Quantitative modeling of the dynamics of adult hippocampal neurogenesis in mice

JOURNAL/nrgr/04.03/01300535-202510000-00027/figure1/v/2024-11-26T163120Z/r/image-tiff Hippocampal neuronal loss causes cognitive dysfunction in Alzheimer's disease. Adult hippocampal neurogenesis is reduced in patients with Alzheimer's disease. Exercise stimulates adult hippocampal neurogenesis in rodents and improves memory and slows cognitive decline in patients with Alzheimer's disease. However, the molecular pathways for exercise-induced adult hippocampal neurogenesis and improved cognition in Alzheimer's disease are poorly understood. Recently, regulator of G protein signaling 6 (RGS6) was identified as the mediator of voluntary running-induced adult hippocampal neurogenesis in mice. Here, we generated novel RGS6 fl/fl ; APP SWE mice and used retroviral approaches to examine the impact of RGS6 deletion from dentate gyrus neuronal progenitor cells on voluntary running-induced adult hippocampal neurogenesis and cognition in an amyloid-based Alzheimer's disease mouse model. We found that voluntary running in APP SWE mice restored their hippocampal cognitive impairments to that of control mice. This cognitive rescue was abolished by RGS6 deletion in dentate gyrus neuronal progenitor cells, which also abolished running-mediated increases in adult hippocampal neurogenesis. Adult hippocampal neurogenesis was reduced in sedentary APP SWE mice versus control mice, with basal adult hippocampal neurogenesis reduced by RGS6 deletion in dentate gyrus neural precursor cells. RGS6 was expressed in neurons within the dentate gyrus of patients with Alzheimer's disease with significant loss of these RGS6-expressing neurons. Thus, RGS6 mediated voluntary running-induced rescue of impaired cognition and adult hippocampal neurogenesis in APP SWE mice, identifying RGS6 in dentate gyrus neural precursor cells as a possible therapeutic target in Alzheimer's disease.

Genetic loss of norepinephrine does not alter adult hippocampal neurogenesis in dopamine beta-hydroxylase deficient mice.

The pathological role of the bile acid receptor TGR5/GPBA in Alzheimer's disease (AD) is not fully understood. We investigated the pharmacological effects and mechanisms of TGR5 in AD model mice. TGR5 expression was assessed in AD mice using immunofluorescence and immunoblotting. Bidirectional modulation of TGR5 expression was achieved via stereotaxic delivery of adeno-associated virus vectors, while localized pharmacological activation was conducted through intracerebral cannula implantation. Cognition was evaluated using the Morris water maze and novel object recognition test. Adult hippocampal neurogenesis was assessed via immunofluorescence. Neuronal activity was analysed using immunofluorescence, fibre photometry and chemogenetics-coupled fibre photometry. Acetylcholine dynamics were monitored using fibre photometry, both alone and in combination with chemogenetic manipulation. TGR5 expression was selectively decreased in the medial septal (MS) cholinergic neurons during middle-late AD stages. Bidirectional genetic regulation of TGR5 in MS cholinergic neurons significantly affected cognition and adult hippocampal neurogenesis in mice. Pharmacological activation of TGR5 in the MS not only increased cholinergic neuronal activity and acetylcholine release, but also enhanced DG glutamatergic neuronal activity, acetylcholine levels and neurogenesis in AD mice. TGR5 modulated cognition and neurogenesis via the MScholinergic(ChAT)→ DGglutamatergic(Glu) circuit. Furthermore, α7 nAChRs in the DG were involved in TGR5-mediated improvements in cognition and neurogenesis. Our findings demonstrate that TGR5 in MS cholinergic neurons is critical during the middle-late stage of AD and provide valuable insights into the underlying neuronal circuit mechanisms. TGR5 (GPBA) represents a potential therapeutic target for AD treatment.

The regulative effects of levetiracetam on adult hippocampal neurogenesis in mice via Wnt/β-catenin signaling

Studies in rats that assessed the relation of hippocampus-dependent learning and adult hippocampal neurogenesis suggested a direct regulatory effect of learning on neurogenesis, whereas a similar study in mice had not found such causal link. We here report a substantial decrease of BrdU-positive cells and other measures of adult hippocampal neurogenesis in mice trained in the hidden (HID) or cued version (VIS) of the Morris water maze as compared to untrained animals (CTR). Particularly, cells on advanced stages of neuronal development contributed to this decrease, whereas earlier progenitors (type 2 cells) were not diminished in HID, but were diminished in VIS as compared to CTR. The differential regulation of type 2 cells in HID and VIS may have been caused by a different degree of physical activity, given that a time-yoked control group did not differ from HID, and type 2 cells reportedly constitute the proliferative dentate gyrus population that primarily responds to physical activity. The decrease of hippocampal neurogenesis by water maze training was reversible by pre-exposing animals to the water maze prior to training, suggesting that stress associated with training may have caused the acute downregulation of adult neurogenesis. We propose that in mice the Morris water maze does not provide a pure enough learning stimulus to study the presumed effects of 'learning' on adult neurogenesis. In addition, however, our data show that physical activity that is intricately linked to many cognitive tasks in rodents might play an important role in explaining effects of learning on cellular hippocampal plasticity.

