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Fear Extinction Requires Reward

2018; Cell Press; Volume: 175; Issue: 3 Linguagem: Inglês

10.1016/j.cell.2018.09.036

1097-4172

Sheena A. Josselyn, Paul W. Frankland,

Plant biochemistry and biosynthesis

Learning theorists long hypothesized that appetitive and aversive motivational states influence one another antagonistically. Here, Felsenberg et al. show that the activity of neurons in Drosophila known to be important in appetitive conditioning is necessary for the extinction of aversive conditioning, thereby uncovering biological evidence for this opponent-process. Learning theorists long hypothesized that appetitive and aversive motivational states influence one another antagonistically. Here, Felsenberg et al. show that the activity of neurons in Drosophila known to be important in appetitive conditioning is necessary for the extinction of aversive conditioning, thereby uncovering biological evidence for this opponent-process. We are watching a movie. The main character is showering. The iconic screech, screech of a string section signals that our main character’s shower is about to be disturbed by another unseen character. We tense up, anticipating the worst. Contrary to our expectations, rather than a knife-wielding Norman Bates, the unseen character turns out to be a cat. We giggle. This giggle suggests that the omission of an expected fearful event is not neutral. Rather, it may actually be rewarding. Indeed, the presence of two mutually antagonistic motivational systems (aversive and appetitive) have long been hypothesized by learning theorists (Konosrki, 1967Konosrki J. Integrative Activity of the Brain: An Interdisciplinary Approach. University of Chicago Press, 1967Google Scholar). According to these opponent-process accounts, aversive and appetitive systems reciprocally inhibit one another; activation of the aversive system inhibits the appetitive system (and vice versa). Although this elegant theory provides a somewhat satisfying explanation for our giggling outburst, the neural circuits underlying the competition between appetitive-aversive processes were not fully identified until now. In this issue of Cell, Felsenberg et al., 2018Felsenberg J. Jacob P.F. Walker T. Barnstedt O. Edmondson-Stait A.J. Pleijzier M.W. Otto N. Schlegel P. Sharifi N. Perisse E. et al.Integration of Parallel Opposing Memories Underlies Memory Extinction.Cell. 2018; 175 (Published online September 20, 2018)https://doi.org/10.1016/j.cell.2018.08.021Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar take advantage of the power of Drosophila to not only uncover biological evidence for this long-hypothesized opponent-process system, but also map the underlying brain circuity. They show that the activity of anatomically defined dopaminergic neurons (DANs) known to be important in appetitive learning are necessary for the extinction of aversive conditioning. This finding suggests that the absence of an expected aversive stimulus is functionally similar to the presence of an appetitive stimulus. Flies can be conditioned to avoid or approach a previously neutral odor if paired with an aversive (e.g., electrical shock) or appetitive (e.g., sugar) stimulus, respectively (Tully and Quinn, 1985Tully T. Quinn W.G. Classical conditioning and retention in normal and mutant Drosophila melanogaster.J. Comp. Physiol. A Neuroethol. Sens. Neural Behav. Physiol. 1985; 157: 263-277Crossref PubMed Scopus (898) Google Scholar). For instance, in aversive conditioning, flies are first exposed to an odor (the conditioned stimulus [CS+]) and a shock (the unconditioned stimulus [US]) followed by a second distinct odor (the CS−) presented without shock. Memory is assessed in an odor preference test in which flies must choose between the CS+ versus CS− odors. Initially, this assay was used in forward genetic screens to identify molecular signaling underlying memory (Tully and Quinn, 1985Tully T. Quinn W.G. Classical conditioning and retention in normal and mutant Drosophila melanogaster.J. Comp. Physiol. A Neuroethol. Sens. Neural Behav. Physiol. 1985; 157: 263-277Crossref PubMed Scopus (898) Google Scholar). More recently, the emergence of an arsenal of new genetic tools to manipulate and image the activity of specific neurons in Drosophila makes this a particularly appealing model to study neural circuits underlying memory. Although an oversimplification of a complex circuit, the CS and US signals of olfactory conditioning converge at the level of the mushroom body (MB) (Heisenberg, 2003Heisenberg M. Mushroom body memoir: from maps to models.Nat. Rev. Neurosci. 2003; 4: 266-275Crossref PubMed Scopus (930) Google Scholar, Owald and Waddell, 2015Owald D. Waddell S. Olfactory learning skews mushroom body output pathways to steer behavioral choice in Drosophila.Curr. Opin. Neurobiol. 2015; 35: 178-184Crossref PubMed Scopus (127) Google Scholar). Aversive or appetitive US information is transmitted by DANs, which innervate the MB. Specifically, protocerebral posterior lateral (PPL) DANs provide aversive signals, whereas protocerebral anterior medial (PAM) DANs provide appetitive signals. Importantly, artificially activating specific DANs can substitute for a US forming either an aversive or an appetitive memory (Waddell, 2013Waddell S. Reinforcement signalling in Drosophila; dopamine does it all after all.Curr. Opin. Neurobiol. 