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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

Metabolic disorders such as obesity and type 2 diabetes can induce several psychiatric disorders. Patients with diabetes often have a high prevalence of cognitive impairment, depression,
and anxiety [1,2]. These psychiatric disorders are also associated with obesity and metabolic
syndrome [3–5]. Obesity and metabolic syndrome likely precede the onset of type 2 diabetes;
therefore, psychiatric disorders could already be present in the early stages of type 2 diabetes.
Indeed, prediabetic mice reportedly exhibit cognitive impairment and depressive-like behavior
[6]. However, little has been reported on the comorbidity of anxiety in different stages of type
2 diabetes and the neural mechanisms. Individuals with anxiety at prediabetic stages are more
likely to develop type 2 diabetes [7]. In addition, patients with type 2 diabetes and anxiety have
a higher risk of mortality than non-diabetic and non-anxious individuals [8]. To effectively
treat and prevent anxiety in patients with type 2 diabetes, it is important to understand its neural mechanisms.
Otsuka Long-Evans Tokushima fatty (OLETF) rats are a type 2 diabetes model developed
by selective breeding of outbred Long-Evans rats [9]. OLETF rats chronically develop type 2
diabetes with age. We previously confirmed that OLETF rats showed a progressive course of
type 2 diabetes: mild hyperglycemia and normal plasma insulin level at 8 weeks old, indicating
the prediabetic stage; hyperglycemia and hyperinsulinemia at 20 weeks old, indicating the
early stage of type 2 diabetes; and severe hyperglycemia and a mixture of hyperinsulinemia
and hypoinsulinemia at 30 weeks old, indicating the progressive stage of type 2 diabetes from
non-insulin-dependent diabetes mellitus to insulin-dependent diabetes mellitus [9,10]. We
recently reported that 20-week-old OLETF rats exhibited increased anxiety-like behavior in
the open-field test, area reduction, and increased cholecystokinin (CCK)-positive neurons in
the corticolimbic system [11]. Previous results obtained in OLETF rats between 10 and 20
weeks old also showed increased anxiety-like behaviors in the elevated plus maze, light–dark
box, and open-field tests [12–14]. However, anxiety-like behavior remains to be compared in
the prediabetic and progressive stages of type 2 diabetes, namely, OLETF rats of different ages.
Brain region shrinkage is reportedly associated with anxiety in patients with type 2 diabetes.
Gray matter volume was reduced in patients with type 2 diabetes with anxiety and depression
compared to patients with type 2 diabetes without anxiety or depression [15]. Furthermore,
patients with obsessive–compulsive disorder and generalized anxiety disorder showed
decreased gray and white matter volume in emotion-related regions, including the medial prefrontal cortex (mPFC), which is associated with anxiety severity [16]. Importantly, we also
demonstrated that 20-week-old OLETF rats in the early stage of type 2 diabetes exhibited
lower brain weight as well as area reductions in the corticolimbic system, including the mPFC
[11]. Therefore, shrinkage of specific regions in the corticolimbic system could be one of the
neuroanatomical mechanisms underlying anxiety in type 2 diabetes. However, whether similar
alterations are observed in OLETF rats in the prediabetic and progressive stages at different
ages remains unclear.
CCK is a neurotransmitter peptide in the central nervous system [17] and is associated with
anxiety. Systemic chemogenetic activation of CCK-positive inhibitory neurons reportedly
increased anxiety-like behavior in the elevated plus maze test [18]. Furthermore, knockdown
of CCK in the basolateral amygdala (BLA) decreased anxiety-like behavior in the elevated plus
maze test [19]. Two types of CCK receptors have been identified: CCK-1 and CCK-2. OLETF
rats lack the CCK-1 receptor due to a congenital genetic abnormality [20]. It has been suggested that OLETF rats exhibit increased anxiety-like behavior because of type 2 diabetes and/
or deficits in CCK-1 receptor activity [12–14]. ...

