Fear Learning Enhances Prefrontal Cortical Suppression of Auditory Thalamic Inputs to the Amygdala in Adults, but Not Adolescents

Abstract

Adolescence is characterized by increased susceptibility to the development of fear- and anxiety-related disorders. Adolescents also show elevated fear responding and aversive learning that is resistant to behavioral interventions, which may be related to alterations in the circuitry supporting fear learning. These features are linked to ongoing adolescent development of medial prefrontal cortical (PFC) inputs to the basolateral amygdala (BLA) that regulate neural activity and contribute to the refinement of fear responses. Here, we tested the hypothesis that the extent of PFC inhibition of the BLA following fear learning is greater in adults than in adolescents, using anesthetized in vivo recordings to measure local field potentials (LFPs) evoked by stimulation of PFC or auditory thalamic (MgN) inputs to BLA. We found that BLA LFPs evoked by stimulation of MgN inputs were enhanced in adults following fear conditioning. Fear conditioning also led to reduced summation of BLA LFPs evoked in response to PFC train stimulation, and increased the capacity of PFC inhibition of MgN inputs in adults. These data suggest that fear conditioning recruits additional inhibitory capacity by PFC inputs to BLA in adults, but that this capacity is weaker in adolescents. These results provide insight into how the development of PFC inputs may relate to age differences in memory retention and persistence following aversive learning.

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

“…Despite these advantages, the time needed for each breeding cycle and other intrinsic challenges of colony management may reduce the rate at which experimental animals become available, delaying research progress. When working with juvenile or adolescent rodents, an alternative is to purchase animals directly from vendors and allow them to acclimate to the facility before testing (e.g., Ferrara et al., 2020; Hefner & Holmes, 2007; Selleck et al., 2018). It is important to note that, since this strategy requires that pups be weaned at the vendor facility prior to shipping, this approach may add variability in terms of handling and weaning.…”

“…Rat developmental studies feature greater variability in the number of animals per cage, with some reaching significantly higher numbers than most mouse studies. Ranges include a maximum of 3 (Ferrara et al., 2020) or 4 (Chocyk et al., 2014) animals per cage to groups of 5‐6 (Perry et al., 2020) or 6 (Ganella et al., 2017). Some studies use up to 4‐8 (McCallum et al., 2010; Yap & Richardson, 2007; Zimmermann et al., 2023) and combine litters (Kim et al., 2011).…”

Memory retrieval, reconsolidation, and extinction: Exploring the boundary conditions of post-conditioning cue exposure

“…Extinction learning is dependent on IL projections to the BLA; direct IL inputs to the BLA engage GABAergic neurons that suppress principal excitatory neurons (Selleck et al, 2018;Bukalo et al, 2021). Extinction increases the excitability of BLAprojecting IL neurons to increase the capacity of the IL to suppress BLA activity (Bloodgood et al, 2018;Ferrara et al, 2020). Inhibiting IL activity during extinction learning impairs its acquisition (Sierra-Mercado et al, 2011;Do-Monte et al, 2015) and epigenetic manipulations within the IL modify the strength and persistence of extinction memories (Lattal et al, 2007;Marek et al, 2011;Bahari-Javan et al, 2012;Stafford et al, 2012;Kwapis and Wood, 2014), suggesting plasticity in this region is critical for extinction.…”

“…Similarly, manipulations that directly suppress BLA excitation enhance extinction. This includes both manipulations that activate GABAergic inputs from the mPFC, and those that inhibit excitatory inputs to the BLA from the auditory thalamus and cortex (Cho et al, 2013;Ferrara et al, 2020). In this manner, extinction memories are thought to recruit BLA inhibition to suppress the original, excitatory fear memory.…”

Special Issue “Molecular Mechanisms of Memory Formation and Modification”

“…These results suggest that two waves of de novo protein synthesis are required for the consolidation of social fear memories. Finally, Ferrara and colleagues used in vivo recordings of local field potentials (LFPs) evoked by stimulation of prefrontal cortical (PFC) or auditory thalamic (MgN) inputs to the basolateral amygdala (BLA) to test if PFC inhibition of the BLA following fear learning was greater in adults than adolescents [ 3 ]. They found that in adult rats, stimulation of MgN inputs enhanced BLA LFP and increased PFC inhibition of MgN inputs following fear conditioning, suggesting that fear conditioning increases inhibitory capacity of PFC inputs to the BLA in adults, but this enhancement is weaker in adolescents.…”