Tracey J. Shors - US grants

DESCRIPTION (Adapted from applicant's abstract): Males and females are known to have distinct congitive capacities and emotional responses. Female rats acquire a classically conditioned eye blink response faster than male rats. Despite enhanced performance under unstressed conditions, females are severely impaired in acquiring the conditioned response by previous exposure to a stressful event, while males are facilitated. This grant proposes experiments to identify the neuronal, synaptic and molecular mechanisms responsible for 1) the facilitated learning in males versus the impaired learning in females after exposure to a stressful and emotional event, and 2) the enhanced performance of females under unstressed conditions. The proposed experiments will address the following questions. I) Is the stress induced impairment of learning in females dependent on estrogen and progesterone and an interaction with glucocorticoids? II) Is the amygdala necessary for the stress induced impairment of learning in females and their enhanced performance under unstressed conditions? III) Are stress induced effects on neuronal excitability in the amygdala associated with the sex differences in memory formation? IV) Are stress induced effects on spine/synaptic density in the amygdala associated with the sex differences in memory formation? V) Are the stress and sex effects on synaptic density and learning associated with the distribution of mRNA to dendritic spines in neurons of the amygdala? Methodologies will include behavioral training, transient lesioning and microinjections, multiple unit recording, Golgi impregnation and high resolution in situ hybridization. Females represent over 50 percent of the human population, yet they are vastly underrepresented in biomedical research. Despite the lack of attention, recent evidence suggests that estrogen is effective in the treatment of Alzheimer's disease, a devastating disease marked by abnormal cognitive and emotional responses and deterioration of the amygdala. The proposed experiments are clinically relevant because they address how estrogen contributes to the effective memory formation in the mammalian brain. In addition, they are relevant to post traumatic stress disorder (PTSD), a disease marked by the persistent behavioral and neuronal consequences of stressful experience.

DESCRIPTION (Adapted from applicant's abstract): Males and females are known to have distinct congitive capacities and emotional responses. Female rats acquire a classically conditioned eye blink response faster than male rats. Despite enhanced performance under unstressed conditions, females are severely impaired in acquiring the conditioned response by previous exposure to a stressful event, while males are facilitated. This grant proposes experiments to identify the neuronal, synaptic and molecular mechanisms responsible for 1) the facilitated learning in males versus the impaired learning in females after exposure to a stressful and emotional event, and 2) the enhanced performance of females under unstressed conditions. The proposed experiments will address the following questions. I) Is the stress induced impairment of learning in females dependent on estrogen and progesterone and an interaction with glucocorticoids? II) Is the amygdala necessary for the stress induced impairment of learning in females and their enhanced performance under unstressed conditions? III) Are stress induced effects on neuronal excitability in the amygdala associated with the sex differences in memory formation? IV) Are stress induced effects on spine/synaptic density in the amygdala associated with the sex differences in memory formation? V) Are the stress and sex effects on synaptic density and learning associated with the distribution of mRNA to dendritic spines in neurons of the amygdala? Methodologies will include behavioral training, transient lesioning and microinjections, multiple unit recording, Golgi impregnation and high resolution in situ hybridization. Females represent over 50 percent of the human population, yet they are vastly underrepresented in biomedical research. Despite the lack of attention, recent evidence suggests that estrogen is effective in the treatment of Alzheimer's disease, a devastating disease marked by abnormal cognitive and emotional responses and deterioration of the amygdala. The proposed experiments are clinically relevant because they address how estrogen contributes to the effective memory formation in the mammalian brain. In addition, they are relevant to post traumatic stress disorder (PTSD), a disease marked by the persistent behavioral and neuronal consequences of stressful experience.

DESCRIPTION (Adapted from applicant's abstract): Males and females are known to have distinct congitive capacities and emotional responses. Female rats acquire a classically conditioned eye blink response faster than male rats. Despite enhanced performance under unstressed conditions, females are severely impaired in acquiring the conditioned response by previous exposure to a stressful event, while males are facilitated. This grant proposes experiments to identify the neuronal, synaptic and molecular mechanisms responsible for 1) the facilitated learning in males versus the impaired learning in females after exposure to a stressful and emotional event, and 2) the enhanced performance of females under unstressed conditions. The proposed experiments will address the following questions. I) Is the stress induced impairment of learning in females dependent on estrogen and progesterone and an interaction with glucocorticoids? II) Is the amygdala necessary for the stress induced impairment of learning in females and their enhanced performance under unstressed conditions? III) Are stress induced effects on neuronal excitability in the amygdala associated with the sex differences in memory formation? IV) Are stress induced effects on spine/synaptic density in the amygdala associated with the sex differences in memory formation? V) Are the stress and sex effects on synaptic density and learning associated with the distribution of mRNA to dendritic spines in neurons of the amygdala? Methodologies will include behavioral training, transient lesioning and microinjections, multiple unit recording, Golgi impregnation and high resolution in situ hybridization. Females represent over 50 percent of the human population, yet they are vastly underrepresented in biomedical research. Despite the lack of attention, recent evidence suggests that estrogen is effective in the treatment of Alzheimer's disease, a devastating disease marked by abnormal cognitive and emotional responses and deterioration of the amygdala. The proposed experiments are clinically relevant because they address how estrogen contributes to the effective memory formation in the mammalian brain. In addition, they are relevant to post traumatic stress disorder (PTSD), a disease marked by the persistent behavioral and neuronal consequences of stressful experience.

