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Research ArticleNew Research, Disorders of the Nervous System

CRF Mediates Stress-Induced Pathophysiological High-Frequency Oscillations in Traumatic Brain Injury

Chakravarthi Narla, Paul S. Jung, Francisco Bautista Cruz, Michelle Everest, Julio Martinez-Trujillo and Michael O. Poulter
eNeuro 30 April 2019, 6 (2) ENEURO.0334-18.2019; DOI: https://doi.org/10.1523/ENEURO.0334-18.2019
Chakravarthi Narla
1Robarts Research Institute, Schulich School of Medicine, University of Western Ontario, London, Ontario N6A 5K8, Canada
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Paul S. Jung
1Robarts Research Institute, Schulich School of Medicine, University of Western Ontario, London, Ontario N6A 5K8, Canada
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Francisco Bautista Cruz
1Robarts Research Institute, Schulich School of Medicine, University of Western Ontario, London, Ontario N6A 5K8, Canada
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Michelle Everest
1Robarts Research Institute, Schulich School of Medicine, University of Western Ontario, London, Ontario N6A 5K8, Canada
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Julio Martinez-Trujillo
1Robarts Research Institute, Schulich School of Medicine, University of Western Ontario, London, Ontario N6A 5K8, Canada
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Michael O. Poulter
1Robarts Research Institute, Schulich School of Medicine, University of Western Ontario, London, Ontario N6A 5K8, Canada
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  • Figure 1.
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    Figure 1.

    CRF application increased the activity of the PCtx in TBI rat. A, Representative images showing activation of PCtx from sham rats, without (top) or with CRF (100 nM; bottom). Each image was taken at the same time interval [2 (during stimulation), 3, and 5 s]. B–D, Quantification of CRFR1 activation shows that the activity of Layer II pyramidal cells and interneurons of DEn are decreased while the activity of Layer III interneurons is increased in non-brain-injured animals over the range of stimulation frequencies used to activate the circuit; *p < 0.05; n = 5 slices from four rats. E, Representative images showing activation of the layers of ipsilateral PCtx from brain-injured rats, without (top) or with CRF bottom). F, G, Quantification of CRFR1 activation shows that the activity of Layer II pyramidal cells is increased while the activity of Layer III interneurons is decreased over the range of stimulation frequencies used in piriform cortical slices from TBI rats to activate the circuit; *p < 0.05. n = 9 slices from seven rats. No response is observed from interneurons of DEn. Arrows in panels indicate the orientation of slice. D, dorsal; V, ventral; M, medial; L, lateral. Red indicates highest ΔF/F; orange, yellow and green indicate medium ΔF/F; blue a reduction in ΔF/F.

  • Figure 2.
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    Figure 2.

    Application of CRF increased contralateral PCtx activity in brain-injured rats. CRFR1 mediated these effects. A, Representative images showing activation of layers of contralateral piriform cortical slices from brain-injured rats, without (top) or with CRF perfusion before recording (bottom). B–D, Quantification of CRFR1 activation shows that the activity of Layer II pyramidal cells and interneurons of DEn are increased while the activity of Layer III interneurons is decreased over the range of stimulation frequencies used in contralateral piriform cortical slices from brain-injured rats to activate the circuit; *p < 0.01; n = 8 slices from six rats.

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    Figure 3.

    CRFR1 mediate CRF responses in brain-injured PCtx. A, Representative images of the activation of the PCtx layers in slices at differing time points before (top) and after the application of CRF (bottom) in the presence of the CRFR1 antagonist antalarmin. B, C, Quantification of CRFR1 activation in the presence of antalarmin in Layer II and Layer III of ipsilateral PCtx; n = 6 slices from five rats.

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    Figure 4.

