Prefrontal NMDA receptors expressed in excitatory neurons control fear discrimination and fear extinction

Abstract

N-methyl-D-aspartate receptors (NMDARs) are critically involved in various learning mechanisms including modulation of fear memory, brain development and brain disorders. While NMDARs mediate opposite effects on medial prefrontal cortex (mPFC) interneurons and excitatory neurons, NMDAR antagonists trigger profound cortical activation. The objectives of the present study were to determine the involvement of NMDARs expressed specifically in excitatory neurons in mPFC-dependent adaptive behaviors, specifically fear discrimination and fear extinction. To achieve this, we tested mice with locally deleted Grin1 gene encoding the obligatory NR1 subunit of the NMDAR from prefrontal CamKIIα positive neurons for their ability to distinguish frequency modulated (FM) tones in fear discrimination test. We demonstrated that NMDAR-dependent signaling in the mPFC is critical for effective fear discrimination following initial generalization of conditioned fear. While mice with deficient NMDARs in prefrontal excitatory neurons maintain normal responses to a dangerous fear-conditioned stimulus, they exhibit abnormal generalization decrement. These studies provide evidence that NMDAR-dependent neural signaling in the mPFC is a component of a neural mechanism for disambiguating the meaning of fear signals and supports discriminative fear learning by retaining proper gating information, viz. both dangerous and harmless cues. We also found that selective deletion of NMDARs from excitatory neurons in the mPFC leads to a deficit in fear extinction of auditory conditioned stimuli. These studies suggest that prefrontal NMDARs expressed in excitatory neurons are involved in adaptive behavior.

Newly acquired and reactivated contextual fear memories are more intense and prone to generalize after activation of prelimbic cortex NMDA receptors

“…These results indicate that this pharmacological intervention also influenced the fear memory intensity and/or specificity at the reconsolidation stage. This theory is supported by prior evidence showing that the PL cortex can modulate the reconsolidation of contextual fear memories (Stern et al, 2014 and is part of a neural circuit regulating fear discrimination and/or generalization (Xu and Südhof, 2013;Sangha et al, 2014;Rozeske et al, 2015;Vieira et al, 2015).…”

“…The rodent prelimbic (PL) cortex is considered homologous to the primate dACC (McDonald, 1998;Stefanacci and Amaral, 2002), and its activity has been involved in consolidation, retrieval and reconsolidation of learned fear (Blum et al, 2006;Choi et al, 2010;Zhang et al, 2011;McReynolds et al, 2014;Stern et al, 2014;Zelikowsky et al, 2014;Do Monte et al, 2015). Activity in PL cortex has also been shown to influence the expression, discrimination and extinction of auditory fear memories (Vidal-Gonzalez et al, 2006;Corcoran and Quirk, 2007;BurgosRobles et al, 2009;Sierra-Mercado et al, 2011;Courtin et al, 2014;Likhtik et al, 2014;Vieira et al, 2015). It is still unknown, however, whether altered PL cortex functioning could interfere with the expression, discrimination (or generalization) and extinction of a contextual fear memory in laboratory animals.…”

“…As the PL cortex NMDA receptors have been involved in aversive learning and memory processing (Gilmartin et al, 2013;Vieira et al, 2015), and the infusion of NMDA into discrete brain regions, such as the dorsolateral periaqueductal gray, has been shown to be potentiate a contextual fear memory trace in rats (Mochny et al, 2013), the working hypotheses were that (i) the PL cortex NMDA receptor activation during consolidation, retrieval or reconsolidation would induce generalized fear expression and/or extinction deficits in animals subjected to a strong contextual fear conditioning protocol (i.e. pairing the Context A with three shocks of 1.0 mA), and (ii) this pharmacological intervention would potentiate the consolidation or reconsolidation of a contextual fear memory trace induced by a weak fear training protocol (Context A pairing with a single shock of 1.0 mA).…”

General and emotion-specific neural effects of ketamine during emotional memory formation

“…Recent animal work emphasizes an involvement of NMDAR-dependent signalling in medial prefrontal cortex (mPFC) and amygdala during emotional processing and emotion-cognition interactions, including emotional learning (Vieira et al, 2015;Hegoburu et al, 2014;Masneuf et al, 2014). These are in line with studies in humans which revealed emotion-specific disruptions during facial emotion encoding and recognition, as well as altered amygdala and prefrontal functioning following ketamine-induced NMDAR blockade (Ebert et al, 2012;Schmidt et al, 2013, Abel et al, 2003.…”

Preclinical studies of stress, extinction, and prefrontal cortex: intriguing leads and pressing questions

“…Conversely, infusion of an NMDA receptor agonist facilitates extinction (Fiorenza et al 2012). Finally, Vieira and colleagues (2015) used a viral construct to locally delete the obligate NR1 subunit of the NMDA receptor on CAMKIIα-expressing neurons in ventral medial prefrontal cortex to demonstrate that NMDA receptors on excitatory neurons in medial prefrontal cortex are critical for extinction. Therefore, alteration in the glutamatergic system could provide the substrate underlying stress-induced alterations in extinction.…”