Neurons in the Nonhuman Primate Amygdala and Dorsal Anterior Cingulate Cortex Signal Aversive Memory Formation under Sedation

Abstract

Background Anesthetics aim to prevent memory of unpleasant experiences. The amygdala and dorsal anterior cingulate cortex participate in forging emotional and valence-driven memory formation. It was hypothesized that this circuitry maintains its role under sedation. Methods Two nonhuman primates underwent aversive tone–odor conditioning under sedative states induced by ketamine or midazolam (1 to 8 and 0.1 to 0.8 mg/kg, respectively). The primary outcome was behavioral and neural evidence suggesting memory formation. This study simultaneously measured conditioned inspiratory changes and changes in firing rate of single neurons in the amygdala and the dorsal anterior cingulate cortex in response to an expected aversive olfactory stimulus appearing during acquisition and tested their retention after recovery. Results Aversive memory formation occurred in 26 of 59 sessions under anesthetics (16 of 29 and 10 of 30, 5 of 30 and 21 of 29 for midazolam and ketamine at low and high doses, respectively). Single-neuron responses in the amygdala and dorsal anterior cingulate cortex were positively correlated between acquisition and retention (amygdala, n = 101, r = 0.51, P < 0.001; dorsal anterior cingulate cortex, n = 121, r = 0.32, P < 0.001). Neural responses during acquisition under anesthetics were stronger in sessions exhibiting memory formation than those that did not (amygdala median response ratio, 0.52 versus 0.33, n = 101, P = 0.021; dorsal anterior cingulate cortex median response ratio, 0.48 versus 0.32, n = 121, P = 0.012). The change in firing rate of amygdala neurons during acquisition was correlated with the size of stimuli-conditioned inspiratory response during retention (n = 101, r = 0.22 P = 0.026). Thus, amygdala and dorsal anterior cingulate cortex responses during acquisition under anesthetics predicted retention. Respiratory unconditioned responses to the aversive odor anesthetics did not differ from saline controls. Conclusions These results suggest that the amygdala–dorsal anterior cingulate cortex circuit maintains its role in acquisition and maintenance of aversive memories in nonhuman primates under sedation with ketamine and midazolam and that the stimulus valence is sufficient to drive memory formation. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Anesthesia and the neurobiology of fear and posttraumatic stress disorder

“…In studies done with invasive neuronal recordings, signal transduction generally still occurs during implicit memory experimental paradigms. In one recent example with nonhuman primates, using a paradigm with aversive tones conditioned to odors, higher doses of midazolam and ketamine did not ablate aversive memory formation, with persistent neuronal activity in the amygdala and dorsal anterior cingulate [34 ▪ ]. This animal work generally supports the notion that hippocampal pathways for explicit memory formation (for neutral stimuli) are more sensitive to anesthetic inhibition, compared to amygdala-based learning circuits that are engaged in aversive stimulation paradigms [29].…”

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“…The role of anesthesia in memory formation is significant. Research by Nir Samuel, et al revealed that circuits within the macaque's amygdala and dorsal anterior cingulate cortex maintain aversive memory acquisition under ketamine and midazolam sedation [22]. In Drosophila, pentazocine released from dorsal paired medial neurons (DPM) inhibits memory formation during isoflurane anesthesia [23].…”