Our new paper, Prelimbic cortex drives discrimination of non-aversion via amygdala somatostatin interneurons is now out online at Neuron. This paper grew out of our interest in the mechanisms the brain uses to discriminate non-threatening stimuli, and suppress fear. Our findings are summarized in this graphic, with a deeper dive into the data below.
Inputs from the medial prefrontal cortex (mPFC) to the amygdala drive activation of inhibitory somatostatin-expressing interneurons (SOM). This desynchronizes amygdala pyramidal cells, decreasing defensive freezing and generalized fear (left). When the mPFC input is absent, this mechanism fails, and more generalized fear is observed.
We first show that when non-threatening stimuli are remembered and fear is suppressed, the inhibitory somatostatin-expressing (SOM) interneurons of the basolateral amygdala become active.
2-photon recordings of somatostatin (SOM) -expressing interneurons in the basolateral amygdala show increased activation to the non-threatening CS- (shown in blue) relative to the threatening CS+ (shown in red).
When just the non-threatening CS- is remembered, there is more activity in SOM interneurons than in parvalbumin-expressing (PV) interneurons of the amygdala.
Interestingly, when we inhibited amygdala SOM interneurons, this resulted in increased fear generalization. The potential cellular mechanism of this behavioral finding is intriguing because SOM interneurons target dendrites of amygdala pyramidal cells, and could act to filter out incoming input, preventing the pyramidal cells from synchronous activation. And indeed, our recordings show that during a non-threatening cue, amygdala activity is less synchronous, but when SOM interneurons are inhibited, it becomes more synchronized in the theta-band response.
During the non-threatening CS-, amygdala activity shows less theta reset than during the aversive CS+ (left). However, when SOM interneurons are inhibited, CS- theta reset increases, indicating more synchronous activation of amygdala cell firing (right).
When SOM interneurons are inhibited in the amygdala during the non-threatening CS- (light blue line), the firing rate of pyramidal cells becomes more modulated by the theta-frequency.
Given that the prelimbic cortex is important for fear discrimination learning, we inhibited it, to see if it affects SOM activity and synchrony in the amygdala, as well as behavior. We found that inhibiting the prelimbic cortex increased generalized fear, decreased SOM interneuron activity in the amygdala, and resulted in increased cue-evoked theta synchrony. We also find, that stimulating prelimbic inputs to the amygdala during memory retrieval, improved discrimination in animals that otherwise showed generalized fear.
SOM cells in the amygdala are active during the CS- when the prelimbic cortex of the mPFC is active (left), but are not active during the CS- when the PL is inhibited (right).
Optogenetic stimulation of PL inputs to the amygdala during retrieval of aversive and non-threatening cues decreases defensive behavior during the non-threatening cue, which results in less generalized fear.
There were many people involved in this work, but I’d like to highlight the following folks:
Joe Stujenske, M.D., Ph.D.
Pia Kelsey-O’Neill, Ph.D.
Carolina Fernandes-Henriques, M.Sc.