Optogenetic Stimulation of Prelimbic Pyramidal Neurons Maintains Fear Memories and Modulates Amygdala Pyramidal Neuron Transcriptome

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.

The Three Musketeers in the Medial Prefrontal Cortex: Subregion-specific Structural and Functional Plasticity Underlying Fear Memory Stages

“…However, the elevation of spine size of IL neurons returned to the level observed in pseudo-conditioned mice [93]. In the PL, it is reported that apical dendrites of pyramidal neurons showed decreased spine density in animals underwent extinction training compared to no extinction group (Table 1) [94].…”

β2-Adrenoceptors in the Medial Prefrontal Cortex Excitatory Neurons Regulate Anxiety-like Behavior in Mice

“…To confirm the specificity and expression pattern of β2-AR in mFPC, we used new β2-AR antibody from another company to co-stain with CaMKIIα and found a similar result ( Supplementary Figure S1a ). Then, to specifically manipulate mPFC β2-AR in real time, we utilized β2-AR optogenetics, which is similar in dynamics to endogenous β2-AR [ 26 , 27 ].…”

“…To dissect the roles of mPFC β2-AR in anxiety-like behavior, we recruit optogenetics to specifically manipulate β2-AR activity [ 26 , 27 ] and miRNA based silencing to knock down β2-AR expression within the pyramidal neurons of the mPFC. Our data show that optogenetic activation of β2-AR is sufficient to induce anxiety-like behavior and β2-AR knock down can induce an anxiolytic effect.…”

Cerebral cortex and hippocampus neural interaction during vagus nerve stimulation under in vivo large-scale imaging

“…The macroscopic observation methods mainly utilized devices, including MRI, PET, and SPECT (Conway et al, 2006;Malbert et al, 2019;Borgmann et al, 2021), whose major advantages lay in the power to observe the functional connectivity of multiple brain regions. The microscopic observation methods primarily utilized electrophysiology and optical fiber photometry, which took advantage of observing microstructures such as cells or neurons (Jaseja, 2010;Laricchiuta et al, 2021). However, few studies effectively combined the two observation technology to decipher complex brain neuronal activities in vivo.…”