- 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.
- 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.
- 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.).
- 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).
- 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.
- 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.
- 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.