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, 13 (1), 172

Minocycline Attenuates Interferon-α-Induced Impairments in Rat Fear Extinction

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Minocycline Attenuates Interferon-α-Induced Impairments in Rat Fear Extinction

Qiang Bi et al. J Neuroinflammation.

Abstract

Background: Extinction of conditioned fear is an important brain function for animals to adapt to a new environment. Accumulating evidence suggests that innate immune cytokines are involved in the pathology of psychotic disorders. However, the involvement of cytokines in fear dysregulation remains less investigated. In the present study, we investigated how interferon (IFN)-α disrupts the extinction of conditioned fear and propose an approach to rescue IFN-α-induced neurologic impairment.

Methods: We used a rat model of auditory fear conditioning to study the effect of IFN-α on the fear memory process. IFN-α was infused directly into the amygdala of rats and examined the rats' behavioral response (freezing) to fear-conditioned stimuli. Immunohistochemical staining was used to examine the glia activity status of glia in the amygdala. The levels of the proinflammatory cytokines interleukin (IL)-1β and tumor necrosis factor (TNF)-α in the amygdala were measured by enzyme-linked immunosorbent assay. We also administrated minocycline, a microglial activation inhibitor, before the IFN-α infusion to testify the possibility to reverse the IFN-α-induced effects.

Results: Infusing the amygdala with IFN-α impaired the extinction of conditioned fear in rats and activated microglia and astrocytes in the amygdala. Administering minocycline prevented IFN-α from impairing fear extinction. The immunohistochemical and biochemical results show that minocycline inhibited IFN-α-induced microglial activation and reduced IL-1β and TNF-α production.

Conclusions: Our findings suggest that IFN-α disrupts the extinction of auditory fear by activating glia in the amygdala and provides direction for clinical studies of novel treatments to modulate the innate immune system in patients with psychotic disorders.

Keywords: Amygdala; Astrocyte; Cytokine; Extinction; Fear conditioning; Microglia.

Figures

Fig. 1
Fig. 1
Effect of interferon (IFN)-α treatment on fear extinction. Mean ± standard error of percent freezing compared to that of the vehicle. Rats (n = 8/group) were treated with 100, 200, or 400 IU IFN-α for the habituation, conditioning, and extinction trials. Vehicle or IFN-α was administrated after the rats experienced the habituation and conditioning trials. *p < 0.05 in the comparison (Tukey’s test) between vehicle and 400 IU IFN-α group. # p < 0.05 in the comparison between vehicle and 200 IU IFN-α group
Fig. 2
Fig. 2
Immunohistochemical analysis of Iba1-immunopositive microglia in the amygdala following vehicle or interferon (IFN)-α administration. ad Representative microphotographs showing changes in the number of Iba1-immunopositive cells in the amygdala after vehicle, 100, 200, or 400 IU IFN-α was administered. e Quantitative analysis of the number of Iba1-immunopositive microglia in predefined areas of the amygdala. **p < 0.01, analysis of variance followed by Tukey’s test; n = 5 animals/group
Fig. 3
Fig. 3
Immunohistochemical analysis of green fluorescent protein (GFAP)-immunopositive astrocytes in the amygdala following vehicle or interferon (IFN)-α administration. ad Representative microphotographs showing changes in the number of GFAP-immunopositive cells in the amygdala after vehicle, 100, 200, or 400 IU IFN-α was administered. e Quantitative analysis of the number of GFAP-immunopositive astrocytes in predefined areas of the amygdala. **p < 0.01; *p < 0.05, analysis of variance followed by Tukey’s test; n = 5 animals/group
Fig. 4
Fig. 4
Immunohistochemical analysis of neuronal nuclear antigen (NeuN)-immunopositive neurons in the amygdala following vehicle or interferon (IFN)-α administration. ad Representative microphotographs showing changes in the number of NeuN-immunopositive cells in the amygdala following vehicle, 100, 200, or 400 IU IFN-α administration. e Quantitative analysis of the number of NeuN-immunopositive neurons in the amygdala
Fig. 5
Fig. 5
Effect of minocycline on interferon (IFN)-α-induced impairment of fear extinction. Mean ± standard error of percent freezing to tone in minocycline, saline + IFN-α, and minocycline + IFN-α-treated rats (n = 10/group) across the habituation, conditioning, extinction, and trials. Saline or minocycline was administered before the behavior experiment. IFN-α was administered after the conditioning trials. *p < 0.05 in the comparison (Tukey’s test) between saline + IFN-α and minocycline + IFN-α group. # p < 0.05 in the comparison between minocycline and minocycline + IFN-α group
Fig. 6
Fig. 6
Effect of minocycline on interferon (IFN)-α-induced microglial activation in the amygdala. ac Representative microphotographs showing changes in Iba1-immunopositive microglia in the amygdala in the saline + INF-α, minocycline + INF-α, and minocycline groups. d Quantitative analysis of the number of Iba1-immunopositive microglia. **p < 0.01; *p < 0.05, analysis of variance followed by Tukey’s test; n = 5 animals/group
Fig. 7
Fig. 7
Effect of minocycline on interferon (IFN)-α-induced astrocytic activation in the amygdala. ac Representative microphotographs showing changes in green fluorescent protein (GFAP)-immunopositive astrocytes in the amygdala in the saline + INF-α, minocycline + INF-α, and minocycline groups. d Quantitative analysis of the number of GFAP-immunopositive astrocytes. **p < 0.01; *p < 0.05, analysis of variance followed by Tukey’s test; n = 5 animals/group
Fig. 8
Fig. 8
Effect of minocycline on interleukin (IL)-1β and tumor necrosis factor (TNF)-α concentrations in the amygdala. Bar graphs illustrate the concentrations of IL-1β (a) and TNF-α (b) in the amygdala in the vehicle, saline + INF-α, minocycline +I NF-α, and minocycline groups. **p < 0.01, analysis of variance followed by Tukey’s test; n = 5 animals/group

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References

    1. Gill J, Vythilingam M, Page GG. Low cortisol, high DHEA, and high levels of stimulated TNF-alpha, and IL-6 in women with PTSD. J Trauma Stress. 2008;21:530–9. doi: 10.1002/jts.20372. - DOI - PMC - PubMed
    1. Gorman JM, Kent JM, Sullivan GM, Coplan JD. Neuroanatomical hypothesis of panic disorder, revised. Am J Psychiatry. 2000;157:493–505. doi: 10.1176/appi.ajp.157.4.493. - DOI - PubMed
    1. Guo M, Liu T, Guo JC, Jiang XL, Chen F, Gao YS. Study on serum cytokine levels in posttraumatic stress disorder patients. Asian Pac J Trop Med. 2012;5:323–5. doi: 10.1016/S1995-7645(12)60048-0. - DOI - PubMed
    1. Fyer AJ. Current approaches to etiology and pathophysiology of specific phobia. Biol Psychiatry. 1998;44:1295–304. doi: 10.1016/S0006-3223(98)00274-1. - DOI - PubMed
    1. Lindqvist D, Wolkowitz OM, Mellon S, Yehuda R, Flory JD, Henn-Haase C, Bierer LM, Abu-Amara D, Coy M, Neylan TC, et al. Proinflammatory milieu in combat-related PTSD is independent of depression and early life stress. Brain Behav Immun. 2014;42:81–8. doi: 10.1016/j.bbi.2014.06.003. - DOI - PubMed
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