Functionally refined encoding of threat memory by distinct populations of basal forebrain cholinergic projection neurons
- National Institute of Neurological Disorders and Stroke, United States
- Yale University, United States
- Kansas City University of Medicine and Biosciences, United States
- LinkedIn, United States
- National Institute of Environmental Health Sciences, United States
- Steris, United States
- Peking University, China
Abstract
Neurons of the basal forebrain nucleus basalis and posterior substantia innominata (NBM/SIp) comprise the major source of cholinergic input to the basolateral amygdala (BLA). Using a genetically-encoded acetylcholine (ACh) sensor in mice, we demonstrate that BLA-projecting cholinergic neurons can 'learn' the association between a naïve tone and a foot shock (training) and release ACh in the BLA in response to the conditioned tone 24h later (recall). In the NBM/SIp cholinergic neurons express the immediate early gene, Fos following both training and memory recall. Cholinergic neurons that express Fos following memory recall display increased intrinsic excitability. Chemogenetic silencing of these learning-activated cholinergic neurons prevents expression of the defensive behavior to the tone. In contrast, we show that NBM/SIp cholinergic neurons are not activated by an innately threatening stimulus (predator odor). Instead, VP/SIa cholinergic neurons are activated and contribute to defensive behaviors in response to predator odor, an innately threatening stimulus. Taken together, we find that distinct populations of cholinergic neurons are recruited to signal distinct aversive stimuli, demonstrating functionally refined organization of specific types of memory within the cholinergic basal forebrain of mice.
Data availability
Source data for the fiber photometry experiments presented in Figure 1 and supplements are provided as individual source data files.
Article and author information
Author details
Prithviraj Rajebhosale
Marina R Picciotto
Funding
National Institute of Neurological Disorders and Stroke (1ZIANS009424)
- David A Talmage
National Institute of Neurological Disorders and Stroke (1ZIANS009416,1ZIANS009422)
- Lorna W Role
National Institute of Neurological Disorders and Stroke (NS22061)
- Lorna W Role
- David A Talmage
National Institute of Mental Health (U01-MH109104)
- Lorna W Role
- David A Talmage
National Institute of Mental Health (MH077681)
- Marina R Picciotto
National Institute on Drug Abuse (DA14241,DA037566)
- Marina R Picciotto
National Institute of Neurological Disorders and Stroke (NS007224)
- Richard B Crouse
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal care and experimental procedures were approved by the Animal Care and Use Committees (ACUC) of the National Institute of Neurological Disorders & Stroke (NINDS) (Protocol #1531), SUNY Research Foundation at Stony Brook University (Protocol #1618), and Yale University (Protocol #2019-07895).
Copyright
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
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Functionally refined encoding of threat memory by distinct populations of basal forebrain cholinergic projection neurons
eLife 13:e86581.
https://doi.org/10.7554/eLife.86581
Further reading
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Outcomes can vary even when choices are repeated. Such ambiguity necessitates adjusting how much to learn from each outcome by tracking its variability. The medial prefrontal cortex (mPFC) has been reported to signal the expected outcome and its discrepancy from the actual outcome (prediction error), two variables essential for controlling the learning rate. However, the source of signals that shape these coding properties remains unknown. Here, we investigated the contribution of cholinergic projections from the basal forebrain because they carry precisely timed signals about outcomes. One-photon calcium imaging revealed that as mice learned different probabilities of threat occurrence on two paths, some mPFC cells responded to threats on one of the paths, while other cells gained responses to threat omission. These threat- and omission-evoked responses were scaled to the unexpectedness of outcomes, some exhibiting a reversal in response direction when encountering surprising threats as opposed to surprising omissions. This selectivity for signed prediction errors was enhanced by optogenetic stimulation of local cholinergic terminals during threats. The enhanced threat-evoked cholinergic signals also made mice erroneously abandon the correct choice after a single threat that violated expectations, thereby decoupling their path choice from the history of threat occurrence on each path. Thus, acetylcholine modulates the encoding of surprising outcomes in the mPFC to control how much they dictate future decisions.
