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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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In-vivo Electrophysiology of inhibition of ACC neurons by optogenetics.(a) Schematic showing the mechanism of post-synaptic silencing of excitatory neurons due to optogenetic-stimulation of inhibitory neurons in ACC. (b) Representative neuronal firing in ChR2 transgenic mouse without (left) and with (right) light stimulation for 250 ms. (c) Rate histogram of neuronal spikes with varying intensity of light stimulation in the ACC. (d) Rate histogram of neuronal spikes with varying frequencies of light stimulation in the ACC. (e) Intensity-dependent firing rate of neurons in the ACC. (f) Frequency-dependent firing rate of ACC neurons. Rebound activity of excitatory neurons after switching off the laser is encircled. *P < 0.05 vs. control (laser off).
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pone.0117746.g002: In-vivo Electrophysiology of inhibition of ACC neurons by optogenetics.(a) Schematic showing the mechanism of post-synaptic silencing of excitatory neurons due to optogenetic-stimulation of inhibitory neurons in ACC. (b) Representative neuronal firing in ChR2 transgenic mouse without (left) and with (right) light stimulation for 250 ms. (c) Rate histogram of neuronal spikes with varying intensity of light stimulation in the ACC. (d) Rate histogram of neuronal spikes with varying frequencies of light stimulation in the ACC. (e) Intensity-dependent firing rate of neurons in the ACC. (f) Frequency-dependent firing rate of ACC neurons. Rebound activity of excitatory neurons after switching off the laser is encircled. *P < 0.05 vs. control (laser off).

Mentions: To verify post-synaptic inhibition in ACC as the mechanism by which light activation of GAD-1+ neurons may suppress pain perception, electrophysiological recordings were made from spontaneous spiking activity of ACC, without peripheral stimulation (Fig. 2A). Also, light intensity and frequency of stimulation was varied to determine effect of stimulation parameters for efficient modulation of neural activities of the ACC. As shown in Fig. 2B, the spiking of ACC neurons decreased with light stimulation (on) as compared to the off-condition. The effect of various light intensities on spiking rate (Fig. 2C and E) showed that excitatory neurons of ACC could be silenced (*P < 0.05 vs. laser off) likely by stimulating the inhibitory inter-neurons at 10 Hz. The threshold saturation laser intensity was observed to be ∼3.5 mW/mm2. S2A and C Fig. shows the inter-spike interval (ISI) as a function of intensity corresponding to Fig. 2C and 2E respectively. The mean ISI (S2C Fig.) was found to increase as a function of laser intensity and saturate at ∼3.0 mW/mm2 implying efficient laser-induced silencing of depolarizing ACC neurons.


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)

In-vivo Electrophysiology of inhibition of ACC neurons by optogenetics.(a) Schematic showing the mechanism of post-synaptic silencing of excitatory neurons due to optogenetic-stimulation of inhibitory neurons in ACC. (b) Representative neuronal firing in ChR2 transgenic mouse without (left) and with (right) light stimulation for 250 ms. (c) Rate histogram of neuronal spikes with varying intensity of light stimulation in the ACC. (d) Rate histogram of neuronal spikes with varying frequencies of light stimulation in the ACC. (e) Intensity-dependent firing rate of neurons in the ACC. (f) Frequency-dependent firing rate of ACC neurons. Rebound activity of excitatory neurons after switching off the laser is encircled. *P < 0.05 vs. control (laser off).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0117746.g002: In-vivo Electrophysiology of inhibition of ACC neurons by optogenetics.(a) Schematic showing the mechanism of post-synaptic silencing of excitatory neurons due to optogenetic-stimulation of inhibitory neurons in ACC. (b) Representative neuronal firing in ChR2 transgenic mouse without (left) and with (right) light stimulation for 250 ms. (c) Rate histogram of neuronal spikes with varying intensity of light stimulation in the ACC. (d) Rate histogram of neuronal spikes with varying frequencies of light stimulation in the ACC. (e) Intensity-dependent firing rate of neurons in the ACC. (f) Frequency-dependent firing rate of ACC neurons. Rebound activity of excitatory neurons after switching off the laser is encircled. *P < 0.05 vs. control (laser off).
Mentions: To verify post-synaptic inhibition in ACC as the mechanism by which light activation of GAD-1+ neurons may suppress pain perception, electrophysiological recordings were made from spontaneous spiking activity of ACC, without peripheral stimulation (Fig. 2A). Also, light intensity and frequency of stimulation was varied to determine effect of stimulation parameters for efficient modulation of neural activities of the ACC. As shown in Fig. 2B, the spiking of ACC neurons decreased with light stimulation (on) as compared to the off-condition. The effect of various light intensities on spiking rate (Fig. 2C and E) showed that excitatory neurons of ACC could be silenced (*P < 0.05 vs. laser off) likely by stimulating the inhibitory inter-neurons at 10 Hz. The threshold saturation laser intensity was observed to be ∼3.5 mW/mm2. S2A and C Fig. shows the inter-spike interval (ISI) as a function of intensity corresponding to Fig. 2C and 2E respectively. The mean ISI (S2C Fig.) was found to increase as a function of laser intensity and saturate at ∼3.0 mW/mm2 implying efficient laser-induced silencing of depolarizing ACC neurons.

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