasticity ◽

10.1155/2014/454696 ◽

2014 ◽

Vol 2014 ◽

pp. 1-12 ◽

Cited By ~ 34

Author(s):

Martin Regensburger ◽

Iryna Prots ◽

Beate Winner

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Current Knowledge ◽

Treatment Options ◽

Hippocampal Neurogenesis ◽

Adult Brain ◽

Adult Hippocampal Neurogenesis ◽

Future Research ◽

Disease Mechanisms ◽

Newborn Neurons

In Parkinson’s disease (PD) and other synucleinopathies, chronic neurodegeneration occurs within different areas of the central nervous system leading to progressive motor and nonmotor symptoms. The symptomatic treatment options that are currently available do not slow or halt disease progression. This highlights the need of a better understanding of disease mechanisms and disease models. The generation of newborn neurons in the adult hippocampus and in the subventricular zone/olfactory bulb system is affected by many different regulators and possibly involved in memory processing, depression, and olfaction, symptoms which commonly occur in PD. The pathology of the adult neurogenic niches in human PD patients is still mostly elusive, but different preclinical models have shown profound alterations of adult neurogenesis. Alterations in stem cell proliferation, differentiation, and survival as well as neurite outgrowth and spine formation have been related to different aspects in PD pathogenesis. Therefore, neurogenesis in the adult brain provides an ideal model to study disease mechanisms and compounds. In addition, adult newborn neurons have been proposed as a source of endogenous repair. Herein, we review current knowledge about the adult neurogenic niches in PD and highlight areas of future research.

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Adult Hippocampal Neurogenesis in Alzheimer’s Disease: An Overview of Human and Animal Studies with Implications for Therapeutic Perspectives Aimed at Memory Recovery

Neural Plasticity ◽

10.1155/2022/9959044 ◽

2022 ◽

Vol 2022 ◽

pp. 1-18

Author(s):

Stefano Farioli-Vecchioli ◽

Valentina Ricci ◽

Silvia Middei

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Adult Neurogenesis ◽

Animal Studies ◽

Neurodegenerative Disorder ◽

Memory Loss ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Newborn Neurons ◽

Impaired Neurogenesis

The mammalian hippocampal dentate gyrus is a niche for adult neurogenesis from neural stem cells. Newborn neurons integrate into existing neuronal networks, where they play a key role in hippocampal functions, including learning and memory. In the ageing brain, neurogenic capability progressively declines while in parallel increases the risk for developing Alzheimer’s disease (AD), the main neurodegenerative disorder associated with memory loss. Numerous studies have investigated whether impaired adult neurogenesis contributes to memory decline in AD. Here, we review the literature on adult hippocampal neurogenesis (AHN) and AD by focusing on both human and mouse model studies. First, we describe key steps of AHN, report recent evidence of this phenomenon in humans, and describe the specific contribution of newborn neurons to memory, as evinced by animal studies. Next, we review articles investigating AHN in AD patients and critically examine the discrepancies among different studies over the last two decades. Also, we summarize researches investigating AHN in AD mouse models, and from these studies, we extrapolate the contribution of molecular factors linking AD-related changes to impaired neurogenesis. Lastly, we examine animal studies that link impaired neurogenesis to specific memory dysfunctions in AD and review treatments that have the potential to rescue memory capacities in AD by stimulating AHN.

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Mitochondrial and Autophagic Regulation of Adult Neurogenesis in the Healthy and Diseased Brain

International Journal of Molecular Sciences ◽

10.3390/ijms22073342 ◽

2021 ◽

Vol 22 (7) ◽

pp. 3342

Author(s):

Hansruedi Büeler

Keyword(s):