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参考文献

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

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

Dinel AL, Andre´ C, Aubert A, Ferreira G, Laye´ S, Castanon N. Cognitive and emotional alterations are

related 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

Rebolledo-Solleiro D, Rolda´n-Rolda´n G, Dı´az D, Velasco M, Larque´ C, Rico-Rosillo G, et al. Increased

anxiety-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

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 Sci

USA. 2015; 112: 15731–15736. https://doi.org/10.1073/pnas.1511593112 PMID: 26644559

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

Deschênes SS, Burns RJ, Graham E, Schmitz N. Prediabetes, depressive and anxiety symptoms, and

risk 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

Naicker K, Johnson JA, Skogen JC, Manuel D, Øverland S, Sivertsen B, et al. Type 2 diabetes and

comorbid symptoms of depression and anxiety: Longitudinal associations with mortality risk. Diabetes

Care. 2017; 40: 352–358. https://doi.org/10.2337/dc16-2018 PMID: 28077458

Kawano K, Hirashima T, Mori S, Saitoh Y, Kurosumi M, Natori T. Spontaneous long-term hyperglycemic

rat 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 reductions

and increased cholecystokinin positive neurons in diabetic OLETF rats: implication for anxiety-like

behavior. J Physiol Sci. 2020; 70: 42. https://doi.org/10.1186/s12576-020-00771-0 PMID: 32938363

PLOS ONE | https://doi.org/10.1371/journal.pone.0256655 September 10, 2021

21 / 24

PLOS ONE

Emotional behavior in rats at prediabetic stage

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 of

strain, 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 between

anxiety 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 in

patients 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 basolateral

amygdala 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 for

Depression- 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 cholecystokinin

microinjected 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 GABA

interaction 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 in

cholecystokinin-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 within

the cortex and hippocampus. Front Neuroanat. 2015; 9: 124. https://doi.org/10.3389/fnana.2015.00124

PMID: 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 cellular

design to microcircuit function. Science. 2014; 345: 1255263. https://doi.org/10.1126/science.1255263

PMID: 25082707

30.

Sampedro-Piquero P, Castilla-Ortega E, Zancada-Menendez C, Santı´n LJ, Begega A. Environmental

enrichment as a therapeutic avenue for anxiety in aged Wistar rats: Effect on cat odor exposition and

GABAergic interneurons. Neuroscience. 2016; 330: 17–25. https://doi.org/10.1016/j.neuroscience.

2016.05.032 PMID: 27235742

PLOS ONE | https://doi.org/10.1371/journal.pone.0256655 September 10, 2021

22 / 24

PLOS ONE

Emotional behavior in rats at prediabetic stage

31.

Luo ZY, Huang L, Lin S, Yin YN, Jie W, Hu NY, et al. Erbin in Amygdala Parvalbumin-Positive Neurons

Modulates 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/s00068993(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 increases

parvalbumin-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 is

involved 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 against

ischemia/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

¨ stenson C, Nystro¨m T, Fisahn A, et al. Type 2 diabetes alters hippoLietzau G, Darsalia V, Pintana H, O

campal 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

39.

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 mediated

neuronal 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 Glucose

Metabolism 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 to

Create 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 rats

with 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/s00726001-0139-x PMID: 12373548

49.

Pe´rez De La Mora M, Herna´ndez-Go´mez AM, Arizmendi-Garcı´a Y, Jacobsen KX, Lara-Garcı´a 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 behaviour

and [3H]GABA release. Eur J Neurosci. 2007; 26: 3614–3630. https://doi.org/10.1111/j.1460-9568.

2007.05963.x PMID: 18088282

PLOS ONE | https://doi.org/10.1371/journal.pone.0256655 September 10, 2021

23 / 24

PLOS ONE

Emotional behavior in rats at prediabetic stage

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-grooming

and 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/s11011-0149540-5 PMID: 24763911

53.

Hussain S, Mansouri S, Sjo¨holm Å, Patrone C, Darsalia V. Evidence for cortical neuronal loss in male

type 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 enhancer

reverses age-related memory decline in mice. Elife. 2020; 9: e62048. https://doi.org/10.7554/eLife.

62048 PMID: 33258451

PLOS ONE | https://doi.org/10.1371/journal.pone.0256655 September 10, 2021

24 / 24

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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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