Ablation of STAT3 in Purkinje Cells Reorganizes Cerebellar Synaptic Plasticity in Long-Term Fear Memory Network

Abstract

Emotional memory processing, such as fear memory, engages a large neuronal network of brain regions including the cerebellum. However, the molecular and cellular mechanisms of the cerebellar cortex modulating the fear memory network is largely unknown. Here, we illustrate a novel mechanism by which synaptic signaling in cerebellar Purkinje cells (PCs) via STAT3 regulates long-term fear memory. Firstly, we generated PC-specific STAT3 knockout (STAT3PKO) mice. Transcriptome analyses revealed that STAT3 deletion results in transcriptional changes that lead to an increase in the expression of glutamate receptors. The amplitude of AMPA receptor-mediated excitatory postsynaptic currents at parallel fiber to PC synapses was larger in STAT3PKO mice than in wild-type littermates. Conditioning at the parallel fiber induced long-term depression of parallel fiber-PC synapses in STAT3PKO mice while the same manipulation induced long-term potentiation in wild-type littermates. Interestingly, STAT3PKO mice showed an aberrantly enhanced long-term fear memory. Neuronal activity in fear-related regions increased in fear-conditioned STAT3PKO mice. Our data suggest that STAT3-dependent molecular regulation in PCs is indispensable for proper expression of fear memory processing.

Evaluating sickness-induced anxiety versus lethargy at the behavioral and neuronal activity level

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A rare variant in D-amino acid oxidase implicates NMDA receptor signaling and cerebellar gene networks in risk for bipolar disorder

“…Emotional learning in the cerebellum, as well as social behavior and cognition, is mediated by specialized circuits in the cerebellar vermis (64). In fear conditioning paradigms, repeated foot shock resulted in long-term potentiation of parallel fiber synapses in the vermis, and this effect was attenuated in GluD2 knockout mice (65,66). The aversive stimulus in fear conditioning is very similar to foot shock in the learned helplessness test.…”

Novel cerebello-amygdala connections provide missing link between cerebellum and limbic system

“…Consistent with this, deficits in cerebellar function are associated with impaired emotional attention and perception, as seen in depression, anxiety, schizophrenia and post-traumatic stress disorder 19–22 , as well as cognitive and emotional disturbances collectively known as cerebellar cognitive affective syndrome 23 . Animal models have recapitulated some of these findings, with selective mutations, damage or inactivation of the rodent cerebellum resulting in altered acquisition or extinction of learned defensive responses, and impaired social and goal-directed behavior, without motor deficits 24–33 .…”

“…Animal models have recapitulated some of these findings, with selective mutations, damage or inactivation of the rodent cerebellum resulting in altered acquisition or extinction of learned defensive responses, and impaired social and goal-directed behavior, without motor deficits [24][25][26][27][28][29][30][31][32][33] .…”