A01 A02 A03 A04 A05 A06 A07 A09 A10 A11 A12 A13 A14 A18 A19 A21 F01 F02 INF

A21 - Cerebellar contribution to fear extinction

Melanie Mark

One of the key elements to survival is the ability of our brain to recall threatening situations from the past so our self-defense mechanism can respond swiftly. Cerebellar lesion and stimulation studies in rodents and humans suggest a contribution of the cerebellum to anxiety and fear extinction behavior. However, a clear understanding of the circuitry and learning mechanisms within the cerebellum contributing to fear extinction is missing. Thus, the goal of this project is to investigate the cerebellar contribution and its intrinsic mechanisms to fear extinction in wildtype and cerebellar degenerative mouse models for episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6). We will attempt to rescue fear conditioning, extinction or retrieval deficits with optogenetic, chemogenetic and pharmacological strategies in the next funding period.

Guiding questions of A21:

  • What regions and cell types of the cerebellum are active during the different phases of fear extinction?
  • Can we control (i. e. delay or accelerate) fear extinction from the cerebellar cortex or deep cerebellar nuclei using optogenetics?
  • How is the cerebellum involved in prediction errors during fear extinction?
  • Do our cerebellar degenerative mouse models for EA2 and SCA6 display deficits in fear conditioning, retrieval or extinction? Can we rescue these deficits in EA2 and SCA6 mice with optogenetic strategies?

Melanie Mark

Projektleiterin A21

Ruhr-Universität Bochum

Johanna Pakusch

Doktorandin A21

Ruhr-Universität Bochum

10 project relevant publications

Bohne P, Schwarz MK, Herlitze S, Mark MD (2019) A New Projection From the Deep Cerebellar Nuclei to the Hippocampus via the Ventrolateral and Laterodorsal Thalamus in Mice. Front Neural Circuits. 13: 51.

Eickelbeck D, Karapinar R, Jack A, Suess ST, Barzan R, Azimi Z, Surdin T, Grömmke M, Mark MD, Gerwert K, Jancke D, Wahle P, Spoida K, Herlitze S (2019) CaMello-XR enables visualization and optogenetic control of Gq/11 signals and receptor trafficking in GPCR-specific domains. Commun Biol. 2: 60.

Fekete A, Nakamura Y, Yang Y-M, Herlitze S, Mark MD, DiGregorio DA, Wang L-Y (2019) Underpinning heterogeneity in synaptic transmission by presynaptic ensembles of distinct morphological modules. Nat Commun. 10(1): 826.

Gutierrez DV, Mark MD, Masseck O, Maejima T, Kuckelsberg D, Hyde RA, Krause M, Kruse W, Herlitze S (2011) Optogenetic Control of Motor Coordination by Gi/o Protein-coupled Vertebrate Rhodopsin in Cerebellar Purkinje Cells. J Biol Chem. 286(29): 25848–25858.

Kruse W, Krause M, Aarse J, Mark MD, Manahan-Vaughan D, Herlitze S (2014) Optogenetic modulation and multielectrode analysis of cerebellar networks in vivo. PLoS One. 9(8): e105589.

Maejima T, Wollenweber P, Teusner LUC, Noebels JL, Herlitze S, Mark MD (2013) Postnatal loss of P/Q-type channels confined to rhombic-lip-derived neurons alters synaptic transmission at the parallel fiber to purkinje cell synapse and replicates genomic Cacna1a mutation phenotype of ataxia and seizures in mice. J Neurosci. 33(12): 5162–5174.

Mark MD, Krause M, Boele H-J, Kruse W, Pollok S, Kuner T, Dalkara D, Koekkoek S, Zeeuw CI de, Herlitze S (2015) Spinocerebellar Ataxia Type 6 Protein Aggregates Cause Deficits in Motor Learning and Cerebellar Plasticity. J Neurosci. 35(23): 8882–8895.

Mark MD, Maejima T, Kuckelsberg D, Yoo JW, Hyde RA, Shah V, Gutierrez D, Moreno RL, Kruse W, Noebels JL, Herlitze S (2011) Delayed Postnatal Loss of P/Q-Type Calcium Channels Recapitulates the Absence Epilepsy, Dyskinesia, and Ataxia Phenotypes of Genomic Cacna1A Mutations. J Neurosci. 31(11): 4311–4326.

Mark MD, Wollenweber P, Gesk A, Kösters K, Batzke K, Janoschka C, Maejima T, Han J, Deneris ES, Herlitze S (2019) RGS2 drives male aggression in mice via the serotonergic system. Commun Biol. 2(1): 1–17.

Spoida K, Eickelbeck D, Karapinar R, Eckhardt T, Mark MD, Jancke D, Ehinger BV, König P, Dalkara D, Herlitze S, Masseck OA (2016) Melanopsin Variants as Intrinsic Optogenetic On and Off Switches for Transient versus Sustained Activation of G Protein Pathways. Curr Biol. 26(9): 1206–1212.