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Medial prefrontal area reductions, altered expressions of cholecystokinin, parvalbumin, and activating transcription factor 4 in the corticolimbic system, and altered emotional behavior in a progressive rat model of type 2 diabetes

越智亮介広島大学

2022.03.23

概要

Background
Metabolic disorder, such as diabetes, can be accompanied with psychiatric disorders. Wehave reported that 20-week-old Otsuka Long-Evans Tokushima fatty (OLETF) rats, a modelof progressive type 2 diabetes with age, exhibit increased anxiety-like behavior with brainarea reductions and increased cholecystokinin (CCK)-positive neurons in the corticolimbicsystem (Ochi et al., J Physiol Sci, 70(1):42, 2020). Parvalbumin (PV)-positive neurons in thecorticolimbic system are also involved in anxiety. However, these alterations in differentstages of type 2 diabetes remain unclear. In addition, increased expressions ofapoptosis-related factors, such as activating transcription factor 4 (ATF4) and caspase-3, arefound in some of diabetic animals. However, these apoptosis-related properties in OLETFrats at different ages remain unclear. Our purpose was to investigate emotional behaviorsand its possible mechanisms in OLETF rats at different diabetic stages, 8 and 30 weeks ofage.

Methods
OLETF rats were used, and Long Evans Tokushima Otsuka (LETO) rats were served asnon-diabetic controls. At 8 or 30 weeks of age, an oral glucose tolerance test was performed toanalyze the glucose tolerance of rats. After the oral glucose tolerance test at each age, anopen field test was performed to examine the emotional states. After the open field test ateach age, the brain samples were collected, brain regional areas in the corticolimbic systemwere evaluated, and immunohistochemistry for CCK and PV was carried out to examinepossible mechanisms of altered emotional behaviors in OLETF rats. In addition,immunohistochemistry for caspase-3 and ATF4 was conducted to examine possiblemechanisms of brain area reductions and decreased numbers of neurons.

Results
OLETF rats showed mild hyperglycemia with normal insulin level and severe hyperglycemiawith a mixture of hyper- or hypo-insulinemia at 8 and 30 weeks of age, respectively. In theopen field test, locomotion in the center zone was less and latency to leave the center zonewas longer in OLETF rats than in LETO rats at 8 and 30 weeks of age, respectively. Thearea of the medial prefrontal cortex was smaller in OLETF rats than in LETO rats at bothages. The densities of CCK-positive neurons were higher in OLETF rats than in LETO ratsin the anterior cingulate and infralimbic cortices and hippocampal CA3 at both ages, and inthe lateral and basolateral amygdala at only 8 weeks of age. The densities of PV-positiveneurons were lower in OLETF rats than in LETO rats in the prelimbic and infralimbiccortices at both ages, and in the hippocampal CA2 at only 8 weeks of age. Nocaspase-3-positive reaction was found in both strains regardless of age, whereas thepercentage of ATF4 co-expression in CCK- and PV-positive neurons was higher in OLETFrats than in LETO rats at both ages in the anterior cingulate cortex and basolateralamygdala, respectively.

Discussion
According to the properties in the oral glucose tolerance test, OLETF rats were in theprediabetic stage and progressive stage of diabetes at 8 and 30 weeks of age, respectively.OLETF rats showed altered emotional behaviors in the anxiogenic situations (i.e., centerzone in the open field test), medial prefrontal area reduction, and altered numbers of CCKand PV-positive neurons in the corticolimbic system, which were already found at theprediabetic stage and were maintained regardless of the progression of diabetes. Theseresults suggest that altered emotional behaviors and neurobiological changes in thecorticolimbic system are already found at the prediabetic stage. In addition, we investigatedwhether apoptosis is involved in the reductions of the medial prefrontal area andPV-positive neurons in the corticolimbic system in OLETF rats. Although nocaspase-3-posistive reaction was observed, the ATF4 co-expressions in CCK- and PV-positiveneurons in the corticolimbic system were increased in OLETF rats from the prediabeticstage, which indicates that the expression of the specific apoptosis-related factor could beincreased at the prediabetic stage.

