Time-Dependent Recruitment of Prelimbic Prefrontal Circuits for Retrieval of Fear Memory.

Kelvin Quiñones-Laracuente,Gregory J Quirk,Alexis Vega-Medina

doi:10.3389/fnbeh.2021.665116

Kelvin Quiñones-Laracuente, Gregory J Quirk + Show 1 more

Open Access

https://doi.org/10.3389/fnbeh.2021.665116

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Abstract

The long-lasting nature of fear memories is essential for survival, but the neural circuitry for retrieval of these associations changes with the passage of time. We previously reported a time-dependent shift from prefrontal-amygdalar circuits to prefrontal-thalamic circuits for the retrieval of auditory fear conditioning. However, little is known about the time-dependent changes in the originating site, the prefrontal cortex. Here we monitored the responses of prelimbic (PL) prefrontal neurons to conditioned tones at early (2 h) vs. late (4 days) timepoints following training. Using c-Fos, we find that PL neurons projecting to the amygdala are activated early after learning, but not later, whereas PL neurons projecting to the paraventricular thalamus (PVT) show the opposite pattern. Using unit recording, we find that PL neurons in layer V (the origin of projections to amygdala) showed cue-induced excitation at earlier but not later timepoints, whereas PL neurons in Layer VI (the origin of projections to PVT) showed cue-induced inhibition at later, but not earlier, timepoints, along with an increase in spontaneous firing rate. Thus, soon after conditioning, there are conditioned excitatory responses in PL layer V which influence the amygdala. With the passage of time, however, retrieval of fear memories shifts to inhibitory responses in PL layer VI which influence the midline thalamus.

Highlights

Memories of threatening experiences can last a lifetime (LeDoux, 2000; Gale et al, 2004), but the location of such fear memories within the brain is thought to change over time
Combining c-Fos expression with retrograde tracers, we showed that PL neurons projecting to BLA are activated by the tone conditioned stimulus at early, but not late, timepoints after fear conditioning, whereas PL neurons projecting to paraventricular thalamus (PVT) showed the opposite pattern
Our unit recording supported the findings for BLA-projecting neurons, revealing excitatory conditioned tone responses in layer V neurons at early, but not late, timepoints

Summary

Introduction

Memories of threatening experiences can last a lifetime (LeDoux, 2000; Gale et al, 2004), but the location of such fear memories within the brain is thought to change over time (for reviews see: Frankland and Bontempi, 2005; Do Monte et al, 2016). Control of retrieval of fear memories by PL initially involves direct projections to the basolateral amygdala (BLA, 6 h following conditioning), but later shifts to indirect activation of the central nucleus of the amygdala (CeM) via projections to the paraventricular thalamus (PVT) (7 days following conditioning) (DoMonte et al, 2015; Penzo et al, 2015; Choi and McNally, 2017). Time-Dependent Fear Retrieval Prelimbic Circuits that project to PVT thalamus (Do-Monte et al, 2015). PL neurons that project to PVT are located in layer VI of PL (Vertes, 2002; Li and Kirouac, 2012), and c-Fos expression profiles have confirmed that conditioned activity in PL shifts from superficial to deep layers with the passage of time (DeNardo et al, 2019). Whereas the majority of prior studies focused on excitatory tone responses in PL (Burgos-Robles et al, 2009; Sotres-Bayon et al, 2012), there is an emerging role of inhibitory responses of PL neurons in aversive conditioning (Courtin et al, 2014; Diehl et al, 2020)

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