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:
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.
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.