Study Of Adult Neurogenesis Research Articles

Adult Neurogenesis: A Review of Current Perspectives and Implications for Neuroscience Research

Background: The study of new neuron formation in the adult brain has sparked controversy and ignited interest among scientists in recent times, these include its occurrence and location in the adult human brain, functional significance, variation in study methods, translation from animal model to human, and ethical challenges involving neural stem cell research. Aim: To provide a comprehensive understanding of adult neurogenesis, functional significance, and challenges and explore the latest advances in the study of adult neurogenesis. Methodology: An extensive and systematic search of electronic databases (Medline, Scopus, Web of Science) was conducted using keywords related to adult neurogenesis and techniques involved in its study. Results: The mechanism of adult neurogenesis was found to occur in specific brain regions such as the subgranular zone of the dentate gyrus and subventricular zone of the lateral ventricle. Adult neurogenesis is vital neural plasticity, providing a potential mechanism for the brain to adapt and reorganize in response to environmental cues and experiences. Cutting-edge research and sophisticated imaging techniques, such as two-photon microscopy, MRI, optogenetic, and stem-cell-based therapies have provided deeper insight into the study of adult neurogenesis. Conclusion: The study of neurogenesis is important for understanding nervous system development, physiology, pathology, and exploring neuroplasticity. Its advancement is challenged by some ethical concerns regarding embryonic, pluripotent stem cells, and the need for safe, and noninvasive study methods. Although recent breakthroughs in neuroimaging, microscopic techniques, and genetic tools are aiding real-time study of adult neurogenesis.

Deconstructing Neurogenesis, Transplantation and Genome-Editing as Neural Repair Strategies in Brain Disease.

Neural repair in injury and disease presents a pressing unmet need in regenerative medicine. Due to the intrinsically reduced ability of the brain to replace lost and damaged neurons, reversing long-term cognitive and functional impairments poses a unique problem. Over the years, advancements in cellular and molecular understanding of neurogenesis mechanisms coupled with sophistication of biotechnology tools have transformed neural repair into a cross-disciplinary field that integrates discoveries from developmental neurobiology, transplantation and tissue engineering to design disease- and patient-specific remedies aimed at boosting either native rehabilitation or delivering exogenous hypoimmunogenic interventions. Advances in deciphering the blueprint of neural ontogenesis and annotation of the human genome has led to the development of targeted therapeutic opportunities that have the potential of treating the most vulnerable patient populations and whose findings from benchside suggest looming clinical translation. This review discusses how findings from studies of adult neurogenesis have informed development of interventions that target endogenous neural regenerative machineries and how advances in biotechnology, including the use of new gene-editing tools, have made possible the development of promising, complex neural transplant-based strategies. Adopting a multi-pronged strategy that is tailored to underlying neural pathology and that encompasses facilitation of endogenous regeneration, correction of patient’s genomic mutations and delivery of transformed neural precursors and mature disease-relevant neuronal populations to replace injured or lost neural tissue remains no longer a fantasy.

Stem Cell Aging? Blame It on the Niche.

The molecular basis for the neural stem cell quiescence-to-activation transition has become an important focus in the study of adult neurogenesis. Recently in Cell, Kalamakis etal. (2019) show that aged neural stem cells face greater barriers to exiting quiescence, imposed by the niche through inflammation and altered Wnt signaling.

Effect of physical activity on structural asymmetry of mouse hippocampus

The relevance of studies of adult neurogenesis is evident in connection with the potential use of these new neurons to replace neurons lost in the process of life. Despite considerable efforts, little is known about the fnal fate of these cells, the functional signifcance of their connections and the regulation of their development. It is known that physical activity signifcantly increases the number of fssile progenitors, the precursors of new neurons in the dentate gyrus of the hippocampus. The existing immunohistochemical methods for labeling new neurons do not allow tracing the temporal dynamics of changes in the volume of brain structures in the same animal, induced by external impacts, such as voluntary exercise. This makes it an urgent task to develop and improve methods for long­term control of changes that occur in the adult hippocampus due to the induction of neurogenesis. The main purpose of this work was to non­invasively track, by using magnetic resonance imaging (MRI), the temporal dynamics of changes in the volume of the hippocampus in the same animals that had voluntary physical activity. It was found that voluntary exercise did not change the total volume of the mouse hippocampus. However, the difference in the volume ratio between the right and left parts of the hippocampus was signifcantly lower compared with the control group. The reconstruction and analysis of protein­protein interactions that ensure the survival of a large number of new neurons and their integration into existing neural networks in the hippocampus have been carried out. The proposed approach allows the non­invasive registration of changes in the ratio of the volumes of these paired brain structures.

