Adult-generated Neurons Research Articles

An analogue of the Prolactin Releasing Peptide reduces obesity and promotes adult neurogenesis

Hypothalamic Adult Neurogenesis (hAN) has been implicated in regulating energy homeostasis. Adult-generated neurons and adult Neural Stem Cells (aNSCs) in the hypothalamus control food intake and body weight. Conversely, diet-induced obesity (DIO) by high fat diets (HFD) exerts adverse influence on hAN. However, the effects of anti-obesity compounds on hAN are not known. To address this, we administered a lipidized analogue of an anti-obesity neuropeptide, Prolactin Releasing Peptide (PrRP), so-called LiPR, to mice. In the HFD context, LiPR rescued the survival of adult-born hypothalamic neurons and increased the number of aNSCs by reducing their activation. LiPR also rescued the reduction of immature hippocampal neurons and modulated calcium dynamics in iPSC-derived human neurons. In addition, some of these neurogenic effects were exerted by another anti-obesity compound, Liraglutide. These results show for the first time that anti-obesity neuropeptides influence adult neurogenesis and suggest that the neurogenic process can serve as a target of anti-obesity pharmacotherapy.

Short-Term, Voluntary Exercise Affects Morpho-Functional Maturation of Adult-Generated Neurons in Rat Hippocampus.

Physical exercise is a well-proven neurogenic stimulus, promoting neuronal progenitor proliferation and affecting newborn cell survival. Besides, it has beneficial effects on brain health and cognition. Previously, we found that three days of physical activity in a very precocious period of adult-generated granule cell life is able to antedate the appearance of the first GABAergic synaptic contacts and increase T-type Ca2+ channel expression. Considering the role of GABA and Ca2+ in fostering neuronal maturation, in this study, we used short-term, voluntary exercise on a running wheel to investigate if it is able to induce long-term morphological and synaptic changes in newborn neurons. Using adult male rats, we found that: (i) three days of voluntary physical exercise can definitively influence the morpho-functional maturation process of newborn granule neurons when applied very early during their development; (ii) a significant percentage of new neurons show more mature morphological characteristics far from the end of exercise protocol; (iii) the long-term morphological effects result in enhanced synaptic plasticity. Present findings demonstrate that the morpho-functional changes induced by exercise on very immature adult-generated neurons are permanent, affecting the neuron maturation and integration in hippocampal circuitry. Our data contribute to underpinning the beneficial potential of physical activity on brain health, also performed for short times.

Functional Integration of Adult-Generated Neurons in Diabetic Goto-Kakizaki Rats.

Adult-born neurons in the dentate gyrus (DG) make important contributions to learning as they integrate into neuronal networks. Neurogenesis is dramatically reduced by a number of conditions associated with cognitive impairment, including type 2 diabetes mellitus (T2DM). Increasing neurogenesis may thus provide a therapeutic target for ameliorating diabetes-associated cognitive impairments, but only if new neurons remain capable of normal function. To address the capacity for adult-generated neurons to incorporate into functional circuits in the hyperglycemic DG, we measured Egr1 expression in granule cells (GCs), BrdU labeled four weeks prior, in Goto-Kakizaki (GK) rats, an established model of T2DM, and age-matched Wistars. The results indicate that while fewer GCs are generated in the DG of GK rats, GCs that survive readily express Egr1 in response to spatial information. These data demonstrate that adult-generated GCs in the hyperglycemic DG remain functionally competent and support neurogenesis as a viable therapeutic target.

Increasing Adult Hippocampal Neurogenesis Promotes Resilience in a Mouse Model of Depression.

