Korean J Physiol Pharmacol.  2017 Sep;21(5):487-493. 10.4196/kjpp.2017.21.5.487.

Inhibition of anterior cingulate cortex excitatory neuronal activity induces conditioned place preference in a mouse model of chronic inflammatory pain

Affiliations
  • 1Department of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 08826, Korea. kaang@snu.ac.kr
  • 2Interdisciplinary Program in Neuroscience, College of Natural Sciences, Seoul National University, Seoul 08826, Korea.
  • 3Department of Anatomy, Brain Science & Engineering Institute, Kyungpook National University School of Medicine, Daegu 41944, Korea.
  • 4Center for Neuron and Disease, Frontier Institutes of Life Science and of Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China.
  • 5Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada.

Abstract

The anterior cingulate cortex (ACC) is known for its role in perception of nociceptive signals and the associated emotional responses. Recent optogenetic studies, involving modulation of neuronal activity in the ACC, show that the ACC can modulate mechanical hyperalgesia. In the present study, we used optogenetic techniques to selectively modulate excitatory pyramidal neurons and inhibitory interneurons in the ACC in a model of chronic inflammatory pain to assess their motivational effect in the conditioned place preference (CPP) test. Selective inhibition of pyramidal neurons induced preference during the CPP test, while activation of parvalbumin (PV)-specific neurons did not. Moreover, chemogenetic inhibition of the excitatory pyramidal neurons alleviated mechanical hyperalgesia, consistent with our previous result. Our results provide evidence for the analgesic effect of inhibition of ACC excitatory pyramidal neurons and a prospective treatment for chronic pain.

Keyword

Anterior cingulate cortex; Conditioned place preference; Optogenetics; Pain

MeSH Terms

Animals
Chronic Pain
Gyrus Cinguli*
Hyperalgesia
Interneurons
Mice*
Neurons*
Optogenetics
Prospective Studies
Pyramidal Cells

Figure

  • Fig. 1 Experimental schematic of the conditioned place preference testThe CFA-injected mice were first freely exposed to the apparatus for 15 min (Day 1, Pre-test). Next, the mice were conditioned with light in the compartment with less preference, and without light in the compartment with more preference (Days 2~7, conditioning). After 6 days of conditioning, the mice were assessed for changed preference for the conditioning compartments (Day 8, Post-test).

  • Fig. 2 Conditioned place preference in the CaMKII-eNpHR group.(A) Sample image of eNpHR expression in the ACC. (B) Result of exploration time in the less preferred compartment on Day 1 (Pre-test). There was no significant difference between the EYFP (31.62±1.74%, n=10) and eNpHR (28.39±0.98%; n=14) groups in exploration time (p=0.0978, unpaired t-test). (C) Result of the time spent in the conditioned compartment on Day 8 (Post-test, normalized to the pre-test exploration time). There was a significant difference between the EYFP (0.97±0.06, n=10) and eNpHR (1.25±0.10; n=14) groups (p=0.0441, unpaired t-test).

  • Fig. 3 Conditioned place preference in the PV-ChR2 group.(A) Sample image of ChR2 expression in the ACC. (B) Result of exploration time in the less preferred compartment on Day 1 (Pre-test). There was no significant difference between the cre(−) (29.50±3.23%, n=4) and cre(+) (27.11±1.90%, n=8) groups in exploration time (p=0.5110, unpaired t-test). (C) Result of the time spent in the conditioned compartment on Day 8 (Post-test, normalized to the pre-test exploration time). There was no significant difference between the cre(−) (1.06±0.03, n=4) and cre(+) (1.16±0.12, n=8) groups (p=0.7481, unpaired t-test).

  • Fig. 4 Results of immunohistochemistry and electronic von Frey test in the CaMKII-hM4Di group.(A) Experimental schematic of the electronic von Frey test. Mice were allowed to recover from brain surgery for about 3 weeks. On Day 0, CFA was injected into the hind paw of each mouse, after determining the baseline response to the electronic von Frey apparatus. On Day 3, CNO was administered to each mouse 40 min before the experiment, and the response to the von Frey apparatus was measured. (B) Mechanical threshold responses to the electronic von Frey test on Days 0 and 3. There was no significant difference between the mCherry (4.81±0.09 g; n=20) and hM4Di (4.94±0.10 g; n=19) groups in the baseline responses (p=0.507, post hoc Bonferroni test) on Day 0. After CNO administration to both groups, the mechanical threshold showed a significant difference between groups (hM4Di [4.70±0.16; n=19], mCherry [3.76±0.19; n=20], p<0.001, post hoc Bonferroni test) on Day 3. The mCherry group displayed significantly different mechanical thresholds between days (Day 0 vs. Day 3, p<0.001). The mechanical threshold of the hM4Di group was not significantly different between days (Day 0 vs. Day 3, p=0.15). Repeated-measures two-way ANOVA with post hoc Bonferroni correction demonstrated a significant effect of CNO on Day 3 (p<0.001), significant effect of DREADD (p=0.002), significant difference between days (p <0.001), and a significant effect of interaction between two factors (Virus x Time, p=0.0013). (C) Images of the ACC of the mCherry (left) and hM4Di (right) groups after immunohistochemistry. (D) The ratio of activated neurons labeled by c-Fos among mCherry(+) neurons in the mCherry group was significantly different from that in the hM4Di group (p=0.0002, unpaired t-test).