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1. Alagiakrishnan K, Sclater A. Psychiatric disorders presenting in the elderly with type 2 diabetes mellitus.Am J Geriatr Psychiatry. 2012; 20: 645–652. https://doi.org/10.1097/JGP.0b013e31823038db PMID:21989315

2. Smith KJ, Be´land M, Clyde M, Garie´py G, Page´ V, Badawi G, et al. Association of diabetes with anxiety:A systematic review and meta-analysis. J Psychosom Res. 2013; 74: 89–99. https://doi.org/10.1016/j.jpsychores.2012.11.013 PMID: 23332522

3. Dinel AL, Andre´ C, Aubert A, Ferreira G, Laye´ S, Castanon N. Cognitive and emotional alterations arerelated to hippocampal inflammation in a mouse model of metabolic syndrome. PLoS One. 2011; 6:e24325. https://doi.org/10.1371/journal.pone.0024325 PMID: 21949705

4. Rebolledo-Solleiro D, Rolda´n-Rolda´n G, Dı´az D, Velasco M, Larque´ C, Rico-Rosillo G, et al. Increasedanxiety-like behavior is associated with the metabolic syndrome in non-stressed rats. PLoS One. 2017;12: e0176554. https://doi.org/10.1371/journal.pone.0176554 PMID: 28463967

5. Bocarsly ME, Fasolino M, Kane GA, Lamarca EA, Kirschen GW, Karatsoreos IN, et al. Obesity diminishes synaptic markers, alters Microglial morphology, and impairs cognitive function. Proc Natl Acad SciUSA. 2015; 112: 15731–15736. https://doi.org/10.1073/pnas.1511593112 PMID: 26644559

6. Zborowski VA, Heck SO, Marques LS, Bastos NK, Nogueira CW. Memory impairment and depressivelike phenotype are accompanied by downregulation of hippocampal insulin and BDNF signaling pathways in prediabetic mice. Physiol Behav. 2021; 237: 113346. https://doi.org/10.1016/j.physbeh.2021.113346 PMID: 33545209

7. Deschênes SS, Burns RJ, Graham E, Schmitz N. Prediabetes, depressive and anxiety symptoms, andrisk of type 2 diabetes: A community-based cohort study. J Psychosom Res. 2016; 89: 85–90. https://doi.org/10.1016/j.jpsychores.2016.08.011 PMID: 27663115

8. Naicker K, Johnson JA, Skogen JC, Manuel D, Øverland S, Sivertsen B, et al. Type 2 diabetes andcomorbid symptoms of depression and anxiety: Longitudinal associations with mortality risk. DiabetesCare. 2017; 40: 352–358. https://doi.org/10.2337/dc16-2018 PMID: 28077458

9. Kawano K, Hirashima T, Mori S, Saitoh Y, Kurosumi M, Natori T. Spontaneous long-term hyperglycemicrat with diabetic complications: Otsuka Long-Evans Tokushima Fatty (OLETF) strain. Diabetes. 1992;41: 1422–1428. https://doi.org/10.2337/diab.41.11.1422 PMID: 1397718

10. Goto N, Fujita N, Nino W, Hisatsune K, Ochi R, Nishijo H, et al. Hemodynamic response during hyperbaric treatment on skeletal muscle in a type 2 diabetes rat model. Biomed Res. 2020; 41: 23–32. https://doi.org/10.2220/biomedres.41.23 PMID: 32092737