Shors, Tracey
0217403
STRESS, SPINES & NEW MEMORIES

Dendritic spines are tiny protrusions that exist by the tens of thousands on many excitatory neurons in the brain, including those in the hippocampal formation. Spines are potential sites of synapse formation and thus represent a means for neuronal integration. Based on their potential for conferring associations between neurons, it has been hypothesized that they are involved in the encoding of experience. Exposure to an acute stressful experience greatly increases the density of dendritic spines in the hippocampal formation of the male rat. This effect is robust and persistent - lasting at least 24 hrs after the event has ceased. The effect is also regionally specific in that it is evident on pyramidal neurons in area CA1 of the hippocampus but not in the somatosensory cortex. The primary goal of the proposed experiments is to identify the neuronal and hormonal mechanisms that are responsible for the experience-induced change in spine density. Specifically, experiments will be done to determine whether activation of the NMDA type of glutamate receptors is necessary for inducing the persistent increase in spine density. It will also be determined whether the presence of the major stress hormones, glucocorticoids, is necessary for the stress effects on synaptic anatomy. Although dendritic spines were identified over 100 years ago, their functional significance has remained elusive. The results from these studies should provide important insight into their functional significance and the mechanisms that mediate their plasticity.

DESCRIPTION (provided by applicant): It has become increasingly clear that males and females differ even more dramatically than we previously thought. Not only do they exhibit differing responses to stress and environmental experience, but they can also respond in opposite directions. In rats, exposure to an acute stressful event enhances associative learning in males while dramatically impairing performance in females (Wood et al 2001, Wood &Shors 1998;Shors et al., 1998, 2002). These opposite effects of stress on memory formation are accompanied by similarly opposite effects on the presence of dendritic spines in the hippocampal formation (Shors et al 2001). Moreover, these opposite effects of stress are mediated by different hormonal systems between the sexes (Wood et al 2001, Beylin &Shors 2002). Sex differences usually arise from activational and organizational effects of sex hormones which fluctuate across the lifespan, especially in females. The experiments described in this competing continuation capitalize on hormonal fluctuations and changes in emotionality that occur during very early development, puberty, post-partum and menopause. They are designed to associate and dissociate changes in learning ability and responses to stressful experience with changes in hormones and density of dendritic spines in the hippocampal formation. Finally, experiments are designed to explore a potential relationship between sex differences in learning and the expression of growth hormone (GH) in the hippocampus, a gene that is preferentially induced by learning (Donahue et al., 2002). Techniques include trace eyeblink conditioning in the rat, Golgi impregnation and light microscope analysis, real-time polymerase chain reaction, in situ hybridization, radioimmunoassay, and surgical manipulation of glucocorticoids and ovarian hormones. Overall, these studies will identity the neuronal and hormonal mechanisms that underlie sex differences in learning and opposite responses to stressful experience in males versus females. Because mental disorders often emerge or are exacerbated during these life changes, the studies will provide insight into sex differences in mental illness, especially those experienced so frequently by women: post-traumatic stress disorder (PTSD), unipolar, post-partum and post-menopausal depression, as well as Alzheimer's disease.

The discovery of stem cells in the adult brain has generated a great deal of excitement in the neurosciences. Thousands of new cells are produced each day in a healthy hippocampus, a key brain area for learning and memory. However, soon after the cells are born, many of them die unless they are exposed to a learning experience. Thus, new neurons in the adult are rescued from death by learning. With this award, a number of important questions about the relationship between learning and neurogenesis will be answered: What do new neurons do once they are rescued from death? Are they used for memory or for acquiring new information? Are new cells retained with each new learning experience and if so, do they then contribute to learning in the future? Also, do the absolute numbers that are born relate to the numbers kept alive by learning? And finally, what physiological mechanisms and brain rhythms keep them alive? To answer these questions, behavioral, electrophysiological, molecular and biochemical techniques will be used. These studies are important because they will identify the critical features of learning that keep new neurons alive and in turn how those new neurons then contribute to optimal learning in the future. The discovery of neurogenesis has transformed the way we think about the adult brain and generated much interest in the public, especially educators of children and young adults. These findings will be disseminated to the public with writings in lay magazines (i.e. Shors, Scientific American, 2009) and public presentations (i.e. Quark Park, a public art installation about science). The project will train postdoctoral, graduate and undergraduate students in this new field of research which intersects biology, psychology, physiology, as well as biomedical and stem cell engineering.