Adult hippocampal neurogenesis and cognitive flexibility - linking memory and mood

Almost one-third of adult Americans will have an anxiety disorder in their lifetime, with enormous personal, societal, and financial costs. Among the most disabling of these disorders are posttraumatic stress disorder (PTSD), obsessive compulsive disorder (OCD), social anxiety disorder, generalized anxiety disorder and panic disorder. Although there are evidence-based treatments for these disorders, usually selective serotonin reuptake inhibitors (SSRIs, e.g. fluoxetine) or cognitive-behavioral therapy, as many as 50% of patients do not respond, and even those who do respond often continue to have clinically significant residual symptoms and impairment. Therefore, there is a considerable need for new therapies for these disorders, yet well-validated translational targets for such therapies remain unidentified, as is true for most psychiatric disorders. This proposal will investigate a novel treatment strategy for patients with pathological anxiety: stimulating hippocampal stem cells to produce new neurons that will enhance the neural process of pattern separation. The mature mammalian brain contains two regions where stem cells continuously generate new neurons, a process termed adult neurogenesis; the subventricular zone contributes new neurons to the olfactory bulb, and the subgranular zone of the dentate gyrus (DG) produces new excitatory cells in the hippocampus. The DG and neurogenesis within the DG, appear to play a key role in pattern separation during hippocampal memory formation. Pattern separation is thought to function by transforming similar sensory inputs into discrete, non-overlapping representations to disambiguate memories of similar experiences. In healthy organisms, generating and maintaining distinct memories of similar experiences is important for many learning processes. Of relevance to this proposal, this ability allows an organism to distinguish dangerous from safe situations. Impaired pattern separation may lead to excessive generalization of previously encountered aversive events to new “innocuous” experiences, a feature often found in anxiety disorders. For example, for someone who developed PTSD as a result of 9/11, the sight of a plane flying over New York City may trigger a flashback. Patients who have experienced a panic attack in one setting (e.g., an elevator at work) often describe generalization of fear to similar settings (e.g., all elevators, then all closed spaces). This excessive generalization of fear leads patients to avoid people, places, and things, which in turn leads to functional impairment. Adult neurogenesis is a unique form of plasticity that entails the production of new neurons from neural stem cells. It occurs in only a few structures in the adult mammalian brain. The two main areas where neurogenesis occurs are the subventricular zone that lines the ventricles and gives rise to neuronal precursors that migrate toward the olfactory bulb, and the subgranular zone that lines the DG of the hippocampus and gives rise to DG granule cells. It is unclear why the olfactory bulb and hippocampus need this special type of plasticity in addition to other forms (e.g, remodeling of axons, dendrites and spines). A possible clue comes from the observation that neurogenesis is regulated by environmental factors. In the hippocampus, neurogenesis is stimulated by enriched environments, exercise, and learning and is inhibited by stress and aging. Even the stages of neurogenesis are influenced by these environmental factors. Enrichment and exercise stimulate the proliferation of neural stem cells, their differentiation into neurons and the survival of the resulting young neurons; conversely, stress and old age decrease proliferation, the choice of a neuronal fate, and the survival of the young neurons. Changes in neurogenesis may represent adaptations to a changing environment. Another clue to the significance of neurogenesis comes from the recently discovered function of adult-born granule cells in the DG. We and others have shown in rodents that adult neurogenesis in the DG is critical for the process called pattern separation [1] and for some of the anxiolytic effects of SSRIs [2,3]. In recent studies using radiocarbon dating techniques, it was found that neurogenesis occurs at significant levels in the human hippocampus throughout adulthood [4]. Specifically, the majority of DG cells are subject to exchange, with about 1400 new GCs added to the adult human DG daily, corresponding to an annual turnover rate of 1.75%. This is a striking finding, as it suggests that levels of neurogenesis in adult humans are comparable to those found in middle-aged rats or mice, species in which the importance of neurogenesis has been clearly established. These findings underscore the potential of harnessing this form of plasticity for the treatment of brain disorders. The evidence that hippocampal neurogenesis is important for pattern separation comes from both loss of function studies and gain of function studies in rodents. Specifically, ablation of neurogenesis with X-irradiation or genetic manipulations results in impaired pattern separation in contextual discrimination and in place avoidance [1]. Conversely, increasing neurogenesis (with exercise or a genetic manipulation that targets the neural stem cells and their progeny) results in improved pattern separation in a contextual discrimination task and in a spatial discrimination task [1]. The evidence that neurogenesis modulates anxiety-related behaviors comes also from loss and gain of function studies. Ablation of neurogenesis with X-irradiation or genetic manipulations results in decreased response to antidepressants both in anxiety tests and in stress responses [2, 3]. Gain of function studies show that increases in neurogenesis as a result of antidepressants, exercise, and specific genetic manipulations that target neural stem cells and their progeny result in decreased anxiety [2, 3]. In addition we have recently shown that a genetic manipulation that increases the survival of young granule cells in the DG results in decreased anxiety in an anxiety model. Together these data suggest that neurogenesis modulates anxiety-related behaviors. We propose that the excessive generalization seen in patients with pathological anxiety is due to impaired hippocampal functioning and specifically a deficit in the neural process of pattern separation, which relies upon the dentate gyrus and is sensitive to neurogenesis. Our preclinical findings indicate that stimulating DG neurogenesis improves pattern separation and also reduces anxiety behaviors in mice. As a result we hypothesize that pharmacological or environmental manipulations aimed at stimulating neurogenesis will be beneficial for the treatment of anxiety disorders.