2013; 23: 324-329Crossref PubMed Scopus (163) Google Scholar). Dopamine derived from PPL or PAM DAN populations directs synaptic depression of synapses from odor-specific MB Kenyon cells (KCs) onto particular MB output neurons (MBONs) that mediate approach (e.g., V2, MVP2) or avoidance (e.g., M4β′/M6) behaviors, respectively. So the anatomical stage is set for an oppositional approach/avoidance relationship. But how precisely do these aversive and appetitive signals interact? In the present work, the authors first conditioned an aversive response and then extinguished this response by presenting the CS+ odor alone without shock. To examine whether appetitive PAM DANs were important for the extinction of the conditioned aversive response, the authors temporally silenced these neurons during odor re-exposure. Flies in which the output of appetitive DANs was disrupted behaved as if the extinction training did not occur. This finding mirrors a previous observation from this group that showed that extinction of an appetitive memory requires the function of aversive DANs (Felsenberg et al., 2017Felsenberg J. Barnstedt O. Cognigni P. Lin S. Waddell S. Re-evaluation of learned information in Drosophila.Nature. 2017; 544: 240-244Crossref PubMed Scopus (71) Google Scholar). It is well known that following extinction training, conditioned fear may return. In many experimental animals, extinguished conditioned fear responses return with the passage of time (spontaneous recovery), following an aversive event (reinstatement), or in a new non-extinguished context (renewal), suggesting that extinction produces new learning rather than erases the original memory trace. To view these competing engrams (i.e., the original conditioned aversive trace and the new extinction trace), Felsenberg and colleagues expressed a genetically encoded calcium sensor (GCaMP) to monitor the activity of the approach (MVP2) and avoidance (M4β′/M6) MBONs. As expected, following aversive conditioning, CS+-induced dendritic responses in approach neurons were decreased. Although it might be expected that this aversive conditioning would be accompanied by an increase in dendrite responses in avoidance (M4 β′/M6) neurons, no difference was observed in responses to CS+ and CS− odors. Following extinction training, however, decreased dendritic signals were detected in both approach and avoidance MBONs. This decrease in the response of M6 dendrites was similar to that previously observed following appetitive olfactory training with a sugar reward (Owald et al., 2015Owald D. Felsenberg J. Talbot C.B. Das G. Perisse E. Huetteroth W. Waddell S. Activity of defined mushroom body output neurons underlies learned olfactory behavior in Drosophila.Neuron. 2015; 86: 417-427Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar). Based on these findings, as well as light and electron-microscope-level connectomics, the authors propose a model in which MVP2 neurons mediate feedforward inhibition in the network, which indirectly potentiates odor responses in M4β′/M6 axons to drive avoidance behavior. Finding that extinction decreased odor responses in M6 (but not M4β′) dendrites suggests that the original aversive and the new extinction engrams are integrated within the M6 neurons, determining the robustness of conditioned avoidance. That is, parallel but opposing streams of information are decoded at the level of M6-avoidance-promoting neurons. This exquisite work identifies the presence of and pinpoints the anatomical locus for the aversive-appetitive opponent process hypothesized by Konorski and other learning theorists. But is there evidence for a similar process in mammals? Is the circuit motif identified in flies conserved in other species? Of course, the neuroanatomy of rodents differs somewhat from flies. But several studies converge to suggest that a similar circuit organization might underlie the opponent aversive-appetitive process in rodents. First, enhanced DA release in subregions of the nucleus accumbens (particularly in medial shell) has been observed during the shock omission period of fear extinction (Badrinarayan et al., 2012Badrinarayan A. Wescott S.A. Vander Weele C.M. Saunders B.T. Couturier B.E. Maren S. Aragona B.J. Aversive stimuli differentially modulate real-time dopamine transmission dynamics within the nucleus accumbens core and shell.J. Neurosci. 2012; 32: 15779-15790Crossref PubMed Scopus (115) Google Scholar). Second, optogenetic inhibition of DANs projecting from the ventral tegmental area (VTA) to the medial shell area of the nucleus accumbens during this shock omission period prevents extinction (Luo et al., 2018Luo R. Uematsu A. Weitemier A. Aquili L. Koivumaa J. McHugh T.J. Johansen J.P. A dopaminergic switch for fear to safety transitions.Nat. Commun. 2018; 9: 2483Crossref PubMed Scopus (91) Google Scholar), similar to the effects described here in flies. Therefore, the general organization of circuits regulating fear (and avoidance) appear to be conserved from flies to rodents. It is possible by extension, therefore, that a similar circuit accounts for our nervous giggling during horror movies. Integration of Parallel Opposing Memories Underlies Memory ExtinctionFelsenberg et al.CellSeptember 20, 2018In BriefThe omission of punishment is remembered as a rewarding experience, and this positive memory then competes against prior aversive memory to mediate the extinction of avoidance behavior. Full-Text PDF Open Access