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Review
. 2019 Jan;236(1):163-182.
doi: 10.1007/s00213-018-5104-4. Epub 2018 Nov 10.

Mechanisms of fear learning and extinction: synaptic plasticity-fear memory connection

Natalia V Luchkina  1 , Vadim Y Bolshakov  2
Affiliations
Review

Mechanisms of fear learning and extinction: synaptic plasticity-fear memory connection

Natalia V Luchkina et al. Psychopharmacology (Berl). 2019 Jan.

Abstract

Rationale: The ability to memorize threat-associated cues and subsequently react to them, exhibiting escape or avoidance responses, is an essential, often life-saving behavioral mechanism that can be experimentally studied using the fear (threat) conditioning training paradigm. Presently, there is substantial evidence supporting the Synaptic Plasticity-Memory (SPM) hypothesis in relation to the mechanisms underlying the acquisition, retention, and extinction of conditioned fear memory.

Objectives: The purpose of this review article is to summarize findings supporting the SPM hypothesis in the context of conditioned fear control, applying the set of criteria and tests which were proposed as necessary to causally link lasting changes in synaptic transmission in corresponding neural circuits to fear memory acquisition and extinction with an emphasis on their pharmacological diversity.

Results: The mechanisms of synaptic plasticity in fear circuits exhibit complex pharmacological profiles and satisfy all four SPM criteria-detectability, anterograde alteration, retrograde alteration, and mimicry.

Conclusion: The reviewed findings, accumulated over the last two decades, provide support for both necessity and sufficiency of synaptic plasticity in fear circuits for fear memory acquisition and retention, and, in part, for fear extinction, with the latter requiring additional experimental work.

Keywords: Animal model; Behavior; Extinction; Fear conditioning; Synaptic plasticity; Synaptic transmission.

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Conflict of interest statement

Conflict of interest statement: On behalf of all authors, the corresponding author (Dr. Bolshakov) states that there is no conflict of interest.

Figures

Fig. 1
Fig. 1
A diagram illustrating brain circuitry of fear-related learning. During fear conditioning, the conditioned stimulus (CS) carrying auditory information (blue) is transmitted to the lateral nucleus of the amygdala (LA) by direct thalamic and indirect cortical pathways (LeDoux 2000; Maren 2001; Dityatev and Bolshakov 2005). Thalamic input to the LA arises in the medial subdivision of the medial geniculate nucleus and the adjacent posterior intralaminar nucleus of the thalamus (MGm/PIN). The auditory thalamus also sends projections to the auditory cortex (ACx). The latter, in turn, projects to the LA, thus forming indirect cortico-amygdala pathway. The LA receives somatosensory signals (red), coding the unconditioned stimulus (US) information from the somatosensory thalamus and cortex (Cruikshank et al. 1992; Shi and Cassell 1998; Shi and Davis 1999; Lanuza et al. 2008). The convergence of CS and US on LA neurons results in lasting synaptic enhancements in auditory CS inputs to the LA, contributing to the encoding of conditioned fear memory (Maren and Quirk, 2004). The signals are then relayed to other components of the learned fear circuits, including BLA, and eventually to the central nucleus of the amygdala (CeA). CeA mediates physiological manifestations of fear through divergent projections to the hypothalamus and brainstem areas (Maren and Quirk 2004). The ventral hippocampus (vHPC) projects to the BLA and is important for the encoding of context-dependency of fear-related behaviors (Herry et al. 2010; Orsini and Maren 2012). Medial prefrontal cortex (mPFC) modulates fear-related behaviors, both fear learning and extinction of fear memory, through its direct projections to the BLA (Milad and Quirk 2002; Likhtik et al. 2005; Quirk et al. 2006).
Fig. 2
Fig. 2
Schematic illustration of the criteria proposed previously to evaluate a causal link between plastic changes in specific brain areas and corresponding brain area-specific memory (Martin et al. 2000). Fear memory and synaptic plasticity at cortical and thalamic projections to the LA are shown here as an example. Similar criteria (i.e., detectability, anterograde and retrograde alterations, and mimicry criteria), can be applied for testing the necessity and sufficiency of plastic changes underlying other amygdala-based forms of learning, such as fear extinction.
Fig. 3
Fig. 3
Relapse of fear following fear extinction. Fear is reduced following fear extinction, as assessed during extinction retrieval test the next day after training. However, fear can return by the following mechanisms: spontaneous recovery with the passage of time after fear extinction, reinstatement due to an exposure to the unsignalled US or renewal with exposure to the fear conditioning context that is different from extinction context (Myers and Davis 2007; Singewald et al. 2015).
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