People and animals encounter stressful events on a daily basis. In response to these stressors, some people suffer maladaptive, debilitating consequences, while others seem relatively indifferent to that same stressor. In light of this fact, the primary goal of my research has been to determine how organisms respond and adapt to psychologically stressful events. To this end, my laboratory has 3 primary lines of inquiry that can be roughly described as (a) basic mechanisms of stress, with a strong emphasis on the hypothalamic-pituitary-adenal (HPA) axis; (b) neural-immune interactions, whereby the glial-neuronal interface has emerged as a pivotal point of focus; and (c) alcohol-cytokine interactions as a basis for understanding certain aspects of the addictive process. These 3 lines of inquiry are described in greater detail below.
Basic mechanisms of stress
Cellular regulation of the neuroendocrine stress response is a primary focus of my laboratory. I have been classically trained in techniques common to both neuroscience and neuroendocrinology, including measurement of stress-related hormones (ACTH, CORT), steroid hormone receptors (MR, GR, CRH receptors), and gene expression in sites principally involved in the neuroendocrine stress response (hippocampus, hypothalamus, pituitary, adrenal glands, etc). Using these techniques, we seek to understand basic mechanisms of the stress response and how the stress response is re-architected by prior experience and individual differences. To this end, we expend considerable effort to delineate (i) long term consequences of acute stressor exposure for behavioral and neuroendocrine status, (ii) how exposure to one stressor may relegate the stress response to a sensitized state, and (iii) the implications of stress sensitization for psychiatric illness (particularly depression).
Intense stressors produce a strikingly similar complement of neural, endocrine and behavioral adaptations to those observed following immune activation. This led us to the hypothesis that common neural factors might be involved in mitigating responses to these diverse challenges. For instance, certain stressors increase expression of pro-inflammatory cytokines in the CNS, elicit a fever response that persist as long as 24-48 hr, and induce a shift in liver metabolism indicative of acute phase (i.e., immune) activation. Combined with functional work showing that anti-inflammatory compounds block certain responses to stressor exposure (while others remain completely intact), we have now been referring to these changes as “stress-induced sickness responses.” Interestingly, stressors that activate some aspects of immunity appear also to render the stress response to a sensitized state. Thus, our work on the involvement of immune-related factors in the CNS provides a novel perspective on mechanisms of stress sensitization, and forms the basis for one line of inquiry for my laboratory.
At the mechanistic level, our data have led us to the hypothesis that microglia serve as a critical interface between the immune system and more traditional components of the stress response, particularly the hypothalamic-pituitary-adrenal axis. Our latest findings (about to be submitted) implicate these unique cells as being (a) highly responsive to stress, (b) the likely cellular source of cytokines during times of stress, and (c) as a likely source of plasticity in behavioral, neuroendocrine, and immune responding produced by stressor exposure. Thus, we are actively pursuing microglial-neuronal interactions in order to further our understanding of how the CNS responds and adapts to stressor exposure. Moreover, we have recently begun a series of studies examining the role of stress-related hormones in modulating L-dopa induced dyskenesia using a hemi-Parkinsonian model. We have had tremendous success already in developing a model for examining stress interactions with neurodegenerative processes and have some initial insight into potential neuroinflammatory mechanisms that may be at play. These are the beginning steps towards tangible clinical outcomes that may be affected by stress-precipitated increases in central pro-inflammatory cytokines.
The latest direction for my laboratory examines neural-immune consequences of alcohol exposure, precipitated in part by my affiliation with the Developmental Exposure Alcohol Research Center (DEARC) in upstate New York. We are relatively new to alcohol research, but have recently obtained compelling data to suggest that some of the very same pro-inflammatory cytokines and microglial mechanisms responsible for outcomes of stressor exposure are at play during acute ethanol withdrawal. Specifically, our data indicate that interleukin-1 (IL-1) expression shows a biphasic response to acute ethanol exposure, where IL-1 transcription is initially reduced (during intoxication) but ultimately increased (during withdrawal), an effect that may ultimately account for many “hangover” like effects produced by alcohol. Our data fit extremely well with recent notions regarding impaired immune function after alcohol exposure involving reduced toll-like receptor signaling by immune cells, yet contribute a critical extension of these findings to the CNS. Though our endeavors in alcohol research are quite recent, we have a number of specific hypotheses regarding the involvement of neural-immune processes in the response to alcohol, and recently received funding through NIAAA (see CV for details) to develop them into a larger portion of our research repertoire.
Though I describe these 3 areas of inquiry as separate entities, in truth they are quite inseparable. For instance, as we make progress in our understanding of basic mechanisms of stress and stress sensitization, our data invariably inform the direction of another project. Together, this multi-system approach allows us to take into account physiology of the organism as a whole rather than studying one specific system. I take a parallel view of graduate training and collaborations: an interactive approach yields a higher quality product and invigorates the research agenda.