Chemogenetic Modulation of the Posterior Insular Cortex Alters Both Affective and Sensory Pain-related Behavior

The insula is a multimodal cortical area involved in interoception, and somatic and autonomic control. Human imaging studies have consistently shown that the insula is activated during noxious somatosensory stimulation. However, the distinct function of the insula in processing noxious stimuli is poorly understood. The purpose of this study is to investigate how bidirectional chemogenetic modulation of the insula influences sensory and affective behaviors. Selective targeting of the posterior insula (PIC) was determined by anatomical labeling from the sensory thalamus. Modulation of the PIC was performed using excitatory and inhibitory designer receptors exclusively activated by designer drugs (DREADDs), with the agonists compound 21 or clozapine-N-oxide for transient activation. Affective behaviors were evaluated through conditioned place aversion (CPA), thermal preference assay, and hot plate test. Sensory threshold tests performed were Hargreaves and von Frey. The PIC, not the anterior insula, receives direct projections from the thalamic posterior triangular nucleus (PoT), a target of an ascending somatosensory tract. Activating the PIC produced a place aversion in naive mice and a heightened aversion to warmth without altering thermal or mechanical threshold. Conversely, inhibiting the PIC in naive mice increased hot plate latency. Interestingly, activating only the PoT to PIC projections produced thermal hyperalgesia. Our results show that the PIC is an important region for both affective and sensory processing of somatosensory stimuli. Activation of the PIC alone produced negative valence in CPA and an aversion to warmth without altering sensory threshold, while activating the PoT to PIC circuit produced a decrease in thermal threshold. These results suggest that the PIC could be involved in a separate circuit to generate negative affect. Overall, the PIC contributes to the multidimensional experience of pain and thus therapeutics aimed at reducing PIC activity could be effective in alleviating the suffering associated with pain. Grant support from R01 NS107356. The insula is a multimodal cortical area involved in interoception, and somatic and autonomic control. Human imaging studies have consistently shown that the insula is activated during noxious somatosensory stimulation. However, the distinct function of the insula in processing noxious stimuli is poorly understood. The purpose of this study is to investigate how bidirectional chemogenetic modulation of the insula influences sensory and affective behaviors. Selective targeting of the posterior insula (PIC) was determined by anatomical labeling from the sensory thalamus. Modulation of the PIC was performed using excitatory and inhibitory designer receptors exclusively activated by designer drugs (DREADDs), with the agonists compound 21 or clozapine-N-oxide for transient activation. Affective behaviors were evaluated through conditioned place aversion (CPA), thermal preference assay, and hot plate test. Sensory threshold tests performed were Hargreaves and von Frey. The PIC, not the anterior insula, receives direct projections from the thalamic posterior triangular nucleus (PoT), a target of an ascending somatosensory tract. Activating the PIC produced a place aversion in naive mice and a heightened aversion to warmth without altering thermal or mechanical threshold. Conversely, inhibiting the PIC in naive mice increased hot plate latency. Interestingly, activating only the PoT to PIC projections produced thermal hyperalgesia. Our results show that the PIC is an important region for both affective and sensory processing of somatosensory stimuli. Activation of the PIC alone produced negative valence in CPA and an aversion to warmth without altering sensory threshold, while activating the PoT to PIC circuit produced a decrease in thermal threshold. These results suggest that the PIC could be involved in a separate circuit to generate negative affect. Overall, the PIC contributes to the multidimensional experience of pain and thus therapeutics aimed at reducing PIC activity could be effective in alleviating the suffering associated with pain. Grant support from R01 NS107356.