Basal forebrain cholinergic neurons are part of the threat memory engram

Rajebhosale, Prithviraj; Ananth, Mala; Crouse, Richard B.; Jiang, Li; G, López Hernández; Arty, Christian; Wang, S; Jone, Alice; Zhong, Chongbo; Desai, Niraj S.; Y, Li; Picciotto, Marina R.; Lw, Role; Da, Talmage

doi:10.1101/2021.05.02.442364

Cited by 12 publications

(19 citation statements)

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“…While dopamine has also been proposed to encode salience across valence based on novelty induced dopamine release, we did not observe NE release to non-associated cues, suggesting a bias towards valence (Kutlu et al, 2021), we did not observe significant NE release to a novel, non-associated cue. Acetylcholine has been hypothesized to be a valence-free prediction error which responds to both positive and negative valence (Crouse et al, 2020;Hangya et al, 2015;Rajebhosale et al, 2021;Sturgill et al, 2020). It is likely that an interacting array of neuromodulators produces teaching signals necessary for prediction of incoming outcomes across valence.…”

Section: Discussionmentioning

confidence: 99%

“…More recent work has attempted to explain dopamine release dynamics by incorporating the effects of temporal uncertainty to explain dopamine release seen in multistage operant tasks. While dopamine and other neuromodulators are released in response to aversive as well as rewarding cues (Crouse et al, 2020;Hangya et al, 2015;Matsumoto & Hikosaka, 2009;Rajebhosale et al, 2021;Sturgill et al, 2020), the neuromodulatory basis of aversive prediction errors remains poorly understood.…”

Section: Introductionmentioning

confidence: 99%

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Prefrontal norepinephrine represents a threat prediction error under uncertainty

Basu

Yang

et al. 2022

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Animals must learn to predict constantly varying threats in the environment to survive by enacting defensive behaviors. Dopamine is involved in the prediction of rewards, encoding a reward prediction error in a similar manner to temporal difference learning algorithm. However, the corresponding molecular and computational form of threat prediction errors is not as well-characterized, although norepinephrine and other neuromodulators and neuropeptides participate in fear learning. Here, we utilized fluorescent norepinephrine recordings over the course of fear learning in concert with reinforcement learning modeling to identify its role in the prediction of threat. By varying timing and sensory uncertainty in the formation of threat associations, we were able to define a precise computational role for norepinephrine in this process. Norepinephrine release approximates the strength of fear associations, and its temporal dynamics are compatible with a prediction error signal. Intriguingly, the release of norepinephrine is influenced by time and sensory feedback, serving as an antithesis of the classical reward prediction error role of dopamine. Thus, these results directly demonstrate a combined cognitive and affective role of norepinephrine in the prediction of threat, with implications for neuropsychiatric disorders such as anxiety and PTSD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Prefrontal norepinephrine represents a threat prediction error under uncertainty

Basu

Yang

et al. 2022

Preprint

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“…Yet, the point estimate of increased response to the CS- did not entirely explain the group difference in the acquisition of conditioned fear; some residual deficit may be attributable to a decreased response to the CS+ in the schizophrenia group. The response to the CS+ is thought to reflect cue-induced adaptive dopamine release 7 , similar to prediction error learning related dopamine release 45 . Studies using reinforcement learning paradigms have shown that while deficits in learning from rewards is associated with negative symptoms, learning from aversive outcomes may be spared in schizophrenia 41 .…”

Section: Discussionmentioning

confidence: 99%

“…Those prior results are consistent with our current findings of relatively intact responses to the CS+ (a negative reinforcer). Finally, changes in other neurotransmitters, such as glutamate 42,43 , acetylcholine 44,45 and serotonin 46 , which play a role in fear conditioning, may also contribute to the impairments observed in schizophrenia in associative learning.…”

Section: Fear Conditioning In Schizophrenia Versus Anxiety Disordersmentioning

confidence: 99%

Impairment in acquisition of conditioned fear in schizophrenia: a pooled analysis of four studies

