Investigating the effects of orexin receptors inhibition in the nucleus incertus on passive avoidance learning in male rats

Subject Areas : Journal of Comparative Pathobiology

Fatemeh Eslamisaravi ¹ , Esmaeil Akbari ² , Vahab Babapour ³ , Morteza Zendehdel ⁴

1 - Department of Basic Sciences, Faculty of Veterinary Medicine, Science and Research Branch, Islamic Azad University, Tehran, Iran
2 - Department of Physiology and Pharmacology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
3 - Department of Basic Sciences, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
4 - Department of Basic Sciences, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran

Received: 2024-12-11 Accepted : 2025-02-24

Keywords: Orexin receptors, Nucleus incertus, Avoidance learning, Rat,

Abstract :

Learning and memory processes are influenced by various regions of the brain. The current study is designed to examine the effects of the inactivation of orexin receptors type 1 and 2 located in the NI of rat brains on the processing of avoidance learning and long-term potentiation (LTP). In different phases of this study, rats received dimethyl sulfoxide (DMSO, control group), orexin receptor type 1 antagonist (SB-334867-A), and orexin receptor type 2 antagonist (TCS-OX2-29) via cannula. Behavioral tests related to passive avoidance learning were conducted in two phases: consolidation and retrieval. Drug injections were administered immediately after training or 15 minutes before the start of the retrieval test in the NI. Additionally, in electrophysiological experiments, injections were performed 30 minutes prior to LTP induction to investigate the role of orexin receptors in LTP induction. The results indicated that the consolidation phase was significantly disrupted by antagonist injections in both behavioral tests (p < 0.05), while the retrieval phase was not affected (p ≥ 0.05). Furthermore, in electrophysiological testing, the amplitude of population spike (PS) experienced a significant reduction (p < 0.05), whereas the slope of the population excitatory postsynaptic potential (EPSP) did not change (p ≥ 0.05). Ultimately, this study demonstrated that the inhibition of orexin receptors type 1 and 2 in the NI leads to impairments in avoidance learning processes and synaptic long-term potentiation induction.

 

 

References:

