René Hen, PhD
New York State Psychiatric Institute
The Kavli Institute for Brain Science Columbia University
Role of the Hippocampus in Anxiety and Depression
A traumatic experience can have lasting consequences. For those with post-traumatic stress disorder, a seemingly innocent stimulus, such as a sound or smell, can lead to feelings of intense anxiety or panic. One explanation for this rests in a malfunction in the hippocampus, an area of the brain involved in memory formation. When a new memory is formed, it goes through a process of pattern separation, which helps to distinguish that memory from memories of similar experiences. If pattern separation is not complete, the overlapping memories could make it difficult to distinguish safe memories from those associated with danger, leading to the inappropriate responses to safe stimuli seen in PTSD. In his talk, Dr. Hen proposed that an impairment in pattern separation could be due to a malfunction in the creation of new hippocampal neurons in the dentate gyrus. His research has shown that stimulating the creation of new neurons in the dentate gyrus aided in pattern separation and decreased anxiety in a mouse model. He proposed that this could be a potential target for PTSD treatment.
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 post-traumatic 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 percent 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 presentation 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 are important for many learning processes. Of relevance to this presentation, this ability allows an organism to distinguish dangerous situations 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.
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.