Accumulating evidence indicates that the cerebellum is critically involved in modulating non-motor behaviors, including cognition and emotional processing. Both imaging and lesion studies strongly suggest that the cerebellum is a component of the fear memory network. Given the well-established role of the cerebellum in adaptive prediction of movement and cognition, the cerebellum is likely to be engaged in the prediction of learned threats. The cerebellum is activated by fear learning, and fear learning induces changes at multiple synaptic sites in the cerebellum. Furthermore, recent technological advances have enabled the investigation of causal relationships between intra- and extra-cerebellar circuits and fear-related behaviors such as freezing. Here, we review the literature on the mechanisms underlying the modulation of cerebellar circuits in a mammalian brain by fear conditioning at the cellular and synaptic levels to elucidate the contributions of distinct cerebellar structures to fear learning and memory. This knowledge may facilitate a deeper understanding and development of more effective treatment strategies for fear-related affective disorders including post-traumatic stress or anxiety related disorders.

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In tauopathic conditions, such as Alzheimer's disease (AD), highly soluble and natively unfolded tau polymerizes into an insoluble filament; however, the mechanistic details of this process are not clear. In AD brains, only a small segment of tau forms -helix-stacked protofilaments, while its flanking regions form disordered fuzzy coats. Here, we demonstrated that the tau AD nucleation core (tau-AC) sufficiently induced self-aggregation and recruited full-length tau to filaments. Unexpectedly, phospho-mimetic forms of tau-AC (at Ser324 or Ser356) showed markedly reduced aggregation and seeding propensities. Biophysical analysis revealed that the N-terminus of tau-AC facilitated the fibrillization kinetics, while its phosphorylation induced conformation changes, sterically shielding the nucleation motif. Tau-AC oligomers were efficiently internalized into cells via endocytosis and induced endogenous tau aggregation. In primary hippocampal neurons, tau-AC impaired axon initial segment plasticity upon chronic depolarization and was mislocalized in the somatodendritic compartments. Furthermore, we observed significantly impaired memory retrieval in mice intrahippocampally injected with tau-AC fibrils, which corresponded to the neuropathological staining and neuronal loss in the brain. These findings identified tau-AC species as a key neuropathological driver in AD, suggesting novel strategies for therapeutic intervention.

In tauopathic conditions, such as Alzheimer's disease (AD), highly soluble and natively unfolded tau polymerizes into an insoluble filament; however, the mechanistic details of this process are not clear. In AD brains, only a small segment of tau forms -helix-stacked protofilaments, while its flanking regions form disordered fuzzy coats. Here, we demonstrated that the tau AD nucleation core (tau-AC) sufficiently induced self-aggregation and recruited full-length tau to filaments. Unexpectedly, phospho-mimetic forms of tau-AC (at Ser324 or Ser356) showed markedly reduced aggregation and seeding propensities. Biophysical analysis revealed that the N-terminus of tau-AC facilitated the fibrillization kinetics, while its phosphorylation induced conformation changes, sterically shielding the nucleation motif. Tau-AC oligomers were efficiently internalized into cells via endocytosis and induced endogenous tau aggregation. In primary hippocampal neurons, tau-AC impaired axon initial segment plasticity upon chronic depolarization and was mislocalized in the somatodendritic compartments. Furthermore, we observed significantly impaired memory retrieval in mice intrahippocampally injected with tau-AC fibrils, which corresponded to the neuropathological staining and neuronal loss in the brain. These findings identified tau-AC species as a key neuropathological driver in AD, suggesting novel strategies for therapeutic intervention.

No abstract