Investigating the effects of olfactory critical period odorant exposure on the trace amine-associated receptor4 olfactory circuit

研究嗅觉关键期气味暴露对痕量胺相关受体4嗅觉回路的影响

• 批准号: 10749403
• 负责人: Jordan Duran Gregory
• 金额: $ 4.77万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10749403
• 关键词: Ablation; Adolescent; Adult; Amines; Anosmia; Apical; Axon; Behavior; Behavioral; Brain; Brain region; Calcium; Cells; Chronic; Cues; Data; Dendrites; Detection; Development; Electrophysiology (science); Emotional; Environment; Exposure to; Faculty; Goals; Image; Instinct; Knowledge; Learning; Life; Maps; Mediating; Methimazole; Morphology; Mus; Natural regeneration; Odorant Receptors; Odors; Olfactory Epithelium; Olfactory Pathways; Organizational Change; Output; Pathway interactions; Pattern; Phenethylamines; Play; Reporting; Research; Role; Saline; Sensory; Slice; Structure; T-Lymphocyte; Techniques; Testing; Time; Training; Universities; avoidance behavior; behavioral response; career; critical developmental period; critical period; experience; experimental study; in vivo; inhibitory neuron; member; mitral cell; neural circuit; olfactory bulb; olfactory bulb glomeruli; olfactory sensory neurons; postnatal period; preference; receptor; reinnervation; resilience; response; stem cells; two-photon; voltage clamp

Project Summary Innate behavioral responses to emotionally salient cues in the environment are thought to be set in the brain through hardwired circuits. In mice, the olfactory detection and processing pathways are well characterized, with olfactory sensory neurons (OSNs) that express the same one odorant receptor (OR) coalescing to form two glomeruli per olfactory bulb (OB). Mitral cells and tufted cells (M/TCs) send a single apical dendrite into these glomeruli to receive input, and project their axons to various downstream brain regions. This highly organized glomerular map is maintained throughout the mouse’s life. However, the olfactory bulb has a developmental critical period from postnatal days 0 to 14 (P0 – P14), during which enrichment with a neutral odorant produces lasting changes: both the volume of the glomeruli and responsiveness of M/TCs to the enriched odorant increase. However, less is known about how critical period exposure to odorants with innate valence alters OB circuits. A recent study has shown that exposure to the innately aversive odorant phenethylamine (PEA) during the olfactory critical period produces behavioral changes and alters axon projection patterns of OSNs expressing the trace-amine associated receptor class 4 (TAAR4 or T4). Mice exposed to PEA during the critical period no longer show innate aversion to PEA in adulthood; furthermore, these mice have on average five T4 glomeruli per hemisphere rather than the typical two. Currently, this is the only report of changes in the OB circuitry and behaviors following exposure to an innately aversive odorant during the olfactory critical period. What remains unknown is how either the OSNs or the M/TCs within the T4 glomerular module change in their PEA responsiveness following critical period PEA exposure. Additionally, whether these behavioral and structural changes persist following complete OSN ablation and reinnervation of the OB has yet to be investigated. To fill this gap in knowledge, I propose experiments to test the critical period exposure to the aversive odorant PEA alters OB circuitry response patterns to produce persistent behavioral and structural changes to elicit attraction to PEA. In Aim 1, I will first use 2-photon calcium imaging to identify changes in OSN and MC/TC odor responses within the T4 glomerular module following critical period PEA exposure. I will then determine whether critical period PEA exposure changes the intrinsic excitability of M/T cells using whole cell voltage clamp electrophysiology in OB slices. In Aim 2, I will determine whether the behavioral and glomerular organization changes elicited by critical period PEA exposure persist after OSN ablation via methimazole (MMZ) treatment and subsequent reinnervation of the OB, using chronic in vivo structural 2-photon imaging of T4 glomeruli and repeated odor preference testing in saline vs. MMZ treated mice. These data will advance our understanding of the effects of critical period experience on neural circuit development to produce lasting behavioral changes in mice.

项目总结