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Research Interests

 

Stress, Prefrontal Cortex, and Psychopathology

Stress has been hypothesized to play a major role in several disorders, and the neurotransmitter systems and brain structures that are altered by stress have been implicated in a variety of psychological disorders. Thus, assessment of the effects of stress on these neurotransmitter systems and structures may have important implications for the causes and prevention of these disorders. Prefrontal cortex is a target for hormones involved in the stress response and has been implicated in disorders such as schizophrenia and depression that are exacerbated or precipitated by stress. Thus, understanding the effects of stress on prefrontal cortex is critical for understanding the influence of stress on psychopathology.

My lab is examining the effects of chronic stress and stress hormones on behaviors mediated by prefrontal cortex, as well as the changes in neural pharmacology and morphology that underlie these effects. We have demonstrated that both chronic stress and exposure to the stress hormone corticosterone reorganize dendrites of neurons in prefrontal cortex. We are now beginning to more fully characterize these effects, assess their functional significance, and elucidate mechanisms underlying them.

 

Computer-assisted reconstructions of Golgi-stained pyramidal neurons in layer II-III of medial prefrontal cortex in an untreated and a corticosterone-treated rat. Apical dendritic material is increased proximal to the soma and decreased distal to the soma. Right. Mean intersections of apical dendrites with 10-mm concentric spheres summed across the proximal, middle, and distal third of the arbor for untreated, vehicle-, and corticosterone-treated rats. Vertical bars represent S.E.M. values; asterisks (*) indicate significant difference relative to untreated rats.
Computer-assisted reconstructions of Golgi-stained neurons in layer II–III of medial prefrontal cortex in unstressed (left) and stressed (right) rats. Scale bar = 50 mm. These neurons were selected because they are representative of apical dendritic lengths above (top), near (middle), and below (bottom) their respective group means. Right. Mean intersections of apical dendrites with 10 µm concentric spheres in unstressed and stressed rats. Data have been summed into 20 µm bins. Apical dendritic material distal to the soma was reduced in stressed rats, and the pattern of changes was similar to that seen in corticosterone-treated rats. Vertical bars represent SEM values. Asterisks (*) indicate significant differences relative to unstressed rats.

 

 

Individual Differences and Genetic Risk for Stress-Induced Psychopathology

Stress does not have uniform effects across individuals.  For instance, although depressed individuals are more likely to have experienced a major stressor in the period preceding diagnosis, for many individuals, the experience of a stressful life event does not result in depression.  Similarly, not everyone experiencing a traumatic stressor develops post traumatic stress disorder.  Thus, we are investigating individual differences in prefrontal stress effects.  A current focus of the lab is examining differential effects of chronic stress on prefrontal structure and function in males versus females, and potential contributions of gonadal hormones to those differences.

LeftComputer-assisted reconstructions of Golgi-stained pyramidal neurons in layer II-III of medial prefrontal cortexfor sham, ovariectomized, and ovariectomized plus estrogen replacement female rats. Apical dendritic length is increased in stressed female rats, and this effect is estrogen-dependent. Right. Mean length of apical dendrites of pyramdial neurons in prefrontal cortex for sham, ovariectomized, and ovariectomized plus estrogen replacement female rats. Vertical bars represent S.E.M. values; asterisks (*) indicate significant difference relative to untreated rats.

 

In collaboration with colleagues at the National Institute on Alcohol Abuse and Alcoholism, the National Institute for Mental Health, and the University of Southern California School of Pharmacology, we are using transgenic mice to investigate the roles of alterations in the serotonergic and glutamatergic systems in increased risk for neuropsychiatric disease as well as contributions of these neurotransmitter systems in stress-induced dendritic changes.  These studies will provide data relevant for understanding the neurobiological mechanisms underlying both altered corticolimbic function and risk for mood disorders in the presence of environmental stressors.

 

LeftComputer-assisted reconstructions of Golgi-stained pyramidal neurons in medial prefrontal cortex of a wild-type and a serotonin-transporter knockout mouse. Pyramidal neurons in the infralimbic cortex have longer dendrites in the knockout mice. Right. Mean intersections of apical dendrites with 10 µm concentric spheres in wild-type and serotonin-transporter knockout mice. Data have been summed into 20 µm bins. Overall, ppical dendritic material was increased in the knockout mice. Vertical bars represent SEM values.

 

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