Synaptic Plasticity and Synchrony in the Anterior Cingulate Cortex Circuitry: A Neural Network Approach to Causality of Chronic Visceral Pain and Associated Cognitive Deficits

Part of the Advances in Neurobiology book series (NEUROBIOL, volume 21)


Human brain imaging studies have demonstrated the importance of cortical neuronal networks in the perception of pain in patients with functional bowel disease such as irritable bowel syndrome (IBS).

Studies have identified an enhanced response in the anterior cingulate cortex (ACC) to colorectal distension in viscerally hypersensitive (VH) rats. Electrophysiological recordings show long-lasting potentiation of local field potential (LFP) in the medial thalamus (MT)-ACC synapses in VH rats. Theta burst stimulation in the MT reliably induced long-term potentiation (LTP) in the MT-ACC pathway in normal rats, but was occluded in the VH state. Further, repeated tetanization of MT increased ACC neuronal activity and visceral pain responses of normal rats, mimicking VH rats. These data provide conclusive evidence that chronic visceral pain is associated with alterations of synaptic plasticity in the ACC circuitry. The ACC synaptic strengthening may engage signal transduction pathways that are in common with those activated by electrical stimulation, and serve as an attractive cellular model of functional visceral pain.

Evidences have shown that most patients with IBS have psychiatric comorbidity. Using rat gambling task (RGT), we discovered an impairment of decision-making behavior in VH rats. Electrophysiological study showed a reduction of LTP in the basolateral amygdala (BLA)-ACC synapses in VH rats. Multiple-electrode array recordings of local field potential (LFP) in freely behaving rats revealed that chronic visceral pain led to disruption of ACC spike timing and BLA local theta oscillation. Finally, cross-correlation analysis revealed that VH was associated with suppressed synchronization of theta oscillation between the BLA and ACC, indicating reduced neuronal communications between these two regions. These data suggest that functional disturbances in BLA-ACC neural circuitry may be relevant causes for the deficits in decision-making in chronic pain state.

The viscero-sensation is a faculty of perception that does not depend upon any outward sense, but acts to influence the elicited behavioral response. Clinically, vagus nerve stimulation (VNS) has shown several beneficial effects for mood enhancement. Our recent study characterized that VNS facilitates decision-making and unveiled several important roles for VNS in regulating LFP and spike phases, as well as enhancing spike-phase coherence between key brain areas involved in cognitive performance.

It is conceivable that the visceral pain experience may be better explained as a biopsychosocial model of pain and reflected in a matrix of neuronal structures. Understanding of desynchrony in the ACC network and cognitive deficits is likely to provide exciting and powerful future treatment for chronic visceral pain related debilitating mood, anxiety, and cognitive disorders.


Anterior cingulate cortex Basolateral amygdala Cognitive deficit Decision-making N-methyl-D-aspartate (NMDA) receptor Phase-locking Synaptic plasticity Spike field coherence Theta synchronization Visceral hypersensitivity 



Anterior cingulate cortex


Aminophosphonopentanoic acid


Area under the curve


Analysis of variance


Basolateral amygdala


Colorectal distension


Cyanonitroquinoxaline dione


Egg albumin


Green fluorescent protein


Irritable bowel syndrome


Local field potential


Long-term potentiation


Medial thalamus




[(R)-[(S)-1-(4-bromo-phenyl)-ethylamino]-(2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl)-methyl]-phosphonic acid


Perigenual anterior cingulate cortex


RNA interference


Small interfering RNA


Rat gambling task


Spike-field coherence


Spike-triggered average


Theta burst stimulation


Viscerally hypersensitive


Visceromotor response



This work was supported by the National Institute of Neurological Disorders and Stroke grant RO1 NS051466-01 (to Y.L.). National Institutes of Health Grant: RO1 DK51717 (to Y.L.).

Research Grants Council of Hong Kong (grant number 11166116, 11101315, 11100914 and CityU number 160811, 160812, and 160713 to Y. Li), the Innovation and Technology Support Programme (ITS/300/15 to Y. Li), Health and Medical Research Fund of Hong Kong (01122006 to Y. Li0 and City University of Hong Kong Neuroscience Research Infrastructure Grant (9610211 to Y. Li). This work was also supported by City University of Hong Kong Centre for Biosystems, Neuroscience, and Nanotechnology Grant (9360148 to S. Pang and Y. Li). I thanks Prof Chung Owyang Gastroenterology Research Unit, Department of Internal Medicine, University of Michigan, for his long term support.


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Authors and Affiliations

  1. 1.Department of Biomedical SciencesCity University of Hong KongKowloonHong Kong
  2. 2.Centre for Biosystems, Neuroscience, and NanotechnologyCity University of Hong KongKowloonHong Kong
  3. 3.School of Veterinary Medicine, City University of Hong KongKowloonHong Kong

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