DIETARY GLYCEMIC INDEX DIFFERENTIALLY MODULATES COGNITIVE AND SOCIAL BEHAVIORS IN ADULT MALE WAG/RIJ RATS

Öz

Aim: Absence epilepsy is frequently accompanied by cognitive and social comorbidities, which may be influenced by environmental and metabolic factors. This study examined whether diets differing in glycemic index (GI) modulate cognitive and social behaviors in adult WAG/Rij rats, a well-established genetic model of absence epilepsy. Methods: Male WAG/Rij rats (n = 30) were randomly assigned to three groups: control diet, low glycemic index (LGI) diet, and high glycemic index (HGI) diet. Cognitive performance and exploratory behavior were assessed using the novel object recognition (NOR) test. Social interaction and social recognition memory were evaluated using the three-chamber paradigm. Results: The LGI group showed improved novel object recognition compared to controls (p < 0.05), whereas the HGI group exhibited reduced performance compared to both control (p < 0.05) and LGI groups (p < 0.001). Exploratory behavior (rearing) was higher in the LGI group than in controls (p = 0.0062), with no differences between other groups. Self-grooming and baseline social preference did not differ significantly (p > 0.05). However, social discrimination was impaired in the HGI group compared to control (p = 0.0089) and LGI groups (p = 0.0115), with no difference between control and LGI groups. Conclusions: An LGI diet enhances exploratory activity and recognition memory, whereas an HGI diet selectively impairs object recognition and social discrimination without affecting baseline sociability. These findings suggest that dietary GI differentially modulates cognitive and social behaviors in WAG/Rij rats.

Anahtar Kelimeler

• Absence epilepsy
• cognition
• glycemic index
• social behaviors
• WAG/Rij rats

Etik Beyan

Bu çalışma, Kocaeli Üniversitesi Hayvan Deneyleri Yerel Etik Kurulu tarafından onaylanmıştır (Karar No: KOÜ HADYEK 6/8-2025, Karar Tarihi: 25.06.2025). Tüm deneysel prosedürler ulusal ve uluslararası etik kurallara uygun olarak yürütülmüştür.

DİYETİN GLİSEMİK İNDEKSİ, ERİŞKİN ERKEK WAG/RIJ SIÇANLARINDA BİLİŞSEL VE SOSYAL DAVRANIŞLARI FARKLI ŞEKİLDE DÜZENLER

Öz

Amaç: Absans epilepsi, çevresel ve metabolik faktörlerden etkilenebilen bilişsel ve sosyal eşlik eden durumlarla sıklıkla birlikte görülür. Bu çalışma, glisemik indeks (Gİ) açısından farklılık gösteren diyetlerin, absans epilepsinin iyi tanımlanmış genetik bir modeli olan erişkin WAG/Rij sıçanlarda bilişsel ve sosyal davranışları modüle edip etmediğini incelemeyi amaçlamıştır. Yöntem: Erkek WAG/Rij sıçanlar (n = 30) rastgele üç gruba ayrılmıştır: kontrol diyeti, düşük glisemik indeksli (DGİ) diyet ve yüksek glisemik indeksli (YGİ) diyet. Bilişsel performans ve keşif davranışı, yeni nesne tanıma (YNT) testi ile değerlendirilmiştir. Sosyal etkileşim ve sosyal tanıma belleği ise üç bölmeli test paradigması kullanılarak incelenmiştir. Bulgular: DGİ diyet grubu, kontrol grubuna kıyasla daha yüksek yeni nesne tanıma performansı göstermiştir (p < 0.05). Buna karşılık, YGİ diyet grubu hem kontrol (p < 0.05) hem de DGİ gruplarına göre daha düşük performans sergilemiştir (p < 0.001). Keşif davranışı (rearing) DGİ grubunda kontrole göre daha yüksek bulunmuştur (p = 0.0062); diğer gruplar arasında fark saptanmamıştır. Kendini temizleme davranışı ve temel sosyal tercih açısından gruplar arasında anlamlı fark bulunmamıştır (p > 0.05). Ancak sosyal ayırt etme performansı, YGİ grubunda kontrol (p = 0.0089) ve DGİ gruplarına (p = 0.0115) göre anlamlı düzeyde bozulmuştur. Kontrol ve DGİ grupları arasında fark gözlenmemiştir. Sonuç: DGİ diyeti keşif aktivitesi ve tanıma belleğini artırırken, YGİ diyeti temel sosyalliği etkilemeden nesne tanıma ve sosyal ayırt etme performansını seçici olarak bozmuştur. Bu bulgular, diyetin glisemik indeksinin WAG/Rij sıçanlarda bilişsel ve sosyal davranışları farklı şekillerde modüle ettiğini göstermektedir.

Anahtar Kelimeler

• Absans epilepsi
• bilişsel işlevler
• glisemik indeks
• sosyal davranışlar
• WAG/Rij sıçanları

Etik Beyan

This study was approved by the Kocaeli University Animal Experiments Local Ethics Committee (Approval No: KOÜ HADYEK 6/8-2025, Decision Date: 25.06.2025). All experimental procedures were conducted in accordance with national and international ethical guidelines.

