Elucidating an Affective Pain Circuit that Creates a Threat Memory

Abstract

SUMMARY Animals learn to avoid harmful situations by associating a neutral stimulus with a painful one, resulting in a stable threat memory. In mammals, this form of learning requires the amygdala. Although pain is the main driver of aversive learning, the mechanism that transmits pain signals to the amygdala is not well resolved. Here we show that neurons expressing calcitonin gene-related peptide (CGRP) in the parabrachial nucleus are critical for relaying pain signals to the central nucleus of amygdala, and that this pathway may transduce the affective motivational aspects of pain. Genetic silencing of CGRP neurons blocks pain responses and memory formation, while their optogenetic stimulation produces defensive responses and a threat memory. The pain-recipient neurons in the central amygdala expressing CGRP receptors are also critical for establishing a threat memory. The identification of the neural circuit conveying affective pain signals may be pertinent for treating pain conditions with psychiatric comorbidities.

A tale of two circuits: CCK NTS neuron stimulation controls appetite and induces opposing motivational states by projections to distinct brain regions

“…A two-way ANOVA detected a significant interaction of group and treatment ( F (1,14) = 8.077, p = 0.0131). This result is consistent with the direct, excitatory connection between CCK NTS neurons and CGRP neurons within the external lateral PBN found in previous work (Roman et al 2016), because photostimulating CGRP neurons has been shown to induce aversive behaviors such as freezing (Han et al, 2015) and CTA (Carter et al, 2015). Although an aversion was elicited in the RTPP test and Fos was induced in the PBN (Fig.…”

“…Following a meal, CCK NTS neurons become activated and relay visceral input from the vagus to brain regions known to mediate changes in feeding (Rinaman, 2010). Interestingly, the same brain regions that are important for feeding behavior have also been shown to influence behavioral responses to emotionally relevant stimuli associated with fear, stress, and pain (Bernard and Besson, 1990; Bester et al, 2000; Casada and Dafny, 1992; Chagra et al, 2011; Han et al, 2015; LeDoux, 2000). Two such regions receiving especially dense innervation from CCK NTS neurons are the PBN and PVH.…”

Selective neuronal silencing using synthetic botulinum molecules alleviates chronic pain in mice

“…Information related to injury reaches the brain largely through NK1R-positive projection neurons of the superficial dorsal horn that terminate massively in the parabrachial area of the brainstem and to a lesser extent within the thalamus (35,51). The parabrachial area is crucial for supplying information to forebrain areas that generate the affective-motivational component of pain (52,53) whereas thalamic afferents terminate within cortical areas concerned with both pain discrimination and affect (51). Forebrain activation can in turn regulate dorsal horn sensitivity by activating descending controls from the brainstem to the spinal cord (3,12,54).…”

The neural circuits of innate fear: detection, integration, action, and memorization

“…This amygdalar sub-region receives nociceptive signals from the parabrachial nucleus (PB, Bernard and Besson 1990), responds to nociceptive stimuli (Neugebauer and Li 2002) and its inactivation impairs fear learning (Wilensky et al 2006). Moreover, recent studies have nicely identified a putative circuit mediating CS -US associative learning centered in the CEA, composed of spinoparabrachial afferents conveying the affective component of nociceptive information to the CEA (Han et al 2015;Sato et al 2015;Sugimura et al 2016). Taken together this evidence suggests that both the BLA complex and the CEA contribute to footshock fear memory encoding; however, the interplay within these two structures in the processing of footshock fear learning remains poorly understood.…”

“…In particular, a recent study has shown that the CEA directly integrates US nociceptive signals from the parabrachial nucleus and CS stimuli deriving from the auditory thalamus via the LA (Han et al 2015).…”