One threat cue evokes two prefrontal response patterns

After sound–shock pairing, dmPFC spiking and freezing are recorded in males. Some excitatory cells respond briefly at onset, termed T cells; others sustain responses, termed S cells, with duration resembling sound and freezing duration.

Changing threat-cue duration changes S-cell response duration while T cells retain a brief onset pattern. Unpaired sounds do not evoke similarly clear responses, distinguishing onset-related and sustained activity.

Original figure 1Spiking during threat-memory retrieval

Amygdala-recipient and amygdala-projecting populations differ

LA-recipient dmPFC populations favor transient responses, while BLA-projecting populations favor sustained responses, with limited labeling overlap. Inhibiting BLA-projecting cells reduces sustained firing and freezing without an obvious transient-firing reduction.

Slice recordings support direct T-associated input to S-associated populations. Brief upstream activation alone evokes only transient S responses, motivating examination of sensory input and neuromodulation for sustained activity.

Original figure 2Prefrontal inputs, outputs and connections

The populations differ in their readiness for modulation

RNA profiles differ in ion-channel, adhesion-molecule and NE-related receptor genes, with higher beta-1 adrenergic receptor expression in S populations. S cells also have higher input resistance, wider spikes and smaller spike amplitudes.

Baseline intrinsic excitability does not significantly differ. Population distinctions involve properties, inputs and modulation-related receptors rather than uniform firing propensity, directing attention to NE.

Original figure 3Molecular and electrophysiological T/S properties

Beta-receptor modulation supports sustained responses

Sound-associated TeA input strongly recruits S cells. Ventricular beta-adrenergic blockade reduces freezing and sustained S firing without significantly changing transient T firing, separating sensitivity to modulation.

In slices, beta-receptor agonism raises excitatory-event frequency, lowers inhibitory-event frequency and changes S-cell membrane potential and intrinsic excitability, without significant event-amplitude changes. Modulation increases responsiveness to ongoing input.

Original figure 4TeA input and beta-receptor modulation

Threat cues recruit LC and elevate prefrontal NE signals

NE sensor signals rise rapidly to paired sounds and decline slowly afterward, without a clear rise to unpaired sounds. LC and TH-labeled populations respond to paired cues; inhibiting dmPFC-projecting LC cells reduces freezing.

LC receives TeA and dmPFC input. T-associated input drives recorded LC cells, whereas S-associated input evokes no corresponding responses. Some LC cells receive prefrontal input and project back, linking brief memory-associated activity with NE modulation.

Original figure 5Prefrontal NE and LC responses

Prefrontal onset input and sound converge in LC

In LC slices, TeA inputs evoke clear responses and T-population inputs evoke synaptic currents. Most recorded dmPFC-projecting LC cells respond to prefrontal input, bringing memory-linked onset activity and sensory input to one modulatory node.

Original figure 6Sensory and prefrontal inputs to LC

Another sound can evoke freezing before NE signals subside

After a ten-second threat cue, NE signals persist while freezing usually ends with the sound. An unpaired cue evokes freezing after a ten-second gap but not a thirty-second gap; slowing NE reuptake allows the later cue to evoke a response.

A two-second threat cue followed by twenty-eight seconds of unpaired sound sustains responses and freezing. Brief initiation plus subsequent sensory input supports a longer response within the neuromodulatory window.

Original figure 7Temporal windows and hybrid cues

Behavior from one memory depends on subsequent input

Hybrid cues sustain LC and prefrontal NE signals. Brief activation of selected LC populations followed by unpaired sound also evokes freezing. Combined prefrontal/TeA stimulation transiently enhances LC responses to TeA input; TeA stimulation alone does not.

This adult male-mouse study identifies a state-modulated transition between retrieval and behavioral expression. Brief memory-linked input initiates recruitment, later sound sustains activity and NE changes the opportunity for cues to affect behavior.

Original figure 8Hybrid cues and transient LC response enhancement