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Odour discrimination in mice with perturbed granule cells, assayed by automated behavioural testing

Reinert, Janine Kristin

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Olfaction, the sense of smell, is one of the most important sensory stimuli for any organism, from unicellular bacteria to highly complex metazoans like humans. Volatile chemicals constituting olfactory cues can carry a vast range of information, enabling animals to detect and locate food, mates or shelter. The structure of the olfactory system has remained remarkably conserved, indicating that the precise anatomy is integral to the detection and discrimination of odours. Previous studies have shown that the connectivity of olfactory bulb mitral and granule cells plays a crucial role in odour discrimination in mice, yet several aspects of granule cell function remain unclear. To investigate the impact of modified granule cell function on odour discrimination in mice, we first established a novel automated operant conditioning setup. This setup allowed us to train large (>20 animals) groups of mice on a go/no-go odour discrimination task with minimal experimenter interference. It was used for detailed analysis olfactory behaviour by assessing parameters such as the discrimination time, the speed at which animals were able to discriminate and odour and initiate a corresponding behavioural response. As neurobiological function follows form, we focussed on the specialized dendrodendritic connection between the principal output neurons of the mammalian olfactory bulb, the mitral cells, and the most abundant inhibitory interneurons of the olfactory bulb, the granule cells. As inhibition of mitral cells from granule cell has been shown to directly affect the discrimination of odour mixtures, we sought to modulate the strength of this inhibition using two different approaches. The first strategy was based on increasing the inhibitory output through the overall increase of granule cells. Towards this end, a novel transgenic mouse line was used, in which the pool of neuronal stem cells can be temporarily increased resulting in an olfactory bulb specific increase of physiologically normal and functionally integrated granule cells. Utilizing the automated behaviour setup, we were able to show that discrimination accuracy, but not the discrimination time of highly similar mixtures of two enantiomers is increased in mice harbouring an increased number of granule cells. The second approach was based on reducing the inhibitory output of granule cells by reducing the global activation of granule cells following local dendritic activation, a feature which is thought to be gated by T-type calcium channels. Therefore, we established a simultaneous triple knock-down of all three T-type subunits using adeno-associated virus-based shRNA expression in granule cells. We found that mice with reduced T-type expression did not show the typical increase in discrimination times when comparing simple with complex odours, suggesting that a lack of global activation affects discrimination of simple odours. In summary, these findings highlight the importance of granule cell-derived inhibitory input onto mitral cells for the discrimination of highly similar odour stimuli. Taking into account the subtle nature of the molecular modifications and the flexibility of the novel approach to behavioural phenotyping, these results clearly outline the path to a large-scale, systematic investigation into the limits of olfaction.

Item Type: Dissertation
Supervisor: Kuner, Prof. Dr. Thomas
Date of thesis defense: 30 July 2019
Date Deposited: 20 Aug 2019 07:38
Date: 2019
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Medizinische Fakultät Heidelberg > Institut für Anatomie und Zellbiologie
Subjects: 500 Natural sciences and mathematics
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