Many studies evaluated the functional role of adult hippocampal neurogenesis (AHN) and its key role in cognitive functions and mood regulation. The effects of promoting AHN on the recovery of stress-induced symptoms have been well studied, but its involvement in stress resilience remains elusive. We used a mouse model enabling us to foster AHN before the exposure to unpredictable chronic mild stress (UCMS) to evaluate the potential protective effects of AHN on stress, assessing the depressive-like phenotype and executive functions. For this purpose, an inducible transgenic mouse model was used to delete the pro-apoptotic gene Bax from neural progenitors four weeks before UCMS, whereby increasing the survival of adult-generated neurons. Our results showed that UCMS elicited a depressive-like phenotype, highlighted by a deteriorated coat state, a higher immobility duration in the tail suspension test (TST), and a delayed reversal learning in a water maze procedure. Promoting AHN before UCMS was sufficient to prevent the development of stressed-induced behavioral changes in the TST and the water maze, reflecting an effect of AHN on stress resilience. Taken together, our data suggest that increasing AHN promotes stress resilience on some depressive-like symptoms but also in cognitive symptoms, which are often observed in MD.

Enriched environment ameliorates adult hippocampal neurogenesis deficits in Tcf4 haploinsufficient mice

BackgroundTranscription factor 4 (TCF4) has been linked to human neurodevelopmental disorders such as intellectual disability, Pitt-Hopkins Syndrome (PTHS), autism, and schizophrenia. Recent work demonstrated that TCF4 participates in the control of a wide range of neurodevelopmental processes in mammalian nervous system development including neural precursor proliferation, timing of differentiation, migration, dendritogenesis and synapse formation. TCF4 is highly expressed in the adult hippocampal dentate gyrus – one of the few brain regions where neural stem / progenitor cells generate new functional neurons throughout life.ResultsWe here investigated whether TCF4 haploinsufficiency, which in humans causes non-syndromic forms of intellectual disability and PTHS, affects adult hippocampal neurogenesis, a process that is essential for hippocampal plasticity in rodents and potentially in humans. Young adult Tcf4 heterozygote knockout mice showed a major reduction in the level of adult hippocampal neurogenesis, which was at least in part caused by lower stem/progenitor cell numbers and impaired maturation and survival of adult-generated neurons. Interestingly, housing in an enriched environment was sufficient to enhance maturation and survival of new neurons and to substantially augment neurogenesis levels in Tcf4 heterozygote knockout mice.ConclusionThe present findings indicate that haploinsufficiency for the intellectual disability- and PTHS-linked transcription factor TCF4 not only affects embryonic neurodevelopment but impedes neurogenesis in the hippocampus of adult mice. These findings suggest that TCF4 haploinsufficiency may have a negative impact on hippocampal function throughout adulthood by impeding hippocampal neurogenesis.

Hormonal Regulation of Mammalian Adult Neurogenesis: A Multifaceted Mechanism.

Adult neurogenesis—resulting in adult-generated functioning, integrated neurons—is still one of the most captivating research areas of neuroplasticity. The addition of new neurons in adulthood follows a seemingly consistent multi-step process. These neurogenic stages include proliferation, differentiation, migration, maturation/survival, and integration of new neurons into the existing neuronal network. Most studies assessing the impact of exogenous (e.g., restraint stress) or endogenous (e.g., neurotrophins) factors on adult neurogenesis have focused on proliferation, survival, and neuronal differentiation. This review will discuss the multifaceted impact of hormones on these various stages of adult neurogenesis. Specifically, we will review the evidence for hormonal facilitation (via gonadal hormones), inhibition (via glucocorticoids), and neuroprotection (via recruitment of other neurochemicals such as neurotrophin and neuromodulators) on newly adult-generated neurons in the mammalian brain.

Neuroinflammation and depression: A review.

