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Instytut Biologii Doświadczalnej im. Marcelego Nenckiego PAN
Contributor:Hunt, Mark Jeremy (1976– ) : Supervisor
Publisher:Nencki Institute of Experimental Biology PAS
Place of publishing: Date issued/created: Description:VIII, 92 pages : ilustrations ; 30 cm ; Bibliography ; Summary in Polish
Degree name: Degree discipline : Degree grantor:Nencki Institute of Experimental Biology PAS ; degree obtained: 27.06.2025
Type of object: Subject and Keywords:HFO ; Olfactory bulb ; NMDA receptor ; Dopamine receptor ; Ketamine ; MK801
Abstract:
NMDAR antagonists, particularly ketamine, have gained significant attention in clinical settings for their applications, especially in emerging treatments for depression, though their precise mechanisms of action remain incompletely understood. In preclinical research, NMDAR antagonists are used to model psychotic-like states, and are known to broadly influence brain rhythms in both animal and human models. Notably, NMDAR antagonists enhance the power of high-frequency oscillations (HFO), observed across species and in many brain regions. Recent studies have identified the olfactory bulb (OB) as a primary source of NMDAR-dependent HFO in the rat brain. This thesis builds on these findings to investigate the role of the OB in HFO generation, focusing on its input and output connections. The starting point of my research was an observation that under ketamine-xylazine sedation in rats, HFO power in the OB attenuated when airflow to the nostrils was blocked. Building on this foundation, I investigated whether odours or enhanced intranasal airflow could influence HFO. My results showed that increased nares air pressure, but not odours, drove HFO in the OB. Next, to overcome the limitations of ketamine-xylazine sedation, I shifted the subsequent experiments to freely moving animals. In these experiments, I found that naris block attenuated NMDAR-dependent HFO power in the OB, as well as in the prefrontal cortex and ventral striatum. Additionally, fast sniffing entrained NMDAR-dependent HFO. Having shown that nasal input drives HFO in the OB, I next examined these oscillations in the piriform cortex (PC), the major projection pathway of the OB. I demonstrated that reversible inhibition of the OB attenuated NMDAR-dependent HFO power, both locally in the OB and in the PC. Given that the PC sends feedback projections to the OB, I inhibited the PC and observed a gradual reduction in NMDAR-dependent HFO power locally in the PC, with no changes in the OB. This suggests that the OB is the primary generator of NMDAR-dependent HFO, and that HFO observed in the PC, relies on this primary generator. The OB serves as the initial processing station in the olfactory pathway, where olfactory information is processed and dopamine plays a key role in this process. Therefore, I investigated the effects of D1R and D2R stimulation or inhibition on NMDAR-dependent HFO in the OB. My results show that the generation of NMDAR- dependent HFO is dopamine-independent; however, exogenous stimulation of D2R reduces both the power and frequency of this rhythm. The results presented in this thesis underscore the critical role of the OB and nasal respiration in generating HFO following NMDAR antagonist administration. While NMDAR antagonists, particularly ketamine, are recognized for their neuropsychiatric effects, the underlying neuronal networks influenced by these compounds remain only partially understood. My findings indicate that, in the context of HFO, the OB is a key brain region impacted by NMDAR antagonists, which, along with downstream effects on corticostriatal areas, may at least partially contribute to the neuropsychiatric effects of these compounds.
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Copyright holder:Publication made available with the written permission of the author
Digitizing institution:Nencki Institute of Experimental Biology of the Polish Academy of Sciences
Original in:Library of the Nencki Institute of Experimental Biology PAS
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