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Pain inhibition by optogenetic activation of specific anterior cingulate cortical neurons.

Gu L, Uhelski ML, Anand S, Romero-Ortega M, Kim YT, Fuchs PN, Mohanty SK - PLoS ONE (2015)

Bottom Line: Cumulative evidence from both humans and animals suggests that the anterior cingulate cortex (ACC) is important for pain-related perception, and thus a likely target for pain relief therapy.Moreover, we confirmed specific electrophysiological responses from different neuronal units in the thalamus, in response to particular types of painful stimuli (i,e., formalin injection, pinch), which we found to be modulated by optogenetic control of the ACC inhibitory neurons.These results underscore the inhibition of the ACC as a clinical alternative in inhibiting chronic pain, and leads to a better understanding of the pain processing circuitry of the cingulate cortex.

View Article: PubMed Central - PubMed

Affiliation: Biophysics and Physiology Group, Department of Physics, University of Texas at Arlington, Arlington, TX-76019, United States of America.

ABSTRACT
Cumulative evidence from both humans and animals suggests that the anterior cingulate cortex (ACC) is important for pain-related perception, and thus a likely target for pain relief therapy. However, use of existing electrode based ACC stimulation has not significantly reduced pain, at least in part due to the lack of specificity and likely co-activation of both excitatory and inhibitory neurons. Herein, we report a dramatic reduction of pain behavior in transgenic mice by optogenetic stimulation of the inhibitory neural circuitry of the ACC expressing channelrhodopsin-2. Electrophysiological measurements confirmed that stimulation of ACC inhibitory neurons is associated with decreased neural activity in the ACC. Further, a distinct optogenetic stimulation intensity and frequency-dependent inhibition of spiking activity in the ACC was observed. Moreover, we confirmed specific electrophysiological responses from different neuronal units in the thalamus, in response to particular types of painful stimuli (i,e., formalin injection, pinch), which we found to be modulated by optogenetic control of the ACC inhibitory neurons. These results underscore the inhibition of the ACC as a clinical alternative in inhibiting chronic pain, and leads to a better understanding of the pain processing circuitry of the cingulate cortex.

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GAD1 and GFP positive labeled cells in the anterior cingulate cortex.A: GFP, B: GAD1, C: DAPI, D: GFP+ labeled cells overlaid with GAD1 and DAPI. High magnification image at the anterior cingulate cortex (E: DAPI, F: GAD1, G: GFP, H: co-expression). (I) Number of cells expressing GFP+, GAD1+, or GFP & GAD1 in the ACC. Confocal images of immunostaining of the ACC neurons with GAD1-FITC (J), and YFP-Alexa 555 (K). Scale bar: 50 μm.
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pone.0117746.g001: GAD1 and GFP positive labeled cells in the anterior cingulate cortex.A: GFP, B: GAD1, C: DAPI, D: GFP+ labeled cells overlaid with GAD1 and DAPI. High magnification image at the anterior cingulate cortex (E: DAPI, F: GAD1, G: GFP, H: co-expression). (I) Number of cells expressing GFP+, GAD1+, or GFP & GAD1 in the ACC. Confocal images of immunostaining of the ACC neurons with GAD1-FITC (J), and YFP-Alexa 555 (K). Scale bar: 50 μm.

Mentions: To examine the expression of ChR2 in specific cell types, we immunostained the ACC region in transgenic mice with cell-specific antibodies, along with the GFP antibody. Fig. 1 shows GAD1 and GFP positive labeled cells in the anterior cingulate cortex. GAD1 is known to be expressed in GABAergic neurons. Co-expression (Fig. 1D) revealed that in the ACC region, ChR2 is expressed in inhibitory neurons in the transgenic mice. Fig. 1 E-H shows high magnification image at the ACC showing co-expression of GFP and GAD1 cells. Fig. 1I shows that significant number of inhibitory neurons express ChR2 (GFP+) in the ACC and 80% of neurons expressing ChR2 in the ACC are found to be inhibitory. Fig. 1 J & K show confocal images of neurons in ACC immunostained with GAD1-FITC and YFP-Alexa 555 respectively. Z-stack composite images of two different regions in ACC, immunostained with GAD1-FITC (green) and YFP-Alexa 555 (red) are shown in S1 Fig.