Dorsal and ventral hippocampal adult-born neurons contribute to context fear memory.

The hippocampus contains one of the few neurogenic niches within the adult brain-the subgranular zone of the dentate gyrus. The functional significance of adult-born neurons in this region has been characterized using context fear conditioning, a Pavlovian paradigm in which animals learn to associate a location with danger. Ablation or silencing of adult-born neurons impairs both acquisition and recall of contextual fear conditioning, suggesting that these neurons contribute importantly to hippocampal memory. Lesion studies indicate that CFC depends on neural activity in both the dorsal and ventral hippocampus, subregions with unique extrahippocampal connectivity and behavioral functions. Because most studies of adult neurogenesis have relied on methods that permanently ablate neurogenesis throughout the entire hippocampus, little is known about how the function of adult-born neurons varies along the dorsal-ventral axis. Using a Nestin-CreERT2 mouse line to target the optogenetic silencer Archaerhodopsin to adult-born neurons, we compared the contribution of dorsal and ventral adult-born neurons to acquisition, recall, and generalization of CFC. Acquisition of CFC was impaired when either dorsal or ventral adult-born neurons were silenced during training. Silencing dorsal or ventral adult-born neurons during test sessions decreased context-evoked freezing but did not impair freezing in a hippocampus-independent tone-shock freezing paradigm. Silencing adult-born neurons modestly reduced generalization of fear. Our data indicate that adult-born neurons in the dorsal and ventral hippocampus contribute to both memory acquisition and recall. The comparatively large behavioral effects of silencing a small number of adult-born neurons suggest that these neurons make a unique and powerful contribution to hippocampal function.

A New Method for In Vitro Detection of Bromodeoxyuridine in Serum: A Proof of Concept in a Songbird Species, the Canary

Systemic injection of a thymidine analogue such as bromodeoxyuridine (BrdU) in vertebrates is commonly used to detect and study cell production during development, adulthood, and pathology, particularly in studies of adult neurogenesis. Although researchers are applying this technique to multiple species in various physiological conditions, the rate of BrdU clearance from the serum remains unknown in most cases. Changes in this clearance rate as a function of the species, sex or endocrine condition could however profoundly affect the interpretation of the results. We describe a rapid, sensitive, but simple bioassay for post-injection detection and quantification of BrdU in serum. This procedure was shown to be suitable for determining the length of time a thymidine analogue remains in the bloodstream of one avian species and seems applicable to any vertebrate provided sufficiently large blood samples can be collected. This technique was used to demonstrate that, in canaries, BrdU injected at a dose of 100 mg/kg is no longer available for incorporation into DNA between 30 and 60 min post-injection, a delay shorter than anticipated based on the available literature. Preliminary data suggest a similar fast clearance in Japanese quail and mice.

Doxycycline increases neurogenesis and reduces microglia in the adult hippocampus

Adult hippocampal neurogenesis results in the continuous formation of new neurons and is a process of brain plasticity involved in learning and memory. Although inducible-reversible transgenic mouse models are increasingly being used to investigate adult neurogenesis, transgene control requires the administration of an activator, doxycycline (Dox), with unknown effects on adult neurogenesis. Here, we tested the effect of Dox administration on adult neurogenesis in vivo. We found that 4 weeks of Dox treatment at doses commonly used for gene expression control, resulted in increased neurogenesis. Furthermore, the dendrites of new neurons displayed increased spine density. Concomitantly, Iba1-expressing microglia was reduced by Dox treatment. These results indicate that Dox treatment may interfere with parameters of relevance for the use of inducible transgenic mice in studies of adult neurogenesis or brain inflammation.

