Hunger Promotes Fear Extinction by Activation of an Amygdala Microcircuit

Abstract

Emotions control evolutionarily conserved behavior that is central to survival in a natural environment. Imbalance within emotional circuitries, however, may result in malfunction and manifestation of anxiety disorders. Thus, a better understanding of emotional processes and in particular the interaction of the networks involved is of considerable clinical relevance. Although neurobiological substrates of emotionally controlled circuitries are increasingly evident their mutual influences are not. To investigate interactions between hunger and fear, we performed Pavlovian fear conditioning in fasted wildtype mice and in mice with genetic modification of a feeding-related gene. Furthermore we analyzed in these mice the electrophysiological microcircuits underlying fear extinction. Short-term fasting before fear acquisition specifically impaired long-term fear memory, while fasting before fear extinction facilitated extinction learning. Furthermore, genetic deletion of the Y4 receptor reduced appetite and completely impaired fear extinction, a phenomenon that was rescued by fasting. A marked increase in feed-forward inhibition between the basolateral and central amygdala has been proposed as a synaptic correlate of fear extinction and involves activation of the medial intercalated cells. This form of plasticity was lost in Y4KO mice. Fasting before extinction learning, however, resulted in specific activation of the medial intercalated neurons and re-established the enhancement of feed-forward inhibition in this amygdala microcircuit of Y4KO mice. Hence, consolidation of fear and extinction memories is differentially regulated by hunger suggesting that fasting and modification of feeding-related genes could augment the effectiveness of exposure therapy and provide novel drug-targets for treatment of anxiety disorders.

Optogenetic activation of the central amygdala generates addiction‐like preference for reward

“…In addition, given that rats eventually shifted their behaviour when confronted with a high level of shock, the first explanation that CeA activation heightens motivation in such a way that it overpowers aversive consequences appears more likely. This interpretation is further supported by a study showing that hunger‐induced activation of a CeA‐BLA microcircuit promotes extinction of fear responses, suggesting that intense motivation driven by the CeA may override existing fear of aversive consequences (Verma et al., ).…”

Pancreatic polypeptide and its central Y4 receptors are essential for cued fear extinction and permanent suppression of fear

“…Recent evidence suggests that central NPY inhibits the expression and promotes the extinction of learned fear (Gutman et al , ; Fendt et al , ; Verma et al , ). Furthermore, we demonstrated that short‐term fasting impairs fear consolidation but facilitates fear extinction by increasing feedforward inhibition in an amygdala microcircuit (Verma et al , ). This feedforward inhibition was reduced in Y4KO mice resulting in impaired fear extinction.…”

Posttraumatic stress disorder: A metabolic disorder in disguise?

“…For example, fasting prior to fear conditioning impairs fear acquisition, but fasting prior to extinction improves extinction learning (Verma et al, 2015). NPY may play a critical role as it modulates both NE and CRH activity, resulting in the attenuation of anxiety-like behavior and HPA axis activity (Hastings et al, 2004; Rasmusson et al, 2000; Sah and Geracioti, 2013).…”