Some recent clinical and preclinical evidence suggests that neuroinflammation is a key factor that interacts with the three neurobiological correlates of major depressive disorder: depletion of brain serotonin, dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis and alteration of the continuous production of adult-generated neurons in the dentate gyrus of the hippocampus. This review discusses the main players in brain immunity as well as how inflammation interacts with the above three mechanisms. It is reported that kynurenine (KYN) pathway alteration in favour of its excitotoxic component and HPA axis dysregulation have the common effect of increasing extracellular glutamate levels and glutamate neurotransmission, which can impact hippocampal neurogenesis. This pathophysiological cascade appears to be triggered or sustained and reinforced by any chronic inflammatory condition involving increased circulating markers of inflammation that are able to cross the blood-brain barrier and activate microglia; it can also be the consequence of primary brain neuroinflammation, such as in neurodegenerative disorders with early manifestations that are frequently depressive symptoms. Further recent data indicate that primary microglial activation may also result from a direct impact of chronic stress on vascular function. The intricated dynamic crosstalk between neuroinflammation and other relevant neurobiological correlates of depression add to evidence that neuroinflammation may be a key therapeutic target for future therapeutic strategies in major depressive disorder.

Targeting Seizure-Induced Neurogenesis in a Clinically Relevant Time Period Leads to Transient But Not Persistent Seizure Reduction.

Mesial temporal lobe epilepsy (mTLE), the most common form of medically refractory epilepsy in adults, is usually associated with hippocampal pathophysiology. Using rodent models of mTLE, many studies including work from our laboratory have shown that new neurons born around the onset of severe acute seizures known as status epilepticus (SE) are crucial for the process of epileptogenesis and targeting seizure-induced neurogenesis either genetically or pharmacologically can impact the frequency of chronic seizures. However, these studies are limited in their clinical relevance as none of them determines the potential of blocking new neurons generated after the epileptogenic insult to alleviate the development of chronic seizures. Therefore, using a pilocarpine-induced SE model of mTLE in mice of either sex, we show that >4 weeks of continuous and concurrent ablation of seizure-induced neurogenesis after SE can reduce the formation of spontaneous recurrent seizures by 65%. We also found that blocking post-SE neurogenesis does not lead to long-term seizure reduction as the effect was observed only transiently for 10 d with >4 weeks of continuous and concurrent ablation of seizure-induced neurogenesis. Thus, these findings provide evidence that seizure-induced neurogenesis when adequately reduced in a clinically relevant time period has the potential to transiently suppress recurrent seizures, but additional mechanisms need to be targeted to permanently prevent epilepsy development.SIGNIFICANCE STATEMENT Consistent with morphological and electrophysiological studies suggesting aberrant adult-generated neurons contribute to epilepsy development, ablation of seizure-induced new neurons at the time of the initial insult reduces the frequency of recurrent seizures. In this study, we show that continuous targeting of post-insult new neurons in a therapeutically relevant time period reduces chronic seizures; however, this effect does not persist suggesting possible additional mechanisms.

The Impact of Ethologically Relevant Stressors on Adult Mammalian Neurogenesis

Adult neurogenesis—the formation and functional integration of adult-generated neurons—remains a hot neuroscience topic. Decades of research have identified numerous endogenous (such as neurotransmitters and hormones) and exogenous (such as environmental enrichment and exercise) factors that regulate the various neurogenic stages. Stress, an exogenous factor, has received a lot of attention. Despite the large number of reviews discussing the impact of stress on adult neurogenesis, no systematic review on ethologically relevant stressors exists to date. The current review details the effects of conspecifically-induced psychosocial stress (specifically looking at the lack or disruption of social interactions and confrontation) as well as non-conspecifically-induced stress on mammalian adult neurogenesis. The underlying mechanisms, as well as the possible functional role of the altered neurogenesis level, are also discussed. The reviewed data suggest that ethologically relevant stressors reduce adult neurogenesis.

Adult Neurogenesis, Glia, and the Extracellular Matrix.

In the adult mammalian hippocampus, new neurons arise from stem and progenitor cell division, in a process known as adult neurogenesis. Adult-generated neurons are sensitive to experience and may participate in hippocampal functions, including learning and memory, anxiety and stress regulation, and social behavior. Increasing evidence emphasizes the importance of new neuron connectivity within hippocampal circuitry for understanding the impact of adult neurogenesis on brain function. In this Review, we discuss how the functional consequences of new neurons arise from the collective interactions of presynaptic and postsynaptic neurons, glial cells, and the extracellular matrix, which together form the "tetrapartite synapse."