Tuominen

Romaniuk

et al. 2021

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Background: Individuals with schizophrenia show impairments in associative learning. One well-studied, quantifiable form of associative learning is Pavlovian fear conditioning. However, to date, studies of fear conditioning in schizophrenia have been inconclusive, possibly because they lacked sufficient power. Methods: To address this issue, data were pooled from 4 independent fear conditioning studies that included a total of 77 individuals with schizophrenia and 74 control subjects. Skin conductance responses (SCRs) during fear conditioning to stimuli that were paired (the CS+) and not paired (CS-) with an aversive, unconditioned stimulus were measured, and the success of acquisition of differential conditioning (the magnitude of CS+ vs CS- SCRs) and responses to CS+ and CS- separately were assessed. Results: Acquisition of differential conditioned fear responses was significantly lower in individuals with schizophreania than in healthy controls (Cohen's d = 0.53). This effect was primarily related to a significantly higher response to the CS- stimulus in the schizophrenia compared to the control group. The magnitude of this response to the CS- in the schizophrenia group was correlated with the severity of delusional ideation. Other symptoms or antipsychotic dose were not associated with fear conditioning measures. Conclusions: Individuals with schizophrenia who endorse delusional beliefs are over-responsive to neutral stimuli during fear conditioning. This finding is consistent with prior models of aberrant learning in psychosis.

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“…Behavioral and electrophysiology studies illustrate that the NBM-BLA circuit facilitates learning by controlling the consolidation of salient cues. For example, NBM cholinergic neurons fire rapidly in response to appetitive or aversive stimuli ( Zhang et al, 2004 ; Hangya et al, 2015 ; Rajebhosale et al, 2021 ) and cause transient and scaled increases in BLA acetylcholine levels ( Mark et al, 1996 ; Jing et al, 2020 ; Liu et al, 2021 ). Optogenetic stimulation of ChAT + terminal fields in the BLA enhances cue-reward learning ( Crouse et al, 2020 ) and prolongs fear extinction ( Jiang et al, 2016 ; Kellis et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Chronic Intermittent Ethanol Exposure Dysregulates Nucleus Basalis Magnocellularis Afferents in the Basolateral Amygdala

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Price

Parrish

et al. 2022

eNeuro

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Nucleus basalis magnocellularis (NBM) cholinergic projections to the basolateral amygdala (BLA) regulate the acquisition and consolidation of fear-and anxiety-like behaviors.However, it is unclear whether the alterations in the NBM-BLA circuit promote negative affect during ethanol withdrawal. Therefore, we performed ex vivo whole-cell patch clamp electrophysiology in both the NBM and the BLA of male Sprague-Dawley rats following 10 days of chronic intermittent ethanol (CIE) exposure and 24 hours of withdrawal (WD). We found that CIE exposure and withdrawal enhanced the neuronal excitability of NBM putative 'cholinergic' neurons. We subsequently used optogenetics to directly manipulate NBM terminal activity within the BLA and measure cholinergic modulation of glutamatergic afferents and BLA pyramidal neurons. Our findings indicate that CIE and withdrawal upregulate NBM cholinergic facilitation of glutamate release via activation of presynaptic nicotinic acetylcholine receptors. Ethanol withdrawal-induced increases in NBM terminal activity also enhance BLA pyramidal neuron firing. Collectively, our results provide a novel characterization of the NBM-BLA circuit and suggest that CIE-dependent modifications to NBM afferents enhance BLA pyramidal neuron activity during ethanol withdrawal. 3 Significance statementChronic alcohol dysregulates the neural circuitry controlling behavioral responses to stress, emotion, and motivation, and produces maladaptive behaviors that cause relapse. Since nucleus basalis magnocellularis (NBM) cholinergic projections to the basolateral amygdala (BLA) regulate the acquisition/consolidation of fear and anxiety, we used electrophysiology to understand how alcohol withdrawal alters NBM neurons and measure downstream effects on their BLA projections. Our results provide a novel characterization of the NBM-BLA circuit and illustrate that alcohol withdrawal strengthens NBM cholinergic neurotransmission and upregulates glutamate signaling in the BLA through the activation of nicotinic acetylcholine receptors. Collectively, these findings illustrate that modifications in NBM projections may disrupt the excitatory/inhibitory balance in the BLA and help promote BLA pyramidal neuron activity during alcohol withdrawal.

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Basal forebrain cholinergic neurons are part of the threat memory engram

Cited by 12 publications

References 67 publications

Prefrontal norepinephrine represents a threat prediction error under uncertainty

Prefrontal norepinephrine represents a threat prediction error under uncertainty

Impairment in acquisition of conditioned fear in schizophrenia: a pooled analysis of four studies

Chronic Intermittent Ethanol Exposure Dysregulates Nucleus Basalis Magnocellularis Afferents in the Basolateral Amygdala

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