1. Qian ZJ, Ricci AJ. Effects of cochlear hair cell ablation on spatial learning/memory. Scientific Reports. 2020;10(1):20687.
2. Okano H, Hirano T, Balaban E. Learning and memory. Proceedings of the National Academy of Sciences. 2000;97(23):12403-4.
3. Suarez AMS, Martinez MEM, Mendoza LRM. Brain and learning. International Journal of Social Sciences and Humanities. 2019;3(2):128-35.
4. Hölscher C. Synaptic plasticity and learning and memory: LTP and beyond. Journal of neuroscience research. 1999;58(1):62-75.
5. Harris KM. Structural LTP: from synaptogenesis to regulated synapse enlargement and clustering. Current opinion in neurobiology. 2020;63:189-97.
6. Bird CM, Burgess N. The hippocampus and memory: insights from spatial processing. Nature reviews neuroscience. 2008;9(3):182-94.
7. Szőnyi A, Sos KE, Nyilas R, Schlingloff D, Domonkos A, Takács VT, et al. Brainstem nucleus incertus controls contextual memory formation. Science. 2019;364(6442):eaaw0445.
8. Ryan PJ, Ma S, Olucha-Bordonau FE, Gundlach AL. Nucleus incertus—an emerging modulatory role in arousal, stress and memory. Neuroscience & Biobehavioral Reviews. 2011;35(6):1326-41.
9. Banerjee A, Shen P-J, Ma S, Bathgate RA, Gundlach AL. Swim stress excitation of nucleus incertus and rapid induction of relaxin-3 expression via CRF1 activation. Neuropharmacology. 2010;58(1):145-55.
10. Goto M, Swanson LW, Canteras NS. Connections of the nucleus incertus. Journal of Comparative Neurology. 2001;438(1):86-122.
11. Blasiak A, Siwiec M, Grabowiecka A, Blasiak T, Czerw A, Blasiak E, et al. Excitatory orexinergic innervation of rat nucleus incertus–Implications for ascending arousal, motivation and feeding control. Neuropharmacology. 2015;99:432-47.
12. Chieffi S, Carotenuto M, Monda V, Valenzano A, Villano I, Precenzano F, et al. Orexin system: the key for a healthy life. Frontiers in physiology. 2017;8:357.
13. Sakurai T. The role of orexin in motivated behaviours. Nature Reviews Neuroscience. 2014;15(11):719-31.
14. Sakurai T. Orexins and orexin receptors: implication in feeding behavior. Regulatory peptides. 1999;85(1):25-30.
15. Sakurai T, Mieda M, Tsujino N. The orexin system: roles in sleep/wake regulation. Annals of the New York Academy of Sciences. 2010;1200(1):149-61.
16. Nollet M, Leman S. Role of orexin in the pathophysiology of depression: potential for pharmacological intervention. CNS drugs. 2013;27:411-22.
17. Nunez A, Cervera‐Ferri A, Olucha‐Bordonau F, Ruiz‐Torner A, Teruel V. Nucleus incertus contribution to hippocampal theta rhythm generation. European Journal of Neuroscience. 2006;23(10):2731-8.
18. Sakurai T. The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness. Nature Reviews Neuroscience. 2007;8(3):171-81.
19. Kastman HE, Blasiak A, Walker L, Siwiec M, Krstew EV, Gundlach AL, et al. Nucleus incertus Orexin2 receptors mediate alcohol seeking in rats. Neuropharmacology. 2016;110:82-91.
20. Akbari E, Motamedi F, Naghdi N, Noorbakhshnia M. The effect of antagonization of orexin 1 receptors in CA1 and dentate gyrus regions on memory processing in passive avoidance task. Behavioural brain research. 2008;187(1):172-7.
21. zokaei l, akbari e, Zendehdel M, Babapour V. The role of orexin 1 and 2 receptors in the accumbens area on passive avoidance memory processing in rats. Journal of Comparative Pathobiology. 2024;20(83):4247-54.
22. Paxinos G, Watson C. The rat brain in stereotaxic coordinates: hard cover edition: Elsevier; 2006.
23. Zokaei L, Akbari E, Babapour V, Zendehdel M. The Modulatory Role of Orexin 1 Receptor in Nucleus Accumbens (NAc) on Spatial Memory in Rats. Archives of Razi Institute. 2023;78(4):1285.
24. Lashgari R, Khakpour-Taleghani B, Motamedi F, Shahidi S. Effects of reversible inactivation of locus coeruleus on long-term potentiation in perforant path-DG synapses in rats. Neurobiology of learning and memory. 2008;90(2):309-16.
25. Nategh M, Nikseresht S, Khodagholi F, Motamedi F. Nucleus incertus inactivation impairs spatial learning and memory in rats. Physiology & Behavior. 2015;139:112-20.
26. Nategh M, Nikseresht S, Khodagholi F, Motamedi F. Inactivation of nucleus incertus impairs passive avoidance learning and long term potentiation of the population spike in the perforant path-dentate gyrus evoked field potentials in rats. Neurobiology of learning and memory. 2016;130:185-93.
27. Scammell TE, Winrow CJ. Orexin receptors: pharmacology and therapeutic opportunities. Annual review of pharmacology and toxicology. 2011;51(1):243-66.
28. Telegdy G, Adamik A. The action of orexin A on passive avoidance learning. Involvement of transmitters. Regulatory peptides. 2002;104(1-3):105-10.
29. Ardeshiri MR, Hosseinmardi N, Akbari E. The effect of orexin 1 and orexin 2 receptors antagonisms in the basolateral amygdala on memory processing in a passive avoidance task. Physiology & behavior. 2017;174:42-8.
30. Gil-Miravet I, Mañas-Ojeda A, Ros-Bernal F, Castillo-Gómez E, Albert-Gascó H, Gundlach AL, et al. Involvement of the nucleus incertus and relaxin-3/RXFP3 signaling system in explicit and implicit memory. Frontiers in Neuroanatomy. 2021;15:637922.
31. Olucha‐Bordonau FE, Albert‐Gascó H, Ros‐Bernal F, Rytova V, Ong‐Pålsson EK, Ma S, et al. Modulation of forebrain function by nucleus incertus and relaxin‐3/RXFP 3 signaling. CNS Neuroscience & Therapeutics. 2018;24(8):694-702.
32. Smith CM, Ryan PJ, Hosken IT, Ma S, Gundlach AL. Relaxin-3 systems in the brain—the first 10 years. Journal of chemical neuroanatomy. 2011;42(4):262-75.
33. Noorani SK, Hojati V, Akbari E, Ehsani S, Sakurai T, Ardeshiri MR. The role of interaction between orexin receptors and β2 adrenergic receptors in basolateral amygdala in dentate gyrus synaptic plasticity in male rats. Brain Research Bulletin. 2021;177:164-71.
34. Abounoori M, Maddah MM, Ardeshiri MR. Orexin neuropeptides modulate the hippocampal-dependent memory through basolateral amygdala interconnections. Cerebral Circulation-Cognition and Behavior. 2022;3:100035.
35. Muller D, Nikonenko I, Jourdain P, Alberi S. LTP, memory and structural plasticity. Current molecular medicine. 2002;2(7):605-11.