Prefrontal circuits signaling active avoidance retrieval and extinction

Abstract

Objective Neurons in PL and IL project densely to two areas implicated in active avoidance: the basolateral amygdala (BLA) and the ventral striatum (VS). We therefore combined c-Fos immunohistochemistry with retrograde tracers to characterize signaling in platform-mediated active avoidance. Methods Male rats were infused with retrograde tracers (CTB, FB) into basolateral amygdala and ventral striatum and conditioned to avoid tone-signaled footshocks by stepping onto a nearby platform. In a subsequent test session, rats received either 2 unreinforced tones (avoidance retrieval) or 15 unreinforced tones (avoidance extinction) followed by analysis of c-Fos combined with fluorescent imaging of retrograde tracers. Results Retrieval of avoidance did not activate IL neurons, but did activate PL neurons projecting to BLA, and to a lesser extent VS. Extinction of avoidance activated IL neurons projecting to both BLA and VS, as well as PL neurons projecting to VS. Conclusions Our observation that avoidance retrieval is signaled by PL projections to BLA suggests that PL may modulate VS indirectly via BLA, and agrees with other findings implicating BLA in active avoidance. Less expected was the signaling of extinction via PL inputs to VS, which may converge with IL inputs to VS to inhibit expression of avoidance.

Alteration of BDNF in the medial prefrontal cortex and the ventral hippocampus impairs extinction of avoidance

“…It is unlikely that the effect of anti-BDNF in PL is due to an unintended diffusion into neighboring IL, because infusing the same volume of anti-BDNF into PL or IL had differing effects on extinction of conditioned freezing [14]. Consistent with our PL findings, it was recently reported that pre-training lesions of PL impair extinction of lever-press active avoidance [43], and extinction of avoidance in our task activates PL neurons projecting to ventral striatum (Martínez-Rivera et al, 2018 in press) [44].…”

Functional and Dysfunctional Neuroplasticity in Learning to Cope with Stress

“…Active avoidance training increases expression of c-Fos in the shell substructure of the nucleus accumbens (NAcSh) [28], expression of the early growth response protein 1 (Egr1) in the orbitofrontal and dorsal anterior cingulate cortex (CG1), and in the hippocampal CA1 region [29]. It also fosters expression of the activity-regulated cytoskeleton-associated protein (Arc/Arg3.1) in the dentate gyrus (DG) of the hippocampus [29].…”

“…It also fosters expression of the activity-regulated cytoskeleton-associated protein (Arc/Arg3.1) in the dentate gyrus (DG) of the hippocampus [29]. Retrieval of the acquired avoidance enhances expression of Egr1 in the DG and increases c-Fos expression in neurons of the prefrontal cortex (pFC) projecting toward the basolateral amygdala (BLA) and the ventral striatum (VS) [28,29]. Extinction of active avoidance increases c-Fos expression in neurons of the pFC projecting toward the BLA and the VS, as well as brain-derived neurotrophic factor (BDNF) expression in the ventral hippocampus (vHPC) [28,30].…”

“…Retrieval of the acquired avoidance enhances expression of Egr1 in the DG and increases c-Fos expression in neurons of the prefrontal cortex (pFC) projecting toward the basolateral amygdala (BLA) and the ventral striatum (VS) [28,29]. Extinction of active avoidance increases c-Fos expression in neurons of the pFC projecting toward the BLA and the VS, as well as brain-derived neurotrophic factor (BDNF) expression in the ventral hippocampus (vHPC) [28,30]. Finally, rats showing the highest density of Arc/Arg3.1-expressing neurons in the CG1 also show the highest number of avoidances and the fastest escape latencies supporting the primary role of cortical plasticity in the acquisition of active avoidance [29]; either silencing neural activity in the NAcSh or disconnecting the basal amygdala (BA) and the NAcSh disrupts acquired avoidance indicating the need for functional connectivity between the BA and the NAcSh for the retrieval of the active avoidance memory [31], and reducing BDNF production in vHPC neurons impairs the recall of avoidance extinction indicating a role of vHPC plasticity in the long-term memory of extinction [30].…”

“…Moreover, temporary inactivation of either the dorsal hippocampus or of the infralimbic (IL) component of the mpFC immediately after the first FST experience reduces retrieval of immobility 24 h later indicating the involvement of these brain areas in the consolidation of the acquired passive coping [34,50]. An active IL component is selectively required for the extinction of the Pavlovian associative and of goal-directed learning, including active avoidance [28,51]. Thus, the role played by the IL component in the stabilization of passive coping as a long-term memory supports a homology between extinction learning and acquisition of a passive coping strategy [34,50] in agreement with previous findings [52].…”