11. Ochi R, Fujita N, Goto N, Nguyen ST, Le DT, Matsushita K, et al. Region-specific brain area reductionsand increased cholecystokinin positive neurons in diabetic OLETF rats: implication for anxiety-likebehavior. J Physiol Sci. 2020; 70: 42. https://doi.org/10.1186/s12576-020-00771-0 PMID: 32938363PLOS ONEEmotional behavior in rats at prediabetic stagePLOS ONE | https://doi.org/10.1371/journal.pone.0256655 September 10, 2021 21 / 24

12. Yamamoto Y, Akiyoshi J, Kiyota A, Katsuragi S, Tsutsumi T, Isogawa K, et al. Increased anxiety behavior in OLETF rats without cholecystokinin-A receptor. Brain Res Bull. 2000; 53: 789–792. https://doi.org/10.1016/s0361-9230(00)00407-x PMID: 11179844

13. Li XL, Aou S, Hori T, Oomura Y. Spatial memory deficit and emotional abnormality in OLETF rats. Physiol Behav. 2002; 75: 15–23. https://doi.org/10.1016/s0031-9384(01)00627-8 PMID: 11890948

14. Schroeder M, Weller A. Anxiety-like behavior and locomotion in CCK1 knockout rats as a function ofstrain, sex and early maternal environment. Behav Brain Res. 2010; 211: 198–207. https://doi.org/10.1016/j.bbr.2010.03.038 PMID: 20347877

15. Raffield LM, Brenes GA, Cox AJ, Freedman BI, Hugenschmidt CE, Hsu FC, et al. Associations betweenanxiety and depression symptoms and cognitive testing and neuroimaging in type 2 diabetes. J Diabetes Complications. 2016; 30: 143–149. https://doi.org/10.1016/j.jdiacomp.2015.09.010 PMID:26476474

16. Kim GW, Yoon W, Jeong GW. Whole-brain volume alteration and its correlation with anxiety severity inpatients with obsessive-compulsive disorder and generalized anxiety disorder. Clin Imaging. 2018; 50:164–170. https://doi.org/10.1016/j.clinimag.2018.03.008 PMID: 29567629

17. Vanderhaeghen JJ, Mey JDE, Gilles C. Immunohistochemical localization of cholecystokinin- and gastrin- like peptides in the brain and hypophysis of the rat. Proc Natl Acad Sci USA. 1980; 77: 1190–1194.https://doi.org/10.1073/pnas.77.2.1190 PMID: 6987667

18. Whissell PD, Bang JY, Khan I, Xie YF, Parfitt GM, Grenon M, et al. Selective activation of cholecystokinin-expressing GABA (CCK-GABA) neurons enhances memory and cognition. eNeuro. 2019; 6:ENEURO.0360-18. https://doi.org/10.1523/ENEURO.0360-18.2019 PMID: 30834305

19. Del Boca C, Lutz PE, Le Merrer J, Koebel P, Kieffer BL. Cholecystokinin knock-down in the basolateralamygdala has anxiolytic and antidepressant-like effects in mice. Neuroscience. 2012; 218: 185–195.https://doi.org/10.1016/j.neuroscience.2012.05.022 PMID: 22613736

20. Takiguchi S, Takata Y, Funakoshi A, Miyasaka K, Kataoka K, Fujimura Y, et al. Disrupted cholecystokinin type-A receptor (CCKAR) gene in OLETF rats. Gene. 1997; 197: 169–175. https://doi.org/10.1016/s0378-1119(97)00259-x PMID: 9332364

21. Vialou V, Bagot RC, Cahill ME, Ferguson D, Robison AJ, Dietz DM, et al. Prefrontal Cortical Circuit forDepression- and Anxiety- Related Behaviors Mediated by Cholecystokinin: Role of μFosB. J Neurosci.2014; 34: 3878–3887. https://doi.org/10.1523/JNEUROSCI.1787-13.2014 PMID: 24623766

22. Belcheva I, Belcheva S, Petkov V V., Petkov VD. Asymmetry in behavioral responses to cholecystokininmicroinjected into rat nucleus accumbens and amygdala. Neuropharmacology. 1994; 33: 995–1002.https://doi.org/10.1016/0028-3908(94)90158-9 PMID: 7845556

