Sound Induces Analgesia Through Corticothalamic Circuits

Chronic pain imposes a huge personal and financial burden,affecting about 30%of people worldwide and placing a heavy burden on both society and families.Due to the diversity and heterogeneity of its pathogenesis,Chronic pain is short of ideal therapeutic drugs and intervention means in clinic.In addition,not every pain patient can get relief from existing pain medications.Studies have shown that standard therapeutic analgesics approved by the FDA work in only 70%of patients.Therefore,the development of new therapeutic approaches is an urgent need for patients,which has important clinical value.And non-drug physiotherapy is a hot research topic in the field.Music has been widely demonstrated in relieving neuro-related diseases,such as pain,negative emotions,sleep disorders and so on in a long time,and it has the advantages of being non-invasive,easily accessible,and without side effects.But the underlying neural mechanisms are unknown.The Auditory Cortex(ACx)is the highest processing center for auditory information and can involve in physical activities such as defense,learning,and movement through projective relationships with other nucleus.Then,sound/music is likely to relief pain through the projection between auditory cortex and nociceptive system.As a higher center of sensory processing and a relay station for sensory conduction,the somatosensory thalamus plays an important role in the conduction and procession of pain.Several studies have shown that the posterior nucleus of thalamus(PO)and the ventral posterior nucleus of thalamus(VP)participate in pain perception in different parts of the body through projection with the cortex.PO is involved in the regulation of pain signals through neural projection to the insular cortex(IC)and amygdala,and preferentially responds to noxious stimulation.Neuroimaging also showed significant changes in blood flow in the thalamus region of pain patients.These studies indicate that the thalamus is essential for pain reception and processing,which is the focus of this study.So how does the auditory system regulate the somatosensory system in the process of acoustic analgesia?We investigated whether music may elicit analgesic effects in mice with inflammatory pain.First,we delivered sound at a sound pressure level(SPL)of～50 or～60 dB with different melody to the mice through a closely positioned audio speaker(ambient noise at 45-dB SPL).We found that the nociceptive threshold was elevated only after exposure to the sound which intensity difference between ambient noise is 5dB SPL.In view of the key role of ACx in the processing of sound information,we injected an adeno-associated viral vector into ACx and detected abundant signals in thalamic nuclei,including the PO and VP.In vivo multitetrode recordings in freely moving CFA mice showed that the spontaneous neuronal activity in the ACx was decreased in response to white noise at 5-dB SNR.Five-dB SNR white noise-induced analgesia was mimicked upon selective inactivation of ACxGlu neurons.Conversely,bilateral optical activation of ACxGlu neurons abolished the 5-dB SNR white noiseinduced analgesia in CFA mice.We then characterized both ACxGlu→POGlu and ACxGlu→VPGlu circuits in greater detail by using viral tracing,immunofluorescence staining and Whole-cell recordings combined with optogenetics in brain slices.We conducted in vivo multitetrode and fiber photometry recordings in freely moving CFA mice.PO rather than VP neurons were rapidly activated by punctate mechanical stimulation of inflamed hindpaws.PO neuronal activity was significantly enhanced in CFA mice compared with controls,which was attenuated by 5-dB SNR white noise.In addition,similar sound-induced inhibitory effects on PO neurons were observed after optical inhibition of the ACxGlu terminals in the PO.By contrast,optical activation of the ACxGlu→PO circuit abolished both neuronal inhibition in the PO and analgesia induced by 5-dB SNR sound.The POACx neurons were then selectively manipulated to experimentally validate their participation in sound-induced analgesia.We found bilateral chemogenetic inhibition of POACx neurons recapitulated 5-dB SNR soundinduced analgesia.By contrast,chemogenetic activation of these neurons blocked the 5-dB SNR sound-induced analgesia.Then we found that the 5-dB SNR sound-induced elevation of the forepaw nociceptive threshold was mimicked upon chemogenetic inhibition of VPACx neurons and was blocked upon activation of these neurons though the same way.Taken together,our results demonstrate that the observed analgesia from 5-dB SNR sound is mediated by the ACx→PO circuit for hindpaws and by the ACx→VP circuit for forepaws.This study not only proved the innervation of the auditory system and the pain system structurally,but also provided experimental evidence and theoretical support for the clinical intervention of using music to analgesia.