Ph.D., Department of Biochemistry
University of Bristol
Bristol, England, U.K.
| interleukin 6|| JAK/STAT3 pathway|
| stress|| HPA axis|
| mood disorders|| cognitive flexibility|
I study the role of interleukin 6 (IL-6) and its downstream signaling pathway, the JAK/STAT3 pathway, in normal brain function and in stress-induced psychopathology. IL-6 is involved in the peripheral inflammatory response to pathogens and initiates the fever response. However, it also functions as a growth and proliferation factor under normal, non-inflammatory conditions. IL-6 is not just produced by peripheral immune cells, but it is also present within the central nervous system, in glia (astrocytes and microglia) and in neurons; therefore this cytokine likely has CNS-specific functions, which are presently largely unknown.
The hypothalamus is a brain area where IL-6 is particularly abundant and some evidence indicates that IL-6 is involved in the regulation of the hypothalamus-pituitary-adrenal (HPA) axis, the main stress response system of the body. One of my first questions after I joined the laboratory of Dr. D. Morilak at UTHSCSA, was to investigate the role of IL-6 and JAK/STAT3 in HPA axis responses. In work funded by a NARSAD Young Investigator Award, I found that IL-6 and STAT3 modulate the way the HPA axis responds to different intensities and durations of stress (Girotti et al, 2011, 2013). Since abnormal responses of the HPA axis are observed in several psychopathologies that are exacerbated by chronic stress (such as depression, anxiety disorders and post-traumatic stress disorder), it is possible that hypothalamic IL-6 expression or its downstream signaling molecules, JAk2/STAT3, are altered in these conditions.
Besides their role in the hypothalamus, IL-6 and STAT3 have also an important role in facilitating cognitive function mediated by prefrontal cortex areas. During her thesis work, Jennifer Donegan, a former graduate student in the Morilak’s lab, found that IL-6 and STAT3 signaling under non-inflammatory conditions are required for a rat to perform well in a task of cognitive flexibility, named “reversal learning”, where the animal is required to shift attention from a previously rewarding contingency that has become non-rewarding to the now-rewarding contingency that was previously negative (Donegan et al 2014). An inability to adjust to new environmental contingencies and a lack of cognitive flexibility are hallmarks of several psychiatric disorders, including schizophrenia, obsessive-compulsive disorder, autism and depression. Therefore, Jennifer’s data suggests that IL-6/STAT3 dysregulation may contribute to cognitive dysfunction in these diseases.
Previous work in the Morilak’s laboratory showed that reversal learning is also dependent on intact serotonergic neurotransmission, specifically via 5HT2A receptors. Therefore, Jennifer and I postulated that one mechanism by which IL-6/JAK/STAT3 activation could mediate reversal learning was through an interaction with the 5HT2A receptor signaling pathway. We began to tackle this question in collaboration with Dr. Kelly Berg in the Department of Pharmacology, who provided us with a cultured neuronal cell line that expresses functional 5HT2A receptors and responds to IL-6 stimulation. In these experiments we found that indeed such cross-talk between the two pathways exists (Donegan et al 2015). These ideas form the basis of a recently funded R21.
Some of the questions I am currently working on are:
In future experiments, we will begin to identify the underlying circuitries, using viral-mediated cell-specific knock down of STAT3 expression or function to investigate whether STAT3 in a specific subpopulation of neurons is responsible for the behaviors.
Accomplishments, Awards and Honors
NIH-NIMH R21 - Girotti (PI) Morilak (Co-I) - A novel role for IL6/STAT3 signaling in orbitofrontal cortex in reversal learning (2013-2015)
CBN Pilot Grant - Girotti (PI) - Investigating the cross-talk between norepinephrine signaling and interleukin 6 pathway in neuronal cell lines (2014-2015)
NARSAD Young Investigator Grant Award (2013-2015)
Appointments, Boards, Committees and Memberships
Member of the Society for Neuroscience - 2004 to present
Lectures and Presentations
Society for Biological Psychiatry, 67th Annual Scientific Convention - Philadelphia, PA - Spring 2013
Williamson, DE., Ramage, AE., Girotti, M., Morilak, DE., Olivera, RL., Walss-Bass, C.
Stress-Induced Increases in Inflammation are Associated with White Matter Integrity and Increased Depressive Symptoms in Adolescent Males (Oral Presentation)
Catecholamine Research in the 21st Century: Abstracts and Graphical Abstracts, 10th International Catecholamine Symposium - Oxford, UK - Fall 2012
Morilak, DA., Bingham, B., Donegan, JJ., Girotti M., Jett, JD.
Jekyll and Hyde: Noradrenergic modulation in acute and chronic stress. In L. Eiden (Ed.) Elsevier, p. 247
17th Annual Pharmacology Graduate Student Symposium - San Antonio, TX - Fall 2010
Effects of chronic intermittent cold stress on the profile of inflammatory signals following acute immune and non-immune challenges in the rat brain (Oral Presentation)