Generalization and discrimination of inhibitory avoidance differentially engage anterior and posterior retrosplenial subregions.

Introduction: In a variety of behavioral procedures animals will show selective fear responding in shock-associated contexts, but not in other contexts. However, several factors can lead to generalized fear behavior, where responding is no longer constrained to the conditioning context and will transfer to novel contexts. Methods: Here, we assessed memory generalization using an inhibitory avoidance paradigm to determine if generalized avoidance behavior engages the retrosplenial cortex (RSC). Male and female Long Evans rats received inhibitory avoidance training prior to testing in the same context or a shifted context in two distinct rooms; one room that had fluorescent lighting (Light) and one that had red LED lighting (Dark). Results: We found that animals tested in a light context maintained context-specificity; animals tested in the same context as training showed longer latencies to cross and animals tested in the shifted context showed shorter latencies to cross. However, animals tested in the dark generalized their avoidance behavior; animals tested in the same context and animals tested in the shifted context showed similarly-high latencies to cross. We next examined expression of the immediate early gene zif268 and perineuronal nets (PNNs) following testing and found that while activity in the basolateral amygdala corresponded with overall levels of avoidance behaviors, anterior RSC (aRSC) activity corresponded with learned avoidance generally, but posterior RSC (pRSC) activity seemed to correspond with generalized memory. PNN reduction in the RSC was associated with memory formation and retrieval, suggesting a role for PNNs in synaptic plasticity. Further, PNNs did not reduce in the RSC in animals who showed a generalized avoidance behavior, in line with their hypothesized role in memory consolidation. Discussion: These findings suggest that there is differential engagement of retrosplenial subregions along the rostrocaudal axis to generalization and discrimination.

Fear extinction is impaired in aged rats.

Normal aging is accompanied by broad loss of cognitive function in humans and rodents, including declines in cognitive flexibility. In extinction, a conditional stimulus (CS) that was previously paired with a footshock is presented alone. This procedure reliably reduces conditional freezing behavior in young adult rats. Here, we aimed to investigate how normal aging affects extinction learning. Using young (3 months) and aged (20 months) male and female Long Evans rats, we compared extinction (using 20 CS-alone presentations) to a no extinction control (equal exposure to the conditioning chamber without CS presentations) following delay fear conditioning. We found that young animals in the extinction group showed a decrease in freezing following extinction; aged animals did not. We next examined changes in neural activity using expression of the immediate early gene zif268. In young animals, extinction corresponded with decreased expression of zif268 in the basolateral amygdala and anterior retrosplenial cortex; this was not observed in aged animals. Further, aged animals showed increased zif268 expression in each region examined, suggesting that dysfunction in neural activity precedes cognitive deficits. These results demonstrate that aging impacts both extinction learning and neural activity.

Fear Reduced Through Unconditional Stimulus Deflation Is Behaviorally Distinct From Extinction and Differentially Engages the Amygdala.

Background: Context fear memory can be reliably reduced by subsequent pairings of that context with a weaker shock. This procedure shares similarities with extinction learning: both involve extended time in the conditioning chamber following training and reduce context-elicited fear. Unlike extinction, this weak-shock exposure has been hypothesized to engage reconsolidation-like processes that weaken the original memory. Methods: We directly compared the weak-shock procedure with extinction using male and female Long Evans rats. Results: Both repeated weak-shock exposure and extinction resulted in decreased context freezing relative to animals that received context fear conditioning but no subsequent context exposure. Conditioning with the weak shock was not enough to form a persistent context-shock association on its own, suggesting that the weak-shock procedure does not create a new memory. Weak-shock exposure in a new context can still reduce freezing elicited by the training context, suggesting that it reduces responding through a different process than extinction, which does not transcend context. Finally, reduced fear behavior produced through both extinction and weak-shock exposure was mirrored by reduced zif268 expression in the basolateral amygdala. However, only the weak-shock procedure resulted in changes in lysine-48 polyubiquitin tagging in the synapse of the basolateral amygdala, suggesting that this procedure produced long-lasting changes in synaptic function within the basolateral amygdala. Conclusions: These results suggest that the weak-shock procedure does not rely on the creation of a new inhibitory memory, as in extinction, and instead may alter the original representation of the shock to reduce fear responding.