Adult hippocampal neurogenesis occurs in the absence of Presenilin 1 and Presenilin 2

Mutations in the presenilin genes (PS1 and PS2) are a major cause of familial-Alzheimer’s disease (FAD). Presenilins regulate neurogenesis in the developing brain, with loss of PS1 inducing aberrant premature differentiation of neural progenitor cells, and additional loss of PS2 exacerbating this effect. It is unclear, however, whether presenilins are involved in adult neurogenesis, a process that may be impaired in Alzheimer’s disease within the hippocampus. To investigate the requirement of presenilins in adult-generated dentate granule neurons, we examined adult neurogenesis in the PS2−/− adult brain and then employ a retroviral approach to ablate PS1 selectively in dividing progenitor cells of the PS2−/− adult brain. Surprisingly, the in vivo ablation of both presenilins resulted in no defects in the survival and differentiation of adult-generated neurons. There was also no change in the morphology or functional properties of the retroviral-labeled presenilin-null cells, as assessed by dendritic morphology and whole-cell electrophysiology analyses. Furthermore, while FACS analysis showed that stem and progenitor cells express presenilins, inactivation of presenilins from these cells, using a NestinCreERT2 inducible genetic approach, demonstrated no changes in the proliferation, survival, or differentiation of adult-generated cells. Therefore, unlike their significant role in neurogenesis during embryonic development, presenilins are not required for cell-intrinsic regulation of adult hippocampal neurogenesis.

Excitable Adult-Generated GABAergic Neurons Acquire Functional Innervation in the Cortex after Stroke.

SummaryIschemic stroke enhances the proliferation of adult-generated precursor cells that ectopically migrate toward the infarct. Studies have correlated precursor cell proliferation and subsequent adult neurogenesis with enhanced stroke recovery, yet it remains unclear whether stroke can generate new neurons capable of functional integration into the injured cortex. Here, using single and bitransgenic reporter mice, we identify spatial and temporal features of a multilineage cellular response to focal ischemia. We reveal that a small population of stroke-induced immature neurons accumulate within the peri-infarct region of the adult sensorimotor cortex, exhibit voltage-dependent conductances, fire action potentials, express GABAergic markers, and receive sparse GABAergic synaptic inputs. Collectively, these findings reveal that GABAergic neurons arising from the lateral ventricle have the capacity to integrate into the stroke-injured cortex, although their limited number and exiguous synaptic integration may limit their ability to participate in stroke recovery.

Phosphorylation of the neurogenic transcription factor SOX11 on serine 133 modulates neuronal morphogenesis

The intellectual disability gene, Sox11, encodes for a critical neurodevelopmental transcription factor with functions in precursor survival, neuronal fate determination, migration and morphogenesis. The mechanisms regulating SOX11’s activity remain largely unknown. Mass spectrometric analysis uncovered that SOX11 can be post-translationally modified by phosphorylation. Here, we report that phosphorylatable serines surrounding the high-mobility group box modulate SOX11’s transcriptional activity. Through Mass Spectrometry (MS), co-immunoprecipitation assays and in vitro phosphorylation assays followed by MS we verified that protein kinase A (PKA) interacts with SOX11 and phosphorylates it on S133. In vivo replacement of SoxC factors in developing adult-generated hippocampal neurons with SOX11 S133 phospho-mutants indicated that phosphorylation on S133 modulates dendrite development of adult-born dentate granule neurons, while reporter assays suggested that S133 phosphorylation fine-tunes the activation of select target genes. These data provide novel insight into the control of the critical neurodevelopmental regulator SOX11 and imply SOX11 as a mediator of PKA-regulated neuronal development.