From chemical neuroanatomy to an understanding of the olfactory system.

The olfactory system of mammals is the appropriate model for studying several aspects of neuronal physiology spanning from the developmental stage to neural network remodelling in the adult brain. Both the morphological and physiological understanding of this system were strongly supported by classical histochemistry. It is emblematic the case of the Olfactory Marker Protein (OMP) staining, the first, powerful marker for fully differentiated olfactory receptor neurons and a key tool to investigate the dynamic relations between peripheral sensory epithelia and central relay regions given its presence within olfactory fibers reaching the olfactory bulb (OB). Similarly, the use of thymidine analogues was able to show neurogenesis in an adult mammalian brain far before modern virus labelling and lipophilic tracers based methods. Nowadays, a wealth of new histochemical techniques combining cell and molecular biology approaches is available, giving stance to move from the analysis of the chemically identified circuitries to functional research. The study of adult neurogenesis is indeed one of the best explanatory examples of this statement. After defining the cell types involved and the basic physiology of this phenomenon in the OB plasticity, we can now analyze the role of neurogenesis in well testable behaviours related to socio-chemical communication in rodents.

From pattern to purpose: how comparative studies contribute to understanding the function of adult neurogenesis

The study of adult neurogenesis has had an explosion of fruitful growth. Yet numerous uncertainties and challenges persist. Our review begins with a survey of species that show evidence of adult neurogenesis. We then discuss how neurogenesis varies across brain regions and point out that regional specializations can indicate functional adaptations. Lifespan and aging are key life-history traits. Whereas 'adult neurogenesis' is the common term in the literature, it does not reflect the reality of neurogenesis being primarily a 'juvenile' phenomenon. We discuss the sharp decline with age as a universal trait of neurogenesis with inevitable functional consequences. Finally, the main body of the review focuses on the function of neurogenesis in birds and mammals. Selected examples illustrate how our understanding of avian and mammalian neurogenesis can complement each other. It is clear that although the two phyla have some common features, the function of adult neurogenesis may not be similar between them and filling the gaps will help us understand neurogenesis as an evolutionarily conserved trait to meet particular ecological pressures.

Systemic 5-bromo-2-deoxyuridine induces conditioned flavor aversion and c-Fos in the visceral neuraxis.

5-bromo-2-deoxyuridine (BrdU) is often used in studies of adult neurogenesis and olfactory learning, but it can also have toxic effects on highly proliferative tissue. We found that pairing Kool-Aid flavors with acute systemic injections of BrdU induced strong conditioned flavor aversions. Intermittent injections during Kool-Aid-glucose conditioning interfered with learning of a conditioned flavor-nutrient preference. Acute injection of BrdU also elevated plasma corticosterone levels and induced c-Fos in the visceral neuraxis. Thus, acute or intermittent systemic injections of BrdU (50-200 mg/kg) have aversive effects that may interfere with learning.

Study of adult neurogenesis in the gallotia galloti lizard during different seasons

In a previous study we found a seasonal distribution of cell proliferation (the first stage of adult neurogenesis) in the telencephalic ventricular walls of the adult Gallotia galloti lizard. The aim of the present work was to determine the influence of seasonality on the subsequent migration of the resulting immature neurons. We used wild animals injected with bromodeoxyuridine and kept in captivity within 30 days. To confirm the neuronal identity of these cells, we used double immunohistochemical 5-bromo-2′-deoxyuridine (BrdU) and doublecortin (DCX, an early neuronal marker) labeling, as well as autoradiography after the administration of methyl-[ 3H]thymidine ([ 3H]T). We found that: (1) the rate of cell division and/or migration from the ventricular walls varied with the season, especially in regions related with olfaction. (2) Immature neuron-like cells appeared to migrate in an apparently radial and tangential way towards different parts of the telencephalic parenchyma. (3) We did not observe ultrastructurally mature neurons until at least 90 days later, a period considerably greater than that reported for other species of vertebrates in similar studies.

