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Abstract
Fear extinction requires coordinated neural activity within the amygdala and medial prefrontal cortex (mPFC). Any behavior has a transcriptomic signature that is modified by environmental experiences, and specific genes are involved in functional plasticity and synaptic wiring during fear extinction. Here, we investigated the effects of optogenetic manipulations of prelimbic (PrL) pyramidal neurons and amygdala gene expression to analyze the specific transcriptional pathways associated to adaptive and maladaptive fear extinction. To this aim, transgenic mice were (or not) fear-conditioned and during the extinction phase they received optogenetic (or sham) stimulations over photo-activable PrL pyramidal neurons. At the end of behavioral testing, electrophysiological (neural cellular excitability and Excitatory Post-Synaptic Currents) and morphological (spinogenesis) correlates were evaluated in the PrL pyramidal neurons. Furthermore, transcriptomic cell-specific RNA-analyses (differential gene expression profiling and functional enrichment analyses) were performed in amygdala pyramidal neurons. Our results show that the optogenetic activation of PrL pyramidal neurons in fear-conditioned mice induces fear extinction deficits, reflected in an increase of cellular excitability, excitatory neurotransmission, and spinogenesis of PrL pyramidal neurons, and associated to strong modifications of the transcriptome of amygdala pyramidal neurons. Understanding the electrophysiological, morphological, and transcriptomic architecture of fear extinction may facilitate the comprehension of fear-related disorders.
Highlights
This article is an open access articleIn variable and challenging environments with various contextual situations, the individuals face a number of approaching dangers
Electrophysiological Results: Cellular Excitability of PrL Pyramidal Neurons test the ability of the optogenetics to modulate activity Neurons of PrL cortex in fear2.2
Neurons of OPTO FEAR animals clearly showed a higher number of action potentials in comparison to neurons of SHAM FEAR animals, at all current levels considered as indicated by cumulative curve (Correlation test, SHAM FEAR group: Pearson r = 0.99, R2 = 0.99, n = 8 neurons from 5 mice; OPTO FEAR group: Pearson r = 0.98, R2 = 0.97, n = 8 neurons from 5 mice; p < 0.0001, Figure 2A)
Summary
This article is an open access articleIn variable and challenging environments with various contextual situations, the individuals face a number of approaching dangers. The knowledge of potential threats allows developing fear of threatening situations, choosing among the various behaviors the safest ones, and detecting future dangers. When a relevant stimulus (or a context) is associated with an aversive event, fear associations are learned and form a memory. Learned fear has been widely studied using Contextual Fear Conditioning (CFC), a very useful paradigm to analyze the neuronal and molecular bases of fear associative learning and memory [2,3]. In experimental models in which the CFC paradigm is implemented, the conditioned stimulus (CS), such as a specific cue or context, is associated with the unconditioned stimulus (US), such as foot-shock [3,4]. After the association has taken place, CS alone is able to induce the conditioned response (CR) of fear, such as freezing behavior
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