Top-down (State dependent) Modulation of Sensory Processing in the Mouse Olfactory Bulb

• Applicant: Professor Dr. Markus Rothermel
• Subject Area: Cognitive, Systems and Behavioural Neurobiology ; Sensory and Behavioural Biology ; Human Cognitive and Systems Neuroscience
• Term: from 2014 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 250583768

• Final Report Year: 2022

Final Report Abstract

Activity in any brain region, including visual, somatosensory and olfactory areas, can be statedependently modulated e.g. by attention, expectation, and perceptual tasks. “Top‐down” systems are thought to be key players in mediating these processes. However, the exact neuronal mechanism by which top-down systems modulate sensory processing, as well as their relative contribution to complex behavioral tasks, is not well understood. My research group investigates top-down modulations using the olfactory system as a model. The first part of my Emmy Noether period focused on investigating top-down modulation effects from two distinct brain areas, the horizontal band of broca (HDB) and the anterior olfactory nucleus (AON), on olfactory bulb (OB) output neuron activity in the anesthetized preparation. Our findings demonstrate that topdown inputs from different sources can exert strong, differential modulation effects on OB output activity. While cholinergic HDB modulation is always excitatory, GABAergic HDB modulation effects are sensory input dependent. AON top-down modulation effects on the other hand are inhibitory in all tested conditions. The data presented in this report not only complemented the work in the anesthetized preparation but by adding a behavioral component, significantly enhanced their value and thereby strongly contributed to the successful publications of our results. Additional manuscripts are currently prepared for submission. Aim: Testing for behavioral consequence of extrinsically modulating top-down input activity We used optogenetic tools to selectively modulate cholinergic/GABAergic HDB or cortical AON activity while mice performed different behavioral tasks. Behavioral consequences of optogenetically modulating glutamatergic AON axons in the OB. In contrast to piriform cortex (Choi et al., 2011), activating AON neurons does not substitute olfactory input in our behavioral paradigms. Interestingly the same holds true for inhibiting AON activity which is thought to decrease GC activity thereby leading to MT excitation. While technical details might account for some of the differences (e.g. we deliberately used a low number of optogenetic stimulation trials to avoid training mice to report to optogenetic stimulation itself), these findings further underline a nonredundant role of the AON and piriform cortex in olfactory coding. Optogenetically inhibiting the AON significantly increased lick responses during S-trials in an odor discrimination task and we hypothesize that this effect is mediated via the disruptive effect of increased MT activity on odor discrimination. In agreement with our anesthetized electrophysiological recordings demonstrating a pronounced suppression of OB output neuron activity in response to AON stimulation we observed that in awake mice, AON activation dynamically suppresses odor detection independently of odor identity and concentration. Future studies are aimed at revealing the nature of this AON-mediated effect. Behavioral consequences of optogenetically modulating GABAergic or cholinergic HDB axons in the OB. According to our anesthetized data, activating GABAergic HDB projections modulates MT activity in a sensory input-dependent way. However, our awake experiments did not reveal any effect on odor detection when modulating GABAergic activity. Similarly, the excitatory bias of OB mitral cells observed in response to cholinergic HDB stimulation did not cause “false odor precepts” in the complete absence of sensory input or differences in performance in a two-odor discrimination task. However, we were able to enhance odor detection at the threshold level with cholinergic HDB activation pointing in the same direction as published data demonstrating that cholinergic top-down modulation can reinstate odor investigation/interest. In summary, my Emmy Noether research group made essential contributions to investigating the neurophysiological bases of sensory perception while challenging existing models of sensory information filtering. In the long run, these studies will provide a crucial step for a deeper understanding of how brain circuits shape perception and, in addition, might help alleviate medical conditions in which these systems are involved.

Publications

• Neuromodulation of early sensory processing in the olfactory system. Neuroforum (2019); 25(1)
  Brunert D, Rothermel M
  
• Cortical multisensory integration-a special role of the agranular insular cortex? Pflugers Arch - Eur J Physiol. (2020)
  Brunert D, Rothermel M
  
• Dual-Specificity Phosphatases in Mental and Neurological Disorders. Progress in Neurobiology (2020)
  An N, Bassil K, Al Jowf GI, Steinbusch HWM, Rothermel M, de Nijs L, Rutten BPF
  
• Dynamic impairment of olfactory behavior and signaling mediated by an olfactory corticofugal system. J Neurosci. (2020)
  Medinaceli Quintela R, Bauer J, Wallhorn L, Le K, Brunert D, Rothermel M
  
• Effect of odor pleasantness on heat-induced pain: An fMRI study. Brain Imaging and Behavior (2020)
  Jo HG, Wudarczyk O, Leclerc M, Regenbogen C, Lampert A, Rothermel M, Habel U
  
• Input dependent modulation of olfactory bulb activity by HDB GABAergic projections. Scientific Reports ,10, 10696 (2020)
  Böhm E, Brunert D, Rothermel M
  
• Synchronous Infra-Slow Oscillations Organize Ensembles of Accessory Olfactory Bulb Projection Neurons into Distinct Microcircuits. J Neurosci. (2020); 40(21):4203-4218
  Tsitoura C, Malinowski ST, Mohrhardt J, Degen R, DiBenedictis BT, Gao Y, Watznauer K, Gerhold K, Nagel M, Weber M, Rothermel M, Hanganu-Opatz IL, Ben-Shaul Y, Davison IG, Spehr M
  
• The Impact of Mitochondrial Dysfunction on Dopaminergic Neurons in the Olfactory Bulb and Odor Detection. Mol. Neurobiol. (2020)
  Paß T, Aßfalg M, Tolve M, Blaess S, Rothermel M, Wiesner RJ, Ricke KM
  
• Assessing the impact of pain-linked Nav1.7 variants: an example of two variants with no biophysical effect. Channels (2021)
  Le Cann K, Meents J, Bhagavath Eswaran VS, Dohrn MF, Maier A, Bialer M, Bott R, Hautvast P, Erickson A, Rolke R, Rothermel M, Körner J, Kurth I, Lampert A
  
• Extrinsic neuromodulation in the rodent olfactory bulb. Cell Tissue Res (2021)
  Brunert D, Rothermel M
  
• The difficulty to model Huntington’s Disease in vitro using striatal Medium Spiny Neurons differentiated from human induced pluripotent stem cells. Scientific Reports (2021)
  Le Cann K, Foerster A, Rösseler C, Erickson A, Hautvast P, Giesselmann S, Pensold D, Kurth I, Rothermel M, Mattis VB, Zimmer-Bensch G, von Hörsten S, Denecke B, Clarner T, Meents J, Lampert A