Kaynakça

1. Glauser TA, Cnaan A, Shinnar S, et al. Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy. N Engl J Med. 2010;362(9):790-799. https://doi.org/10.1056/NEJMoa0902014
2. Rinaldi VE, Di Cara G, Mencaroni E, Verrotti A. Therapeutic options for childhood absence epilepsy. Pediatr Rep. 2021;13(4):658-667. https://doi.org/10.3390/pediatric13040078
3. Fonseca Wald ELA, Klinkenberg S, Voncken TPC, et al. Cognitive development in absence epilepsy during long-term follow-up. Child Neuropsychol.2019;25(8):1003-1021. https://doi.org/10.1080/09297049.2019.1614156
4. Jackson DC, Dabbs K, Walker NM, et al. The neuropsychological and academic substrate of new/recent-onset epilepsies. J Pediatr. 2013;162(5):1047-1053.e1. https://doi.org/10.1016/j.jpeds.2012.10.046
5. Masur D, Shinnar S, Cnaan A, et al. Pretreatment cognitive deficits and treatment effects on attention in childhood absence epilepsy. Neurology.2013;81(18):1572-1580. https://doi.org/10.1212/WNL.0b013e3182a9f3ca
6. Fonseca Wald ELA, Hendriksen JGM, Drenthen GS, et al. Towards a better understanding of cognitive deficits in absence epilepsy: a systematic review and meta-analysis. Neuropsychol Rev. 2019;29(4):421-449. https://doi.org/10.1007/s11065-019-09419-2
7. Coenen AML, van Luijtelaar ELJM. Genetic animal models for absence epilepsy: a review of the WAG/Rij strain of rats. Behav Genet. 2003;33(6):635-655. https://doi.org/10.1023/A:1026179013847
8. Sarkisova K, van Luijtelaar G. The WAG/Rij strain: a genetic animal model of absence epilepsy with comorbidity of depression. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(4):854-876. https://doi.org/10.1016/j.pnpbp.2010.11.010

