PHARMACOLOGY RESEARCH FACULTY
Selected Publications
  • Donegan, JJ., Girotti, M., Weinberg, MS. and Morilak, DA. (2013) Facilitation of cognitive flexibility in rat orbitofrontal cortex: a novel role for brain interleukin 6. Under revision in J. Neurosci.
  • Girotti, M., Donegan, JJ. and Morilak, DA. (2013) Hypothalamic IL-6/gp130 receptor signaling is required for the HPA axis response to chronic intermittent cold stress; Psychoneuroendocrinology, 2013 Jul;38(7):1158-69; Epub 2012 Dec 4.
  • Girotti, M., Donegan, JJ. and Morilak, DA. (2011) Chronic Intermittent Cold Stress Sensitizes Neuro-Immune Reactivity in the Rat Brain. Psychoneuroendocrinology Sep;36(8):1164-74.
  • Bhaskaran, S., Butler, JA., Becerra, S., Fassio V, Girotti, M.. (2011) Breaking Caenorhabditis elegans The Easy Way Using the Balch Homogenizer – An Old Tool For a New Application. Anal Biochem. Jun 15;413(2):123-32
Milena Girotti
 

Milena Girotti

Assistant Professor/Research
Ph.D., Department of Biochemistry
University of Bristol
Bristol, England, U.K.

Office: 210-567-5069
Email: girotti@uthscsa.edu

 
 

Keywords


cytokines, inflammation, stress, HPA axis, mood disorders, interleukin 6

 

Research Summary


I study the role of inflammatory signals in normal brain function and in psychopathology with a specific focus on interleukin 6 (IL-6) and its downstream signaling pathway. This cytokine 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. Indeed, in work funded by a NARSAD Young Investigator Award, I have recently found that, in rats, IL-6 and STAT3 are required for the sustained elevation of the stress hormones corticosterone and ACTH observed during repeated cold stress exposure, but they are not required for the elevation of the stress hormones after just one acute cold exposure. This suggests that IL-6 and STAT3 modulate the way the HPA axis responds to different intensities and durations of stress. 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 modulating the hormonal response to stress, IL-6 and STAT3 may also contribute to coping style choice toward a stressful situation. In human studies, individuals who adopt an active coping style in situations of stress experience fewer adverse physiological and psychological effects of stress, compared to individuals who choose a passive, or helpless coping style. Coping style can be modeled in the rat using a behavioral test called shock probe defensive burying test. In this test, after receiving a brief shock from an electrified probe, the rat’s behavior is scored, specifically, passive behavior (immobility) and active behavior of bedding displacement and burying of the probe (bury). In preliminary data I found that changing levels of expression of IL-6 and STAT3 activation in the lateral septum, a stress responsive area involved in burying behavior, alters time spent in a passive state or in an active state.

 

Finally, IL-6 and STAT3 have also an important role in facilitating cognitive function mediated by prefrontal cortex areas. Jennifer Donegan, a graduate student in the Morilak’s lab, has 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, where the animal is required to adapt to changing rules in order to receive a reward. 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.

 

Currently, I am interested in understanding the mechanism through which IL-6 and STAT3 affects coping style and cognitive flexibility at a molecular, cellular and circuitry level. These are some of the questions I would like to address:

  1. What are the mechanisms for the IL-6/STAT3 effects on coping style?
    We have evidence that noradrenergic transmission in the lateral septum is required for active coping style. With funds from a pilot project sponsored by the Center for Behavioral Neuroscience (CBN pilot grants) and in collaboration with Dr. Kelly Berg (Pharmacology UTHSCSA) I will explore the possibility of an interaction between IL-6/STAT3 signaling and the α1 adrenergic receptor system in neuronal cell lines.
  2. What are the mechanisms for IL-6/STAT3 effects on cognitive flexibility?
    With funds from a recently awarded R21, and in collaboration with Dr. Kelly Berg, I will test potential interactions of IL-6/STAT3 with the serotonin 2A receptor system (which has also been implicated in cognitive flexibility), both in cultured neurons and in primary neurons.
    I will also determine whether serotonergic transmission in vivo is required for the beneficial effects of IL-6 and STAT3 on cognitive flexibility.
  3. To begin to understand the cellular basis of the IL-6/STAT3 effects, I will explore the immunolocalization of activated (phosphorylated) STAT3 within the lateral septum, the medial prefrontal cortex and the orbitofrontal cortex, to establish the populations of neurons (glutamatergic or GABAergic) that respond to IL-6 activation.
 

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 American Neuroendocrine Society - current


Member of the Society for Neuroscience - 2004 to present


• Lectures, Posters and Presentations •

Society for Neuroscience Annual Conference - San Diego, CA. - Fall 2013
Girotti, M., Donegan, JJ., Fucich, EA., Morilak, DA.
Ketamine restores active coping behavior after stress in the rat defensive burying test (Poster Presentation)


Society for Neuroscience Annual Conference - San Diego, CA. - Fall 2013
Donegan, JJ., Girotti, M. and Morilak, DA.
Orbitofrontal IL-6 and JAK-STAT signaling attenuate stress-induced reversal learning deficits in the rat (Poster Presentation)


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)


American College of Neuropsychopharmacology Meeting - Hollywood, FL - Winter 2012
Lodge, DA., Carreno, F., Shah, A., Jett, J., Girotti, M., Delgado, P., Morilak, D., Frazer, A.
Neuronal systems underlying the antidepressant response of ketamine (Poster 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


Society for Neuroscience Annual Conference - San Diego, CA - Fall 2010
Girotti, M., Donegan, JJ. and Morilak, DA.
Chronic intermittent cold stress alters the profile of pro-inflammatory signals in response to lipopolysaccharide and footshock in the rat hypothalamus (Poster Presentation)


Society for Neuroscience Annual Conference - San Diego, CA - Fall 2010
Donegan, JJ., Girotti, M. and Morilak, DA.
Chronic metabolic stress sensitizes the immune responses to LPS in the rat prefrontal cortex


17th Annual Pharmacology Graduate Student Symposium - San Antonio, TX - Fall 2010
Girotti, M.
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)


Neurobiology of Stress Workshop - Boulder, CO. - Summer 2010
Girotti, M., Donegan, JJ. and Morilak DA. Effects of chronic intermittent cold stress on pro-inflammatory signals elicited by acute footshock in the rat hypothalamus (Poster Presentation)


Neurobiology of Stress Workshop - Boulder, CO. - Summer 2010
Donegan, JJ., Girotti, M. and Morilak DA. Chronic intermittent cold stress causes sensitized responses to lipopolysaccharide in the hypothalamus and prefrontal cortex of rats (Poster Presentation)