Specific Projects

  1. Stressor controllability, learned helplessness, and serotonin. We have had a long standing interest in psychological variables that determine the behavioral and physiological impact of stressors, as well as on the neural mechanisms that mediate the effects of these variables. We have found that the degree of behavioral control which organisms can exert over a stressor determines whether the stressor will alter the functioning of the organism, with only uncontrollable stressors exerting deleterious effects on functioning. Investigation of the underlying neural mechanism(s) by which stressor controllability modulates stress effects currently focuses on alterations of serotonergic neurons in the dorsal raphe nucleus. The evidence suggests that exposure to uncontrollable stresssors sensitizes these neurons for a period of time, resulting in exaggerated release of serotonin in projection regions of the dorsal raphe, the putative proximate cause of the behavioral and physiological effects of uncontrollable stressors. Current studies are exploring the mechanisms by which these neurons are sensitized by uncontrollable stressors, as well as the consequences of this sensitization. These experiments utilize measurement of immediate-early gene expression, in vivo measurement of neurotransmitter release, retrograde tract tracing, and behavioral analysis.
  2. Stressor controllability, drug addiction, and serotonin-dopamine interactions. Exposure to stressors is known to alter addicitve reactions to drugs of abuse, and we are exploring whether stressor controllability modulates such effects, as well as whether serotonergic mechanisms might not be responsible. We have found that uncontrollable stressors, relative to controllable stressors, exaggerate the rewarding properties of opioid drugs such as morphine. Furthermore, this potentiation of opioid action is, at least in part, mediated by sensitized serotonergic neurons with cell bodies located in the dorsal raphe nucleus. We are currently investigating the implications of these results for addiction more generally, and whether interactions between serotonergic projections to the nucleus accumbens and/or medial prefrontal cortex interact with dopaminergic processes in these regions to produce the enhanced rewarding effects of opioids. These experiments utilize lesions, in vivo microdialysis, measurement of immediate-early gene expression, and measurement of conditioned place preference and locomotor responses to drugs.
  3. Stress and immune function. Exposure to stressors is also known to alter immune function. It is by now well established that stress can impact on immunity, but the mechanisms remain obscure, and this is our focus. Our general paradigm is to inject an antigen (typically KLH), then administer a stressor, and assess in vivo production of antibody (IgM, IgG, and various isotypes) over a 3 or 4 week period. Under some conditions the stressor interferes with antibody formation, and the question is how. We have isolated the cause to a stress-induced interference of antigen-specific CD4+ T cells of the Th1 subtype to develop normally, with a consequent insufficiency of Th1 cytokines that are required for Th2 development. Th2 cytokines, in turn, are required for antigen-specific B cell development. So, the question now is what does stress do to interfere with Th1 development, and evidence is converging on the idea that it is a byproduct of stress-induced activation of macrophages, and perhaps neutrophils. Acute stressors actually enhance innate immunity (we have a lot of recent work indicating that this is so), and one mechanism by which it does so is by inducing macrophages to produce nitric oxide (NO). This is adaptive since NO interferes with pathogen growth and replication, but NO also interferes with T cell proliferation. So, it is possible that stress-induced interference with specific immunity may be an unfortunate consequence of the enhancement of innate immunity.Current research tests this hypothesis with in vivo antibody measurements by ELISA, ELISA for cytokines, NO measurement in culture, in vitro assays such as the mixed lymphocyte reaction, cell subsetting with flow cytometry, and study of the effects of stress on innate immunity (macrophage activity as assessed by chemiluminescence, inflammation to killed bacteria, etc.).
  4. Immune-to-brain communication. The brain and the immune system form a bi-directional communication system so that each regulates the function of the other. We have a growing interest in how products of the immune system, such as the pro-inflammatory cytokines, regulate central nervous system function and the implications of this immune-to-brain loop for mood, cognition, and pain. That is, we are interested in the sensory functions of the immune system by which it informs the brain that a pathogen is in the periphery. Projects focus on: 1) How the cytokine signal reaches the brain to alter neural activity. The major theme is that cytokines can activate peripheral afferent nerves such as the vagus, thereby generating neural input to the brain as well as blood-borne input, 2) The generation of cytokines within the brain in response to signaling from the immune system and the role of these cytokines in mediating host defense, 3) The impact of immune-to-brain signaling and brain cytokine production on anxiety and depression, the idea being that these are sufficent causes of anxiety and/or depression, 4) The impact of immune-to-brain signaling and brain cytokine production on learning and memory, the basic finding being that these processes disrupt memory formation that requires the intact functioning of the hippocampus (see below), and 5) Pain (see below).
  5. Immune-induced exaggerated pain. Damage of peripheral nerves and surrounding tissues cause pain enhancement in humans. Such damage can arise for a variety of reasons: trauma, inflammation, infection, and drug neurotoxicities. One aim of our ongoing studies of pain dysregulation is to understand how infection, inflammation, toxicity and trauma of peripheral tissues and peripheral nerves leads to amplification of pain. The focus here is on immune activation: identifying what activated immune cells are key players in this process, identifying the sites along the pain pathway where they amplify pain, understanding the impact these immune products have on pain transmission, and identifying novel strategies for controlling the negative effects that immune activation has on pain.
  6. Glially-induced exaggerated pain. Chronic pain is very poorly, if at all, controlled, by currently available therapeutics. We believe that the reason for this failure lies, at least in the part, in the fact that clinically available drugs were developed to target neurons. The work of our laboratory has documented that non-neuronal cells called glia (microglia, astrocytes) are critically involved in the initiation and maintenance of chronic pain. Thus our laboratory is focused on understanding what "triggers" glia to become activated so to begin releasing pain-enhancing substances, and how we can intervene with this pathological side of glia so to prevent and control chronic pain. We are actively pursuing pharmacological and gene therapy approaches to suppress glially-driven pain enhancement with the goal of identifying new strategies for controlling such pathological pain processes in people. In addition, our group has recently discovered that clinically relevant opioids also activate glia, again causing them to release pain-enhancing substances. We have now linked such opioid-induced glial activation to the decreased efficacy of acute opioids in suppressing pain and to the phenomena of opioid tolerance and opioid withdrawal. Similar to our goals of controlling glial dysregulation of pain, we similarly seek to understand how to control the negative impact that glial activation has on opioid analgesia. For both pain and opioid analgesics, the ultimate goal is to find means by which clinical pain control can be improved so to relieve human suffering.
  7. Immune-induced impairment of learning and memory. Although products of the immune system alter patterns of neural activity, the implications of immune-regulation of neural function for behavior are poorly understood. This is particularly true of cognitive function. We have been investigating the effects of immune activation on learning and memory because agents that activate immune cells lead to pronounced changes in hippocampal neurochemistry. The basic finding has been that immune activation by a variety of means (e.g., peripheral LPS, IL-1, and gp120 administration) interferes with the memory for learning tasks that depend on intact hippocampal functioning, such as fear conditioning to contextual cues. Moreover, this interference is mediated by the induction of IL-1 in the hippocampus. However, immune activation does not interfere with tasks that do not require an intact hippocampus, such as fear conditioning to specific cues. We are currently investigating a) the stage of learning/memory processes that is impacted, b) the neural mechanisms responsible, c) the immune-to-brain pathways involved, and d) the implications of this cognitive interference for other behaviors.