Compensatory Contextual Fear Memory Pathways Develop in the Infralimbic Cortex within 3 Days after the First Test in the Absence of the Dorsal Hippocampus

Abstract

The dorsal hippocampus (DH) is primarily involved in the formation of contextual fear-conditioned (CxFC) memory. However, CxFC memory can be formed even in the absence of the DH. In addition to the DH, the infralimbic cortex (IL), a sub-region of the medial prefrontal cortex (mPFC), also plays an important role in the consolidation of CxFC memory. However, role of IL in the development of compensatory CxFC memory is not known. Here, we have examined (a) the development of the compensatory circuitry of CxFC memory within 3 days after the first test in the absence of the DH and (b) the role of IL in the induction of compensatory CxFC memory in the absence of the DH. The DH-lesioned rats re-trained for CxFC 1 day after the first testing exhibited significantly less freezing compared to the control group. However, the DH-lesioned rats, re-trained for CxFC 3 days after the first testing, showed a robust freezing response. It suggests that the fully functional compensatory circuitry of contextual fear memory develops after multiple training separated by 3 days. Furthermore, we observed that reversible inactivation of the IL of the DH-lesioned rats during the first training waned the formation of compensatory CxFC. It suggests that (a) the IL receives contextual fear memory information during the first trial in the absence of the DH and (b) perturbation in fear memory information encoding in the IL during the first trial impairs the development of the compensatory network in the absence of the DH.

Sleep, NMDA Receptor Subunits, and the Compensatory Pathway: Understanding Contextual Fear Conditioning in the Absence of the Dorsal Hippocampus

“…We have previously established that a three-day time interval between the two conditioning trials is essentially required for the compensatory circuitry of contextual fear to become functional after DH loss (Kant and Jha, 2019b, 2023). To address the question of whether sleep plays any role in the induction of compensatory circuitry of contextual fear, DH-lesioned animals were sleep deprived during three days or 72 h intervals (54 h of SD and 18 h of recovery sleep) between the 1 st and 2 nd CxFC trial.…”

“…We investigated the effect of sleep on the induction of compensatory pathways for contextual fear memory in the absence of the DH. We designed the experiments based on our previously established protocol (Kant and Jha, 2023) where a compensatory contextual fear memory is formed in DH-lesioned animals through two contextual fear conditioning (CxFC) sessions separated by a 3-day interval (72-h). On day 1, baseline freezing was recorded in surgically prepared animals, after 2 d of habituation in the neutral behavioral chamber.…”

“…However, studies suggest alternative neural circuits can compensate for the DH loss. Additional training trials can gradually develop contextual fear within these alternative circuits, indicating their remarkable adaptive potential (Coelho et al ., 2018; Cowansage et al ., 2014; Kant and Jha, 2019a, 2023; M. S. Fanselow, 2010; Poulos et al ., 2010; Yu et al ., 2021; Zelikowsky et al ., 2013).…”

“…In the absence of the DH, the micro-circuitries of the medial prefrontal cortex (mPFC), particularly the infralimbic (IL) and prelimbic (PL) cortices, facilitate contextual fear conditioning (Zelikowsky et al ., 2013). Furthermore, recent findings indicate that compensatory contextual fear memory can develop following multiple conditioning trials separated by three days, even in the absence of the DH (Kant and Jha, 2019b, 2023). Notably, the input of contextual fear memory to the IL during the initial conditioning session is crucial for inducing and progressing the compensatory network in the absence of DH (Kant and Jha, 2023).…”

“…Furthermore, recent findings indicate that compensatory contextual fear memory can develop following multiple conditioning trials separated by three days, even in the absence of the DH (Kant and Jha, 2019b, 2023). Notably, the input of contextual fear memory to the IL during the initial conditioning session is crucial for inducing and progressing the compensatory network in the absence of DH (Kant and Jha, 2023). However, beyond timing and extensive training, other factors influencing compensatory contextual fear memory processes in alternative brain circuitry remain to be explored.…”