The Role of Olfactory Stimuli in Neural Circuit & Cognitive Assessment

The neural pathways important for olfactory processing overlap extensively with pathways important for cognitive functioning.

Animal brain constantly receive rich sensory stimuli, such as odors, sounds, light and touch, from the surrounding environment. Of these inputs, only a small subset is behaviorally meaningful. In a complex and dynamic environment, it is crucial for animals to efficiently allocate the limited resources of their brain to process behaviorally relevant stimuli. To achieve this goal, the brain flexibly adjusts its circuits to preferentially process behaviorally relevant information. As we all know, effective behavioral analysis is an important part of brain science research, especially to understand the neural mechanisms of learned behaviors. The brain has evolved to use experience-dependent plastic mechanisms to refine neural circuits in sensory systems. In recent years, the importance of the sense of smell to humans has gradually been recognized. Olfaction is the primary sensory input for mice to explore their surroundings, and is one of the important sensory modes of cognitive behavior. Research has shown that rodents are very good at smell discrimination, memory, decision-making, impulsivity and other cognition-related behavioral tests. The neural pathways important for olfactory processing overlap extensively with pathways important for cognitive functioning.

The rodent olfactory behavioral testing has been used in many studies, and greatly facilitates the understanding of neural circuits underlying olfaction and odor-based cognition. In the olfactory circuit study, researchers found that adult-born neurons effectively sharpen mitral cells tuning and improve the power to discriminate among odors[1]. In addition, adult-born neurons have also been shown to affect many behavioral phenomena related to olfaction, such as working memory[2], olfactory perceptual learning[3], odor-reward associations[4], and innate behaviors[5]. In another study, the researchers found that the entorhinal cortex-hippocampus pathway is a key circuit for encoding reward association learning through the experiment of odor stimulation associated with water licking reward feedback[6]. Many neuropsychiatric disorders present with cognitive dysfunction, such as cognitive inflexibility, defined as the inability to flexibly adjust behavior to the demands of a changing environment. In the study of obsessive-compulsive disorder, the researchers used the classic odor reversal learning task combined with fiber photometry and optogenetics to find that cell-type-specific activity dynamics in the orbitofrontal cortex-striatal circuit underlying normal reversal learning. They identified the orbitofrontal cortex GABAergic interneurons as the key therapeutic target to treat cognitive inflexibility in obsessive-compulsive disorder[7]. As one of the phenotypes of cognitive function assessment, behavioral flexibility is an important ability to respond appropriately to unexpected events in a changing environment. Behavioral flexibility studies in aging models show that the BLA might be a critical brain area for integrating previous information with new changes in odor cues or delay time to appropriately alter behavior[8].

As we all know, behavioral training of odor stimuli is widely used in research, but most of the olfactory behavioral training require researchers to build their own olfactory platform. The construction of the experimental platform takes a lot of time and energy. For this reason, we have developed a fully automatic training system with minimal manual intervention for odor-based mouse cognitive behaviors. The system associates odor stimulation with drinking water reward feedback, and builds a learning task to quickly help users carry out mouse cognitive assessment experiments. The system supports 8 mice training at the same time, can be expanded to combine with optogenetics, electrophysiology and other equipment, and including sound cubicle, mouse head-fixing, licking rewards, odor control, signal transmission, IR camera and desktop software. The system helps to carry out research on neurological diseases, cognitive learning mechanisms, and olfactory neural circuit, greatly enhancing the experimental efficiency.

[1] Grelat, A.; Benoit, L.; Wagner, S.; Moigneu, C.; Lledo, P. M.; Alonso, M. Adult-Born Neurons Boost Odor-Reward Association. Proc Natl Acad Sci U S A 2018, 115 (10), 2514-2519.

[2] Liu, D.; Gu, X.; Zhu, J.; Zhang, X.; Han, Z.; Yan, W., et al. Medial Prefrontal Activity During Delay Period Contributes to Learning of a Working Memory Task. Science 2014, 346 (6208), 458-63.

[3] Lee, J. Y.; Jun, H.; Soma, S.; Nakazono, T.; Shiraiwa, K.; Dasgupta, A., et al. Dopamine Facilitates Associative Memory Encoding in the Entorhinal Cortex. Nature 2021, 598 (7880), 321-326.

[4] Moreno, M. M.; Linster, C.; Escanilla, O.; Sacquet, J.; Didier, A.; Mandairon, N. Olfactory Perceptual Learning Requires Adult Neurogenesis. Proc Natl Acad Sci U S A 2009, 106 (42), 17980-5.

[5] Sakamoto, M.; Imayoshi, I.; Ohtsuka, T.; Yamaguchi, M.; Mori, K.; Kageyama, R. Continuous Neurogenesis in the Adult Forebrain Is Required for Innate Olfactory Responses. Proc Natl Acad Sci U S A 2011, 108 (20), 8479-84.

[6] Shani-Narkiss, H.; Vinograd, A.; Landau, I. D.; Tasaka, G.; Yayon, N.; Terletsky, S., et al. Young Adult-Born Neurons Improve Odor Coding by Mitral Cells. Nat Commun 2020, 11 (1), 5867.

[7] Yang, Z.; Wu, G.; Liu, M.; Sun, X.; Xu, Q.; Zhang, C., et al. Dysfunction of Orbitofrontal Gabaergic Interneurons Leads to Impaired Reversal Learning in a Mouse Model of Obsessive-Compulsive Disorder. Curr Biol 2021, 31 (2), 381-393 e4.

[8] Zhang, J.; Liu, D.; Fu, P.; Liu, Z. Q.; Lai, C.; Yang, C. Q., et al. Social Isolation Reinforces Aging-Related Behavioral Inflexibility by Promoting Neuronal Necroptosis in Basolateral Amygdala. Mol Psychiatry 2022, 27 (10), 4050-4063.