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
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Recognizing and responding to threat cues is essential to survival. Freezing is a predominant threat behavior in rats. We have recently shown that a threat cue can organize diverse behaviors beyond freezing, including locomotion (Chu et al., 2024). However, that experimental design was complex, required many sessions, and had rats receive many foot shock presentations. Moreover, the findings were descriptive. Here, we gave female and male Long Evans rats cue light illumination paired or unpaired with foot shock (eight total) in a conditioned suppression setting using a range of shock intensities (0.15, 0.25, 0.35, or 0.50 mA). We found that conditioned suppression was only observed at higher foot shock intensities (0.35 mA and 0.50 mA). We constructed comprehensive temporal ethograms by scoring 22,272 frames across 12 behavior categories in 200-ms intervals around cue light illumination. The 0.50 mA and 0.35 mA shock-paired visual cues suppressed reward seeking, rearing, and scaling, as well as light-directed rearing and light-directed scaling. These shock-paired visual cues further elicited locomotion and freezing. Linear discriminant analyses showed that ethogram data could accurately classify rats into paired and unpaired groups. Using complete ethogram data produced superior classification compared to behavior subsets, including an immobility subset featuring freezing. The results demonstrate diverse threat behaviors – in a short and simple procedure – containing sufficient information to distinguish the visual fear conditioning status of individual rats.