23. Rezayat M, Roohbakhsh A, Zarrindast MR, Massoudi R, Djahanguiri B. Cholecystokinin and GABAinteraction in the dorsal hippocampus of rats in the elevated plus-maze test of anxiety. Physiol Behav.2005; 84: 775–782. https://doi.org/10.1016/j.physbeh.2005.03.002 PMID: 15885255

24. Singh L, Lewis AS, Field MJ, Hughes J, Woodruff GN. Evidence for an involvement of the brain cholecystokinin B receptor in anxiety. Proc Natl Acad Sci USA. 1991; 88: 1130–1133. https://doi.org/10.1073/pnas.88.4.1130 PMID: 1996314

25. Sherrin T, Todorovic C, Zeyda T, Tan CH, Hon PWT, Zhu YZ, et al. Chronic stimulation of corticotropinreleasing factor receptor 1 enhances the anxiogenic response of the cholecystokinin system. Mol Psychiatry. 2009; 14: 291–307. https://doi.org/10.1038/sj.mp.4002121 PMID: 18195718

26. Miyasaka K, Kobayashi S, Ohta M, Kanai S, Yoshida Y, Nagata A, et al. Anxiety-related behaviors incholecystokinin-A, B, and AB receptor gene knockout mice in the plus-maze. Neurosci Lett. 2002; 335:115–118. https://doi.org/10.1016/s0304-3940(02)01176-x PMID: 12459512

27. Whissell PD, Cajanding JD, Fogel N, Kim JC. Comparative density of CCK- and PV-GABA cells withinthe cortex and hippocampus. Front Neuroanat. 2015; 9: 124. https://doi.org/10.3389/fnana.2015.00124PMID: 26441554

28. Vereczki VK, Veres JM, Mu¨ller K, Nagy GA, Ra´cz B, Barsy B, et al. Synaptic Organization of Perisomatic GABAergic Inputs onto the Principal Cells of the Mouse Basolateral Amygdala. Front Neuroanat.2016; 10: 20. https://doi.org/10.3389/fnana.2016.00020 PMID: 27013983

29. Hu H, Gan J, Jonas P. Interneurons. Fast-spiking, parvalbumin+ GABAergic interneurons: from cellulardesign to microcircuit function. Science. 2014; 345: 1255263. https://doi.org/10.1126/science.1255263PMID: 25082707

30. Sampedro-Piquero P, Castilla-Ortega E, Zancada-Menendez C, Santı´n LJ, Begega A. Environmentalenrichment as a therapeutic avenue for anxiety in aged Wistar rats: Effect on cat odor exposition andGABAergic interneurons. Neuroscience. 2016; 330: 17–25. https://doi.org/10.1016/j.neuroscience.2016.05.032 PMID: 27235742PLOS ONEEmotional behavior in rats at prediabetic stagePLOS ONE | https://doi.org/10.1371/journal.pone.0256655 September 10, 2021 22 / 24

31. Luo ZY, Huang L, Lin S, Yin YN, Jie W, Hu NY, et al. Erbin in Amygdala Parvalbumin-Positive NeuronsModulates Anxiety-like Behaviors. Biol Psychiatry. 2020; 87: 926–936. https://doi.org/10.1016/j.biopsych.2019.10.021 PMID: 31889536

32. Iuvone L, Geloso MC, Dell’Anna E. Changes in Open Field Behavior, Spatial Memory, and Hippocampal Parvalbumin Immunoreactivity Following Enrichment in Rats Exposed to Neonatal Anoxia. Exp Neurol. 1996; 139: 25–33. https://doi.org/10.1006/exnr.1996.0077 PMID: 8635565

