Involvement of the GABAergic pathway from lateral hypothalamic area to paraventricular thalamic nucleus in...

Both lateral hypothalamic area (LHA) and paraventricular thalamic nucleus (PVT) constitute pivotal nodes within the regulatory network of the central nervous system, where the γ-aminobutyric acidergic (GABAergic) neurons contribute significantly to the modulation of pain. In order to investigate the underlying mechanism of the GABAergic pathway from LHA to PVT in pain modulation, fiber photometry calcium signal recording, immunofluorescence histochemical staining, and neuroanatomical tract tracing were used in the present study. Fiber photometry recordings revealed that calcium signals of glutamate decarboxylase-positive (GAD⁺) neurons in the LHA were significantly increased in response to innocuous and noxious stimulation. Furthermore, in the spared nerve injury (SNI) mouse model of neuropathic pain, 37.26 ± 7.23% of GAD⁺ neurons in the LHA were activated, as indicated by c-FOS protein expression in the nuclei. Neuroanatomical tract tracing results showed that axons originating from GAD⁺ neurons in the LHA projected to the PVT, where these terminals established close appositions with calcium/calmodulin-dependent protein kinase IIα-positive (CaMKIIα⁺) neurons within the PVT. Furthermore, analysis of publicly available anatomical datasets confirmed the presence of fibers originating from the LHA and projecting to the PVT. Moreover, in the SNI model, GAD⁺ and c-FOS protein-positive (c-FOS⁺) double-labeled neurons comprised 19.45 ± 3.92% of the total projection neurons within the LHA-PVT pathway. These results collectively indicate that the GABAergic LHA-PVT pathway is activated in the SNI model of neuropathic pain, suggesting its involvement in the modulation of nociception.