Stem Cell ◽

Mood Disorders ◽

Adult Neurogenesis ◽

Cell Function ◽

Natural Aging ◽

Hippocampal Neurogenesis ◽

Adult Brain ◽

Adult Hippocampal Neurogenesis ◽

Induced Mood ◽

Newborn Neurons

Adult neurogenesis is a highly regulated process during which new neurons are generated from neural stem cells in two discrete regions of the adult brain: the subventricular zone of the lateral ventricle and the subgranular zone of the dentate gyrus in the hippocampus. Defects of adult hippocampal neurogenesis have been linked to cognitive decline and dysfunction during natural aging and in neurodegenerative diseases, as well as psychological stress-induced mood disorders. Understanding the mechanisms and pathways that regulate adult neurogenesis is crucial to improving preventative measures and therapies for these conditions. Accumulating evidence shows that mitochondria directly regulate various steps and phases of adult neurogenesis. This review summarizes recent findings on how mitochondrial metabolism, dynamics, and reactive oxygen species control several aspects of adult neural stem cell function and their differentiation to newborn neurons. It also discusses the importance of autophagy for adult neurogenesis, and how mitochondrial and autophagic dysfunction may contribute to cognitive defects and stress-induced mood disorders by compromising adult neurogenesis. Finally, I suggest possible ways to target mitochondrial function as a strategy for stem cell-based interventions and treatments for cognitive and mood disorders.

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Is adult hippocampal neurogenesis really relevant for the treatment of psychiatric disorders?

Current Neuropharmacology ◽

10.2174/1570159x18666200818194948 ◽

2020 ◽

Vol 18 ◽

Author(s):

Marco Carli ◽

Stefano Aringhieri ◽

Shivakumar Kolachalam ◽

Biancamaria Longoni ◽

Giovanna Grenno ◽

...

Keyword(s):

Psychiatric Disorders ◽

Emotional Processing ◽

Imaging Techniques ◽

Hippocampal Neurogenesis ◽

Adult Brain ◽

Adult Hippocampal Neurogenesis ◽

Mood Stabilizers ◽

Post Traumatic Stress ◽

Newborn Neurons ◽

Hippocampal Circuitry

: Adult neurogenesis consists in the generation of newborn neurons from neural stem cells taking place in the adult brain. In mammals, this process is limited to very few areas of the brain, and one of these neurogenic niches is the subgranular layer of the dentate gyrus (DG) of the hippocampus. Adult newborn neurons are generated from quiescent neural progenitors (QNPs), which differentiate through different steps into mature granule cells (GCs), to be finally integrated into the existing hippocampal circuitry. In animal models, adult hippocampal neurogenesis (AHN) is relevant for pattern discrimination, cognitive flexibility, emotional processing and resilience to stressful situations. Imaging techniques allow to visualize newborn neurons within the hippocampus through all their stages of development and differentiation. In humans, the evidence of AHN is more challenging, and, based on recent findings, it persists through the adulthood, even if it declines with age. Whether this process has an important role in human brain function and how it integrates into the existing hippocampal circuitry is still a matter of exciting debate. Importantly, AHN deficiency has been proposed to be relevant in many psychiatric disorders, including mood disorders, anxiety, post-traumatic stress disorder and schizophrenia. This review aims to investigate how AHN is altered in different psychiatric conditions and how pharmacological treatments can rescue this process. In fact, many psychoactive drugs, such as antidepressants, mood stabilizers and atypical antipsychotics (AAPs), can boost AHN with different results. In addition, some non-pharmacological approaches are discussed as well.

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Does Impairment of Adult Neurogenesis Contribute to Pathophysiology of Alzheimer's Disease? A Still Open Question

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2020.578211 ◽

2021 ◽

Vol 13 ◽

Author(s):