9. Sitnikova E. Behavioral and cognitive comorbidities in genetic rat models of absence epilepsy (focusing on GAERS and WAG/Rij rats). Biomedicines. 2024;12(1):122. https://doi.org/10.3390/biomedicines12010122
10. Fedosova EA, Shatskova AB, Sarkisova KY. Maternal methyl-enriched diet improves episodic memory but does not affect conditioned fear memory in offspring of WAG/Rij rats. J Evol Biochem Physiol. 2024;60(3):1260-1270. https://doi.org/10.1134/S0022093024030311
11. Karson A, Utkan T, Balcı F, Arıcıoğlu F, Ateş N. Age-dependent decline in learning and memory performances of WAG/Rij rat model of absence epilepsy. Behav Brain Funct. 2012;8:51. https://doi.org/10.1186/1744-9081-8-51
12. Balikci A, Ilbay G, Ates N. Neonatal tactile stimulations affect genetic generalized epilepsy and comorbid depression-like behaviors. Front Behav Neurosci. 2020;14:132. https://doi.org/10.3389/fnbeh.2020.00132
13. Sarkisova K, van Luijtelaar G. The impact of early-life environment on absence epilepsy and neuropsychiatric comorbidities. IBRO Neurosci Rep. 2022;13:436-468. https://doi.org/10.1016/j.ibneur.2022.10.012
14. Ilbay G, Dogan ZI, Balıkcı A, Erdogan S, Karaoglan Kahilogulları A. Effects of postnatal caffeine exposure on absence epilepsy and comorbid depression: results of a study in WAG/Rij rats. Brain Sci. 2022;12(3):361. https://doi.org/10.3390/brainsci12030361
15. Lemos C, Rial D, Gonçalves FQ, et al. High sucrose consumption induces memory impairment in rats associated with electrophysiological modifications but not with metabolic changes in the hippocampus. Neuroscience. 2016;315:196-205. https://doi.org/10.1016/j.neuroscience.2015.12.018
16. Sangüesa G, Cascales M, Griñán C, et al. Impairment of novel object recognition memory and brain insulin signaling in fructose- but not glucose-drinking female rats. Mol Neurobiol. 2018;55(8):6984-6999. https://doi.org/10.1007/s12035-017-0863-1
17. Tran DMD, Westbrook RF. Dietary effects on object recognition: the impact of high-fat high-sugar diets on recollection and familiarity-based memory. J Exp Psychol Anim Learn Cogn. 2018;44(3):217-228. https://doi.org/10.1037/xan0000170
18. Benton D, Ruffin MP, Lassel T, et al. The delivery rate of dietary carbohydrates affects cognitive performance in both rats and humans. Psychopharmacology (Berl). 2003;166(1):86-90. https://doi.org/10.1007/s00213-002-1334-5
19. Philippou E, Constantinou M. The influence of glycemic index on cognitive functioning: a systematic review of the evidence. Adv Nutr. 2014;5(2):119-130. https://doi.org/10.3945/an.113.004960
20. Kim TH, Petrou S, Reid CA. Low glycaemic index diet reduces seizure susceptibility in a syndrome-specific mouse model of generalized epilepsy. Epilepsy Res. 2014;108(1):139-143. https://doi.org/10.1016/j.eplepsyres.2013.10.014
21. Ahmadi BBM, Afarinesh MR, Jafaripour L, Sheibani V. Alteration in social interaction and tactile discrimination of juvenile autistic-like rats following tactile stimulation and whisker deprivation. Brain Behav. 2023;13(5):e2993. https://doi.org/10.1002/brb3.2993
22. Conner MR, Jang D, Anderson BJ, Kritzer MF. Biological sex and sex hormone impacts on deficits in episodic-like memory in a rat model of early, pre-motor stages of Parkinson's disease. Front Neurol. 2020;11:942. https://doi.org/10.3389/fneur.2020.00942
23. Kight KE, Argue KJ, Bumgardner JG, Bardhi K, Waddell J, McCarthy MM. Social behavior in prepubertal neurexin 1α deficient rats: a model of neurodevelopmental disorders. Behav Neurosci. 2021;135(6):782-803. https://doi.org/10.1037/bne0000482
24. Beilharz JE, Maniam J, Morris MJ. Diet-induced cognitive deficits: the role of fat and sugar, potential mechanisms and nutritional interventions. Nutrients. 2015;7(8):6719-6738. https://doi.org/10.3390/nu7085307
25. Coirini H, Rey M, Gonzalez Deniselle MC, Kruse MS. Long-term memory function impairments following sucrose exposure in juvenile versus adult rats. Biomedicines. 2022;10(11):2723. https://doi.org/10.3390/biomedicines10112723
26. Chávez-Gutiérrez E, Fuentes-Venado CE, Rodríguez-Páez L, et al. High fructose and high fat diet impair different types of memory through oxidative stress in a sex- and hormone-dependent manner. Metabolites. 2022;12(4):341. https://doi.org/10.3390/metabo12040341
27. Michetti C, Ferrante D, Parisi B, et al. Low glycemic index diet restrains epileptogenesis in a gender-specific fashion. Cell Mol Life Sci. 2023;80(12):356. https://doi.org/10.1007/s00018-023-04988-1
28. McGregor M, Richer K, Ananth M, Thanos PK. The functional networks of a novel environment: neural activity mapping in awake unrestrained rats using positron emission tomography. Brain Behav. 2020;10(8):e01646. https://doi.org/10.1002/brb3.1646
29. Seibenhener ML, Wooten MC. Use of the open field maze to measure locomotor and anxiety-like behavior in mice. J Vis Exp. 2015;(96):e52434. https://doi.org/10.3791/52434
30. Kalueff AV, Stewart AM, Song C, Berridge KC, Graybiel AM, Fentress JC. Neurobiology of rodent self-grooming and its value for translational neuroscience. Nat Rev Neurosci. 2016;17(1):45-59. https://doi.org/10.1038/nrn.2015.8
31. Reppucci CJ, Veenema AH. The social versus food preference test: a behavioral paradigm for studying competing motivated behaviors in rodents. MethodsX. 2020;7:101119. https://doi.org/10.1016/j.mex.2020.101119
32. Pirri F, Burke FF, McCormick CM. A protocol for investigating long-term social discrimination memory: evidence in female and male Long Evans rats. PLoS One. 2024;19(11):e0311920. https://doi.org/10.1371/journal.pone.0311920
33. Wang X, Zhan Y. Regulation of social recognition memory in the hippocampal circuits. Front Neural Circuits. 2022;16:839931. https://doi.org/10.3389/fncir.2022.839931
34. Reichelt AC, Loughman A, Bernard A, et al. An intermittent hypercaloric diet alters gut microbiota, prefrontal cortical gene expression and social behaviours in rats. Nutritional Neuroscience. 2018;https://doi.org/10.1080/1028415X.2018.1537169
35. Reichelt AC, Loughman A, Bernard A, et al. An intermittent hypercaloric diet alters gut microbiota, prefrontal cortical gene expression and social behaviours in rats. Nutr Neurosci. 2020;23(8):613-627. https://doi.org/10.1080/1028415X.2018.1537169
36. Reichelt AC, Gibson GD, Abbott KN, Hare DJ. A high-fat high-sugar diet in adolescent rats impairs social memory and alters chemical markers characteristic of atypical neuroplasticity and parvalbumin interneuron depletion in the medial prefrontal cortex. Food Funct. 2019;10(4):1985-1998. https://doi.org/10.1039/C8FO02118J
37. Sitnikova E, Pupikina M. Behavioral phenotyping of WAG/Rij rat model of absence epilepsy: the link to anxiety and sex factors. Biomedicines. 2025;13(9):2075. https://doi.org/10.3390/biomedicines13092075