    PKA and PKC antagonism in ipsilateral and contralateral PCtx in the presence of CRF. A, Quantification of the effect of BIS on CRFR1 activation in ipsilateral piriform cortical slices from brain-injured animals; *p < 0.05, n = 8 slices from eight rats/group. B, Quantification of the effect of the PKC inhibitor, PMA, on CRF-mediated activation of CRFR1 in ipsilateral piriform cortical slices from brain-injured animals; *p < 0.05, n = 9 slices from eight rats/group. C, Quantification of the effect of the PKA antagonist H89 on CRF-mediated activation of CRFR1 in ipsilateral piriform cortical slices from brain-injured animals; *p < 0.05, n = 9 slices from seven rats/group. D, Quantification of the effect of forskolin, an adenylate cyclase activator with or without subsequent administration of H89 on ipsilateral piriform cortical slices from brain-injured animals; *p < 0.05, n = 8 slices from six rats/group. E, Quantification of the effect of forskolin (an adenylyl cyclase activator) with or without subsequent administration of H89, on CRFR1 activation in contralateral piriform cortical slices from brain-injured animals; *p < 0.05, n = 7 slices from six rats/group. F, Quantification of the effect of the PKA inhibitor H89 on CRF-mediated activation of CRFR1 in contralateral piriform cortical slices from brain-injured animals; *p < 0.05, n = 6 slices from six rats/group. G, Quantification of the effect of the PKC antagonist BIS on CRF-mediated activation of CRFR1 in contralateral piriform cortical slices from brain-injured animals; *p < 0.05, n = 6 slices from six rats/group.

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    Figure 5.

    Stress induces a larger electrographic response in the amygdala of TBI than in sham rats A, Recording of TBI rat amygdala response from a sham operated rat showed only small electrographic response to a tail inch stress, while in B, TBI-injured rats showed a large increase in electrical activity. C, A 100-ms sample of a response where ripples (red band pass filtered >120 < 250 Hz) and fast ripples (blue high pass filtered >250 Hz) are clearly visible. D, Mean normalized power spectra of sham (n = 5) and TBI (n = 5). HFOs compared to lower frequencies showed a 2.5-fold change in power in TBI rats, but little change in sham rats. E, F, A comparison of frequency content of sham rats' response using Morlet wavelet analysis shows that sham rats have only small responses to the stressor, while in TBI rats, large increases in electrical activity during stressor. The inset Morlet using a smaller window shows well-resolved fast ripple activity (* marks approximate time from which the window was obtained; white scale bar is 100 ms).

  • Figure 6.
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    Figure 6.

    CRFR1 antagonism in vivo in brain-injured animals reduced electrographic response and HFOs during stress. A, Tail pinch response from a TBI rat followed by the response after the application of CP 154526, a CRFR1 antagonist, which is followed by a recovery trace after 24 h of drug washout. Duration of stress is indicated by the bar placed above the control response which was for 2 min. B, Morlet spectrograms which correspond to the traces shown in A.

  • Figure 7.
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    Figure 7.

    CRF mediates the phase/amplitude coupling during stressor. A, upper traces, Examples of fast ripple activity and θ band in control, CP 154526, and after 24-h drug wash out from TBI rats under stress filtered into θ (3–8 Hz, blue) and fast ripples (250–500 Hz, red) bands. B, Comparison of MIs between low-frequency phase on x-axis and higher frequency amplitude between 250 and 500 Hz on y-axis. Fast ripples (>250 Hz) are significantly and highly coupled over the frequency bins corresponding to θ rhythm. Ripple activity is also coupled to a lesser extent in the same range. This relationship is abolished by CRFR1 antagonism. Very low-frequency activity (2–4 Hz) is apparently coupled over a wide range of high-frequency activity. The MI values corresponding to this coupling during antagonist are below chance. After 24 h, the PAC returned.

  • Figure 8.
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    Figure 8.

    Phase-amplitude coupling from data recorded during a stressor in TBI rats. The oscillation-triggered comodulogram shows coupling between fast ripples and an underlying 5-Hz oscillation without antagonist and after washout of antagonist. During antagonist, destructive interference of the pooled LFPs shows no significant coupling.

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CRF Mediates Stress-Induced Pathophysiological High-Frequency Oscillations in Traumatic Brain Injury
Chakravarthi Narla, Paul S. Jung, Francisco Bautista Cruz, Michelle Everest, Julio Martinez-Trujillo, Michael O. Poulter
eNeuro 30 April 2019, 6 (2) ENEURO.0334-18.2019; DOI: 10.1523/ENEURO.0334-18.2019

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CRF Mediates Stress-Induced Pathophysiological High-Frequency Oscillations in Traumatic Brain Injury
Chakravarthi Narla, Paul S. Jung, Francisco Bautista Cruz, Michelle Everest, Julio Martinez-Trujillo, Michael O. Poulter
eNeuro 30 April 2019, 6 (2) ENEURO.0334-18.2019; DOI: 10.1523/ENEURO.0334-18.2019
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Keywords

  • traumatic brain injury
  • stress
  • voltage sensitive dye imaging ripples
  • epilepsy
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