Astroglial changes in the zona incerta in response to motor cortex stimulation in a rat model of chronic neuropathy

Abstract

Although astrocytes are known to regulate synaptic transmission and affect new memory formation by influencing long-term potentiation and functional synaptic plasticity, their role in pain modulation is poorly understood. Motor cortex stimulation (MCS) has been used to reduce neuropathic pain through the incertothalamic pathway, including the primary motor cortex (M1) and the zona incerta (ZI). However, there has been no in-depth study of these modulatory effects and region-specific changes in neural plasticity. In this study, we investigated the effects of MCS-induced pain modulation as well as the relationship between the ZI neuroplasticity and MCS-induced pain alleviation in neuropathic pain (NP). MCS-induced threshold changes were evaluated after daily MCS. Then, the morphological changes of glial cells were compared by tissue staining. In order to quantify the neuroplasticity, MAP2, PSD95, and synapsin in the ZI and M1 were measured and analyzed with western blot. In behavioral test, repetitive MCS reduced NP in nerve-injured rats. We also observed recovered GFAP expression in the NP with MCS rats. In the NP with sham MCS rats, increased CD68 level was observed. In the NP with MCS group, increased mGluR1 expression was observed. Analysis of synaptogenesis-related molecules in the M1 and ZI revealed that synaptic changes occured in the M1, and increased astrocytes in the ZI were more closely associated with pain alleviation after MCS. Our findings suggest that MCS may modulate the astrocyte activities in the ZI and synaptic changes in the M1. Our results may provide new insight into the important and numerous roles of astrocytes in the formation and function. Chronic neuropathic pain (NP) is the result of primary lesion in peripheral nerve and/or central nervous system (CNS) dysfunction in the absence of nociceptor stimulation 1. This multidimensional clinical entity is mediated by various pathophysiological mechanisms, making its treatment difficult 2,3. Neuropathic pain refractory to medication has been treated with invasive methods, such as selective lesioning and electrical stimulation of the central or peripheral nervous system 4. MCS was initially applied to central pain secondary to thalamic stroke 5,6. Over time, its usage expanded to various types of chronic pain. Repetitive MCS relieves approximately 45 to 75% of pain 7,8 , making it a viable option for patients with severe drug-refractory symptoms. Motor cortex stimulation (MCS) treatment was first used in the early 1990s to treat a patient with chronic, drug-resistant NP 9. Despite the clinical use of MCS for pain reduction, the mechanisms underlying its effects remain unclear. The incertothalamic pathway was recently described as a novel system for regulating nociceptive processing in the thalamus 10,11. In this pathway, the zona incerta (ZI) inhibits the flow of nociceptive and somatosensory information in the posterior thalamus (Po), and this is mediated by the cholinergic system 10,12. Modulation of the ZI activity by repeated MCS was shown to...

Microglial Engulfment of Spines in the Ventral Zona Incerta Regulates Anxiety-Like Behaviors in a Mouse Model of Acute Pain

“…An MCS-induced neuropathic pain model has investigated the relationship between pain alleviation and ZI neuroplasticity. MCS modulates the astrocyte activities in the ZI and synaptic changes in the M1 (Cha et al, 2020). Prominently, chemogenetic activation of contralateral ZI V GABA in CFA1D mice reverses anxiety-like behaviors in pain.…”

Modulation of Neuropathic Pain by Glial Regulation in the Insular Cortex of Rats

“…Increasing evidence of glial modulation in pain studies indicates that astrocytes and microglia are closely related to transmission of pain signals ( Inoue and Tsuda, 2018 ; Cha et al, 2020b ). Earlier studies have shown that astrocytes surround the synapses of neurons and play a key role in neural signaling transmission ( Singh and Abraham, 2017 ).…”

“…The rats were allowed to convalesce for 3 days after the cannula implantation. The surgical procedure for nerve injury was performed following the methods described in our previous reports ( Lee et al, 2000 ; Cha et al, 2020a , b ). After recovery from the cannula implantation, an animal model of NP was prepared by ligation and cutting of sciatic nerve branches.…”

d-Serine produces antidepressant-like effects in mice through suppression of BDNF signaling pathway and regulation of synaptic adaptations in the nucleus accumbens

“…Synaptic plasticity is regarded as a cellular substrate of learning and memory (Kamalova et al 2020 ). d -Serine plays a significant role in activating NMDAR-dependent synaptic plasticity (Cha et al 2020 ). NAC neurons are among those that lightly express LTD, which is susceptible to stress.…”