Abstract
Fear memory enhances connectivity in cortical and limbic circuits but whether treatments disrupting fear reset connectivity to pre-trauma level is unknown. Here we report that C56BL/6J mice exposed to a tone-shock association in context A (conditioning), and briefly re-exposed to the same tone-shock association in context B (reactivation), exhibit strong freezing to the tone alone delivered 48 h later in context B (long term fear memory). This intense fear response is associated with a massive increase in dendritic spines and phospho-Erk (p-ERK) signaling in basolateral amygdala (BLA) but neurons. We then show that propranolol (a central/peripheral β-adrenergic receptor blocker) administered before, but not after, the reactivation trial attenuates long term fear memory assessed drug free 48 h later, and completely prevents the increase in spines and p-ERK signaling in BLA neurons. An increase in spines, but not of p-ERK, was also detected in the dorsal hippocampus (DH) of the conditioned mice. DH spines, however, were unaffected by propranolol suggesting their independence from the ERK/β-ARs cascade. We conclude that propranolol selectively blocks dendritic spines and p-ERK signaling enhancement in the BLA; its effect on fear memory is, however, less pronounced suggesting that the persistence of spines at other brain sites decreases the sensitivity of the fear memory trace to treatments selectively targeting β ARs in the BLA.
Highlights
Traumatic experience durably impacts on neural connectivity
We show that propranolol administered before, but not after, the reactivation trial attenuates long term fear memory assessed drug free 48 h later, and completely prevents the increase in spines and p-ERK signaling in basolateral amygdala (BLA) neurons
We found that this long term fear response is significantly attenuated by pre-reactivation injections of the central/peripheral β-ARs blocker propranolol, but not of the selective peripheral β-ARs blocker sotalol
Summary
Traumatic experience durably impacts on neural connectivity. In humans, comparisons of EEG signal coherence in adult individuals reporting childhood, adulthood, or no history of traumatic experience points to a positive correlation between connectivity over frontal, central, temporal and parietal areas and intensity of the trauma (Cook et al, 2009). Tone fear conditioning (TFC) drives structural alterations in basolateral amygdala (BLA) neurons consistent with an enhancement in the strength and in the number of synapses. These include an enlargement of postsynaptic spine densities, movements of the polymerization-regulatory protein profilin to dendritic spines (Lamprecht et al, 2006), increased number of spinophilin-immunoreactive spines (Radley et al, 2006), a greater ratio of postsynaptic density (PSD) area to docked vesicles at synapses (Ostroff et al, 2010, 2012) and a net increase in spine density (Heinrichs et al, 2013). It is conceivable that connectivity in fear-activated circuits should be reduced upon fear erasure, whether pharmacological treatments reducing fear memory reset physiological levels of connectivity is unknown
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