Peptidergic modulation of fear responses by the Edinger-Westphal nucleus

Abstract

Many neuronal populations that release fast-acting excitatory and inhibitory neurotransmitters in the brain also contain slower acting neuropeptides. These facultative peptidergic cell types are common, but it remains uncertain whether obligate peptidergic neurons exist. Our fluorescence in situ hybridization, genetically-targeted electron microscopy, and electrophysiological characterization data strongly suggest that neurons of the non-cholinergic, centrally-projecting Edinger-Westphal nucleus in mice are fundamentally obligately peptidergic. We further show, using fiber photometry, monosynaptic retrograde tracing, anterograde projection mapping, and a battery of behavioral assays, that this peptidergic population both promotes fear responses and analgesia and activates in response to loss of motor control and pain. Together, these findings elucidate an integrative, ethologically relevant function for the Edinger-Westphal nucleus and functionally align the nucleus with the periaqueductal gray, where it resides. This work advances our understanding of the peptidergic modulation of fear and provides a framework for future investigations of putative obligate peptidergic systems.

Edinger-Westphal peptidergic neurons enable maternal preparatory nesting

“…Injection of tracers showed that these midline neurons project to many different brain regions, both rostrally and caudally, and constitute what is known as the “centrally projecting EW” (EWcp), distinct from the cholinergic peripherally projecting neurons ( Dos Santos Júnior et al., 2015 ; Kozicz et al., 2011 ). Recently, behavioral studies have shown that the activity of murine EWcp neurons increases arousal during tasks involving conditioning ( Lovett-Barron et al., 2017 ), memorization ( Li et al., 2018 ), or fear modulation ( Priest et al., 2021 ). Moreover, neurons of this region control the transitions between sleep phases ( Zhang et al., 2019 ).…”

Identifying long-range synaptic inputs using genetically encoded labels and volume electron microscopy

“…The identity of this second target population is presently unknown. Neurons that use peptidergic neurotransmission and do not co-release glutamate or GABA have recently been described in the Edinger-Westphal nucleus medial and ventral to the PAG 58 whose CART + neurons were shown to modulate fear responses in rodents 58 . Neurons releasing peptidergic neuromodulators have been described in dPAG 59 , including a population that releases enkephalins 60 .…”

Identifying Long-range Synaptic Inputs Using Genetically Encoded Labels and Volume Electron Microscopy

“…Neurons that use peptidergic neurotransmission and do not co-release glutamate or GABA have recently been described in the Edinger-Westphal nucleus medial and ventral to the PAG 39 whose CART+ neurons were shown to modulate fear responses in rodents 39 . Neurons releasing peptidergic neuromodulators have been described in dPAG 40 , including a population that releases enkephalins 41 .…”