A neural circuit from the pedunculopontine tegmental nucleus to the central medial thalamic nucleus for the regulation of nociceptive and anxiety-like behaviors in male mice with chronic inflammatory pain

Background: Chronic pain and anxiety exhibit a high degree of comorbidity, in which these conditions can mutually exacerbate each other. We investigated whether glutamatergic neurons in the pedunculopontine tegmental nucleus (PPTg Glu ) and their projections to the central medial thalamic nucleus (CM) regulate nociceptive and anxiety-like behaviors in a Complete Freund’s Adjuvant (CFA)-induced chronic pain model. Methods: We used c-Fos staining, chemogenetics, and optogenetics to assess the role of PPTg Glu neurons and the PPTg Glu -CM pathway in regulating nociceptive and anxiety-like behaviors. Rabies-mediated retrograde tracing was used to map the anatomical connection from PPTg Glu neurons to glutamatergic neurons in the CM (CM Glu ). Optogenetics combined with electrophysiological recordings was used to verify the functional connectivity of this pathway. Results: Plantar injection of CFA induced anxiety-like behaviors. This behavioral comorbidity was associated with the activation of glutamatergic neurons in the PPTg, as indicated by c-Fos staining. Chemogenetic inhibition of the PPTg Glu alleviated both evoked and spontaneous nociceptive behaviors, as well as anxiety-like behaviors in CFA-treated mice. Conversely, optogenetic activation of these neurons was sufficient to elicit both evoked and spontaneous nociceptive behaviors, as well as anxiety-like behaviors in naïve mice. To identify the underlying circuit, we first employed both anterograde and retrograde tracing to map the anatomical connectivity between the PPTg and the CM. We then verified the functional connectivity of this specific PPTg Glu -CM Glu pathway using optogenetics combined with electrophysiological recordings. Finally, pathway-specific manipulations demonstrated that chemogenetic inhibition of the PPTg Glu -CM pathway relieved nociceptive and anxiety-like behaviors, whereas optogenetic activation of this pathway was sufficient to induce these behaviors in naïve mice. Conclusions: CM receives excitatory input from PPTg Glu , and this PPTg Glu -CM pathway modulates nociceptive and anxiety-like behaviors.