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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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Modulation of neuronal activities in the thalamus in response to brush and pinch.(a) Representative raw data of spiking activity (left) and waveforms (right). The waveforms of different firing units are grouped as blue and green colors. (b) Raster scan. (c) Response of different neuronal groups in the thalamus due to pinch and brush. C: Laser off (control), P: Pinch, B: Brush, L: Laser on, P+L: Pinch + Laser on, B+L: Brush + Laser on.
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pone.0117746.g004: Modulation of neuronal activities in the thalamus in response to brush and pinch.(a) Representative raw data of spiking activity (left) and waveforms (right). The waveforms of different firing units are grouped as blue and green colors. (b) Raster scan. (c) Response of different neuronal groups in the thalamus due to pinch and brush. C: Laser off (control), P: Pinch, B: Brush, L: Laser on, P+L: Pinch + Laser on, B+L: Brush + Laser on.

Mentions: To examine the ascending pathway of pain inhibition, in addition to recordings in ACC (Fig. 2) during optogenetic stimulation of ACC, electrophysiological recording of neuronal activities in the ventral posterior complex (VPL/VPM) area of thalamus was carried out, as this region in thalamus were made from is known to be involved in pain processing pathway. Location of optical fiber (L: 0.6 mm; DV: 2 mm, angle of 20°) in ACC is shown in H&E stained, coronal section (AP: +1.0 mm, from bregma) of mouse brain (S5C Fig.). As shown in S5D Fig., upon optogenetic stimulation of ACC, the electrophysiological recordings in VPL/VPM of thalamus was carried out for a range of electrode location(s) (L: 2 ± 0.2 mm; DV: 3.5 ± 0.2 mm). The responses to pinch and brush mechanical stimuli in transgenic mice were recorded in different neuron groups in the thalamus subsequent to stimulation of the ChR2 expressing inhibitory neurons in ACC. Fig. 4A shows the representative raw data of spiking activity (left) and waveforms (right) for brush and pinch stimuli with and without laser. The two distinct firing units, sorted by use of principal component analysis using the Plexon offline sorter, are shown as color-coded. The effect of optogenetic stimulation of ACC-inhibitory neurons on neurons in thalamus can be seen in the representative raster scan of control, brush, and pinch (Fig. 4B). In Fig. 4C, we show the histogram of the two distinct firing units in the thalamus due to pinch and brush. The optogenetic-reduction in the responses evoked due to pinch was found to be greater than that due to brush (Fig. 4C). While changes in spike rate due to pinch are higher than the control (laser off) in first unit (upper panel of Fig. 4C), that due to brush is higher in the second unit (upper panel of Fig. 4 C). While both groups of neurons were sensitive to pinch (noxious stimuli), laser stimulation significantly decreased (n = 5) the firing responses to pinch in group 1 (upper panel of Fig. 4C). The pinch-response in group 2 neurons (lower panel of Fig. 4C) was affected to a lesser extent by optogenetic stimulation. Thus, optogenetic modulation can lead to pain inhibition by selectively enhancing the inhibition circuitries of ACC-PAG-Dorsal horn and ACC-Thalamus-PAG-Dorsal horn [9,40].


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)

Modulation of neuronal activities in the thalamus in response to brush and pinch.(a) Representative raw data of spiking activity (left) and waveforms (right). The waveforms of different firing units are grouped as blue and green colors. (b) Raster scan. (c) Response of different neuronal groups in the thalamus due to pinch and brush. C: Laser off (control), P: Pinch, B: Brush, L: Laser on, P+L: Pinch + Laser on, B+L: Brush + Laser on.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0117746.g004: Modulation of neuronal activities in the thalamus in response to brush and pinch.(a) Representative raw data of spiking activity (left) and waveforms (right). The waveforms of different firing units are grouped as blue and green colors. (b) Raster scan. (c) Response of different neuronal groups in the thalamus due to pinch and brush. C: Laser off (control), P: Pinch, B: Brush, L: Laser on, P+L: Pinch + Laser on, B+L: Brush + Laser on.
Mentions: To examine the ascending pathway of pain inhibition, in addition to recordings in ACC (Fig. 2) during optogenetic stimulation of ACC, electrophysiological recording of neuronal activities in the ventral posterior complex (VPL/VPM) area of thalamus was carried out, as this region in thalamus were made from is known to be involved in pain processing pathway. Location of optical fiber (L: 0.6 mm; DV: 2 mm, angle of 20°) in ACC is shown in H&E stained, coronal section (AP: +1.0 mm, from bregma) of mouse brain (S5C Fig.). As shown in S5D Fig., upon optogenetic stimulation of ACC, the electrophysiological recordings in VPL/VPM of thalamus was carried out for a range of electrode location(s) (L: 2 ± 0.2 mm; DV: 3.5 ± 0.2 mm). The responses to pinch and brush mechanical stimuli in transgenic mice were recorded in different neuron groups in the thalamus subsequent to stimulation of the ChR2 expressing inhibitory neurons in ACC. Fig. 4A shows the representative raw data of spiking activity (left) and waveforms (right) for brush and pinch stimuli with and without laser. The two distinct firing units, sorted by use of principal component analysis using the Plexon offline sorter, are shown as color-coded. The effect of optogenetic stimulation of ACC-inhibitory neurons on neurons in thalamus can be seen in the representative raster scan of control, brush, and pinch (Fig. 4B). In Fig. 4C, we show the histogram of the two distinct firing units in the thalamus due to pinch and brush. The optogenetic-reduction in the responses evoked due to pinch was found to be greater than that due to brush (Fig. 4C). While changes in spike rate due to pinch are higher than the control (laser off) in first unit (upper panel of Fig. 4C), that due to brush is higher in the second unit (upper panel of Fig. 4 C). While both groups of neurons were sensitive to pinch (noxious stimuli), laser stimulation significantly decreased (n = 5) the firing responses to pinch in group 1 (upper panel of Fig. 4C). The pinch-response in group 2 neurons (lower panel of Fig. 4C) was affected to a lesser extent by optogenetic stimulation. Thus, optogenetic modulation can lead to pain inhibition by selectively enhancing the inhibition circuitries of ACC-PAG-Dorsal horn and ACC-Thalamus-PAG-Dorsal horn [9,40].

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