Cited by  1 articles

Imaging and analysis of genetically encoded calcium indicators linking neural circuits and behaviors
Jihae Oh, Chiwoo Lee, Bong-Kiun Kaang
Korean J Physiol Pharmacol. 2019;23(4):237-249.    doi: 10.4196/kjpp.2019.23.4.237.


Reference

1. Bush G, Luu P, Posner MI. Cognitive and emotional influences in anterior cingulate cortex. Trends Cogn Sci. 2000; 4:215–222. PMID: 10827444.
Article
2. Allman JM, Hakeem A, Erwin JM, Nimchinsky E, Hof P. The anterior cingulate cortex. The evolution of an interface between emotion and cognition. Ann N Y Acad Sci. 2001; 935:107–117. PMID: 11411161.
3. Shenhav A, Botvinick MM, Cohen JD. The expected value of control: an integrative theory of anterior cingulate cortex function. Neuron. 2013; 79:217–240. PMID: 23889930.
Article
4. Einarsson EÖ, Pors J, Nader K. Systems reconsolidation reveals a selective role for the anterior cingulate cortex in generalized contextual fear memory expression. Neuropsychopharmacology. 2015; 40:480–487. PMID: 25091528.
Article
5. Frankland PW, Bontempi B, Talton LE, Kaczmarek L, Silva AJ. The involvement of the anterior cingulate cortex in remote contextual fear memory. Science. 2004; 304:881–883. PMID: 15131309.
Article
6. Etkin A, Egner T, Kalisch R. Emotional processing in anterior cingulate and medial prefrontal cortex. Trends Cogn Sci. 2011; 15:85–93. PMID: 21167765.
Article
7. Bliss TV, Collingridge GL, Kaang BK, Zhuo M. Synaptic plasticity in the anterior cingulate cortex in acute and chronic pain. Nat Rev Neurosci. 2016; 17:485–496. PMID: 27307118.
Article
8. Vogt BA. Pain and emotion interactions in subregions of the cingulate gyrus. Nat Rev Neurosci. 2005; 6:533–544. PMID: 15995724.
Article
9. Fuchs PN, Peng YB, Boyette-Davis JA, Uhelski ML. The anterior cingulate cortex and pain processing. Front Integr Neurosci. 2014; 8:35. PMID: 24829554.
Article
10. Dunckley P, Wise RG, Aziz Q, Painter D, Brooks J, Tracey I, Chang L. Cortical processing of visceral and somatic stimulation: differentiating pain intensity from unpleasantness. Neuroscience. 2005; 133:533–542. PMID: 15896917.
Article
11. Johansen JP, Fields HL. Glutamatergic activation of anterior cingulate cortex produces an aversive teaching signal. Nat Neurosci. 2004; 7:398–403. PMID: 15004562.
Article
12. Peyron R, Laurent B, García-Larrea L. Functional imaging of brain responses to pain. A review and meta-analysis (2000). Neurophysiol Clin. 2000; 30:263–288. PMID: 11126640.
Article
13. Strigo IA, Duncan GH, Boivin M, Bushnell MC. Differentiation of visceral and cutaneous pain in the human brain. J Neurophysiol. 2003; 89:3294–3303. PMID: 12611986.
Article
14. Talbot JD, Marrett S, Evans AC, Meyer E, Bushnell MC, Duncan GH. Multiple representations of pain in human cerebral cortex. Science. 1991; 251:1355–1358. PMID: 2003220.
Article
15. Kang SJ, Liu MG, Chen T, Ko HG, Baek GC, Lee HR, Lee K, Collingridge GL, Kaang BK, Zhuo M. Plasticity of metabotropic glutamate receptor-dependent long-term depression in the anterior cingulate cortex after amputation. J Neurosci. 2012; 32:11318–11329. PMID: 22895715.
Article
16. Li XY, Ko HG, Chen T, Descalzi G, Koga K, Wang H, Kim SS, Shang Y, Kwak C, Park SW, Shim J, Lee K, Collingridge GL, Kaang BK, Zhuo M. Alleviating neuropathic pain hypersensitivity by inhibiting PKMzeta in the anterior cingulate cortex. Science. 2010; 330:1400–1404. PMID: 21127255.
17. Shyu BC, Vogt BA. Short-term synaptic plasticity in the nociceptive thalamic-anterior cingulate pathway. Mol Pain. 2009; 5:51. PMID: 19732417.