FoxO Function Is Essential for Maintenance of Autophagic Flux and Neuronal Morphogenesis in Adult Neurogenesis

Autophagy is a conserved catabolic pathway with emerging functions in mammalian neurodevelopment and human neurodevelopmental diseases. The mechanisms controlling autophagy in neuronal development are not fully understood. Here, we found that conditional deletion of the Forkhead BoxO transcription factors FoxO1, FoxO3, and FoxO4 strongly impaired autophagic flux in developing neurons of the adult mouse hippocampus. Moreover, FoxO deficiency led to altered dendritic morphology, increased spine density, and aberrant spine positioning in adult-generated neurons. Strikingly, pharmacological induction of autophagy was sufficient to correct abnormal dendrite and spine development of FoxO-deficient neurons. Collectively, these findings reveal a novel link between FoxO transcription factors, autophagic flux, and maturation of developing neurons.

AhR Deletion Promotes Aberrant Morphogenesis and Synaptic Activity of Adult-Generated Granule Neurons and Impairs Hippocampus-Dependent Memory

Newborn granule cells are continuously produced in the subgranular zone of dentate gyrus throughout life. Once these cells mature, they integrate into pre-existing circuits modulating hippocampus-dependent memory. Subsequently, mechanisms controlling generation and maturation of newborn cells are essential for proper hippocampal function. Therefore, we have studied the role of aryl hydrocarbon receptor (AhR), a ligand-activated bHLH-PAS transcription factor, in hippocampus-dependent memory and granule neuronal morphology and function using genetic loss-of-function approaches based on constitutive and inducible-nestin AhR-/- mice. The results presented here show that the impaired hippocampus-dependent memory in AhR absence is not due to its effects on neurogenesis but to aberrant dendritic arborization and an increased spine density, albeit with a lower number of mature mushrooms spines in newborn granule cells, a finding that is associated with an immature electrophysiological phenotype. Together, our data strongly suggest that AhR plays a pivotal role in the regulation of hippocampal function, by controlling hippocampal granule neuron morphology and synaptic maturation.

Human Adult Neurogenesis: Evidence and Remaining Questions.

Renewed discussion about whether or not adult neurogenesis exists in the human hippocampus, and the nature and strength of the supporting evidence, has been reignited by two prominently published reports with opposite conclusions. Here, we summarize the state of the field and argue that there is currently no reason to abandon the idea that adult-generated neurons make important functional contributions to neural plasticity and cognition across the human lifespan.

Selective alteration of adult hippocampal neurogenesis and impaired spatial pattern separation performance in the RSK2-deficient mouse model of Coffin-Lowry syndrome

Adult neurogenesis is involved in certain hippocampus-dependent cognitive functions and is linked to psychiatric diseases including intellectual disabilities. The Coffin-Lowry syndrome (CLS) is a developmental disorder caused by mutations in the Rsk2 gene and characterized by intellectual disabilities associated with growth retardation. How RSK2-deficiency leads to cognitive dysfunctions in CLS is however poorly understood. Here, using Rsk2 Knock-Out mice, we characterized the impact of RSK2 deficiency on adult hippocampal neurogenesis in vivo. We report that the absence of RSK2 does not affect basal proliferation, differentiation and survival of dentate gyrus adult-born neurons but alters the maturation progression of young immature newborn neurons. Moreover, when RSK2-deficient mice were submitted to spatial learning, in contrast to wild-type mice, proliferation of adult generated neurons was decreased and no pro-survival effect of learning was observed. Thus, learning failed to recruit a selective population of young newborn neurons in association with deficient long-term memory recall. Given the proposed role of the dentate gyrus and of adult-generated newborn neurons in hippocampal-dependent pattern separation function, we explored this function in a delayed non-matching to place task and in an object-place pattern separation task and report severe deficits in spatial pattern separation in Rsk2-KO mice. Together, this study reveals a previously unknown role for RSK2 in the early stages of maturation and learning-dependent involvement of adult-born dentate gyrus neurons. These alterations associated with a deficit in the ability of RSK2-deficient mice to finely discriminate relatively similar spatial configurations, may contribute to cognitive dysfunction in CLS.

Concise Review: Regulatory Influence of Sleep and Epigenetics on Adult Hippocampal Neurogenesis and Cognitive and Emotional Function.

