Elucidating the mechanisms of fear extinction in developing animals: a special case of NMDA receptor-independent extinction in adolescent rats

Abstract

NMDA receptors (NMDARs) are considered critical for the consolidation of extinction but recent work challenges this assumption. Namely, NMDARs are not required for extinction retention in infant rats as well as when extinction training occurs for a second time (i.e., reextinction) in adult rats. In this study, a possible third instance of NMDAR-independent extinction was tested. Although adolescents typically exhibit impaired extinction retention, rats that are conditioned as juveniles and then given extinction training as adolescents (JuvCond-AdolesExt) have good extinction retention. Unexpectedly, this good extinction retention is not associated with an up-regulation of a synaptic plasticity marker in the medial prefrontal cortex, a region implicated in extinction consolidation. In the current study, rats received either the noncompetitive NMDAR antagonist MK801 (0.1 mg/kg, s.c.) or saline before extinction training. In several experiments, rats conditioned and extinguished as juveniles, adolescents, or adults exhibited impaired extinction retention after MK801 compared to saline, but this effect was not observed in JuvCond-AdolesExt rats. Further experiments ruled out several alternative explanations for why NMDAR antagonism did not affect extinction retention in adolescents extinguishing fear learned as a juvenile. These results illustrate yet another circumstance in which NMDARs are not required for successful extinction retention and highlight the complexity of fear inhibition across development.

Developmental Shifts in Amygdala Activity during a High Social Drive State

“…During development, NMDA subunit composition and sensitivity to antagonism changes in the BLA and for BLA-mediated behaviors (De Armentia and Sah, 2003;Delaney et al, 2013;Baker and Richardson, 2017;Bisby et al, 2018), and the ability for NMDA antagonism to regulate social behavior increases with age (Morales and Spear, 2014). Similarly, we found that GluN2Bcontaining NMDAR antagonism decreased adult BLA activity to a greater extent than adolescents.…”

Minimizing Variability in Developmental Fear Studies in Mice: Toward Improved Replicability in the Field

“…The majority of studies analyzing rodent fear behavior in development have a blinded experimenter manually score freezing across the whole behavioral session (Carew & Rudy, 1991; Colon et al., 2018; Glavonic et al., 2023; Pattwell et al., 2012; Revillo et al., 2016; Revillo, Paglini, & Arias, et al., 2014). As this can be quite labor‐intensive, a subset of studies uses a time‐sampling approach, in which a binary freezing/no freezing category is assigned to a particular time interval of 3 s (Baker & Richardson, 2015; Bisby et al., 2018; Harmon‐Jones & Richardson, 2021; Kim et al., 2009, 2011; Kim & Richardson, 2007a,b, 2008; McCallum et al., 2010; Yap & Richardson, 2007; Zimmermann et al., 2023), 5 s (Cain et al., 2003; Hefner & Holmes, 2007), or 10 s (Kutlu et al., 2018; Morgan & Pfaff, 2001). Although manual scoring is time‐consuming and may carry the possibility of observer bias, it allows for quantification of complex behaviors that might be difficult to score automatically (such as grooming and rearing, as in Colon et al., 2018, but see below).…”