Decoding neuropathic pain severity using distinct patterns of corticolimbic metabotropic glutamate receptor 5

Chung, Geehoon,Kim, Chae Young,Kim, Sang Jeong ACADEMIC PRESS 2019 NEUROIMAGE Vol.190 No.-

<P><B>Abstract</B></P> <P>Susceptibility to neuropathic pain and the degree of pain amplification vary among individuals. However, methods for objective evaluation of pain status have not been well established. Using an animal model, we identified the brain signature of neuropathic pain, and developed a method for the objective evaluation of pain degree. We analyzed paw withdrawal thresholds from rats that were subjected to right L5 spinal nerve ligation (SNL) surgery, and regressed them to the metabotropic glutamate receptor 5 (mGluR5) availability levels in the brain using [11C] ABP688 PET image data from our previous research. We found clusters with a significant correlation to paw withdrawal threshold localized in brain areas involved in sensory, cognitive, and affective aspects of pain processing. Strikingly, mGluR5 availability levels in the identified brain regions showed distinct patterns in the neuropathic pain group but not in the control group. We successfully elucidated the degree of pain-sensing behavior using the neuropathic pain-specific pattern of the mGluR5 availability. Our study provides new insight into the signature of neuropathic pain in the brain, and offers a novel diagnostic method for objectively decoding the status of individual neuropathic pain.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Susceptibility to neuropathic pain and the degree of pain vary among individuals. </LI> <LI> The sensory and limbic mGluR5 availability levels correlate with the pain behavior. </LI> <LI> The corticolimbic mGluR5 availability levels form distinct patterns in pain state. </LI> <LI> Pain severity could be predicted using the brain mGluR5 patterns. </LI> </UL> </P>

Metabotropic Glutamate Receptor 5 in the Medial Prefrontal Cortex as a Molecular Determinant of Pain and Ensuing Depression

Chung, Geehoon,Kim, Sang Jeong,Kim, Sun Kwang Frontiers Media S.A. 2018 Frontiers in molecular neuroscience Vol.11 No.-

<P>Pain and depression affect one another, and this bidirectional interaction implies the existence of common or interacting neural pathways. Among the neural circuits relevant to negative affection, the medial prefrontal cortex (mPFC) is known to be involved in both pain and depression. Persistent stress from physical pain and mental distress can evoke maladaptive changes in mPFC circuits to induce depression. Conversely, the unpleasant mood condition alters mPFC circuits to distort the appraisal of aversion and make individuals vulnerable to pain. In this article, recent findings regarding mPFC in chronic pain and/or depression are reviewed, with particular focus on the metabotropic glutamate receptor 5 (mGluR5). Although the involvement of mGluR5 within the mPFC in both pain and depressive disorders has been extensively studied, there are controversies regarding changes in the activity of the mPFC during chronic pain and depression, and the functional roles of mGluR5 on altered mPFC activity. We discuss alterations in the availability of mGluR5 in the mPFC in these disorders, its role in behavioral manifestations, and its possible influence on cellular subpopulations that mediate dysfunction in the mPFC. We also propose molecular mechanisms that may cause expressional changes in mGluR5 within the mPFC circuitry.</P>

Global Cerebral Ischemia-induced Depression Accompanies Alteration of Neuronal Excitability in the Infralimbic Cortex Layer 2/3 Pyramidal Neurons

Jang Dong Cheol,최승환,Chung Geehoon,김선광 한국뇌신경과학회 2023 Experimental Neurobiology Vol.32 No.4

Cerebral ischemia can lead to a range of sequelae, including depression. The pathogenesis of depression involves neuronal change of the medial prefrontal cortex (mPFC). However, how cerebral ischemia-induced changes manifest across subregions and layers of the mPFC is not well understood. In this study, we induced cerebral ischemia in mice via transient bilateral common carotid artery occlusion (tBCCAO) and observed depressive- like behavior. Using whole-cell patch clamp recording, we identified changes in the excitability of pyramidal neurons in the prelimbic cortex (PL) and infralimbic cortex (IL), the subregions of mPFC. Compared to sham control mice, tBCCAO mice showed significantly reduced neuronal excitability in IL layer 2/3 but not layer 5 pyramidal neurons, accompanied by increased rheobase current and decreased input resistance. In contrast, no changes were observed in the excitability of PL layer 2/3 and layer 5 pyramidal neurons. Our results provide a new direction for studying the pathogenesis of depression following ischemic damage by showing that cerebral ischemia induces subregion- and layer-specific changes in the mPFC pyramidal neurons.

Multiplexed Representation of Itch and Pain and Their Interaction in the Primary Somatosensory Cortex

우승희,Kim Yoo Rim,Bak Myeong Seong,Chung Geehoon,Kim Sang Jeong,Kim Sun Kwang 한국뇌신경과학회 2022 Experimental Neurobiology Vol.31 No.5