33. Mascagni F, McDonald AJ. Immunohistochemical characterization of cholecystokinin containing neurons in the rat basolateral amygdala. Brain Res. 2003; 976: 171–184. https://doi.org/10.1016/s0006-8993(03)02625-8 PMID: 12763251

34. Truitt WA, Johnson PL, Dietrich AD, Fitz SD, Shekhar A. Anxiety-like behavior is modulated by a discrete subpopulation of interneurons in the basolateral amygdala. Neuroscience. 2009; 160: 284–294.https://doi.org/10.1016/j.neuroscience.2009.01.083 PMID: 19258024

35. Urakawa S, Takamoto K, Hori E, Sakai N, Ono T, Nishijo H. Rearing in enriched environment increasesparvalbumin-positive small neurons in the amygdala and decreases anxiety-like behavior of male rats.BMC Neurosci. 2013; 14: 13. https://doi.org/10.1186/1471-2202-14-13 PMID: 23347699

36. Kong FJ, Ma LL, Guo JJ, Xu LH, Li Y, Qu S. Endoplasmic reticulum stress/autophagy pathway isinvolved in diabetes-induced neuronal apoptosis and cognitive decline in mice. Clin Sci. 2018; 132:111–125. https://doi.org/10.1042/CS20171432 PMID: 29212786

37. Walter P, Ron D. The unfolded protein response: from stress pathway to homeostatic regulation. Science. 2018; 334: 1081–1086. https://doi.org/10.1126/science.1209038 PMID: 22116877

38. Lin YW, Chen TY, Hung CY, Tai SH, Huang SY, Chang CC, et al. Melatonin protects brain againstischemia/reperfusion injury by attenuating endoplasmic reticulum stress. Int J Mol Med. 2018; 42: 182–192. https://doi.org/10.3892/ijmm.2018.3607 PMID: 29620280

39. Lietzau G, Darsalia V, Pintana H, O¨ stenson C, Nystro¨m T, Fisahn A, et al. Type 2 diabetes alters hippocampal gamma oscillations: A potential mechanism behind impaired cognition. Psychoneuroendocrinology. 2017; 82: 46–50. https://doi.org/10.1016/j.psyneuen.2017.04.012 PMID: 28501550

40. Larsson M, Lietzau G, Nathanson D, Ostenson C-G, Mallard C, Johansson ME, et al. Diabetes negatively affects cortical and striatal GABAergic neurons: an effect that is partially counteracted by exendin4. Biosci Rep. 2016; 36: e00421. https://doi.org/10.1042/BSR20160437 PMID: 27780892

41. Baleriola J, Walker CA, Jean YY, Crary JF, Troy CM, Nagy PL, et al. Axonally synthesized ATF4 transmits a neurodegenerative signal across brain regions. Cell. 2014; 158: 1159–1172. https://doi.org/10.1016/j.cell.2014.07.001 PMID: 25171414

42. Clark RSB, Kochanek PM, Watkins SC, Chen M, Dixon CE, Seidberg NA, et al. Caspase-3 mediatedneuronal death after traumatic brain injury in rats. J Neurochem. 2000; 74: 740–753. https://doi.org/10.1046/j.1471-4159.2000.740740.x PMID: 10646526

43. Fujita N, Goto N, Nakamura T, Nino W, Ono T, Nishijo H, et al. Hyperbaric Normoxia Improved GlucoseMetabolism and Decreased Inflammation in Obese Diabetic Rat. J Diabetes Res. 2019;19. https://doi.org/10.1155/2019/2694215 PMID: 31828157

44. Gulya´s M, Bencsik N, Pusztai S, Liliom H, Schlett K. AnimalTracker: An ImageJ-Based Tracking API toCreate a Customized Behaviour Analyser Program. Neuroinformatics. 2016; 14: 479–481. https://doi.org/10.1007/s12021-016-9303-z PMID: 27166960

