title: Interferon-gamma deficiency modifies the effects of a chronic stressor in mice: Implications for psychological pathology.
abstract: Pro-inflammatory cytokines promote behavioral and neurochemical variations similar to those evident following stressor exposure, and have been implicated in promoting depressive illness. Indeed, immunotherapeutic application of the cytokine, interferon-alpha, promoted depressive illness in cancer and hepatitis C patients. We assessed the possibility that another interferon cytokine family member, interferon-gamma (IFN-gamma), might contribute to the behavioral and biochemical alterations provoked by a chronic stressor regimen that has been used to model neuropsychiatric pathology in rodents. As predicted, IFN-gamma-deficient mice displayed basal differences in behavior (e.g., reduced open field exploration) and altered neurochemical activity (e.g., increased noradrenergic and serotonergic activity within the central amygdala), relative to their wild-type counterparts. Moreover, stressor-induced elevations of corticosterone and the pro-inflammatory cytokine, tumor necrosis factor-alpha, were attenuated in IFN-gamma-deficient mice. Similarly, the IFN-gamma null mice were refractory to the chronic stressor-induced alterations of dopamine metabolism (within the prefrontal cortex, paraventricular nucleus of the hypothalamus and central amygdala) evident in wild-type mice. Yet, the chronic stressor provoked signs of anxiety (e.g., reduced open field exploration) and depression-like behavior (e.g., increased forced swim immobility, reduced consumption of a palatable solution) among both wild-type and IFN-gamma knockout mice alike, suggesting a dissociation of behavioral functioning from the stressor-induced alterations of immunological, hormonal and dopaminergic activity. Together, these data suggest a complex neurobehavioral phenotype, wherein IFN-gamma deletion engenders a state of heightened basal emotionality coupled with increased monoaminergic activity in the amygdala. At the same time, however, IFN-gamma deficiency appears to blunt some of the neurochemical, corticoid and cytokine alterations ordinarily associated with chronic stressor exposure.
authors.affiliation: Institute of Neuroscience, Carleton University, 1125 Colonel By Drive, Ottawa, Ontario, Canada K1S5B6.
authors.forename: Darcy
authors.initials: D
authors.lastname: Litteljohn
authors.forename: Amie
authors.initials: A
authors.lastname: Cummings
authors.forename: Ashley
authors.initials: A
authors.lastname: Brennan
authors.forename: Anudip
authors.initials: A
authors.lastname: Gill
authors.forename: Siri
authors.initials: S
authors.lastname: Chunduri
authors.forename: Hymie
authors.initials: H
authors.lastname: Anisman
authors.forename: Shawn
authors.initials: S
authors.lastname: Hayley
mesh_terms: D000818:Animals; D001007:Anxiety / Q000523:psychology; D001522:Behavior, Animal / Q000502:physiology; D015306:Biogenic Monoamines / Q000378:metabolism; D001921:Brain / Q000473:pathology; D002851:Chromatography, High Pressure Liquid; D002908:Chronic Disease; D003345:Corticosterone / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003863:Depression / Q000523:psychology; D004435:Eating; D005838:Genotype; D007371:Interferon-gamma / Q000172:deficiency* / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013315:Stress, Psychological / Q000235:genetics* / Q000523:psychology*; D013550:Swimming / Q000523:psychology
chemical_list: D015306:Biogenic Monoamines; D016207:Cytokines; D007371:Interferon-gamma; D003345:Corticosterone