Domenica Donatella Li Puma ◽

Roberto Piacentini ◽

Claudio Grassi

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Adult Neurogenesis ◽

Memory Formation ◽

Hippocampal Neurogenesis ◽

Synaptic Function ◽

Adult Hippocampal Neurogenesis ◽

Amyloid Β Protein

Adult hippocampal neurogenesis is a physiological mechanism contributing to hippocampal memory formation. Several studies associated altered hippocampal neurogenesis with aging and Alzheimer's disease (AD). However, whether amyloid-β protein (Aβ)/tau accumulation impairs adult hippocampal neurogenesis and, consequently, the hippocampal circuitry, involved in memory formation, or altered neurogenesis is an epiphenomenon of AD neuropathology contributing negligibly to the AD phenotype, is, especially in humans, still debated. The detrimental effects of Aβ/tau on synaptic function and neuronal viability have been clearly addressed both in in vitro and in vivo experimental models. Until some years ago, studies carried out on in vitro models investigating the action of Aβ/tau on proliferation and differentiation of hippocampal neural stem cells led to contrasting results, mainly due to discrepancies arising from different experimental conditions (e.g., different cellular/animal models, different Aβ and/or tau isoforms, concentrations, and/or aggregation profiles). To date, studies investigating in situ adult hippocampal neurogenesis indicate severe impairment in most of transgenic AD mice; this impairment precedes by several months cognitive dysfunction. Using experimental tools, which only became available in the last few years, research in humans indicated that hippocampal neurogenesis is altered in cognitive declined individuals affected by either mild cognitive impairment or AD as well as in normal cognitive elderly with a significant inverse relationship between the number of newly formed neurons and cognitive impairment. However, despite that such information is available, the question whether impaired neurogenesis contributes to AD pathogenesis or is a mere consequence of Aβ/pTau accumulation is not definitively answered. Herein, we attempted to shed light on this complex and very intriguing topic by reviewing relevant literature on impairment of adult neurogenesis in mouse models of AD and in AD patients analyzing the temporal relationship between the occurrence of altered neurogenesis and the appearance of AD hallmarks and cognitive dysfunctions.

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The intellectual disability PAK3 R67C mutation impacts cognitive functions and adult hippocampal neurogenesis

Human Molecular Genetics ◽

10.1093/hmg/ddz296 ◽

2020 ◽

Vol 29 (12) ◽

pp. 1950-1968

Author(s):

Charlotte Castillon ◽

Laurine Gonzalez ◽

Florence Domenichini ◽

Sandrine Guyon ◽

Kevin Da Silva ◽

...

Keyword(s):

Intellectual Disability ◽

Mouse Model ◽

Spatial Memory ◽

Adult Neurogenesis ◽

Hippocampal Neurons ◽

Memory Task ◽

Clinical Signs ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Adult Born Neurons

Abstract The link between mutations associated with intellectual disability (ID) and the mechanisms underlying cognitive dysfunctions remains largely unknown. Here, we focused on PAK3, a serine/threonine kinase whose gene mutations cause X-linked ID. We generated a new mutant mouse model bearing the missense R67C mutation of the Pak3 gene (Pak3-R67C), known to cause moderate to severe ID in humans without other clinical signs and investigated hippocampal-dependent memory and adult hippocampal neurogenesis. Adult male Pak3-R67C mice exhibited selective impairments in long-term spatial memory and pattern separation function, suggestive of altered hippocampal neurogenesis. A delayed non-matching to place paradigm testing memory flexibility and proactive interference, reported here as being adult neurogenesis-dependent, revealed a hypersensitivity to high interference in Pak3-R67C mice. Analyzing adult hippocampal neurogenesis in Pak3-R67C mice reveals no alteration in the first steps of adult neurogenesis, but an accelerated death of a population of adult-born neurons during the critical period of 18–28 days after their birth. We then investigated the recruitment of hippocampal adult-born neurons after spatial memory recall. Post-recall activation of mature dentate granule cells in Pak3-R67C mice was unaffected, but a complete failure of activation of young DCX + newborn neurons was found, suggesting they were not recruited during the memory task. Decreased expression of the KCC2b chloride cotransporter and altered dendritic development indicate that young adult-born neurons are not fully functional in Pak3-R67C mice. We suggest that these defects in the dynamics and learning-associated recruitment of newborn hippocampal neurons may contribute to the selective cognitive deficits observed in this mouse model of ID.

