Tumor necrosis factor-α modulates GABAergic and Dopaminergic neurons in the ventral periaqueductal gray of female mice.

Abstract

Neuroimmune signaling is increasingly identified as a critical component of various illnesses, including chronic pain, substance use disorder, and depression. However, the underlying neural mechanisms remain unclear. Proinflammatory cytokines, such as tumor necrosis factor- (TNF-), may play a key role by modulating synaptic function and long-term plasticity. The midbrain structure periaqueductal gray (PAG) plays a well-established role in pain processing, and while TNF- inhibitors have emerged as a potential therapeutic strategy for pain-related disorders, the impact of TNF- on PAG neuronal activity has not been thoroughly characterized. Recent studies have identified subpopulations of ventral PAG (vPAG) with opposing effects on nociception, with DA neurons driving pain relief in contrast to GABA neurons. Therefore, we used ex vivo slice physiology to examine the effects of TNF- on neuronal activity of both subpopulations. We selectively targeted GABA and dopamine neurons using a vGAT-reporter and a TH-eGFP reporter mouse line, respectively. Following exposure to TNF-, the intrinsic properties of GABA neurons were altered, resulting in increased excitability along with a reduction in glutamatergic synaptic drive. In DA neurons, TNF- exposure resulted in a robust decrease in excitability along with a modest reduction in glutamatergic synaptic transmission. Furthermore, the effect of TNF- was specific to excitatory transmission onto DA neurons as inhibitory transmission was unaltered. Collectively, these data suggest that TNF- differentially affects the basal synaptic properties of GABA and DA neurons and enhances our understanding of how TNF- mediated signaling modulates vPAG function. New & NoteworthyThe present study describes the effects of tumor necrosis factor- (TNF-) on two distinct subpopulations of neurons in the ventral periaqueductal gray (vPAG). We show that TNF- alters both neuronal excitability and glutamatergic synaptic transmission on GABA neurons and dopamine neurons within the vPAG. This provides critical new information on the role of TNF- in the potential modulation of pain since activation of vPAG GABA neurons drives nociception, whereas activation of DA neurons drives analgesia.