45. Paxinos G, Watson C. The Rat Brain in stereotaxic coordinates. 7th edition. Elsevier Academic Press.2014.

46. Fanne RA, Nassar T, Heyman SN, Hijazi N, Higazi AAR. Insulin and glucagon share the same mechanism of neuroprotection in diabetic rats: Role of glutamate. Am J Physiol—Regul Integr Comp Physiol.2011; 301: 668–673. https://doi.org/10.1152/ajpregu.00058.2011 PMID: 21677268

47. Huang Q, Timofeeva E, Richard D. Corticotropin-releasing factor and its receptors in the brain of ratswith insulin and corticosterone deficits. J Mol Endocrinol. 2006; 37: 213–226. https://doi.org/10.1677/jme.1.02103 PMID: 17032740

48. Hernandez-Go´mez AM, Aguilar-Roblero R, Pe´rez de la Mora M. Role of cholecystokinin-A and cholecystokinin-B receptors in anxiety. Amino Acids. 2002; 23: 283–290. https://doi.org/10.1007/s00726-001-0139-x PMID: 12373548

49. Pe´rez De La Mora M, Herna´ndez-Go´mez AM, Arizmendi-Garcı´a Y, Jacobsen KX, Lara-Garc´ıa D, Flores-Gracia C, et al. Role of the amygdaloid cholecystokinin (CCK)/gastrin-2 receptors and terminal networks in the modulation of anxiety in the rat. Effects of CCK-4 and CCK-8S on anxiety-like behaviourand [3H]GABA release. Eur J Neurosci. 2007; 26: 3614–3630. https://doi.org/10.1111/j.1460-9568.2007.05963.x PMID: 18088282PLOS ONEEmotional behavior in rats at prediabetic stagePLOS ONE | https://doi.org/10.1371/journal.pone.0256655 September 10, 2021 23 / 24

50. Kobayashi S, Ohta M, Miyasaka K, Funakoshi A. Decrease in exploratory behavior in naturally occurring cholecystokinin (CCK)-A receptor gene knockout rats. Neurosci Lett. 1996; 214: 61–64. https://doi.org/10.1016/0304-3940(96)12881-0 PMID: 8873132

51. Estanislau C, Veloso AWN, Filgueiras GB, Maio TP, Dal-Co´l MLC, Cunha DC, et al. Rat self-groomingand its relationships with anxiety, dearousal and perseveration: Evidence for a self-grooming trait. Physiol Behav. 2019; 209: 112585. https://doi.org/10.1016/j.physbeh.2019.112585 PMID: 31226313

52. Gupta D, Radhakrishnan M, Kurhe Y. Insulin reverses anxiety-like behavior evoked by streptozotocininduced diabetes in mice. Metab Brain Dis. 2014; 29: 737–746. https://doi.org/10.1007/s11011-014-9540-5 PMID: 24763911

53. Hussain S, Mansouri S, Sjo¨holm Å, Patrone C, Darsalia V. Evidence for cortical neuronal loss in maletype 2 diabetic Goto-Kakizaki rats. J Alzheimer’s Dis. 2014; 41: 551–560. https://doi.org/10.3233/JAD131958 PMID: 24643136

54. Yang L, Dong Y, Wu C, Li Y, Guo Y, Yang B, et al. Photobiomodulation preconditioning prevents cognitive impairment in a neonatal rat model of hypoxia-ischemia. J Biophotonics. 2019; 12: e201800359.https://doi.org/10.1002/jbio.201800359 PMID: 30652418

55. Krukowski K, Nolan A, Frias ES, Boone M, Ureta G, Grue K, et al. Small molecule cognitive enhancerreverses age-related memory decline in mice. Elife. 2020; 9: e62048. https://doi.org/10.7554/eLife.62048 PMID: 33258451

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Medial prefrontal area reductions, altered expressions of cholecystokinin, parvalbumin, and activating transcription factor 4 in the corticolimbic system, and altered emotional behavior in a progressive rat model of type 2 diabetes

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