Cerebellar modulation of synaptic input to freezing-related neurons in the periaqueductal gray.

Christopher E Vaaga,Indira M Raman,Spencer T Brown

doi:10.7554/elife.54302

Abstract

Innate defensive behaviors, such as freezing, are adaptive for avoiding predation. Freezing-related midbrain regions project to the cerebellum, which is known to regulate rapid sensorimotor integration, raising the question of cerebellar contributions to freezing. Here, we find that neurons of the mouse medial (fastigial) cerebellar nuclei (mCbN), which fire spontaneously with wide dynamic ranges, send glutamatergic projections to the ventrolateral periaqueductal gray (vlPAG), which contains diverse cell types. In freely moving mice, optogenetically stimulating glutamatergic vlPAG neurons that express Chx10 reliably induces freezing. In vlPAG slices, mCbN terminals excite ~20% of neurons positive for Chx10 or GAD2 and ~70% of dopaminergic TH-positive neurons. Stimulating either mCbN afferents or TH neurons augments IPSCs and suppresses EPSCs in Chx10 neurons by activating postsynaptic D2 receptors. The results suggest that mCbN activity regulates dopaminergic modulation of the vlPAG, favoring inhibition of Chx10 neurons. Suppression of cerebellar output may therefore facilitate freezing.

Highlights

To avoid predation, animals must rapidly recognize and respond to threats
Previous tracing studies have demonstrated that the medial (fastigial) cerebellar nuclei (mCbN) projects to the ventrolateral column of the periaqueductal gray (vlPAG) (Gonzalo-Ruiz et al, 1990; Teune et al, 2000), and electrical stimulation of the mCbN elicits short latency field potentials in the vlPAG (Whiteside and Snider, 1953), but this projection has historically been thought to contribute to oculomotor function
We find that mCbN afferents can evoke EPSCs in glutamatergic Chx10-expressing neurons, whose activity is shown to be sufficient to generate freezing in the absence of threat in freely moving mice, as well as in GAD2 neurons, which are expected to provide local inhibition

Summary

Introduction

Animals must rapidly recognize and respond to threats Such defensive behaviors rely on innate neural circuitry both to identify the threatening stimulus within the context of the local environment and to engage one of multiple defensive behaviors, such as freezing or fleeing (Blanchard and Blanchard, 1972; De Franceschi et al, 2016; Fendt and Fanselow, 1999; LeDoux, 2000; Yilmaz and Meister, 2013), depending on the imminence of the threat (Perusini and Fanselow, 2015). For example, depends on the ventrolateral column of the periaqueductal gray (vlPAG), which contains glutamatergic neurons whose activation elicits freezing and whose inactivation blocks non-associative, ‘innate’ freezing to intrinsically threatening stimuli (Tovote et al, 2016). Remaining questions are how neurons of the vlPAG integrate synaptic inputs, whether those inputs might be subject to short-term neuromodulation, and, if so, where such modulation might arise

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Results

Conclusion