Neural stem and progenitor cells continue to generate new neurons in particular regions of the brain during adulthood. One of these neurogenic regions is the dentate gyrus (DG) of the hippocampus, which plays an important role in cognition and emotion. By exploiting this innate neuronal regeneration mechanism in the DG, new technologies have the potential to promote resistance to or recovery from brain dysfunction or degeneration. However, a deeper understanding of how adult DG neurogenesis is regulated by factors such as sleep and epigenetic modifications of gene expression could lead to further breakthroughs in the clinical application of neural stem and progenitor cells. In this review, we discuss the functions of adult-born DG neurons, describe the epigenetic regulation of adult DG neurogenesis, identify overlaps in how sleep and epigenetic modifications impact adult DG neurogenesis and memory consolidation, and suggest ways of using sleep or epigenetic interventions as therapies for neurodegenerative and psychiatric disorders. By knitting together separate strands of the literature, we hope to trigger new insights into how the functions of adult-generated neurons are directed by interactions between sleep-related neural processes and epigenetic mechanisms to facilitate novel approaches to preventing and treating brain disorders such as depression, post-traumatic stress disorder, and Alzheimer's disease. Stem Cells 2018;36:969-976.

Peripheral Etanercept Administration Normalizes Behavior, Hippocampal Neurogenesis, and Hippocampal Reelin and GABAA Receptor Expression in a Preclinical Model of Depression.

Depression is a serious psychiatric disorder frequently comorbid with autoimmune disorders. Previous work in our lab has demonstrated that repeated corticosterone (CORT) injections in rats reliably increase depressive-like behavior, impair hippocampal-dependent memory, reduce the number and complexity of adult-generated neurons in the dentate gyrus, decrease hippocampal reelin expression, and alter markers of GABAergic function. We hypothesized that peripheral injections of the TNF-α inhibitor etanercept could exert antidepressant effects through a restoration of many of these neurobiological changes. To test this hypothesis, we examined the effect of repeated CORT injections and concurrent injections of etanercept on measures of object-location and object-in-place memory, forced-swim test behavior, hippocampal neurogenesis, and reelin and GABA β2/3 immunohistochemistry. CORT increased immobility behavior in the forced swim test and impaired both object-location and object-in-place memory, and these effects were reversed by etanercept. CORT also decreased both the number and complexity of adult-generated neurons, but etanercept restored these measures back to control levels. Finally, CORT decreased the number of reelin and GABA β2/3-ir cells within the subgranular zone of the dentate gyrus, and etanercept restored these to control levels. These novel results demonstrate that peripheral etanercept has antidepressant effects that are accompanied by a restoration of cognitive function, hippocampal neurogenesis, and GABAergic plasticity, and suggest that a normalization of reelin expression in the dentate gyrus could be a key component underlying these novel antidepressant effects.

Adult-generated neurons born during chronic social stress are uniquely adapted to respond to subsequent chronic social stress.

Chronic stress is a recognized risk factor for psychiatric and psychological disorders and a potent modulator of adult neurogenesis. Numerous studies have shown that during stress, neurogenesis decreases; however, during the recovery from the stress, neurogenesis increases. Despite the increased number of neurons born after stress, it is unknown if the function and morphology of those neurons are altered. Here we asked whether neurons in adult mice, born during the final 5 days of chronic social stress and matured during recovery from chronic social stress, are similar to neurons born with no stress conditions from a quantitative, functional and morphological perspective, and whether those neurons are uniquely adapted to respond to a subsequent stressful challenge. We observed an increased number of newborn neurons incorporated in the dentate gyrus of the hippocampus during the 10-week post-stress recovery phase. Interestingly, those new neurons were more responsive to subsequent chronic stress, as they showed more of a stress-induced decrease in spine density and branching nodes than in neurons born during a non-stress period. Our results replicate findings that the neuronal survival and incorporation of neurons in the adult dentate gyrus increases after chronic stress and suggest that such neurons are uniquely adapted in the response to future social stressors. This finding provides a potential mechanism for some of the long-term hippocampal effects of stress.