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Differentiation cascade of adult neurogenesis and a model of neural stem cell maintenance. The key focus of our group is on adult neurogenesis. Production of new neurons from adult stem cells is important for behavior, pathophysiology, aging, and tissue repair in humans and animals. To reveal basic mechanisms governing their maintenance, division, differentiation, and death we generate new animal models and develop new approaches to visualize stem cells and their environment, trace their lineage, and monitor their signaling landscape (J Comp Neurol, 2004, PNAS, 2006; CSH Persp, 2015; Stem Cell Rep, 2018; Behav Brain Res, 2019). We used these new genetic tools and techniques to define discrete steps in the cascade of events leading from stem cells to granule neurons, generating a detailed scheme of the differentiation cascade in the adult hippocampus. These studies also led us to a new model for the quiescence, maintenance, and division of the adult hippocampal stem cells (Cell Stem Cell, 2011). We found that an adult neural stem cell may remain quiescent for their entire postnatal life, but, when activated, rapidly divides several times in quick succession to bud off daughter cells that eventually yield neurons, while the remaining stem cell differentiates into a mature astrocyte, thus leaving the stem cell pool. Hence, in contrast to the conventional model of recurring stem cell quiescence, a hippocampal stem cell can be described as a “single-use” or a “disposable” unit – used in adulthood only once and then abandoned in its stem cell capacity. We also found that astrocytic differentiation of hippocampal stem cells is tightly coupled to their division, that vast majority of dividing stem cells of the hippocampus convert into astrocytes, and, conversely, that new astrocytes of the dentate gyrus derive from these stem cells. We found that continuous loss of stem cells via their division-coupled astrocytic differentiation underlies age-dependent diminished production of new neurons and may contribute to age-related cognitive impairment. We now work to determine whether our model of differentiation-driven stem cell attrition may be relevant to other types of normal and tumor-initiating stem cells and to other settings, particularly in disease models.
Stem Cells in Non-neural Tissues
Much of our strategy is based on engineering reporter mouse lines to visualize, track, and isolate stem cells; some of our reporter lines became widely employed genetic tools, used by over 200 groups worldwide. Although these lines were originally designed to identify stem cells in the nervous system, we soon found that same reporter lines allow to discover stem and progenitor cells in a range of other tissues and organs, as diverse as anterior pituitary, skeletal muscle, testis, hair follicles, liver, pancreas, retina, adrenal medulla, and bone marrow. We identified some of those stem cell species in our group and studied other types in close collaboration with other research groups. Most important results pertain to mesenchymal stem cells (Nature, 2010; Nature, 2012), liver oval cells (Cell, 2014), ovarian stem cells (Nature, 2013), stem cells in the skin (Cell Stem Cell, 2011), precursors to Leydig cells (J Cell Biol, 2004), and adult anterior pituitary stem cells (PNAS, 2009). We now use this reporter-based approach to search for new types of tissue-specific stem and progenitor cells and for cross-talk between different stem cell compartments.
Nitric Oxide Signaling and Role in Development
Over the last two decades, our group investigated the diversity of biological functions mediated by nitric oxide (NO). We were first to discover the essential role that NO plays in development, differentiation, and stem cell regulation. We found that NO potentiates weak calcium signals (Nature, 1993), mediates neuronal differentiation (Nature, 1995), regulates Drosophila imaginal disk development (Cell, 1996), controls brain development (J Neurosci, 2001) and adult neurogenesis (PNAS, 2003), contributes to regulation of hematopoietic stem cells (Mol Ther, 2004; Mol Med, 2008), coordinates cell proliferation and cell movements during early development (Cell Cycle, 2007), and regulates ciliogenesis (Life Sci Alliance, 2021) Our current focus is on a novel function of NO that we uncovered in collaboration with Natalia Peunova at SBU: the role it plays in the development and function of cilia in multiciliated cells of the ciliated epithelium. Our recent results suggest that certain inborn and acquired human ciliopathies and related disorders may also be associated with decreased availability of NO and may benefit from NO-based therapies.
Neurodevelopmental and neurodegenerative disorders are characterized by aberrant proliferation, elimination, and migration of neural precursors. These defects in cell division and migration may be essential contributors to the neurobiological (and ultimately behavioral) manifestations of these disorders. Within last years we developed a suite of 2D and 3D methods for visualizing and quantifying proliferating cells in the whole embryonic, perinatal, and adult mouse brain (Methods Cell Biol, 2008; Front Neuroanat, 2017; Stem Cell Reports, 2018; Sci Reports, 2022; Cells, 2022a; Cells, 2022b), e.g., new algorithms for automatic cell detection and counting in 3D and spatiotemporal 3D image registration for mesoscale studies of brain development (ongoing collaboration with Alex Koulakov, CSHL). We used these methods to generate 3D representations of dividing and migrating progenitor cells in the developing mouse brain and to produce a spatio-temporal (four-dimensional, 4D) pseudotime description of cell division and migration in the mouse brain. We now use this approach to determine the changes in progenitors’ division and migration upon various treatments and in neurodevelopmental mutants.
Circuits Controlling Social Conflict and Behavior
Establishment of social hierarchy through aggressive behavior helps to deflect excessive violence and injury, protects group’s valuable resources, and molds the overall societal structure. Successful acts of aggression may be rewarding, with a series of wins increasing aggressive motivation and propensity to engage in aggressive behavior, and a series of defeats having an opposite, aversive, effect. Social hierarchy is dynamic and may be altered after encounters between animals with a comparable social rank.
A unique signature of the activated brain regions of winner mice
We use paradigms of repeated aggression and of fighting deprivation in mice [see Kudryavtseva Nature Prot, 2014] to examine changes in behavior, neurogenesis, and neuronal activity defining the social conflict (a collaboration with Dr. Natalia Kudryavtseva whio develped this paradigm) . Our results indicate that extended positive fighting experience heightens aggression, increases proliferation of neuronal progenitors and production of young neurons in the hippocampus, and alters neuronal activity in the amygdala; these changes can be modified by depriving the winners of the opportunity for further fights (Front Neurosci, 2015). Furthermore, we found that if adolescent male mice are exposed to adult males with elevated levels of aggression, these adolescents demonstrate a high level of anxiety and helplessness, and diminished hippocampal neurogenesis. Even if such adolescents were returned to a normal environment and allowed to mature, they demonstrated high levels of anxiety and heightened aggression, indicating that hostile social environment in adolescence disturbs psychoemotional state and social behaviors of animals in adult life (PLOS One, 2014).
Network hubs of the neuroanatomically-filtered social conflict whole-brain connectome
Our current focus is on neural circuits underlying acquisition, escalation, and reversal of aggressive behavior in a social conflict setting. Several brain regions and circuits involved in aggressive behavior and social dominancy have been identified; however, the global maps of brain networks involved in establishing, maintaining, and reversing social hierarchy are not known. In close collaboration with Alex Koulakov’s group at CSHL we applied high-throughput global mapping of neuronal activation patterns to determine network activity across the brain regions and infer the circuits involved in aggression, dominancy, and reversal of hierarchical status in our model. We also used the data to identify brain regions that show covarying activation and therefore may be functionally related and to determine whether such clustering can be related to the neuroanatomical mesoscopic connectivity. Further, we compare identified subnetworks to the known connectivity patterns to build mechanistic models of activation in specific subnetworks upon acquisition, escalation, or reversal of the social status.