Prefrontal projections to the thalamic nucleus reuniens mediate fear extinction

Abstract

The thalamic nucleus reuniens (RE) receives dense projections from the medial prefrontal cortex (mPFC), interconnects the mPFC and hippocampus, and may serve a pivotal role in regulating emotional learning and memory. Here we show that the RE and its mPFC afferents are critical for the extinction of Pavlovian fear memories in rats. Pharmacological inactivation of the RE during extinction learning or retrieval increases freezing to an extinguished conditioned stimulus (CS); renewal of fear outside the extinction context was unaffected. Suppression of fear in the extinction context is associated with an increase in c-fos expression and spike firing in RE neurons to the extinguished CS. The role for the RE in suppressing extinguished fear requires the mPFC, insofar as pharmacogenetically silencing mPFC to RE projections impairs the expression of extinction memory. These results reveal that mPFC-RE circuits inhibit the expression of fear, a function that is essential for adaptive emotional regulation.

Canine Adenovirus 2: A Natural Choice for Brain Circuit Dissection

“…The long-lasting gene expression and negligible impact on the physiology of neurons make CAV a competent vector when expressing effectors for functional analyses. Indeed, CAV-Cre mediated the expression of effectors for chemogenetics (Augur et al, 2016;Roth, 2016;Alcaraz et al, 2018;Ramanathan et al, 2018), genetic ablation (Liu et al, 2016), and calcium imaging (Otis et al, 2017(Otis et al, , 2019 for an intermediate time window, ranging from 2 weeks to a couple of months. Beyond 2 months, CAV can steadily express effectors for longer term functional analysis.…”

“…Even though most of our examples of CAV and intersectional method applications concerned circuit anatomy, the same intersectional approaches can be easily tweaked for functional analyses or molecular profiling. For instance, a variety of effector molecules have been conditionally expressed for either chemogenetics (Boender et al, 2014;Augur et al, 2016;Alcaraz et al, 2018;Fernandez et al, 2018;Ramanathan et al, 2018;Kakava-Georgiadou et al, 2019), optogenetic (Eliava et al, 2016;Li et al, 2016), projection-specific genetic ablations (Wu et al, 2012;Liu et al, 2016), optical calcium imaging (Otis et al, 2017(Otis et al, , 2019, and molecular profiling (Ekstrand et al, 2014). Furthermore, the ability of CAV to seamlessly deliver and selectively express effectors can be paired with classical techniques, such as slice or in vivo electrophysiology (Eliava et al, 2016;Li et al, 2016), and a variety of behavior paradigms (Liu et al, 2016;Kakava-Georgiadou et al, 2019).…”

Molecularly-Defined Hippocampal Inputs Regulate Population Dynamics in the Prelimbic Cortex to Suppress Context Fear Memory Recall

“…We also show that vHC-PrL projectors are a molecularly distinct sub-class of vHC neurons, and that a number of genes that are differentially-expressed in projectors are also implicated in PTSD and GAD. Our data add to a growing number of studies elucidating the circuitry underlying fear behavior with projection specificityfor example, IL and BLA-projecting vHC neurons in context-dependent renewal of fear following extinction 42,43 , and ventral midline thalamic-projecting mPFC neurons in fear extinction 44 . We further causally link molecular function in this projection-specific population with context fear recall, expanding on research showing that manipulating BDNF in either the vHC or mPFC affects extinction of conditioned fear 15 and avoidance behavior 45 by directly linking BDNF-TrkB signaling within a projection-specific sub-population with contextually-dependent fear behavior.…”

Coordinated prefrontal state transition leads extinction of reward-seeking behaviors

“…Lesion (Fragale et al, 2016), pharmacological inactivation (Caballero et al, 2019;Ramanathan et al, 2018) and optogenetic stimulation (Marek et al, 2018;Sparta et al, 2014) studies provide increasing evidence that PL is a critical locus for extinction of reward-seeking behaviors and conditioned fear. Using an appetitive operant within-session extinction paradigm, we studied the dynamics of PL leading to the extinction of conditioned reward-seeking behavior in rats.…”