Research

My major research objective is to understand how memories are formed and maintained in the mammalian brain. To do that, I have used two approaches. The first involves the production of new neurons in the mammalian brain. For many years, indeed decades, we thought that the brain did not make new neurons after birth. In the past several years, it has become accepted that the adult brain, including the human brain, does produce new neurons --- and lots of them. In the rat alone, thousands are made each day. We now know that many if not most are made in the hippocampus, a brain region known to be involved in learning and memory. In addition to memory formation, these cells are also sensitive to stress and perhaps even events associated with depression. Thus, these cells are potential sites in the brain where our thoughts are effectively combined and perhaps integrated with our emotions. The discovery (or more accurately, the “rediscovery”) of neurogenesis in the adult has generated a great deal of excitement in the field, because it indicates that we have a great capacity for change and renewal throughout our lifetimes.

The vast majority of new neurons, as mentioned before, are produced in the hippocampus, a brain region known to be critical for certain types of learning. It has been found, that most of these cells die within weeks of their birth. Given that so many cells are born in the hippocampus, we have proposed that they may be related to the formation of new memories, and have accumulated considerable evidence that they are. First, we found that learning enhances their survival. Also we have shown that the learning in an individual animal is associated with a greater number of cells remaining in its hippocampus after training. In other words, “smart” animals had more new neurons in their brain after training than did the “not so smart” animals. Thus, the formation of new memories seems to directly enhance the likelihood that new neurons will remain in the brain, even after the experience of learning is over. These findings fit loosely with the phrase “use it or lose it.” In other studies, we have found that the depletion of these cells is associated with some types of learning deficits. Together, our data suggest that these new neurons are affected by new learning and may even be used in the formation of memories themselves.

The second focus of my laboratory concerns sex differences in learning and how males and females respond to stressful experiences. Using a number of learning tasks, we have found that males and females can learn at very different rates, and that they are affected in opposite ways by exposure to stressful experiences. More specifically, we have reported that exposure to an uncontrollable stressful event greatly enhances new learning in male rats, but severely impairs new learning in female rats. These effects are dependent on the psychological aspects of stress, namely the absence of control. The expression of these sex differences depend on both organizational and activational effects of hormones. Moreover, they are associated with anatomical changes in the brain, including changes in the formation of dendritic spines. From these and other studies, I have recently proposed that significant life events, most often stressful in nature, alter future learned responses by inducing nonspecific and persistent changes in neuroanatomical structures. These changes are induced in the presence of sex and stress hormones, which are released either in response to the event itself or as a consequence of stages of life. These anatomical changes then set the stage, so to speak, to alter the way we learn in the future and how we respond to new experiences. In this way, memorable life events become less about the past and more about the future.

Women are much more likely to experience stress-related mental illnesses such as depression, anxiety and post-traumatic stress disorders. Despite these numbers, females are rarely studied in laboratory experiments. One of my major goals over the next several years is to evaluate learning abilities and responses to stressful experience in the female rat across her lifespan. To date, we have found very different responses to stressful life events during different stages of life, especially those associated with puberty and post-partum, as well as in the aged. These are also periods of life when women are susceptible to depression and other mood disorders. We are currently examining the potential role of neurogenesis in depression and have, as before, found very different responses in males versus females. Briefly, we have found that neurogenesis in the adult hippocampus is sensitive to controllability and the expression of learned helplessness. However, the relationship is only applicable to males. These results, along with others, suggest that sex differences in mental illness may not simply reflect differences in degree of dysfunction, but rather may reflect differences in the underlying neuronal mechanisms and anatomies that regulate them.

It is my hope that these lines of research will lead to important discoveries about how we acquire and maintain memories, these essential features of our existence and personal identity. It is also my hope that this line of research will enhance the appreciation for sex differences in the brain. In fact, our most recent data present the possibility that sex differences in mental illness reflect differences in etiology. If true, we might then consider alternative treatment strategies and behavioral therapies for woman than we do for men.