ErbB4 signaling in the prelimbic cortex regulates fear expression

Abstract

Many psychiatric diseases such as post-traumatic stress disorder (PTSD) are characterized by abnormal processing of emotional stimuli particularly fear. The medial prefrontal cortex (mPFC) is critically involved in fear expression. However, the molecular mechanisms underlying this process are largely unknown. Neuregulin-1 (NRG1) reportedly regulates pyramidal neuronal activity via ErbB4 receptors, which are abundant in parvalbumin (PV)-expressing interneurons in the PFC. In this study, we aimed to determine how NRG1/ErbB4 signaling in the mPFC modulates fear expression and found that tone-cued fear conditioning increased NRG1 expression in the mPFC. Tone-cued fear conditioning was inhibited following neutralization of endogenous NRG1 and specific inhibition or genetic ablation of ErbB4 in the prelimbic (PL) cortex but not in the infralimbic cortex. Furthermore, ErbB4 deletion specifically in PV neurons impaired tone-cued fear conditioning. Notably, overexpression of ErbB4 in the PL cortex is sufficient to reverse impaired fear conditioning in PV-Cre;ErbB4−/− mice. Together, these findings identify a previously unknown signaling pathway in the PL cortex that regulates fear expression. As both NRG1 and ErbB4 are risk genes for schizophrenia, our study may shed new light on the pathophysiology of this disorder and help to improve treatments for psychiatric disorders such as PTSD.

Region- and time-dependent gene regulation in the amygdala and anterior cingulate cortex of a PTSD-like mouse model

“…In addition, downstream signaling components, such as MAPK, cAMP and calcium mediated signaling molecules are involved in synaptic plasticity [15]. The alteration in several neuromodulatory systems such as endocannabinoid signaling, Wnt signaling and ErbB signaling can affect fear memory [16] and anxiety-like behavior by synaptic remodeling in medial prefrontal cortex [17] and AMY [18, 19].…”

Changed Patterns of Genomic Variation Following Recent Domestication: Selection Sweeps in Farmed Atlantic Salmon

“…A fourth behavioral gene, erbb4, was identified on Ssa21 that has evidence of selection in domestic cattle (Qanbari et al, 2014). Expression changes in errb4 in mice regulated fear and mania-like behaviors (hyperactivity, reduced anxiety and depression and increased sucrose preference) (Chen et al, 2017;Cao et al, 2018). Each of these findings suggest behavioral adaptations to the farmed environment, including altered response to threats, and differences in aggression and feeding behavior may be an early consequence of domesticating Atlantic salmon (Huntingford, 2004;Glover et al, 2017).…”

Acute EPA-induced learning and memory impairment in mice is prevented by DHA

“…Contextual fear conditioning test. The contextual fear conditioning test was conducted as reported previously [74][75][76] . Mice were first habituated to the behavioral room, and were then allowed to freely explore the apparatus (MED-VFC-NIR-M; Med Associates) for 3 min.…”