Exposure to silver nanoparticles does not affect cognitive outcome or hippocampal neurogenesis in adult mice

Cessation of voluntary wheel running increases anxiety-like behavior and impairs adult hippocampal neurogenesis in mice

Evidence for the generation of young neurons out of precursor cells in the adult brain, i.e. adult neurogenesis, exists for at least two brain regions. New nerve cells are generated in the subventricular zone of the olfactory bulb and in the subgranular zone of hippocampal dentate gyrus. Young neurons of the subgranular zone migrate along the rostral migratory stream to the olfactory bulb, where they functionally integrate and contribute to the discrimination of odors. In the hippocampus the function of newly formed granule cells is still a matter of debate, yet it is thought that adult neurogenesis functionally contributes to hippocampal functions. Over the last twenty years of extensive research it became clear that adult hippocampal neurogenesis (AHN) in laboratory rodents can be up-and down regulated by different internal and external stimuli. Physical exercise in a running wheel being among the factors that have been most investigated. Since voluntary exercise not only increases adult neurogenesis in the hippocampus but also beneficially affects learning and memory in laboratory mice and rats, a widespread assumption holds a direct relationship between AHN and cognitive brain health also in higher order species, including humans. However, translating findings in laboratory rodents to the human condition faces difficulties. Enormous differences in basal rates of adult neurogenesis have been reported between mammalian species. The low level of AHN in primates and the complete lack of adult neurogenesis in bat species indicate species-specific differences in adult neurogenesis not only on a regulatory but also on a functional level. For a better understanding of species-specific differences in the regulation of AHN, we investigated basal rates of adult neurogenesis in laboratory mice and closely related wild mouse strains as well as the reaction of AHN to motivationally different running conditions. Testing different wild- and laboratory mice in the same environment allowed the identification of species-specific differences as well as possible domestication effects. Basal rates of adult hippocampal neurogenesis in equally-aged and genetically identical laboratory C57BL/6 mice show individual differences possibly reflecting epigenetic factors. However, the initial level of adult neurogenesis does not influence the response to wheel-exercise. Voluntary physical exercise in laboratory mice always increases AHN but this positive effect cannot be additively stimulated by enhanced running and is even lost as soon as the mice are forced to run. Rewarding the mice for their performance leads to an increase in wheel activity but does not translate into a corresponding additive increase in adult neurogenesis. Likewise, a more naturalistic situation, in which laboratory mice must run to obtain their daily food does not lead to an increase in cell proliferation and entails only a small increase in the number of young neurons, far below the one in voluntary running mice. Wild wood mice (Apodemus sylvaticus) and wild-derived western house mice (Mus musculus domesticus), both close relatives of the common laboratory mouse strains, were tested in the same running situations as laboratory C57BL/6 mice. Besides species-differences in basal neurogenesis rate, we find adult neurogenesis in wild mice remaining relatively constant in response to external influences. None of the factors that normally affect AHN in laboratory animals, such as stress, environmental changes or physical exercise, have an effect on adult neurogenesis in these animals. In wood mice, neither voluntary wheel running nor stress or an impoverished cage environment affect the number of newly generated neurons. House mice also show a stable adult neurogenesis, which shows no significant change after voluntary running or running for food. Adult neurogenesis in the dentate gyrus is thus regulated differently in laboratory and wild mice. However, even in laboratory mice it is not as plastic as initially suggested: laboratory mice, which are tested in a more naturalistic and complex running situation, show rather weak plasticity of AHN, resembling wild mice. Hence, it seems that the regulatory difference in adult neurogenesis between laboratory- and wild mice is, that laboratory animals react to a single stimulus in absence of other inputs. We believe that the constant exposure to different stimuli potentially affecting AHN has led to a natural selection that stabilizes adult neurogenesis in the wild. In contrast, during domestication - including inbreeding - much of the homeostatic capacity in regulating adult neurogenesis might have been lost. Taken together, our data imply that genetic (species-specific differences as well as within-species variation) play an important role in determining basal rates of adult neurogenesis, while motivational-contextual factors modulate the response of AHN to physical exercise, albeit chiefly in domesticated laboratory strains . As such differences appear already between phylogenetically closely related species, extrapolating findings in laboratory mice to distantly related taxonomic groups, such as humans, obviously requires much caution.

Spinosin, a C-glycoside flavonoid, enhances cognitive performance and adult hippocampal neurogenesis in mice

The role of adult hippocampal neurogenesis in contextual fear conditioning (CFC) is debated. Several studies demonstrated that blocking adult hippocampal neurogenesis in rodents impairs CFC, while several other studies failed to observe an impairment. We sought to determine whether different CFC methods vary in their sensitivity to the arrest of adult neurogenesis. Adult neurogenesis was arrested in mice using low-dose, targeted x-irradiation, and the effects of irradiation were assayed in conditioning procedures that varied in the use of a discrete conditioned stimulus, the number of trials administered, and the final level of conditioning produced. We demonstrate that irradiation impairs CFC in mice when a single-trial CFC procedure is used but not when multiple-trial procedures are used, regardless of the final level of contextual fear produced. In addition, we show that the irradiation-induced deficit in single-trial CFC can be rescued by providing preexposure to the conditioning context. These results indicate that adult hippocampal neurogenesis is required for CFC in mice only when brief training is provided.

