Interactive Responses of a Thalamic Neuron to Formalin Induced Lasting Pain in Behaving Mice

Thalamocortical (TC) neurons are known to relay incoming sensory information to the cortex via firing in tonic or burst mode. However, it is still unclear how respective firing modes of a single thalamic relay neuron contribute to pain perception under consciousness. Some studies report that bursting could increase pain in hyperalgesic conditions while others suggest the contrary. However, since previous studies were done under either neuropathic pain conditions or often under anesthesia, the mechanism of thalamic pain modulation under awake conditions is not well understood. We therefore characterized the thalamic firing patterns of behaving mice in response to nociceptive pain induced by inflammation. Our results demonstrated that nociceptive pain responses were positively correlated with tonic firing and negatively correlated with burst firing of individual TC neurons. Furthermore, burst properties such as intra-burst-interval (IntraBI) also turned out to be reliably correlated with the changes of nociceptive pain responses. In addition, brain stimulation experiments revealed that only bursts with specific bursting patterns could significantly abolish behavioral nociceptive responses. The results indicate that specific patterns of bursting activity in thalamocortical relay neurons play a critical role in controlling long-lasting inflammatory pain in awake and behaving mice

Differential responses of thalamic reticular neurons to nociception in freely behaving mice

Pain serves an important protective role. However, it can also have debilitating adverse effects if dysfunctional, such as in pathological pain conditions. As part of the thalamocortical circuit, the thalamic reticular nucleus (TRN) has been implicated to have important roles in controlling nociceptive signal transmission. However studies on how TRN neurons, especially how TRN neuronal subtypes categorized by temporal bursting firing patterns—typical bursting, atypical bursting, and non-bursting TRN neurons—contribute to nociceptive signal modulation is not known. To reveal the relationship between TRN neuronal subtypes and modulation of nociception, we simultaneously recorded behavioral responses and TRN neuronal activity to formalin induced nociception in freely moving mice. We found that typical bursting TRN neurons had the most robust response to nociception; changes in tonic firing rate of typical TRN neurons exactly matched changes in behavioral nociceptive responses, and burst firing rate of these neurons increased significantly when behavioral nociceptive responses were reduced. This implies that typical TRN neurons could critically modulate ascending nociceptive signals. The role of other TRN neuronal subtypes was less clear; atypical bursting TRN neurons decreased tonic firing rate after the second peak of behavioral nociception and the firing rate of non-bursting TRN neurons mostly remained at baseline level. Overall, our results suggest that different TRN neuronal subtypes contribute differentially to processing formalin induced sustained nociception in freely moving mice

Data from: Changes in activity of the same thalamic neurons to repeated nociception in behaving mice

The sensory thalamus has been reported to play a key role in central pain sensory modulation and processing, but its response to repeated nociception at thalamic level is not well known. Current study investigated thalamic response to repeated nociception by recording and comparing the activity of the same thalamic neuron during the 1st and 2nd formalin injection induced nociception, with a week interval between injections, in awake and behaving mice. Behaviorally, the 2nd injection induced greater nociceptive responses than the 1st. Thalamic activity mirrored these behavioral changes with greater firing rate during the 2nd injection. Analysis of tonic and burst firing, characteristic firing pattern of thalamic neurons, revealed that tonic firing activity was potentiated while burst firing activity was not significantly changed by the 2nd injection relative to the 1st. Likewise, burst firing property changes, which has been consistently associated with different phases of nociception, were not induced by the 2nd injection. Overall, data suggest that repeated nociception potentiated responsiveness of thalamic neurons and confirmed that tonic firing transmits nociceptive signals

Changes in Activity of the Same Thalamic Neurons to Repeated Nociception in Behaving Mice.

The sensory thalamus has been reported to play a key role in central pain sensory modulation and processing, but its response to repeated nociception at thalamic level is not well known. Current study investigated thalamic response to repeated nociception by recording and comparing the activity of the same thalamic neuron during the 1st and 2nd formalin injection induced nociception, with a week interval between injections, in awake and behaving mice. Behaviorally, the 2nd injection induced greater nociceptive responses than the 1st. Thalamic activity mirrored these behavioral changes with greater firing rate during the 2nd injection. Analysis of tonic and burst firing, characteristic firing pattern of thalamic neurons, revealed that tonic firing activity was potentiated while burst firing activity was not significantly changed by the 2nd injection relative to the 1st. Likewise, burst firing property changes, which has been consistently associated with different phases of nociception, were not induced by the 2nd injection. Overall, data suggest that repeated nociception potentiated responsiveness of thalamic neurons and confirmed that tonic firing transmits nociceptive signals

IntraBI and anti-nociception.

<p>(A) Schematic drawing of electrical stimulation protocols. (B) Comparison of the effect of VB stimulation with varying IntraBI length on formalin induced nociceptive responses. Repeated measures ANOVA was used for statistical analysis over time followed by Games-Howell post hoc. †P<0.05 (C) Bar graph of the time segments representing the peak of the 1^st (0-5 min; F=4.58, P<0.05) and 2^nd (20-25 min; F=4.90, P<0.05) phase nociceptive responses for better comparisons between different stimulation conditions. All data points are mean±SEM. One-way ANOVA followed by Games-Howell post hoc was used to compare each data point with the sham control, *P<0.05.</p

Number of burst pulses within a burst and anti-nociception.

<p>(A) Schematic drawing of electrical stimulation protocols. (B) Comparison of the effect of VB stimulation with different burst pulse number per burst on formalin induced nociceptive responses. Repeated measures ANOVA was used for statistical analysis over time followed by Games-Howell post hoc. †P<0.05 (C) Bar graph of the time segments representing the peak of the 1^st (0-5 min; F=4.56, P<0.05) and 2^nd (20-25 min; F=6.74, P<0.05) phase nociceptive responses for better comparisons between different stimulation conditions. All data points are mean±SEM. One-way ANOVA followed by Games-Howell post hoc was used to compare each data point with the sham control, *P<0.05.</p

Thalamic neuronal activity changes induced by 2^nd formalin or 2^nd saline injection.

<p><b>(A)</b> Overall thalamic neuronal firing rate changes and behavior nociceptive responses induced by 2^nd formalin or saline injection. <b>(B)</b> Sample of a thalamic neuron firing in burst (+) or tonic (•) spikes. <b>(C)</b> Tonic and burst firing of thalamic neurons after 2^nd formalin or saline injection. Blue line indicates tonic firing, red line indicates burst firing, and dotted line is the behavioral responses. <b>(A and C)</b> All data points are mean±SEM. Formalin <i>N</i> = 19 neurons from 2^nd injection recorded in pairs, 5 mice. Saline <i>N</i> = 13 neurons, 4 mice. Two tailed t-test was used to compare each data points with respective baselines. * indicates significant difference at <i>P</i><0.05.</p