Central medial thalamic nucleus dynamically participates in acute itch sensation and chronic itch-induced anxiety-like behavior in male mice.

Itch is an annoying sensation consisting of both sensory and emotional components. It is known to involve the parabrachial nucleus (PBN), but the following transmission nodes remain elusive. The present study identified that the PBN-central medial thalamic nucleus (CM)-medial prefrontal cortex (mPFC) pathway is essential for itch signal transmission at the supraspinal level in male mice. Chemogenetic inhibition of the CM-mPFC pathway attenuates scratching behavior or chronic itch-related affective responses. CM input to mPFC pyramidal neurons is enhanced in acute and chronic itch models. Specifically chronic itch stimuli also alter mPFC interneuron involvement, resulting in enhanced feedforward inhibition and a distorted excitatory/inhibitory balance in mPFC pyramidal neurons. The present work underscores CM as a transmit node of the itch signal in the thalamus, which is dynamically engaged in both the sensory and affective dimensions of itch with different stimulus salience.

Projections from the Rostral Zona Incerta to the Thalamic Paraventricular Nucleus Mediate Nociceptive Neurotransmission in Mice.

Zona incerta (ZI) is an integrative subthalamic region in nociceptive neurotransmission. Previous studies demonstrated that the rostral ZI (ZIR) is an important gamma-aminobutyric acid-ergic (GABAergic) source to the thalamic paraventricular nucleus (PVT), but whether the ZIR-PVT pathway participates in nociceptive modulation is still unclear. Therefore, our investigation utilized anatomical tracing, fiber photometry, chemogenetic, optogenetic and local pharmacological approaches to investigate the roles of the ZIRGABA+-PVT pathway in nociceptive neurotransmission in mice. We found that projections from the GABAergic neurons in ZIR to PVT were involved in nociceptive neurotransmission. Furthermore, chemogenetic and optogenetic activation of the ZIRGABA+-PVT pathway alleviates pain, whereas inhibiting the activities of the ZIRGABA+-PVT circuit induces mechanical hypersensitivity and partial heat hyperalgesia. Importantly, in vivo pharmacology combined with optogenetics revealed that the GABA-A receptor (GABAAR) is crucial for GABAergic inhibition from ZIR to PVT. Our data suggest that the ZIRGABA+-PVT pathway acts through GABAAR-expressing glutamatergic neurons in PVT mediates nociceptive neurotransmission.

Projecting neurons in spinal dorsal horn send collateral projections to dorsal midline/intralaminar thalamic complex and parabrachial nucleus.

Itch is an annoying sensation that always triggers scratching behavior, yet little is known about its transmission pathway in the central nervous system. Parabrachial nucleus (PBN), an essential transmission nucleus in the brainstem, has been proved to be the first relay station in itch sensation. Meanwhile, dorsal midline/intralaminar thalamic complex (dMITC) is proved to be activated with nociceptive stimuli. However, whether the PBN-projecting neurons in spinal dorsal horn (SDH) send collateral projections to dMITC, and whether these projections involve in itch remain unknown. In the present study, a double retrograde tracing method was applied when the tetramethylrhodamine-dextran (TMR) was injected into the dMITC and Fluoro-gold (FG) was injected into the PBN, respectively. Immunofluorescent staining for NeuN, substance P receptor (SPR), substance P (SP), or FOS induced by itch or pain stimulations with TMR and FG were conducted to provide morphological evidence. The results revealed that TMR/FG double-labeled neurons could be predominately observed in superficial laminae and lateral spinal nucleus (LSN) of SDH; Meanwhile, most of the collateral projection neurons expressed SPR and some of them expressed FOS in acute itch model induced by histamine. The present results implicated that some of the SPR-expressing neurons in SDH send collateral projections to the dMITC and PBN in itch transmission, which might be involved in itch related complex affective/emotional processing to the higher brain centers.