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

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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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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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: 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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Running Promotes Spatial Bias Independently of Adult Neurogenesis

10.1101/125260 ◽

2017 ◽

Author(s):

Jason S. Snyder ◽

Shaina P. Cahill ◽

Paul W. Frankland

Keyword(s):

Adult Neurogenesis ◽

Dorsal Striatum ◽

Memory Systems ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Response Strategy ◽

Response Strategies ◽

Spatial Strategies ◽

Conflict Situations ◽

Exercise Induced

ABSTRACTDifferent memory systems offer distinct advantages to navigational behavior. The hippocampus forms complex associations between environmental stimuli, enabling flexible navigation through space. In contrast, the dorsal striatum associates discrete cues and favorable behavioral responses, enabling habit-like, automated navigation. While these two systems often complement one another, there are instances where striatal-dependent responses (e.g. approach a cue) conflict with hippocampal representations of spatial goals. In conflict situations, preference for spatial vs. response strategies varies across individuals and depends on previous experience, plasticity and the integrity of these two memory systems. Here, we investigated the role of adult hippocampal neurogenesis and exercise on mouse search strategies in a water maze task that can be solved with either a hippocampal-dependent place strategy or a striatal-dependent cue-response strategy. We predicted that inhibiting adult neurogenesis would impair hippocampal function and shift behavior towards striatal-dependent cue responses. However, blocking neurogenesis in a transgenic nestin-TK mouse did not affect strategy choice. We then investigated whether a pro-neurogenic stimulus, running, would bias mice towards hippocampal-dependent spatial strategies. While running indeed promoted spatial strategies, it did so even when neurogenesis was inhibited in nestin-TK mice. These findings indicate that exercise-induced increases in neurogenesis are not always required for enhanced cognitive function. Furthermore, our data identify exercise as a potentially useful strategy for promoting flexible, cognitive forms of memory in habit-related disorders that are characterized by excessive responding to discrete cues.

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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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De novo DNA methylation controls neuronal maturation during adult hippocampal neurogenesis

10.1101/2020.09.22.308692 ◽

2020 ◽

Author(s):

Sara Zocher ◽

Rupert W Overall ◽

Gabriel Berdugo-Vega ◽

Nicole Rund ◽

Anne Karasinsky ◽

...

Keyword(s):

Dna Methylation ◽

Cell Fate ◽

Adult Neurogenesis ◽

Hippocampal Neurons ◽

De Novo ◽

Functional Integration ◽

Stem Cell Differentiation ◽

Dna Methyltransferases ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis

SummaryDynamic DNA methylation controls gene-regulatory networks underlying cell fate specification. How DNA methylation patterns change during adult hippocampal neurogenesis and their relevance for adult neural stem cell differentiation and related brain function has, however, remained unknown. Here, we show that neurogenesis-associated de novo DNA methylation is critical for maturation and functional integration of adult-born hippocampal neurons. Cell stage-specific bisulfite sequencing revealed a pronounced gain of DNA methylation at neuronal enhancers, gene bodies and binding sites of pro-neuronal transcription factors during adult neurogenesis, which mostly correlated with transcriptional up-regulation of the associated loci. Inducible deletion of both de novo DNA methyltransferases Dnmt3a and Dnmt3b in adult neural stem cells specifically impaired dendritic outgrowth and synaptogenesis of new-born neurons, resulting in reduced hippocampal excitability and specific deficits in hippocampus-dependent learning and memory. Our results highlight that, during adult neurogenesis, remodeling of neuronal methylomes is fundamental for proper hippocampal function.

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Reactive, Adult Neurogenesis From Increased Neural Progenitor Cell Proliferation Following Alcohol Dependence in Female Rats

Frontiers in Neuroscience ◽

10.3389/fnins.2021.689601 ◽

2021 ◽

Vol 15 ◽

Author(s):

Natalie N. Nawarawong ◽

K. Ryan Thompson ◽

Steven P. Guerin ◽

Chinchusha Anasooya Shaji ◽

Hui Peng ◽

...

Keyword(s):

Alcohol Dependence ◽

Dentate Gyrus ◽

Adult Neurogenesis ◽

Progenitor Cell ◽

Neural Progenitor Cell ◽

Neural Progenitor ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Female Rats ◽

Immature Neurons

Hippocampal neurodegeneration is a consequence of excessive alcohol drinking in alcohol use disorders (AUDs), however, recent studies suggest that females may be more susceptible to alcohol-induced brain damage. Adult hippocampal neurogenesis is now well accepted to contribute to hippocampal integrity and is known to be affected by alcohol in humans as well as in animal models of AUDs. In male rats, a reactive increase in adult hippocampal neurogenesis has been observed during abstinence from alcohol dependence, a phenomenon that may underlie recovery of hippocampal structure and function. It is unknown whether reactive neurogenesis occurs in females. Therefore, adult female rats were exposed to a 4-day binge model of alcohol dependence followed by 7 or 14 days of abstinence. Immunohistochemistry (IHC) was used to assess neural progenitor cell (NPC) proliferation (BrdU and Ki67), the percentage of increased NPC activation (Sox2+/Ki67+), the number of immature neurons (NeuroD1), and ectopic dentate gyrus granule cells (Prox1). On day seven of abstinence, ethanol-treated females showed a significant increase in BrdU+ and Ki67+ cells in the subgranular zone of the dentate gyrus (SGZ), as well as greater activation of NPCs (Sox2+/Ki67+) into active cycling. At day 14 of abstinence, there was a significant increase in the number of immature neurons (NeuroD1+) though no evidence of ectopic neurogenesis according to either NeuroD1 or Prox1 immunoreactivity. Altogether, these data suggest that alcohol dependence produces similar reactive increases in NPC proliferation and adult neurogenesis. Thus, reactive, adult neurogenesis may be a means of recovery for the hippocampus after alcohol dependence in females.

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