Chemogenetic stimulation of the infralimbic cortex reverses alcohol-induced fear memory overgeneralization

Scarlata, Miranda; Lee, S. H.; Lee, D.; Kandigian, S. E.; Hiller, Abigail J.; Dishart, Julian G; Mintz, G. E.; Wang, Z.; Coste, G. I.; Mousley, Alexa Lee; Soler, Ivan; Lawson, K.; Ng, Alexandra J.; Bezek, Jessica; Bergstrom, Hadley C.

doi:10.1038/s41598-019-43159-w

Cited by 23 publications

(25 citation statements)

References 105 publications

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“…Besides, the IL and the adjacent PL typically have opposite roles in learning and memory processing 39 , a feature also valid to fear overgeneralization. Whereas stimulating the IL activity suppresses it 40 , a similar approach applied to the PL can promote it 41 . Unlike Test B, there were no differences between muscimol and vehicle groups during Test A in any experiment conducted here (except experiment 7, in which it was carried out post-extinction).…”

Section: Discussionmentioning

confidence: 99%

Infralimbic cortex controls fear memory generalization and susceptibility to extinction during consolidation

Bayer

Bertoglio

2020

Sci Rep

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Lesioning or inactivating the infralimbic (IL) subregion of the medial prefrontal cortex before acquisition produces more generalized and extinction-resistant fear memories. However, whether and how it modulates memory specificity and extinction susceptibility while consolidation takes place is still unknown. The present study aims to investigate these questions using muscimol-induced temporary inactivation and anisomycin-induced protein synthesis inhibition in the rat IL following contextual fear conditioning. Results indicate that the IL activity immediately after acquisition, but not six hours later, controls memory generalization over a week, regardless of its strength. Such IL function depends on the context-shock pairing since muscimol induced no changes in animals exposed to immediate shocks or the conditioning context only. Animals in which the IL was inactivated during consolidation extinguished similarly to controls within the session but were unable to recall the extinction memory the following day. Noteworthy, these post-acquisition IL inactivation-induced effects were not associated with changes in anxiety, as assessed in the elevated plus-maze test. Anisomycin results indicate that the IL protein synthesis during consolidation contributes more to producing extinction-sensitive fear memories than memory specificity. Collectively, present results provide evidence for the IL's role in controlling generalization and susceptibility to extinction during fear memory consolidation.

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Section: Discussionmentioning

confidence: 99%

Infralimbic cortex controls fear memory generalization and susceptibility to extinction during consolidation

Bayer

Bertoglio

2020

Sci Rep

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“…Approximately 30 days between training and testing has been consistently shown to increase both cued and contextual fear memory generalization, although shorter retention intervals have been reported (Lynch et al, 2013). There is also now a growing body of evidence to suggest that both chronic alcohol exposure and stress exposure promote generalized fear responses in rats and mice (Bender, Otamendi, Calfa, & Molina, 2018;Elliott & Richardson, 2019;Scarlata et al, 2019;Sillivan et al, 2017;Stephens et al, 2005). Finally, context and cued exposure before and after fear learning is another extrinsic factor that can determine the degree of generalization and discrimination.…”

Section: Of 15mentioning

confidence: 99%

“…A value of 1 signifies discrimination while a value of 0.5 indicates complete generalization (Pollack et al, 2018;Scarlata et al, 2019).…”

Section: Discrimination Index = T/(t + N)mentioning

confidence: 99%

“…For these reasons, Pavlovian fear conditioning is currently a leading model for studying circuity thought to be dysregulated in PTSD. Numerous brain systems have been demonstrated to contribute to fear discrimination and generalization processing, including the cingulate cortex (Ortiz et al., ), hippocampus (Besnard & Sahay, ), amygdala (Ciocchi et al., ; Ghosh & Chattarji, ; Grosso, Santoni, Manassero, Renna, & Sacchetti, ), thalamic and subthalamic nuclei (Ferrara, Cullen, Pullins, Rotondo, & Helmstetter, ; Ramanathan, Ressler, Jin, & Maren, ; Venkataraman et al., ; Xu & Sudhof, ), midbrain (Rozeske et al., ), and prefrontal cortices (Fitzgerald et al., ; Pollack et al., ; Rozeske et al., ; Scarlata et al., ). For a review on the neurobiology of fear generalization, see Asok, Kandel, and Rayman () and Sangha, Diehl, Bergstrom, and Drew ().…”

Section: Introductionmentioning

confidence: 99%

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Assaying Fear Memory Discrimination and Generalization: Methods and Concepts

Bergstrom

2020

CP Neuroscience

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Generalization describes the transfer of conditioned responding to stimuli that perceptually differ from the original conditioned stimulus. One arena in which discriminant and generalized responding is of particular relevance is when stimuli signal the potential for harm. Aversive (fear) conditioning is a leading behavioral model for studying associative learning and memory processes related to threatening stimuli. This article describes a step‐by‐step protocol for studying discrimination and generalization using cued fear conditioning in rodents. Alternate conditioning paradigms, including context generalization, differential generalization, discrimination training, and safety learning, are also described. The protocol contains instructions for constructing a cued fear memory generalization gradient and methods for isolating discrete cued‐from‐context cued conditioned responses (i.e., “the baseline issue”). The preclinical study of generalization is highly pertinent in the context of fear learning and memory because a lack of fear discrimination (overgeneralization) likely contributes to the etiology of anxiety‐related disorders and post‐traumatic stress disorder. © 2020 by John Wiley & Sons, Inc. Basic Protocol 1: Tone cued fear generalization gradient Basic Protocol 2: Quantification of freezing Support Protocol: Alternate conditioning paradigms

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“…fear learning). These deficits include impaired extinction learning, heightened, stress-induced reinstatement, and increased fear generalization (Holmes, et al 2012;Bertotto, et al 2006;Broadwater & Spear, 2013;Scarlata et al 2019).…”

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confidence: 99%

Chronic activation of fear engrams induces extinction-like behavior in ethanol-exposed mice

Cincotta

Murawski

Grella

et al. 2020

Preprint

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ABSTRACTAlcohol withdrawal directly impacts the brain’s stress and memory systems, which may underlie individual susceptibility to persistent drug and alcohol-seeking behaviors. Numerous studies demonstrate that forced alcohol abstinence, which may lead to withdrawal, can impair fear-related memory processes in rodents such as extinction learning, however the underlying neural circuits mediating these impairments remain elusive. Here, we tested an optogenetic strategy aimed at mitigating fear extinction impairments in male c57BL/6 mice following exposure to alcohol (i.e., ethanol) and forced abstinence. In the first experiment, extensive behavioral extinction training in a fear-conditioned context was impaired in ethanol-exposed mice compared to controls. In the second experiment, neuronal ensembles processing a contextual fear memory in the dorsal hippocampus were tagged and optogenetically reactivated repeatedly in a distinct context in ethanol-exposed and control mice. Chronic activation of these cells resulted in a context-specific, extinction-like reduction in fear responses in both control and ethanol-exposed mice. These findings suggest that while ethanol can impair fear extinction learning, optogenetic manipulation of a fear engram is sufficient to induce an extinction-like reduction in fear responses.

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Chemogenetic stimulation of the infralimbic cortex reverses alcohol-induced fear memory overgeneralization

Cited by 23 publications

References 105 publications

Infralimbic cortex controls fear memory generalization and susceptibility to extinction during consolidation

Infralimbic cortex controls fear memory generalization and susceptibility to extinction during consolidation

Assaying Fear Memory Discrimination and Generalization: Methods and Concepts

Chronic activation of fear engrams induces extinction-like behavior in ethanol-exposed mice

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