Olfactory threat extinction in the piriform cortex: An age-dependent employment of NMDA receptor-dependent long-term depression

Abstract

Extinction of threat memory is a measure of behavioral flexibility. In the absence of additional reinforcement, the extinction of learned behaviors allows animals and humans to adapt to their changing environment. Extinction mechanisms and their therapeutic implications for maladaptive learning have been extensively studied. However, how aging affects extinction learning is much less understood. Using a rat model of olfactory threat extinction, we show that the extinction of olfactory threat memory is impaired in aged Sprague-Darley rats. Following extinction training, long-term depression (LTD) in the piriform cortex (PC) was inducible ex vivo in aged rats and was NMDA receptor (NMDAR)-independent. On the other hand, adult rats acquired successful olfactory threat extinction, and LTD was not inducible following extinction training. Neuronal cFos activation in the posterior PC correlated with learning and extinction performance in rats. NMDAR blockade either systemically or locally in the PC during extinction training prevented successful extinction in adult rats, following which NMDAR-dependent LTD became inducible ex vivo. This suggests that extinction learning employs NMDAR-dependent LTD mechanisms in the PC of adult rats, thus occluding further LTD induction ex vivo. The rescue of olfactory threat extinction in aged rats by D-cycloserine, a partial NMDAR agonist, suggests that the impairment in olfactory threat extinction of aged animals may relate to NMDAR hypofunctioning and a lack of NMDAR-dependent LTD. These findings are consistent with an age-related switch from NMDAR-dependent to NMDAR-independent LTD in the PC. Optimizing NMDAR function in sensory cortices may improve learning and flexible behavior in the aged population.

Correlational patterns of neuronal activation and epigenetic marks in the basolateral amygdala and piriform cortex following olfactory threat conditioning and extinction in rats

“…Aged rats [ F (2,14) = 15.46, p < 0.001] showed successful olfactory threat conditioning but impaired extinction learning ( Figures 2A, B ). Previous research suggests that impaired olfactory threat learning in aged rats is due to the lack of NMDAR-dependent LTD in the PC ( Sepahvand et al, 2023a ). cFos expression in the BLA showed a trend.…”

“…NMDAR antagonist MK-801 (0.05 mg/kg, Tocris) solution was freshly prepared on testing days by dissolution in sterile 0.9% saline ( Sepahvand et al, 2023a ). The drug was subcutaneously administered to the rats immediately after the recall test of odor threat conditioning, and 30 min prior to each extinction session to test the effect of NMDAR blockade on threat extinction.…”

“…Emergent research suggests that sensory cortices are critically involved in threat conditioning ( Sacco and Sacchetti, 2010 ; Hegoburu et al, 2014 ; Cambiaghi et al, 2016b ; Meissner-Bernard et al, 2019 ; East et al, 2021 ; Mouly et al, 2022 ; You et al, 2022 ) and extinction of threat memory ( Sepahvand et al, 2023a ). Particularly, the olfactory piriform cortex (PC) has extensive mutual connections with the BLA, and has been suggested to be a more permanent repertoire for olfactory threat memory storage ( Li and Wilson, 2023 ; Sepahvand et al, 2023b ).…”

“…Synchronized neuronal activity in the PC and BLA underlies olfactory threat memory formation and ensures precision of encoding ( East et al, 2021 ). Recently, we have reported that the posterior PC (pPC) critically mediates olfactory threat extinction through NMDAR-dependent long-term depression (LTD) ( Sepahvand et al, 2023a ). Aging-associated impairment in olfactory threat extinction is related to the hypofunction of NMDARs in the PC ( Sepahvand et al, 2023a ).…”

“…Recently, we have reported that the posterior PC (pPC) critically mediates olfactory threat extinction through NMDAR-dependent long-term depression (LTD) ( Sepahvand et al, 2023a ). Aging-associated impairment in olfactory threat extinction is related to the hypofunction of NMDARs in the PC ( Sepahvand et al, 2023a ). However, it is not known whether and how the BLA and PC coordinate in olfactory extinction learning, and how their coordination is affected by aging.…”