Mild Deficits in Fear Learning: Evidence from Humans and Mice with Cerebellar Cortical Degeneration

Abstract

Functional brain imaging studies in humans suggest involvement of the cerebellum in fear conditioning, but do not allow conclusions about the functional significance. The main aim of the present study was to examine whether patients with cerebellar degeneration show impaired fear conditioning and whether this is accompanied by alterations in cerebellar cortical activations. To this end, a two-day differential fear conditioning study was conducted in 20 cerebellar patients and 21 control subjects using a 7-Tesla (7T) MRI system. Fear acquisition and extinction training were performed on day 1, followed by recall on day 2. Cerebellar patients learned to differentiate between the CS+ and CS-. Acquisition and consolidation of learned fear, however, was slowed. Additionally, extinction learning appeared to be delayed. The fMRI signal was reduced in relation to the prediction of the aversive stimulus and altered in relation to its unexpected omission. Similarly, mice with cerebellar cortical degeneration (spinocerebellar ataxia type 6, SCA6) were able to learn the fear association, but retrieval of fear memory was reduced. In sum, cerebellar cortical degeneration led to mild abnormalities in the acquisition of learned fear responses in both humans and mice, particularly manifesting post-acquisition training. Future research is warranted to investigate the basis of altered fMRI signals related to fear learning.Significance StatementHumans and mice with pure cerebellar cortical degeneration showed deficits in the acquisition of learned fear, but abnormalities were mild. Given that cerebellar fMRI signals predominantly reflect mossy fiber input, changes in cerebellar activations suggest that input signals related to the prediction and unexpected omission of the aversive US are altered in patients with cerebellar cortical degeneration. Importantly, these differences cannot be explained by cerebellar atrophy because cerebellar fMRI signal related to the presentation of the aversive stimulus (US) was not significantly different from controls. Future research is warranted to study the exact nature of cerebellar input signals related to fear learning.