Dopamine neurons drive fear extinction learning by signaling the omission of expected aversive outcomes

Salinas-Hernández, Ximena I; Vogel, Pascal; Betz, Sebastian; Kalisch, Raffaël; Sigurdsson, Torfi; Duvarci, Sevil

doi:10.7554/elife.38818

Cited by 157 publications

(116 citation statements)

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“…Our study indicates a modulatory role of the FN-vlPAG pathway in fear extinction. Consistent with our results, evidence for negative prediction error was found in vlPAG 40 , as well as in the ventral tegmental area and dorsal raphe 48, 49 , which also receive inputs from the vlPAG.…”

Section: Discussionsupporting

confidence: 91%

Bidirectional control of fear memories by the cerebellum through the ventrolateral periaqueductal grey

Frontera

Aissa

Sala

et al. 2020

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10Fear conditioning is a form of associative learning that is known to involve brain areas, notably the 11 amygdala, the prefrontal cortex and the periaqueductal grey (PAG). Here, we describe the functional 12 role of pathways that link the cerebellum with the fear network. We found that the cerebellar 13 fastigial nucleus (FN) sends glutamatergic projections to vlPAG that synapse onto glutamatergic and 14 GABAergic vlPAG neurons. Chemogenetic and optogenetic manipulations revealed that the FN-vlPAG 15 pathway controls bi-directionally the strength of the fear memory, indicating a role in the association 16 of the conditioned and unconditioned stimuli, a function consistent with vlPAG encoding of fear 17 prediction error. In addition, we found that a FN -thalamic parafascicular nucleus pathway, which 18 may relay cerebellar influence to the amygdala, is involved in anxiety and fear expression but not in 19 fear memory. Our results reveal the contributions to the emotional system of the cerebellum, which 20 exerts a potent control on the strength of the fear memory through excitatory FN-vlPAG projections. 21 22 23 Keywords: cerebellum; limbic circuits; fear memory, chemogenetics, electrophysiology 24 vermis, in relation to negative emotions (e.g. during recall of self-generated emotional episodes 20 ). 50 Consistent with this, localized cerebellar lesions, principally in the midline vermis, account in large 51 part for the emotional disturbances, inappropriate behavior and changes in affect, which are 52 collectively termed the "cerebellar cognitive affective syndrome" 21 and reported in cerebellar 53 patients. Several studies have shown that the cerebellum has functional connections from fear-54 related areas including the PAG, the amygdala, and the prefrontal cortex [22][23][24][25] . In accordance with the 55 existence of such connections, Pavlovian fear conditioning affects cerebellar plasticity 26 , post-56 conditioning cerebellar inactivation affects memory consolidation 27 , and cerebellar lesions -or 57 inactivation-modulate freezing 24,28 ; however, the pathways by which the cerebellum participates to 58 fear learning or expression remain undefined. 59. The cerebellar vermis, which is most consistently associated with emotional pathologies and fear 60 expression 20,24,29 , projects to the fastigial nucleus (FN), a deep cerebellar nucleus (DCN) which 61 projects to many targets from the spinal cord to the diencephalon 22 . The purpose of the present 62 study is to study the contribution of specific FN output pathways to fear learning. Using 63 neuroanatomical tracings, chemogenetic modulation of the cerebellar input to the vlPAG and to the 64 BLA during fear conditioning, optogenetics and extracellular electrophysiological recordings in awake 65 freely moving animals, we demonstrate the contribution of the cerebellum to fear learning through 66 its inputs to the vlPAG. 67 68 4 69 70Results 71 Neuroanatomical link between the cerebellum and vlPAG 72In order to examine cerebellar projections to areas involve...

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Section: Discussionsupporting

confidence: 91%

Bidirectional control of fear memories by the cerebellum through the ventrolateral periaqueductal grey

Frontera

Aissa

Sala

et al. 2020

Preprint

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“…DA neurons originating in the VTA are known to be modulated by aversive stimuli, and have been implicated in fear conditioning and extinction (El-Ghundi, O'Dowd, and George 2001;Young, Joseph, and Gray 1993;Inoue et al 2000;Nader and LeDoux 1999;Guarraci and Kapp 1999;Holtzman-Assif, Laurent, and Westbrook 2010;Delgado et al 2008;Luo et al 2018;Salinas-Hernández et al 2018;Zweifel et al 2011;Pezze and Feldon 2004;Mueller, Bravo-Rivera, and Quirk 2010;Pignatelli et al 2017;Nasehi et al 2016;Pezze, Bast, and Feldon 2003;Budygin et al 2012;Robinson et al 2019;Lammel et al 2011;Jo, Heymann, and Zweifel 2018;Lutas et al 2019;Fadok, Dickerson, and Palmiter 2009;Groessl et al 2018;Bouchet et al 2018;Wenzel et al 2018;Wang and Tsien 2011;Mileykovskiy and Morales 2011) . However, it was unclear if and how neural correlates of fear extinction are topographically organized within the VTA.…”