Pain inhibition by optogenetic activation of specific anterior cingulate cortical neurons.

Gu L, Uhelski ML, Anand S, Romero-Ortega M, Kim YT, Fuchs PN, Mohanty SK - PLoS ONE (2015)

GAD1 and GFP positive labeled cells in the anterior cingulate cortex.A: GFP, B: GAD1, C: DAPI, D: GFP+ labeled cells overlaid with GAD1 and DAPI. High magnification image at the anterior cingulate cortex (E: DAPI, F: GAD1, G: GFP, H: co-expression). (I) Number of cells expressing GFP+, GAD1+, or GFP & GAD1 in the ACC. Confocal images of immunostaining of the ACC neurons with GAD1-FITC (J), and YFP-Alexa 555 (K). Scale bar: 50 μm.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4340873&req=5

pone.0117746.g001: GAD1 and GFP positive labeled cells in the anterior cingulate cortex.A: GFP, B: GAD1, C: DAPI, D: GFP+ labeled cells overlaid with GAD1 and DAPI. High magnification image at the anterior cingulate cortex (E: DAPI, F: GAD1, G: GFP, H: co-expression). (I) Number of cells expressing GFP+, GAD1+, or GFP & GAD1 in the ACC. Confocal images of immunostaining of the ACC neurons with GAD1-FITC (J), and YFP-Alexa 555 (K). Scale bar: 50 μm.
Mentions: To examine the expression of ChR2 in specific cell types, we immunostained the ACC region in transgenic mice with cell-specific antibodies, along with the GFP antibody. Fig. 1 shows GAD1 and GFP positive labeled cells in the anterior cingulate cortex. GAD1 is known to be expressed in GABAergic neurons. Co-expression (Fig. 1D) revealed that in the ACC region, ChR2 is expressed in inhibitory neurons in the transgenic mice. Fig. 1 E-H shows high magnification image at the ACC showing co-expression of GFP and GAD1 cells. Fig. 1I shows that significant number of inhibitory neurons express ChR2 (GFP+) in the ACC and 80% of neurons expressing ChR2 in the ACC are found to be inhibitory. Fig. 1 J & K show confocal images of neurons in ACC immunostained with GAD1-FITC and YFP-Alexa 555 respectively. Z-stack composite images of two different regions in ACC, immunostained with GAD1-FITC (green) and YFP-Alexa 555 (red) are shown in S1 Fig.

Bottom Line: Cumulative evidence from both humans and animals suggests that the anterior cingulate cortex (ACC) is important for pain-related perception, and thus a likely target for pain relief therapy.Moreover, we confirmed specific electrophysiological responses from different neuronal units in the thalamus, in response to particular types of painful stimuli (i,e., formalin injection, pinch), which we found to be modulated by optogenetic control of the ACC inhibitory neurons.These results underscore the inhibition of the ACC as a clinical alternative in inhibiting chronic pain, and leads to a better understanding of the pain processing circuitry of the cingulate cortex.

View Article: PubMed Central - PubMed

Affiliation: Biophysics and Physiology Group, Department of Physics, University of Texas at Arlington, Arlington, TX-76019, United States of America.

ABSTRACT
Cumulative evidence from both humans and animals suggests that the anterior cingulate cortex (ACC) is important for pain-related perception, and thus a likely target for pain relief therapy. However, use of existing electrode based ACC stimulation has not significantly reduced pain, at least in part due to the lack of specificity and likely co-activation of both excitatory and inhibitory neurons. Herein, we report a dramatic reduction of pain behavior in transgenic mice by optogenetic stimulation of the inhibitory neural circuitry of the ACC expressing channelrhodopsin-2. Electrophysiological measurements confirmed that stimulation of ACC inhibitory neurons is associated with decreased neural activity in the ACC. Further, a distinct optogenetic stimulation intensity and frequency-dependent inhibition of spiking activity in the ACC was observed. Moreover, we confirmed specific electrophysiological responses from different neuronal units in the thalamus, in response to particular types of painful stimuli (i,e., formalin injection, pinch), which we found to be modulated by optogenetic control of the ACC inhibitory neurons. These results underscore the inhibition of the ACC as a clinical alternative in inhibiting chronic pain, and leads to a better understanding of the pain processing circuitry of the cingulate cortex.

Show MeSH
Related in: MedlinePlus