Adult hippocampal neurogenesis (AHN) is suppressed by chronic stress. The negative effect of stress is mainly attributed to increased levels of stress hormones (e.g. glucocorticoids, GCs). Exercise enhances AHN, yet it also stimulates GC secretion. To delineate the paradoxical role of GCs, we took the advantage of a unique mouse strain (L/L) which exhibits an inert response to stress-induced secretion of GCs to study the role of GCs in exercise-induced AHN. Our results showed that basal corticosterone (CORT), the main GCs in rodents, levels were similar between the L/L mice and wild-type (WT) mice. However, levels of CORT in the L/L mice were barely altered and significantly lower than those of the WT mice during treadmill running (TR). AHN was enhanced by 4 weeks of TR in the WT mice, but not L/L mice. WT mice that received daily injection of CORT to evoke serum CORT levels similar to those during exercise for 4 weeks did not affect AHN, whereas injection with large amount of CORT inhibited AHN. Taken together, our results indicated that exercise-related elevation of CORT participates in exercise-enhanced AHN. CORT alone is not sufficient to elicit AHN and may inhibit AHN if the levels are high.

Impaired adult hippocampal neurogenesis and its partial reversal by chronic treatment of fluoxetine in a mouse model of Angelman syndrome

Differential 24 h responsiveness of Prox1–expressing precursor cells in adult hippocampal neurogenesis to physical activity, environmental enrichment, and kainic acid–induced seizures

We asked whether cell-cycle associated protein p27kip1 might be involved in the transition of precursor cells to postmitotic maturation in adult hippocampal neurogenesis. p27kip1 was expressed throughout the dentate gyrus with a strong nuclear expression in early postmitotic, calretinin-positive neurons and neuronally determined progenitor cells (type-3 and some type-2b), lower or absent expression in radial glia-like precursor cells (type-1) and type-2a cells and essentially no expression in granule cells. This suggested a transitory role in late proliferative and early postmitotic phases of neurogenesis. Inconsistent with a role limited to cell cycle arrest the acute stimuli, voluntary wheel running (RUN), environmental enrichment (ENR) and kainate-induced seizures increased p27kip1 expressing cells. Sequential short-term combination of RUN and ENR yielded more p27kip1 cells than either stimulus alone, indicating an additive effect. In vitro, p27kip1 was lowly expressed by proliferating precursor cells but increased upon differentiation. In p27kip1-/- mice neurogenesis was reduced in vivo, whereas the number of proliferating cells was increased. Accordingly, the microdissected dentate gyrus of p27kip1-/- mice generated more colonies in the neurosphere assay and an increased number of larger spheres with the differentiation potential unchanged. In p27kip1-/- monolayer cultures, proliferation was increased and cell cycle genes were upregulated. In the Morris water maze p27kip1-/- mice learned the task but were specifically impaired in the reversal phase explainable by the decrease in adult neurogenesis. We conclude that p27kip1 is involved in the decisive step around cell-cycle exit and plays an important role in activity-regulated and functionally relevant adult hippocampal neurogenesis. Stem Cells 2017;35:787-799.

The present study was designated to investigate the effect of oxytocin (OXT) on the retrieval of methamphetamine (METH)-associated reward memories induced by drugs in mice and its underlying mechanisms related to adult hippocampal neurogenesis (AHN) and memory engrams. The data showed that repeated hippocampal microinjections of OXT (1.25 and 2.5 μg) for 8 consecutive days significantly prevented the retrieval of METH-associated reward memories induced by drugs in a time-, dose- and receptor-dependent manner in mice. At the meanwhile, OXT was found to markedly elevate AHN levels, enhancing the proliferation, survival and maturation of newborn neurons by using NestinCreERT2::Rosa26-tdTomato mice and BrdU labeling. Notably, reduction or depletion of AHN by temozolomide (TMZ) or NestinCreERT2 mice combined with adeno-associated viruses (AAVs) (AAV-CAG-DIO-rtTA-EGFP and AAV-TRE-DTA) could attenuate the inhibition of OXT on the retrieval of METH-associated reward memories in mice. By using activity-dependent labeling strategy in mice, it was observed that the retrieval of METH-associated reward memories was mediated by activation of METH-associated memory engrams in the dentate gyrus (DG) region of the hippocampus. Repeated hippocampal microinjections of OXT effectively prevented the activation of these memory engrams, which could be abolished after reducing AHN by TMZ. In summary, this study revealed that OXT effectively prevented the retrieval of METH-associated reward memories induced by drugs in mice, which may be related to its enhancement on AHN as well as inhibition on METH-associated memory engrams in DG.