Krabbe Group

Internal states, including emotional conditions such as anxiety or stress, as well as physiological need states like hunger or thirst, strongly influence our behaviour. By modulating the contextual perception of external cues that signal potential rewards or threats, emotional and metabolic states can dynamically control the internal valuation system and thereby affect the selection of appropriate behavioural strategies. Our research group is interested in the neural circuit mechanisms mediating these forms of adaptive learning and state-dependent decision-making in health and disease.

We focus our work on the interactions between midbrain circuits of the substantia nigra and ventral tegmental area with their output structures, e.g. the striatum and amygdala. To understand how these networks integrate internal states with environmental cues to gate adequate behavioural output, we comprehensively map the functional diversity of defined cell types in these brain areas – ranging from the precise connectivity and molecular profiles of individual neurons to the activity patterns of neuronal populations during a variety of behavioural tasks.

Neuronal degeneration in the same circuits has been implicated in the pathogenesis of Parkinson’s disease (PD). Neuropsychiatric PD features such as anxiety and depression as well as cognitive deficits in learning and decision-making can develop decades before the typical motor symptoms, yet their origins are barely understood. The early occurrence of non-motor pathologies before irreversible neuron loss suggests that abnormal cellular physiology preceding apparent degeneration could play a key role. We are aiming to identify how activity patterns within the above-mentioned circuits change in early stages of PD, and how this dysfunction contributes to cognitive deficits and pathological emotional states

Experimental approaches

We use state-of-the-art techniques such as deep-brain calcium imaging at single-cell resolution in mice to monitor the activity of individual neurons across a variety of behavioural tasks and internal states. To test the causal contributions of defined activity patterns to specific behavioural phenotypes, we are combining these recordings with opto- and pharmacogenetic manipulations to precisely activate or inhibit distinct neuronal populations. Anatomical tracings as well as electrophysiological, histological and molecular approaches further allow us to characterize the diversity of different neural circuit elements in detail. Finally, we apply these tools to mouse models of PD to dissect the maladaptive circuit mechanisms underlying the early neuropsychiatric symptoms of this disorder.

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Methods

• Behavioural analysis
• Multi- and single-photon calcium imaging
• Electrophysiology
• Optogenetic and chemogenetics
• Spatial transcriptomics
• Anatomical tracing
• Histology

5 selected publications

1. Wang Y, Krabbe S, Eddison M, Henry FE, Fleishman G, Lemire AL, Wang L, Korff W, Tillberg PW, Lüthi A, Sternson SM. Multimodal mapping of cell types and projections in the central nucleus of the amygdala. Elife. 2023 Jan 20;12.
2. Krabbe S*, Paradiso E*, D’Aquin S, Bitterman Y, Courtin J, Xu C, Yonehara K, Markovic M, Eichlisberger T, Müller C, Gründemann J, Ferraguti F, Lüthi A (* equal contribution). Adaptive disinhibitory gating by VIP interneurons permits associative learning. Nature Neuroscience 2019, 22(11):1834-1843.
3. Gründemann J*, Bitterman Y*, Lu T, Krabbe S, Grewe BF, Schnitzer M, Lüthi A (* equal contribution). Amygdala ensembles encode behavioral states. Science 2019, 364(6437). pii: eaav8736.
4. Vogel E*, Krabbe S*, Gründemann J, Wamsteeker Cusulin JI, Lüthi A (* equal contribution). Projection-specific dynamic regulation of inhibition in amygdala micro-circuits. Neuron 2016, 91(3):644-51. doi: 10.1016/j.neuron.2016.06.036
5. Krabbe S, Duda J, Schiemann J, Poetschke C, Schneider G, Kandel ER, Liss B, Roeper J, Simpson EH. Increased dopamine D2 receptor activity in the striatum alters the firing pattern of dopamine neurons in the ventral tegmental area. PNAS 2015, 112(12):E1498-506.