Amygdala interneuron subtypes control fear learning through disinhibition

Abstract

Learning is mediated by experience-dependent plasticity in neuronal circuits. Activity in neuronal circuits is tightly regulated by different subtypes of inhibitory interneurons, yet their role in learning is poorly understood. Using a combination of in vivo single-unit recordings and optogenetic manipulations, we show that in the mouse basolateral amygdala, interneurons expressing parvalbumin (PV) and somatostatin (SOM) bidirectionally control the acquisition of fear conditioning--a simple form of associative learning--through two distinct disinhibitory mechanisms. During an auditory cue, PV(+) interneurons are excited and indirectly disinhibit the dendrites of basolateral amygdala principal neurons via SOM(+) interneurons, thereby enhancing auditory responses and promoting cue-shock associations. During an aversive footshock, however, both PV(+) and SOM(+) interneurons are inhibited, which boosts postsynaptic footshock responses and gates learning. These results demonstrate that associative learning is dynamically regulated by the stimulus-specific activation of distinct disinhibitory microcircuits through precise interactions between different subtypes of local interneurons.

Facilitation of contextual fear extinction by orexin-1 receptor antagonism is associated with the activation of specific amygdala cell subpopulations

“…These cell subpopulations are mainly nonpyramidal GABAergic interneurons (McDonald and Mascagni, 2001) and are involved in fear and anxiety processes (Butler et al, 2011;Wolff et al, 2014). In agreement with previous studies, approximately 80% of PV neurons exhibited colocalization with CB, and the number of neurons expressing PV and/or CB was not modified in mice treated with the OX1R antagonist (Figure 2A).…”

“…These cell populations, functionally defined as "fear neurons" and "extinction neurons," overlap with 2 different anatomically defined subtypes of BLA neurons projecting to prelimbic medial prefrontal cortex (PL) or IL, respectively (Senn et al, 2014). Nonpyramidal GABAergic interneurons within the BLA can be classified by the content of several calcium-binding proteins such as calbindin (CB) and/or parvalbumin (PV) (McDonald and Mascagni, 2001;Capogna, 2014), which could differentially control these neuronal circuits since they are involved in fear and anxiety (Butler et al, 2011;Wolff et al, 2014). Whether orexins affect these circuits and GABAergic interneuron subpopulations during emotional memory processes remain unexplored.…”

Mouse chronic social stress increases blood and brain kynurenine pathway activity and fear behaviour: Both effects are reversed by inhibition of indoleamine 2,3-dioxygenase

“…Mouse CSD resulted in excessive fear learning and memory of an aversive CS-US association, indicating that psychosocial stress induced generalized hyper-reactivity to aversion. Pavlovian fear learning-memory is an important translational readout for several reasons, including detailed knowledge of the neurobiology of adaptive fear learning-memory in healthy humans (Fullana et al, 2015) and mice (Duvarci and Pare, 2014;LeDoux, 2000;Wolff et al, 2014), and evidence for increased fear conditioning in MDD (Nissen et al, 2010) and GAD (Greenberg et al, 2013;Lissek et al, 2015). Repeated escitalopram reversed the increased fear expression, specifically, in CSD mice, indicating that the model has predictive validity.…”

“…Now the current study provides some of the first evidence for the reversal of behavioural effects of stress-induced IDO1-KYN pathway activation. Given the importance of amygdala and hippocampus in fear conditioning (Duvarci and Pare, 2014;LeDoux, 2000;Maren et al, 2013;Wolff et al, 2014) and stress-related psychiatric disorders (Harmer, 2013;Phelps and LeDoux, 2005;Price and Drevets, 2010; 31 Sheline et al, 2001), it is noteworthy that amygdala and vHIPP, together with other brain regions, exhibited increased levels of kynurenines. In healthy humans, LPS induced increased amygdala reactivity to fearful faces (Inagaki et al, 2012).…”

“…In humans, CS responsiveness is measured using skin conductance and subjective report (Fullana et al, 2015), and in rodents the defensive behaviour of complete 5 inactivity, or "freezing", is used (for review: (Blanchard et al, 2001;Maren and Quirk, 2004;Phelps and LeDoux, 2005)). Rodent fear conditioned freezing provides a model system for investigating the neurobiology of negative valence processing, including CS-US learning, consolidation and recall of CS-US memory, and activation of conditioned freezing response (LeDoux, 2000;Rescorla, 1988;Wolff et al, 2014). The amygdala, specifically the basolateral complex and central nucleus, is essential for each of these stages (Duvarci and Pare, 2014;Kim and Jung, 2006;Maren and Quirk, 2004).…”