Article
18. Wei F, Li P, Zhuo M. Loss of synaptic depression in mammalian anterior cingulate cortex after amputation. J Neurosci. 1999; 19:9346–9354. PMID: 10531439.
Article
19. Wu LJ, Toyoda H, Zhao MG, Lee YS, Tang J, Ko SW, Jia YH, Shum FW, Zerbinatti CV, Bu G, Wei F, Xu TL, Muglia LJ, Chen ZF, Auberson YP, Kaang BK, Zhuo M. Upregulation of forebrain NMDA NR2B receptors contributes to behavioral sensitization after inflammation. J Neurosci. 2005; 25:11107–11116. PMID: 16319310.
Article
20. Tye KM, Deisseroth K. Optogenetic investigation of neural circuits underlying brain disease in animal models. Nat Rev Neurosci. 2012; 13:251–266. PMID: 22430017.
Article
21. Yizhar O, Fenno LE, Davidson TJ, Mogri M, Deisseroth K. Optogenetics in neural systems. Neuron. 2011; 71:9–34. PMID: 21745635.
Article
22. Iyer SM, Montgomery KL, Towne C, Lee SY, Ramakrishnan C, Deisseroth K, Delp SL. Virally mediated optogenetic excitation and inhibition of pain in freely moving nontransgenic mice. Nat Biotechnol. 2014; 32:274–278. PMID: 24531797.
Article
23. Hickey L, Li Y, Fyson SJ, Watson TC, Perrins R, Hewinson J, Teschemacher AG, Furue H, Lumb BM, Pickering AE. Optoactivation of locus ceruleus neurons evokes bidirectional changes in thermal nociception in rats. J Neurosci. 2014; 34:4148–4160. PMID: 24647936.
Article
24. Lee M, Manders TR, Eberle SE, Su C, D’amour J, Yang R, Lin HY, Deisseroth K, Froemke RC, Wang J. Activation of corticostriatal circuitry relieves chronic neuropathic pain. J Neurosci. 2015; 35:5247–5259. PMID: 25834050.
Article
25. Wang GQ, Cen C, Li C, Cao S, Wang N, Zhou Z, Liu XM, Xu Y, Tian NX, Zhang Y, Wang J, Wang LP, Wang Y. Deactivation of excitatory neurons in the prelimbic cortex via Cdk5 promotes pain sensation and anxiety. Nat Commun. 2015; 6:7660. PMID: 26179626.
Article
26. Zhang Z, Gadotti VM, Chen L, Souza IA, Stemkowski PL, Zamponi GW. Role of prelimbic GABAergic circuits in sensory and emotional aspects of neuropathic pain. Cell Rep. 2015; 12:752–759. PMID: 26212331.
Article
27. Barthas F, Sellmeijer J, Hugel S, Waltisperger E, Barrot M, Yalcin I. The anterior cingulate cortex is a critical hub for pain-induced depression. Biol Psychiatry. 2015; 77:236–245. PMID: 25433903.
Article
28. Gu L, Uhelski ML, Anand S, Romero-Ortega M, Kim YT, Fuchs PN, Mohanty SK. Pain inhibition by optogenetic activation of specific anterior cingulate cortical neurons. PLoS One. 2015; 10:e0117746. PMID: 25714399.
Article
29. Kang SJ, Kwak C, Lee J, Sim SE, Shim J, Choi T, Collingridge GL, Zhuo M, Kaang BK. Bidirectional modulation of hyperalgesia via the specific control of excitatory and inhibitory neuronal activity in the ACC. Mol Brain. 2015; 8:81. PMID: 26631249.
Article
30. Craig AD. A new view of pain as a homeostatic emotion. Trends Neurosci. 2003; 26:303–307. PMID: 12798599.
31. Navratilova E, Porreca F. Reward and motivation in pain and pain relief. Nat Neurosci. 2014; 17:1304–1312. PMID: 25254980.
Article
32. Kvitsiani D, Ranade S, Hangya B, Taniguchi H, Huang JZ, Kepecs A. Distinct behavioural and network correlates of two interneuron types in prefrontal cortex. Nature. 2013; 498:363–366. PMID: 23708967.
Article
33. Medalla M, Barbas H. The anterior cingulate cortex may enhance inhibition of lateral prefrontal cortex via m2 cholinergic receptors at dual synaptic sites. J Neurosci. 2012; 32:15611–15625. PMID: 23115196.
Article
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