Section: Discussionmentioning

confidence: 99%

“…Although most work examining neural correlates of behavior in VTA DA neurons has focused on reward-based tasks, several studies have recorded VTA DA neuron activity during aversive associations (Robinson et al 2019;Lutas et al 2019;Wang and Tsien 2011;Mileykovskiy and Morales 2011) . In particular, VTA DA neurons were shown to represent RPE-like signals during fear extinction, in that they display elevated activity when the shock is omitted at the offset of the cue, signaling better-than-expected outcome (Salinas-Hernández et al 2018;Badrinarayan et al 2012;Jo, Heymann, and Zweifel 2018) . Manipulation of this activity altered the rate of extinction, suggesting that an RPE-like signal in DA neurons drives reinforcement learning for aversive associations as well as rewarding associations (Salinas-Hernández et al 2018;Luo et al 2018) .…”

Section: Introductionmentioning

confidence: 99%

“…In particular, VTA DA neurons were shown to represent RPE-like signals during fear extinction, in that they display elevated activity when the shock is omitted at the offset of the cue, signaling better-than-expected outcome (Salinas-Hernández et al 2018;Badrinarayan et al 2012;Jo, Heymann, and Zweifel 2018) . Manipulation of this activity altered the rate of extinction, suggesting that an RPE-like signal in DA neurons drives reinforcement learning for aversive associations as well as rewarding associations (Salinas-Hernández et al 2018;Luo et al 2018) .…”

Section: Introductionmentioning

confidence: 99%

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Distinct signals in medial and lateral VTA dopamine neurons modulate fear extinction at different times

Cai

Pizano

Gundersen

et al. 2020

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Dopamine (DA) neurons are known to encode reward prediction error (RPE), in addition to other signals, such as salience. While RPE is known to support learning, the role of salience in supporting learning remains less clear. To address this, we recorded and manipulated VTA DA neurons in mice during fear extinction, a behavior we observed to generate spatially segregated RPE and salience signals. We applied deep learning to classify mouse freezing behavior, eliminating the need for human scoring. Our fiber photometry recordings showed that DA neurons in medial and lateral VTA have distinct activity profiles during fear extinction: medial VTA activity more closely reflected RPE, while lateral VTA activity more closely reflected a salience-like signal. Optogenetic inhibition of DA neurons in either region slowed fear extinction, with the relevant time period for inhibition differing across regions. Our results indicate that salience-like signals can have similar downstream consequences to RPE-like signals, although with different temporal dependencies.

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“…Dopamine promotes avoidance responses to aversive stimuli by modulating the activity of the brainstem-projecting prefrontal neurons and nucleus accumbens neurons [15,16]. Dopamine drives both fear learning and reward learning by signaling prediction error [17][18][19][20][21][22][23][24][25]. Enhancing striatal dopamine increases the exploration of novel choices while decreasing the exploitation of learned options [26][27][28].…”

Section: Introductionmentioning

confidence: 99%

Ramping and phasic dopamine activity accounts for efficient cognitive resource allocation during reinforcement learning

Song

2018

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Dopamine activity may transition between two patterns: phasic responses to reward-predicting cues and ramping activity arising when an agent approaches the reward. However, when and why dopamine activity transitions between these modes is not understood. We hypothesize that the transition between ramping and phasic patterns reflects resource allocation which addresses the task dimensionality problem during reinforcement learning (RL). By parsimoniously modifying a standard temporal difference (TD) learning model to accommodate a mixed presentation of both experimental and environmental stimuli, we simulated dopamine transitions and compared it with experimental data from four different studies. The results suggested that dopamine transitions from ramping to phasic patterns as the agent narrows down candidate stimuli for the task; the opposite occurs when the agent needs to re-learn candidate stimuli due to a value change. These results lend insight into how dopamine deals with the tradeoff between cognitive resource and task dimensionality during RL.

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Dopamine neurons drive fear extinction learning by signaling the omission of expected aversive outcomes

Cited by 157 publications

References 70 publications

Bidirectional control of fear memories by the cerebellum through the ventrolateral periaqueductal grey

Bidirectional control of fear memories by the cerebellum through the ventrolateral periaqueductal grey

Distinct signals in medial and lateral VTA dopamine neurons modulate fear extinction at different times

Ramping and phasic dopamine activity accounts for efficient cognitive resource allocation during reinforcement learning

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