Itch and pain are distinct sensations that share anatomically similar pathways: from the periphery to the brain. Over the last decades, several itchspecific neural pathways and molecular markers have been identified at the peripheral and spinal cord levels. Although the perception of sensation is ultimately generated at the brain level, how the brain separately processes the signals is unclear. The primary somatosensory cortex (S1) plays a crucial role in the perception of somatosensory information, including touch, itch, and pain. In this study, we investigated how S1 neurons represent itch and pain differently. First, we established a spontaneous itch and pain mouse model. Spontaneous itch or pain was induced by intradermal treatment with 5-HT or capsaicin on the lateral neck and confirmed by a selective increase in scratching or wiping-like behavior, respectively. Next, in vivo two-photon calcium imaging was performed in awake mice after four different treatments, including 5-HT, capsaicin, and each vehicle. By comparing the calcium activity acquired during different sessions, we distinguished the cells responsive to itch or pain sensations. Of the total responsive cells, 11% were both responsive, and their activity in the pain session was slightly higher than that in the itch session. Itch- and painpreferred cells accounted for 28.4% and 60.6%, respectively, and the preferred cells showed the lowest activity in their counter sessions. Therefore, our results suggest that S1 uses a multiplexed coding strategy to encode itch and pain, and S1 neurons represent the interaction between itch and pain.

Development of a spontaneous pain indicator based on brain cellular calcium using deep learning

Yoon Heera,박명성,Kim Seung Ha,Lee Ji Hwan,Chung Geehoon,Kim Sang Jeong,Kim Sun Kwang 생화학분자생물학회 2022 Experimental and molecular medicine Vol.54 No.-

Chronic pain remains an intractable condition in millions of patients worldwide. Spontaneous ongoing pain is a major clinical problem of chronic pain and is extremely challenging to diagnose and treat compared to stimulus-evoked pain. Although extensive efforts have been made in preclinical studies, there still exists a mismatch in pain type between the animal model and humans (i.e., evoked vs. spontaneous), which obstructs the translation of knowledge from preclinical animal models into objective diagnosis and effective new treatments. Here, we developed a deep learning algorithm, designated AI-bRNN (Average training, Individual test-bidirectional Recurrent Neural Network), to detect spontaneous pain information from brain cellular Ca2+ activity recorded by two-photon microscopy imaging in awake, head-fixed mice. AI-bRNN robustly determines the intensity and time points of spontaneous pain even in chronic pain models and evaluates the efficacy of analgesics in real time. Furthermore, AI-bRNN can be applied to various cell types (neurons and glia), brain areas (cerebral cortex and cerebellum) and forms of somatosensory input (itch and pain), proving its versatile performance. These results suggest that our approach offers a clinically relevant, quantitative, real-time preclinical evaluation platform for pain medicine, thereby accelerating the development of new methods for diagnosing and treating human patients with chronic pain.

An Automated Cell Detection Method for TH-positive Dopaminergic Neurons in a Mouse Model of Parkinson’s Disease Using Convolutional Neural Networks

Kim Doyun,Bak Myeong Seong,Park Haney,Baek In Seon,Chung Geehoon,박재현,Ahn Sora,Park Seon-Young,배현수,Park Hi-Joon,김선광 한국뇌신경과학회 2023 Experimental Neurobiology Vol.32 No.3

Quantification of tyrosine hydroxylase (TH)-positive neurons is essential for the preclinical study of Parkinson’s disease (PD). However, manual analysis of immunohistochemical (IHC) images is labor-intensive and has less reproducibility due to the lack of objectivity. Therefore, several automated methods of IHC image analysis have been proposed, although they have limitations of low accuracy and difficulties in practical use. Here, we developed a convolutional neural network-based machine learning algorithm for TH+ cell counting. The developed analytical tool showed higher accuracy than the conventional methods and could be used under diverse experimental conditions of image staining intensity, brightness, and contrast. Our automated cell detection algorithm is available for free and has an intelligible graphical user interface for cell counting to assist practical applications. Overall, we expect that the proposed TH+ cell counting tool will promote preclinical PD research by saving time and enabling objective analysis of IHC images.

Long-Term Depression of Intrinsic Excitability Accompanied by Synaptic Depression in Cerebellar Purkinje Cells

Shim, Hyun Geun,Jang, Dong Cheol,Lee, Jaegeon,Chung, Geehoon,Lee, Sukchan,Kim, Yong Gyu,Jeon, Da Eun,Kim, Sang Jeong Society for Neuroscience 2017 The Journal of neuroscience Vol.37 No.23

<P>Long-term depression (LTD) at the parallel fiber (PF)-to-cerebellar Purkinje cell (PC) synapse is implicated in the output of PCs, the sole output of the cerebellar cortex. In addition to synaptic plasticity, intrinsic excitability is also one of the components that determines PC output. Although long-term potentiation of intrinsic excitability (LTP-IE) has been suggested, it has yet to be investigated how PF-PC LTD modifies intrinsic excitability of PCs. Here, we show that pairing of the PF and climbing fiber (CF) for PF-PC LTD induction evokes LTD-IE in cerebellar PCs from male C57BL/6 mice. Interestingly, this intrinsic plasticity showed different kinetics from synaptic plasticity, but both forms of plasticity share Ca2+ signaling and protein kinase C pathway as their underlying mechanism. Although small-conductance Ca2+-activated K+ channels play important roles in LTP-IE, no direct implication has been found. After PF-PC LTD induction, neither the temporal summation of dendritic EPSP nor the power of spike frequency adaptation is changed, indicating that cerebellar LTD executes the information processing in a quantitative way without quality changes of synaptic integration and generation of output signals. Our results suggest that LTD-IE may have a synergistic effect with synaptic depression on the total net output of neurons by amplifying the modification of PF synaptic transmission.</P>