Combining confocal laser scanning microscopy with serial section reconstruction in the study of adult neurogenesis.

Current advances in imaging techniques have extended the possibility of visualizing small structures within large volumes of both fixed and live specimens without sectioning. These techniques have contributed valuable information to study neuronal plasticity in the adult brain. However, technical limits still hamper the use of these approaches to investigate neurogenic regions located far from the ventricular surface such as parenchymal neurogenic niches, or the scattered neuroblasts induced by brain lesions. Here, we present a method to combine confocal laser scanning microscopy (CLSM) and serial section reconstruction in order to reconstruct large volumes of brain tissue at cellular resolution. In this method a series of thick sections are imaged with CLSM and the resulting stacks of images are registered and 3D reconstructed. This approach is based on existing freeware software and can be performed on ordinary laboratory personal computers. By using this technique we have investigated the morphology and spatial organization of a group of doublecortin (DCX)+ neuroblasts located in the lateral striatum of the late post-natal guinea pig. The 3D study unraveled a complex network of long and poorly ramified cell processes, often fascicled and mostly oriented along the internal capsule fiber bundles. These data support CLSM serial section reconstruction as a reliable alternative to the whole mount approaches to analyze cyto-architectural features of adult germinative niches.

Considering the evolution of regeneration in the central nervous system

For many years the mammalian CNS has been seen as an organ that is unable to regenerate. However, it was also long known that lower vertebrate species are capable of impressive regeneration of CNS structures. How did this situation arise through evolution? Increasing cellular and molecular understanding of regeneration in different animal species coupled with studies of adult neurogenesis in mammals is providing a basis for addressing this question. Here we compare CNS regeneration among vertebrates and speculate on how this ability may have emerged or been restricted.

Adult Neurogenesis: Can Analysis of Cell Cycle Proteins Move Us "Beyond BrdU"?

One of the greatest scientific discoveries of the 20th century is that the mammalian brain can give rise to new neurons throughout the lifespan. The phenomenon of adult neurogenesis raises hopes of harnessing neural stem cell for brain repair, and has sparked interest in novel roles for these new neurons, such as olfaction, spatial memory, and even regulation of mood. Traditionally, studies on adult neurogenesis have relied on exogenous markers of DNA synthesis, such as bromodeoxyuridine (BrdU), to label and track the birth of new cells. However, the exponential increase in our knowledge of endogenous markers of cycling cells has ushered in a new era of stem cell biology. Here we review the strides made in using endogenous cell cycle proteins to study adult neurogenesis in vivo. We (1) discuss the distribution of endogenous cell cycle proteins in proliferative regions of the adult mammalian brain; (2) review cell cycle phase-specific information gained from analyzing a combination of endogenous cell cycle proteins; and (3) provide data on the regulation of cell cycle proteins by a robust inhibitor of proliferation, morphine. The ability of BrdU to birthdate cells ensures it will always serve a role in studies of adult neurogenesis, thus preventing us from moving entirely 'beyond BrdU'. However, it is hoped that this review will provide interested researchers with the tools needed to apply the powerful and relatively novel approach of analyzing endogenous cell cycle proteins to the study of stem cells in general and adult neurogenesis in particular.

245 Ionizing radiation as an experimental tool in studies of adult neurogenesis in mammalian brain

245 Ionizing radiation as an experimental tool in studies of adult neurogenesis in mammalian brain

Irradiation as an experimental tool in studies of adult neurogenesis

"Loss of function" experiments have been the mainstay approach in studies seeking to determine functional roles of various brain regions in learning and memory. The hippocampal formation consists of several distinct regions that are thought to play different, yet interrelated, roles in the memory processes. Ionizing radiation offers a selective and highly flexible, relatively uninvasive method to further advance such studies. Focused applications of the radiation beam to the head under general anesthesia can selectively reduce ongoing adult neurogenesis in the dentate gyrus without causing any detectable damage to mature neurons. Further refinements of the methodology should offer many opportunities to extend our present knowledge of how and when adult neurogenesis plays a role in learning and memory.