A Neural Circuit from Thalamic Paraventricular Nucleus to Central Amygdala for the Facilitation of Neuropathic Pain

Abstract

As one of the thalamic midline nuclei, the thalamic paraventricular nucleus (PVT) is considered to be an important signal integration site for many descending and ascending pathways that modulate a variety of behaviors, including feeding, emotions, and drug-seeking. A recent study has demonstrated that the PVT is implicated in the acute visceral pain response, but it is unclear whether the PVT plays a critical role in the central processing of chronic pain. Here, we report that the neurons in the posterior portion of the PVT (pPVT) and their downstream pathway are involved in descending nociceptive facilitation regarding the development of neuropathic pain conditions in male rats. Lesions or inhibition of pPVT neurons alleviated mechanical allodynia induced by spared nerve injury (SNI). The excitability of pPVT-central amygdala (CeA) projection neurons was significantly increased in SNI rats. Importantly, selective optogenetic activation of the pPVT-CeA pathway induced obvious mechanical hypersensitivity in naive rats. In addition, we used rabies virus (RV)-based and cell-type-specific retrograde transsynaptic tracing techniques to define a novel neuronal circuit in which glutamatergic neurons in the vlPAG were the target of the pPVT-CeA descending facilitation pathway. Our data suggest that this pPVT Glu1 -CeA-vlPAG Glu1 circuit mediates central mechanisms of descending pain facilitation underlying persistent pain conditions.

Fear Extinction-Based Inter-Individual and Sex Differences in Pain-Related Vocalizations and Anxiety-like Behaviors but Not Nocifensive Reflexes

“…Human studies have investigated the role of the amygdala in pain and fear interactions [73,81], and the amygdala has been implicated in fear-conditioned analgesia in a preclinical setting [82][83][84]. The amygdala has been implicated in pain-like behaviors [85][86][87], anxiety-like behaviors [88][89][90], and in fear learning [12,91]. Pain-related neuroplastic changes lead to hyperexcitability in amygdala output neurons [10], driving pain behaviors in both acute [92,93] and chronic [29,94] pain models.…”

The Contribution of Thalamic Nuclei in Salience Processing

“…In addition, the ratio between excitation and feedforward inhibition of thalamic input to the cortex is important for the regulation of affective pain ( Jurik et al, 2015 ; Meda et al, 2019 ). Activation of the PVT-CeA pathway induces mechanical allodynia ( Liang et al, 2020b ), reflecting a potential role of the PVT in pain-associated salience attribution. The PVT is also engaged in reward-seeking behaviors ( James et al, 2011a ; Browning et al, 2014 ; Choudhary et al, 2018 ).…”

PBN-PVT projection modulates negative affective states in mice

“…The BNST and the CeA have been previously implicated in anxiety-like behaviors (Jennings et al, 2013;Tye et al, 2011). A study also found that PVT mediates descending pain facilitation underlying persistent pain conditions via the PVT-CeA-PAG circuit (Liang et al, 2020). The specific functional roles of different projections of PVT PBN neurons need further examination.…”

“…A study also found that PVT mediates descending pain facilitation underlying persistent pain conditions via the PVT-CeA-PAG circuit (Liang et al, 2020). Different downstream pathways of PVT PBN neurons might have different functions and deciphering the circuit mechanisms needs further examination.…”