Active avoidance requires inhibitory signaling in the rodent prelimbic prefrontal cortex

Abstract

Much is known about the neural circuits of conditioned fear and its relevance to understanding anxiety disorders, but less is known about other anxiety-related behaviors such as active avoidance. Using a tone-signaled, platform-mediated avoidance task, we observed that pharmacological inactivation of the prelimbic prefrontal cortex (PL) delayed avoidance. Surprisingly, optogenetic silencing of PL glutamatergic neurons did not delay avoidance. Consistent with this, inhibitory but not excitatory responses of rostral PL neurons were associated with avoidance training. To test the importance of these inhibitory responses, we optogenetically stimulated PL neurons to counteract the tone-elicited reduction in firing rate. Photoactivation of rostral (but not caudal) PL neurons at 4 Hz impaired avoidance. These findings suggest that inhibitory responses of rostral PL neurons signal the avoidability of a potential threat and underscore the importance of designing behavioral optogenetic studies based on neuronal firing responses.

Prefrontal circuits signaling active avoidance retrieval and extinction

“…It is important to keep in mind that c-Fos levels are poor at signaling reductions in activity, and avoidance-induced reduction in PL activity could impact VS, BLA, or other targets. In support of this, we have recently observed that avoidance in this task is also associated with inhibitory responses in PL neurons (Diehl et al 2018). Thus, retrieval of avoidance memories may integrate PL within the BLA-VS circuit (Fig.…”

“…PL projects to VS (Gabbott et al 2005; Vertes 2004), and it has been suggested that this projection could mediate active avoidance (Bravo-Rivera et al 2014). However, our c-Fos data suggest that PL neurons activated by avoidance project to BLA rather than to VS. We have recently observed that retrieval of platform-mediated avoidance is correlated with excitatory responses of PL neurons at platform entry (Diehl et al 2018). Thus, PL may be in direct communication with BLA to express avoidance memories, similar to Pavlovian fear conditioning (Cho et al 2013).…”

“…What then might be the function of PL inputs to BLA? Recent findings show that pharmacological inactivation of PL delays platform entry during the 30-s tone (Diehl et al 2018), suggesting that PL outputs may facilitate avoidance when there is less urgency. It is important to keep in mind that c-Fos levels are poor at signaling reductions in activity, and avoidance-induced reduction in PL activity could impact VS, BLA, or other targets.…”

New viral‐genetic mapping uncovers an enrichment of corticotropin‐releasing hormone‐expressing neuronal inputs to the nucleus accumbens from stress‐related brain regions

“…The fundamental novel concept emerging from our studies is that several brain regions with CRH + neurons innervate the NAc. These regions (BNST, PVT, mPFC, BLA) contribute to the numerous and nuanced influences of emotional salience, including stress, on reward‐related decisions and behaviors (Diehl et al, ; Do‐Monte et al, ; Knudsen, ; Linnman et al, ; Zhu et al, ). These brain structures contribute different functional output to the overall reward circuitry and to the NAc.…”

Individual variability in behavior and functional networks predicts vulnerability using a predator scent model of PTSD

“…Stronger connectivity between the MS and PL can be linked to stronger fear in low-freezing animals, given that PL promotes fear expression and avoidance 60,61 . Also considering septal neurons are known to mediate the generation of theta oscillations 62,63 , the MS-PL connection may contribute to fear-associated theta rhythm in prefronto-amygdalo-hippocampal pathways 64 .…”