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Adult Hippocampal Neurogenesis in Different Taxonomic Groups: Possible Functional Similarities and Striking Controversies

Cells ◽

10.3390/cells8020125 ◽

2019 ◽

Vol 8 (2) ◽

pp. 125 ◽

Cited By ~ 19

Author(s):

Marcus Augusto-Oliveira ◽

Gabriela Arrifano ◽

João Malva ◽

Maria Crespo-Lopez

Keyword(s):

Cognitive Processes ◽

Adult Neurogenesis ◽

Spatial Navigation ◽

Absolute Number ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Consolidation Process ◽

Apparent Reduction ◽

Taxonomic Groups ◽

Intense Debate

Adult neurogenesis occurs in many species, from fish to mammals, with an apparent reduction in the number of both neurogenic zones and new neurons inserted into established circuits with increasing brain complexity. Although the absolute number of new neurons is high in some species, the ratio of these cells to those already existing in the circuit is low. Continuous replacement/addition plays a role in spatial navigation (migration) and other cognitive processes in birds and rodents, but none of the literature relates adult neurogenesis to spatial navigation and memory in primates and humans. Some models developed by computational neuroscience attribute a high weight to hippocampal adult neurogenesis in learning and memory processes, with greater relevance to pattern separation. In contrast to theories involving neurogenesis in cognitive processes, absence/rarity of neurogenesis in the hippocampus of primates and adult humans was recently suggested and is under intense debate. Although the learning process is supported by plasticity, the retention of memories requires a certain degree of consolidated circuitry structures, otherwise the consolidation process would be hampered. Here, we compare and discuss hippocampal adult neurogenesis in different species and the inherent paradoxical aspects.

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Role of Wnt Signaling in Adult Hippocampal Neurogenesis in Health and Disease

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.00860 ◽

2020 ◽

Vol 8 ◽

Author(s):

Sebastian B. Arredondo ◽

Daniela Valenzuela-Bezanilla ◽

Muriel D. Mardones ◽

Lorena Varela-Nallar

Keyword(s):

Wnt Signaling ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Health And Disease

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Adult hippocampal neurogenesis: an important target associated with antidepressant effects of exercise

Reviews in the Neurosciences ◽

10.1515/revneuro-2016-0076 ◽

2017 ◽

Vol 28 (7) ◽

pp. 693-703 ◽

Cited By ~ 13

Author(s):

Lina Sun ◽

Qingshan Sun ◽

Jinshun Qi

Keyword(s):

Adult Neurogenesis ◽

Healthy Lifestyle ◽

Brain Plasticity ◽

Treatment Method ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Brain Functions ◽

Antidepressant Effects ◽

Exercise Activity ◽

The Brain

AbstractDepression is a prevalent devastating mental disorder that affects the normal life of patients and brings a heavy burden to whole society. Although many efforts have been made to attenuate depressive/anxiety symptoms, the current clinic antidepressants have limited effects. Scientists have long been making attempts to find some new strategies that can be applied as the alternative antidepressant therapy. Exercise, a widely recognized healthy lifestyle, has been suggested as a therapy that can relieve psychiatric stress. However, how exercise improves the brain functions and reaches the antidepressant target needs systematic summarization due to the complexity and heterogeneous feature of depression. Brain plasticity, especially adult neurogenesis in the hippocampus, is an important neurophysiology to facilitate animals for neurogenesis can occur in not only humans. Many studies indicated that an appropriate level of exercise can promote neurogenesis in the adult brains. In this article, we provide information about the antidepressant effects of exercise and its implications in adult neurogenesis. From the neurogenesis perspective, we summarize evidence about the effects of exercise in enhancing neurogenesis in the hippocampus through regulating growth factors, neurotrophins, neurotransmitters and metabolism as well as inflammations. Taken together, a large number of published works indicate the multiple benefits of exercise in the brain functions of animals, particularly brain plasticity like neurogenesis and synaptogenesis. Therefore, a new treatment method for depression therapy can be developed by regulating the exercise activity.

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