Locus coeruleus toggles reciprocal prefrontal firing to reinstate fear

Abstract

Significance Fear relapse represents a significant problem for individuals suffering from stress- and trauma-related disorders such as posttraumatic stress disorder. Here, we show that locus coeruleus norepinephrine activation produces fear relapse in rats. In addition, locus coeruleus activation inverts neuronal firing properties of the prelimbic and infralimbic cortices to drive this fear relapse. Elevated noradrenergic tone and subsequent changes in prefrontal firing properties represent a therapeutic target for combating fear relapse. The medial prefrontal cortex (mPFC) plays an essential role in regulating emotion, including inhibiting fear when danger has passed. The extinction of fear, however, is labile and a number of factors, including stress, cause extinguished fear to relapse. Here we show that fear relapse in rats limits single-unit activity among infralimbic (IL) neurons, which are critical for inhibiting fear responses, and facilitates activity in prelimbic (PL) neurons involved in fear expression. Pharmacogenetic activation of noradrenergic neurons in the locus coeruleus mimics this shift in reciprocal IL–PL spike firing, increases the expression of conditioned freezing behavior, and causes relapse of extinguished fear. Noradrenergic modulation of mPFC firing represents a mechanism for relapse and a potential target for therapeutic interventions to reduce pathological fear.