Network-Level Changes in the Brain Underlie Fear Memory Strength

Abstract

The strength of a fear memory significantly influences whether it drives adaptive or maladaptive behavior in the future. Yet, how mild and strong fear memories differ in underlying biology is not well understood. We hypothesized that this distinction may not be exclusively the result of changes within specific brain regions, but rather the outcome of collective changes in connectivity across multiple regions within the neural network. To test this, rats were fear conditioned in protocols of varying intensities to generate mild or strong memories. Neuronal activation driven by recall was measured using cfos immunohistochemistry in 12 brain regions implicated in fear learning and memory. The interregional coordinated brain activity was computed and graph-based functional networks were generated to compare how mild and strong fear memories differ at the systems level. Our results show that mild fear recall is supported by a well-connected brain network with small-world properties in which the amygdala is well-positioned to be modulated by other regions. In contrast, this connectivity is disrupted in strong fear memories and the amygdala is isolated from other regions. These findings indicate that the neural systems underlying mild and strong fear memories differ, with implications for understanding and treating disorders of fear dysregulation.

Male rats emit aversive 44-kHz ultrasonic vocalizations during prolonged Pavlovian fear conditioning

“…Importantly, it has been demonstrated multiple times that training rats with several electric foot-shocks (i.e., 5-10 shocks) produces a qualitatively different kind of fear-memory compared to training with only 1-2 shocks. Training with more numerous shocks has been shown to result in augmented freezing (e.g., Fanselow and Bolles, 1979, Haubrich et al, 2020, Haubrich and Nader, 2023, Poulos et al, 2016, Wang et al, 2009 which reflects a more intense fear-memory that is resistant to extinction (Haubrich et al, 2020, Haubrich andNader, 2023), resistant to reconsolidation blockade (Haubrich et al, 2020, Wang et al, 2009, Finnie and Nader, 2020, associated with downregulation of NR2B NMDA-receptor subunits as well as elevated amyloid-beta concentrations in the lateral and basal amygdala (Finnie andNader, 2020, Wang et al, 2009). Additionally, it involves activation of the noradrenaline-locus coeruleus system (Haubrich et al, 2020) and collective changes in connectivity across multiple brain regions within the neural network (Haubrich and Nader, 2023).…”

Biphasic Npas4 expression promotes inhibitory plasticity and suppression of fear memory consolidation in mice

“…2F). Strong and maladaptive fear memories trigger disproportionate and generalized fear responses that are also resistant to extinction [39,40]. Thus, we investigated whether inhibition of the late NMDAR activity may prevent maladaptive responses namely the generalization of fear to a neutral context (Fig.…”

Biphasic Npas4 expression promotes inhibitory plasticity and suppression of fear memory consolidation in mice

“…Blocking NMDAR activity, and consequently late Npas4 expression, resulted in enhanced LTM compared to vehicle infused animals (Figure 2 F). Strong and maladaptive fear memories trigger disproportionate and generalized fear responses that are also resistant to extinction 39,40 . Thus, we investigated whether inhibition of the late NMDAR activity may prevent maladaptive responses namely the generalization of fear to a neutral context (Figure 2G,H) and the prevention of fear extinction (Figure 2I,J).…”