Effect of Opioid on Adult Hippocampal Neurogenesis

During the past decade, the study of the mechanisms and functional implications of adult neurogenesis has significantly progressed. Many studies focus on the factors that regulate proliferation and fate determination of adult neural stem/progenitor cells, including addictive drugs such as opioid. Here, we review the most recent works on opiate drugs’ effect on different developmental stages of adult hippocampal neurogenesis, as well as the possible underlying mechanisms. We conclude that opiate drugs in general cause a loss of newly born neural progenitors in the subgranular zone of dentate gyrus, by either modulating proliferation or interfering with differentiation and maturation. We also discuss the consequent impact of regulation of adult neurogenesis in animal’s opioid addiction behavior. We further look into the future directions in studying the convergence between the adult neurogenesis field and opioid addiction field, since the adult-born granular cells were shown to play a role in neuroplasticity and may help to reduce the vulnerability to drug craving and relapse.

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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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Effects and Potential Mechanisms of Alcohol Use Disorder on the Fate Determination of Newly Born Neurons in the Hippocampus

Alcohol and Alcoholism ◽

10.1093/alcalc/agaa083 ◽

2020 ◽

Vol 55 (6) ◽

pp. 598-602

Author(s):

Zahra Shabani ◽

Mohsen Jafarzadeh Gharehziaaddin

Keyword(s):

Hippocampal Neurogenesis ◽

Adult Brain ◽

Adult Hippocampal Neurogenesis ◽

Mammalian Brain ◽

Extrinsic Factors ◽

Proliferation And Differentiation ◽

Underlying Mechanisms

Abstract In the adult mammalian brain, new functional neurons are generated throughout life because of sustained proliferation and differentiation of neural stem cells (NSCs). The subventricular zone (SVZ), lining the lateral ventricle, and the subgranular zone (SGZ) in the dentate gyrus (DG) of the hippocampus are the two major neurogenic regions in the adult brain. This process is not fixed but is highly modulated by numerous intrinsic and extrinsic factors. Neurogenesis has become in the focus of interest for its involvement in repairing the damaged brain and this motivates researchers to detect controlling mechanisms of this process. Recent evidence suggests that alcohol usage can directly influence adult hippocampal neurogenesis, but its mechanisms remain a matter for debate. Thus, this review summarizes in vivo/in vitro studies on the role of alcohol in hippocampal neurogenesis during adulthood and clarifies its underlying mechanisms by highlighting neurotransmitters and their receptors.

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Inducible and Conditional Stimulation of Adult Hippocampal Neurogenesis Rescues Cadmium-Induced Impairments of Adult Hippocampal Neurogenesis and Hippocampus-Dependent Memory in Mice

Toxicological Sciences ◽

10.1093/toxsci/kfaa104 ◽

2020 ◽

Vol 177 (1) ◽

pp. 263-280 ◽

Cited By ~ 1

Author(s):

Hao Wang ◽

Megumi T Matsushita ◽

Liang Zhang ◽

Glen M Abel ◽

Brett C Mommer ◽

...

Keyword(s):

Adult Neurogenesis ◽

Mouse Strain ◽

Environmental Pollutant ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Mitogen Activated Protein Kinase ◽

Full Spectrum ◽

Neural Stem Progenitor Cells ◽

Cd Exposure ◽

Hippocampus Dependent Memory

Abstract Cadmium (Cd) is a heavy metal and an environmental pollutant. However, the full spectrum of its neurotoxicity and the underlying mechanisms are not completely understood. Our previous studies demonstrated that Cd exposure impairs adult hippocampal neurogenesis and hippocampus-dependent memory in mice. This study aims to determine if these adverse effects of Cd exposure can be mitigated by genetically and conditionally enhancing adult neurogenesis. To address this issue, we utilized the transgenic constitutive active MEK5 (caMEK5) mouse strain we previously developed and characterized. This mouse strain enables us to genetically and conditionally activate adult neurogenesis by administering tamoxifen to induce expression of a caMEK5 in adult neural stem/progenitor cells, which stimulates adult neurogenesis through activation of the endogenous extracellular signal-regulated kinase 5 mitogen-activated protein kinase pathway. The caMEK5 mice were exposed to 0.6 mg/l Cd through drinking water for 38 weeks. Once impairment of memory was confirmed, tamoxifen was administered to induce caMEK5 expression and to activate adult neurogenesis. Behavior tests were conducted at various time points to monitor hippocampus-dependent memory. Upon completion of the behavior tests, brain tissues were collected for cellular studies of adult hippocampal neurogenesis. We report here that Cd impaired hippocampus-dependent spatial memory and contextual fear memory in mice. These deficits were rescued by the tamoxifen induction of caMEK5 expression. Furthermore, Cd inhibition of adult hippocampal neurogenesis was also reversed. This rescue experiment provides strong evidence for a direct link between Cd-induced impairments of adult hippocampal neurogenesis and hippocampus-dependent memory.

