The Anterior Insula and its Projection to the Prelimbic Cortex are Involved in the Regulation of 5-HT-Induced Itch.

Itch is an unpleasant sensation that urges people and animals to scratch. Neuroimaging studies on itch have yielded extensive correlations with diverse cortical and subcortical regions, including the insular lobe. However, the role and functional specificity of the insular cortex (IC) and its subdivisions in itch mediation remains unclear. Here, we demonstrated by immunohistochemistry and fiber photometry tests, that neurons in both the anterior insular cortex (AIC) and the posterior insular cortex (PIC) are activated during acute itch processes. Pharmacogenetic experiments revealed that nonselective inhibition of global AIC neurons, or selective inhibition of the activity of glutaminergic neurons in the AIC, reduced the scratching behaviors induced by intradermal injection of 5-hydroxytryptamine (5-HT), but not those induced by compound 48/80. However, both nonselective inhibition of global PIC neurons and selective inhibition of glutaminergic neurons in the PIC failed to affect the itching-scratching behaviors induced by either 5-HT or compound 48/80. In addition, pharmacogenetic inhibition of AIC glutaminergic neurons effectively blocked itch-associated conditioned place aversion behavior, and inhibition of AIC glutaminergic neurons projecting to the prelimbic cortex significantly suppressed 5-HT-evoked scratching. These findings provide preliminary evidence that the AIC is involved, at least partially via aversive emotion mediation, in the regulation of 5-HT-, but not compound 48/80-induced itch.

Dysgranular retrosplenial cortex modulates histaminergic and nonhistaminergic itch processing.

Itch is an unpleasant sensation followed by an intense desire to scratch. Previous researches have advanced our understanding about the role of anterior cingulate cortex and prelimbic cortex in itch modulation, whereas little is known about the effects of retrosplenial cortex (RSC) during this process. Here we firstly confirmed that the neuronal activity of dysgranular RSC (RSCd) is significantly elevated during itch-scratching processing through c-Fos immunohistochemistry and fiber photometry recording. Then with designer receptors exclusively activated by designer drugs approaches, we found that pharmacogenetic inhibition of global RSCd neurons attenuated the number of scratching bouts as well as the cumulative duration of scratching bouts elicited by both 5-HT or compound 48/80 injection into rats' nape or cheek; selective inhibition of the pyramidal neurons in RSCd, or of the excitatory projections from caudal anterior cingulate cortex (cACC) to RSCd, demonstrated the similar effects of decreasing itch-related scratching induced by both 5-HT or compound 48/80. Pharmacogenetic intervention of the neuronal or circuitry activities did not affect rats' motor ability. This study presents direct evidence that pyramidal neurons in RSCd, and the excitatory projection from cACC to RSCd are critically involved in central regulation of both histaminergic and nonhistaminergic itch.

The Anterior Insula and its Projection to the Prelimbic Cortex are Involved in the Regulation of 5-HT-Induced Itch / 神经科学通报·英文版

Itch is an unpleasant sensation that urges people and animals to scratch. Neuroimaging studies on itch have yielded extensive correlations with diverse cortical and subcortical regions, including the insular lobe. However, the role and functional specificity of the insular cortex (IC) and its subdivisions in itch mediation remains unclear. Here, we demonstrated by immunohistochemistry and fiber photometry tests, that neurons in both the anterior insular cortex (AIC) and the posterior insular cortex (PIC) are activated during acute itch processes. Pharmacogenetic experiments revealed that nonselective inhibition of global AIC neurons, or selective inhibition of the activity of glutaminergic neurons in the AIC, reduced the scratching behaviors induced by intradermal injection of 5-hydroxytryptamine (5-HT), but not those induced by compound 48/80. However, both nonselective inhibition of global PIC neurons and selective inhibition of glutaminergic neurons in the PIC failed to affect the itching-scratching behaviors induced by either 5-HT or compound 48/80. In addition, pharmacogenetic inhibition of AIC glutaminergic neurons effectively blocked itch-associated conditioned place aversion behavior, and inhibition of AIC glutaminergic neurons projecting to the prelimbic cortex significantly suppressed 5-HT-evoked scratching. These findings provide preliminary evidence that the AIC is involved, at least partially via aversive emotion mediation, in the regulation of 5-HT-, but not compound 48/80-induced itch.

Orbitofrontal cortex mediates the differential impact of signaled-reward probability on discrimination accuracy.

Orbitofrontal cortex (OFC) function is critical to decision making and behavior based on the value of expected outcomes. While some of the roles the OFC plays in value computations and behavior have been identified, the role of the OFC in modulating cognitive resources based on reward expectancy has not been explored. Here we assessed the involvement of OFC in the interaction between motivation and attention. We tested mice in a sustained-attention task in which explicitly signaling the probability of reward differentially modulates discrimination accuracy. Using pharmacogenetic methods, we generated mice in which neuronal activity in the OFC could be transiently and reversibly inhibited during performance of our signaled-probability task. We found that inhibiting OFC neuronal activity abolished the ability of reward-associated cues to differentially impact accuracy of sustained-attention performance. This failure to modulate attention occurred despite evidence that mice still processed the differential value of the reward-associated cues. These data indicate that OFC function is critical for the ability of a reward-related signal to impact other cognitive and decision-making processes and begin to delineate the neural circuitry involved in the interaction between motivation and attention.