Deconstructing the Gestalt: Mechanisms of Fear, Threat, and Trauma Memory Encoding

Abstract

Threat processing is central to understanding debilitating fear- and trauma-related disorders such as posttraumatic stress disorder (PTSD). Progress has been made in understanding the neural circuits underlying the "engram" of threat or fear memory formation that complements a decades-old appreciation of the neurobiology of fear and threat involving hub structures such as the amygdala. In this review, we examine key recent findings, as well as integrate the importance of hormonal and physiological approaches, to provide a broader perspective of how bodily systems engaged in threat responses may interact with amygdala-based circuits in the encoding and updating of threat-related memory. Understanding how trauma-related memories are encoded and updated throughout the brain and the body will ultimately lead to novel biologically-driven approaches for treatment and prevention.

Keywords: PTSD; amygdala; circuit; fear; memory; physiology; stress; threat.

Figure 1.. Schematic illustration of the main stages of memory encoding following a traumatic event consisting of consolidation, reconsolidation, and extinction.

Soon after experiencing trauma, the memory is in an active state in short-term memory until it gets consolidated and stabilized into long-term memory. Since short-term memories are instantly available to conscious awareness, they are also temporarily available to working memory while being consolidated. The retrieval of a consolidated memory at later time points returns the memory from an inactive state in long-term memory to an active state in working memory. From there, the reactivated memories are stabilized again during a process called reconsolidation. Reconsolidation most readily takes place after brief reactivation, thereby strengthening the long-term memory. During reconsolidation events, the active memory traces are potentially susceptible to modification. Extinction (safety memory which inhibits the original threat memory) is induced upon recurrent reactivation of a memory without adverse consequences. Reconsolidation and extinction represent contrasting processes that work in concert to either strengthen or inhibit threat memory expression over time.

Figure 2.. A simplified schematic of the neural threat circuitry.

The amygdala and its subnuclei are key nodes of threat and trauma-relevant encoding. The lateral amygdala (LA) and the lateral central amygdala (CEA-l) receive input from sensory cortices and thalamic structures (Thal) and represent a major site of threat-related neuronal plasticity. This plasticity is controlled by reciprocal connections between the basal amygdala (BA) and the prelimbic cortex (PL) as well as between the BA and the ventral hippocampus (vHC). Subsequently, the medial part of the central amygdala (CEA-m) projects to the hypothalamus (HYP) and other subcortical and brainstem regions to promote threat. Threat extinction is controlled by different circuits within the same structures. Input from the infralimbic cortex (IL) to the BA and to the intercalated (ITC) cells of the amygdala is crucial in reducing threat output from central amygdala nuclei (CE) to the hypothalamus (HYP) and the periaqueductal grey (PAG).

Figure 3.. Factors that can influence threat memories.

A broad spectrum of factors can have a crucial impact on the encoding of features of enduring trauma and threat-relevant memories. Amongst others these are: environmental factors (e.g. early life adversity, diet), neurocircuitry (e.g. alterations within GABAergic, glutamatergic, serotonergic or dopaminergic circuits), cell-type specificity (e.g. Dkk3, Tac2 in BLA/CeA), hormonal state (.e.g. CRH, glucocorticoid and estrogen levels) and cardiovascular signals (e.g. heart rate). Most often it is an interaction of several of these factors that influence threat memories.

Figure 4.. Failures of extinction conceptualized within an engram framework.

A) Encoding of threat-relevant engram and threat memory extinction in rodents. During extinction, repeated exposure to a CS loses its ability to evoke a conditioned response and weakens the CS engram, generally through context-dependent inhibition. (Notably, Impairment of reconsolidation may directly weaken the CS engram trace). B) Spontaneous recovery can occur when there is a long retention period between extinction and the exposure to a CS resulting in context-independent re-activation of a threat-relevant engram. C) Reinstatement occurs if the US is re-presented without the CS resulting in activation of the previously inhibited threat-relevant engram.