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

International Journal of Molecular Sciences ◽

10.3390/ijms22147339 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7339

Author(s):

Julia Leschik ◽

Beat Lutz ◽

Antonietta Gentile

Keyword(s):

Major Depression ◽

Adult Neurogenesis ◽

Current Knowledge ◽

Functional Relation ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Special Focus ◽

Extrinsic Cues ◽

Health And Disease ◽

Newborn Neurons

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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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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Mitochondrial dysfunction-induced KDM5A degradation impairs adult hippocampal neurogenesis in Alzheimer’s disease

10.21203/rs.3.rs-114597/v1 ◽

2020 ◽

Author(s):

Dong Kyu Kim ◽

Hyobin Jeong ◽

Jingi Bae ◽

Moon-Yong Cha ◽

Moonkyung Kang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Mitochondrial Dysfunction ◽

Progenitor Cells ◽

Neuronal Differentiation ◽

Neural Progenitor Cells ◽

Neural Progenitor ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Amyloid Pathology ◽

Neural Stem Progenitor Cells

Abstract Background Adult hippocampal neurogenesis (AHN) is a process of continuously generating functional mature neurons from neural stem cells in the dentate gyrus. In Alzheimer’s disease (AD) brains, amyloid pathology has deleterious effects on AHN, but molecular mechanisms for dysregulated AHN are unclear. Mitochondria of neural stem/progenitor cells play crucial roles in determining cell fate. Since mitochondrial dysfunction by amyloid pathology is the typical symptom of AD pathogenesis, we aim to study whether mitochondrial dysfunction of neural stem/progenitor cells by amyloid pathology causes the impairment of AHN, and elucidate the molecular mechanism of the phenomenon. Methods To investigate the effect of mitochondrial dysfunction of neural stem/progenitor cells on neuronal differentiation, we expressed mitochondria-targeted amyloid beta (mitoAβ) in neural stem/progenitor cells in vitro and in vivo. Proteomic analysis of the hippocampal tissue implicated mitochondrial dysfunction by mitoAβ as a cause of AHN deficits. We identified epigenetic regulators of neural progenitor cells that are regulated by mitoAβ expression or drug-induced mitochondrial toxicity and proposed a link between mitochondria and AHN. Results Amyloid pathology characteristically inhibited the neuronal differentiation stage, not the proliferation of neural stem/progenitor cells during AHN in early AD model mice. Mitochondrial dysfunction in neural stem/progenitor cells by expressing mitoAβ inhibited the neuronal differentiation and AHN with cognitive impairment. Mechanistic studies revealed that lysine demethylase 5A (KDM5A) was involved in the neuronal differentiation and could be degraded by mitochondrial dysfunction in neural progenitor cells, thereby inhibiting the differentiation and cognitive functions. Conclusions These results reveal the new role of KDM5A as a mediator of retrograde signaling, reflecting mitochondrial status, and that the decrease of KDM5A in neural progenitor cells by mitochondrial dysfunction impairs the neuronal differentiation and AHN, finally leading to memory deficits. These findings and its relationship to mitochondrial dysfunction suggest that mitochondrial failure in neural progenitor cells by amyloid pathology closely associates with reduced AHN in AD.

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Metabolic tuning of inhibition regulates hippocampal neurogenesis in the adult brain

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2006138117 ◽

2020 ◽

Vol 117 (41) ◽

pp. 25818-25829

Author(s):

Xinxing Wang ◽

Hanxiao Liu ◽

Johannes Morstein ◽

Alexander J. E. Novak ◽

Dirk Trauner ◽

...

Keyword(s):

Dentate Gyrus ◽

Energy Homeostasis ◽

Inhibitory Neuron ◽

Hippocampal Neurogenesis ◽

Adult Brain ◽

Adult Hippocampal Neurogenesis ◽

Neuron Activity ◽

Adult Mice ◽

Sphingosine 1 Phosphate ◽

Underlying Mechanisms

Hippocampus-engaged behaviors stimulate neurogenesis in the adult dentate gyrus by largely unknown means. To explore the underlying mechanisms, we used tetrode recording to analyze neuronal activity in the dentate gyrus of freely moving adult mice during hippocampus-engaged contextual exploration. We found that exploration induced an overall sustained increase in inhibitory neuron activity that was concomitant with decreased excitatory neuron activity. A mathematical model based on energy homeostasis in the dentate gyrus showed that enhanced inhibition and decreased excitation resulted in a similar increase in neurogenesis to that observed experimentally. To mechanistically investigate this sustained inhibitory regulation, we performed metabolomic and lipidomic profiling of the hippocampus during exploration. We found sustainably increased signaling of sphingosine-1-phosphate, a bioactive metabolite, during exploration. Furthermore, we found that sphingosine-1-phosphate signaling through its receptor 2 increased interneuron activity and thus mediated exploration-induced neurogenesis. Taken together, our findings point to a behavior-metabolism circuit pathway through which experience regulates adult hippocampal neurogenesis.

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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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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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