Brain Mechanisms of Visceral Pain: Synaptic Metaplasticity and Synchronized Theta Oscillations in the Anterior Cingulate Cortex


Student thesis: Doctoral Thesis

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  • Jun WANG

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Award date19 Jul 2016


Chronic visceral hypersensitivity (VH) leads to a significant clinical disorder which is one of the major factors involved in the pathogenesis of abdominal pain in the irritable bowel syndrome (IBS). Brain imaging studies in human showed greater activation of the anterior cingulate cortex (ACC) in IBS patients during painful rectal distension. Previously, our in vivo electrophysiological studies have clarified sensitization of perigenual anterior cingulate cortex (pACC) in chronic VH rats induced by colorectal anaphylaxis. We have shown that visceral allodynia and hyperalgesia can maintain up to 7 weeks following colonic anaphylaxis without colon inflammation. ACC lesions suppressed the visceral pain responses. Peripheral afferent inputs are not required for the maintaining of ACC sensitization suggesting a mechanism for learning and triggering of painful memories in the ACC neuronal circuit. Activity-dependent cortical plasticity in synaptic strength may serve as a key mechanism for memory formation and storage. Only a few in vivo studies have investigated the ACC synaptic plasticity. Current study was designed to test our hypotheses that the ACC synaptic long-lasting potentiation in chronic visceral pain may engage signal transduction pathways that are in common with those activated by electrical stimuli, and serves as an attractive cellular model of functional visceral pain.
Chronic visceral pain is complex in nature, usually has a temporal evolution and clinical features vary in different phases of pathology. To further characterize the intrinsic neural processing of visceral pain, a short term visceral hypersensitive rat model was applied in the current study. Moreover, synaptic long-term potentiation (LTP) is an artificially induced phenomenon, yet the exact biological nature of the synaptic alterations remains elusive. Giving evidence that theta oscillation in the local field potential (LFP) contributes critically to sensory transduction, learning and memory encoding. Conditioning jejunal distension increases the perception of discomfort in healthy human volunteers. In patients with IBS, repetitive colorectal distention (rCRD) has been reported to induce visceral hypersensitivity. In the current study, we sought to identify the intrinsic theta oscillations and theta-frequency phase-locking in the ACC of an acute visceral pain induced by rCRD.
ACC local field potentials elicited by electric stimulation of medial thalamus (MT) were recorded by single-channel electrode to measure synaptic efficiency. Theta burst stimulation (TBS) was used to induce LTP in MT-ACC synapses. To determine if synaptic long term potentiation in MT-ACC pathway causatively triggers allodynia and hyperalgesia, chronic tetanization of MT, which artificially induced canonical LTP, were applied repeatedly for several days in normal rats. Visceromotor responses (VMR) as a measurement of behavioral visceral pain were conducted. Further, multi-channel electrodes recordings in both MT and ACC simultaneously in awake rats before and at different time points after rCRD paradigm were conducted, and then ACC theta power, phase distributions of single units to the ongoing theta oscillation, and synchronization between MT and ACC were computed to reveal electrophysiological alterations in acute visceral pain state.
Main findings of the present study are: (1) electrophysiological recordings showed long-lasting potentiation of LFP in the MT-ACC synapses in our chronic VH rats model, which was mediated by both NMDA and AMPA receptors. (2) theta burst stimulation applied at medial thalamus reliably induced LTP in the MT-ACC pathway in normal rats, but the LTP induction was blocked in the VH rats. (3) repetitively chronic tetanization of MT enhanced ACC neuronal firings, synaptic transmission as well as visceral pain responses in normal rats, which were mimicking VH state, and mediated by NR2B and CaMKII activities. (4) using repetitive distension of the colon and rectum (rCRD) as a sensitization paradigm in normal subjects, we have identified that the spontaneous firing rates of ACC neurons and the CRD-stimulated neuronal firings were increased after repetitive visceral noxious stimulation. This correlates with increases in visceral pain responses within 6 hours following rCRD. (5) power spectral density analysis showed that the LFP recorded in the ACC displayed increases in theta band power that were modulated by rCRD. (6) neuronal spike activities in the ACC became synchronized with ongoing theta oscillations of LFP in the acute visceral pain state induced by rCRD. (7) cross correlation analysis showed augmented synchronization of thalamo-ACC theta band oscillations, which was consistent with an increase of neuronal communication between the two regions.
In conclusions: the ACC synaptic strengthening in chronic visceral hypersensitivity may engage signal transduction pathways that are in common with those electrical stimulation−induced long term potentiation (canonical LTP), and may serve as a cellular mechanism for functional chronic visceral pain. Our findings further strengthen the hypothesis that theta oscillations and theta-frequency phase-locking as prominent features of neuronal activity in the ACC and candidate neural mechanisms underlying acute visceral pain. The progressive alteration of synchronization between thalamus and ACC can be a candidate mechanism underlying visceral pain learning, and may dynamically contribute to transfer in perceptual learning from acute to chronic visceral pain state.