The basolateral amygdala (BLA) is critical for associating initially neutral cues with appetitive and aversive stimuli and receives dense neuromodulatory acetylcholine (ACh) projections. We measured BLA ACh signaling and activity of neurons expressing CaMKIIα (a marker for glutamatergic principal cells) in mice during cue-reward learning using a fluorescent ACh sensor and calcium indicators. We found that ACh levels and nucleus basalis of Meynert (NBM) cholinergic terminal activity in the BLA (NBM-BLA) increased sharply in response to reward-related events and shifted as mice learned the cue-reward contingency. BLA CaMKIIα neuron activity followed reward retrieval and moved to the reward-predictive cue after task acquisition. Optical stimulation of cholinergic NBM-BLA terminal fibers led to quicker acquisition of the cue-reward contingency. These results indicate BLA ACh signaling carries important information about salient events in cue-reward learning and provides a framework for understanding how ACh signaling contributes to shaping BLA responses to emotional stimuli.

31The basolateral amygdala (BLA) is critical for associating initially neutral cues with 32 appetitive and aversive stimuli and receives dense neuromodulatory acetylcholine (ACh) 33 projections. We measured BLA ACh signaling and principal neuron activity in mice during cue-34 reward learning using a fluorescent ACh sensor and calcium indicators. We found that ACh 35 levels and activity of nucleus basalis of Meynert (NBM) cholinergic terminals in the BLA (NBM-36 BLA) increased sharply in response to reward-related events and shifted as mice learned the 37 tone-reward contingency. BLA principal neuron activity followed reward retrieval and moved to 38 the reward-predictive tone after task acquisition. Optical stimulation of cholinergic NBM-BLA 39 terminal fibers during cue-reward learning led to more rapid learning of the cue-reward 40 contingency. These results indicate that BLA ACh signaling carries important information about 41 salient events in cue-reward learning and provides a framework for understanding how ACh 42 signaling contributes to shaping BLA responses to emotional stimuli. 43 44 1991; Zaborszky et al., 2012). Optical stimulation of BLA-projecting cholinergic terminal fibers 62 (NBM-BLA) during fear conditioning is sufficient to strengthen fear memories (Jiang et al., 2016) 63and may support appetitive behavior (Aitta-aho et al., 2018). Cholinergic NBM neurons increase 64 their firing in response to both rewarding and aversive unconditioned stimuli (Hangya et al., 65 2015). A recent study has also demonstrated that NBM cells fire in response to a conditioned 66 stimulus during trace fear conditioning, indicating that ACh signaling may be involved in learning 67 about cues that predict salient outcomes . 68 5We hypothesized that ACh signaling in the BLA is a critical neuromodulatory signal that 69 responds to both unconditioned stimuli and cues that gain salience, thereby coordinating activity 70 in circuits necessary for learning cue-reward contingencies. To test this hypothesis, we 71 measured relative levels of BLA ACh (ACh signaling), cholinergic NBM-BLA terminal fiber 72 activity (BLA ACh signal origin), and the activity of BLA principal neurons (BLA output) across all 73 phases of learning in an appetitive operant learning task to evaluate how BLA output and ACh 74 signaling are related to behavioral performance in this paradigm. We then optically stimulated 75 cholinergic NBM fibers locally in the BLA while mice learned to nose poke in response to an 76 auditory cue to receive a food reward to determine if accelerating the increase in ACh signaling 77 that occurs as mice learn the task would enhance performance. We also pharmacologically 78 blocked different ACh receptors during the learning task to determine the subtypes involved, 79and varied the timing of optical stimulation of cholinergic NBM-BLA terminal fibers to determine 80 whether time-locked ACh release with the reward-predictive cue is necessary for the 81 improvement of the task performance. These studies provide a novel framewo...

Learning involving interoceptive stimuli likely plays an important role in many diseases and psychopathologies. Within this area, there has been extensive research investigating the interoceptive stimulus effects of abused drugs. In this pursuit, behavioral pharmacologists have taken advantage of what is known about learning processes and adapted the techniques to investigate the behavioral and receptor mechanisms of drug stimuli. Of particular interest is the nicotine stimulus and the use of the two-lever operant drug discrimination task and the Pavlovian drug discriminated goal-tracking task. There is strong concordance between the two methods when using “standard” testing protocols that minimize learning on test days. For example, ABT-418, nornicotine, and varenicline all fully evoked nicotine-appropriate responding. Notably, research from our laboratory with the discriminated goal-tracking task has used an alternative testing protocol. This protocol assesses stimulus substitution based on how well extinction learning using a non-nicotine ligand transfers back to the nicotine stimulus. These findings challenge conclusions based on more “standard” testing procedures (e.g., ABT-418 is not nicotine-like). As a starting point, we propose Thurstone scaling as a quantitative method for more precisely comparing transfer of extinction across doses, experiments, and investigators. We close with a discussion of future research directions and potential implications of the research for understanding interoceptive stimuli.

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Differential rearing decreases psychostimulant-induced hyperactivity. In general, environmental enrichment decreases the locomotor response to low unit doses of psychostimuluants, whereas isolation increases the response. It is not clear whether the changes in locomotor activity are due to an enrichment-induced decrease or an isolation-induced increase. Therefore, the current experiments examined the ability of enrichment rearing, as compared with isolation and standard rearing, to attenuate amphetamine-induced hyperactivity following acute administration, repeated administration, and sensitization of a low (0.3 mg/kg) and moderate (1.0 mg/kg) dose of amphetamine. Rats were reared under enriched, isolated, or standard conditions. Enrichment slowed the acquisition of amphetamine-induced hyperactivity and attenuated the expression of amphetamine-induced sensitization, but only at the low unit dose. Enrichment did not protect against the expression of conditioned hyperactivity at either of the doses tested. The behavior of standard condition rats was generally closer to that of isolated condition rats than enriched condition rats, suggesting that the enrichment attenuates the response to amphetamine as opposed to isolation rearing increasing the response to amphetamine. These results suggest that the effects of enrichment are because of enrichment manipulation and not simply a contrast from the effects of isolation.