Early adversity disrupts the adult use of aversive prediction errors to reduce fear in uncertainty

Wright, Kristina M; DiLeo, Alyssa; McDannald, Michael A.

doi:10.3389/fnbeh.2015.00227

Cited by 27 publications

(41 citation statements)

References 46 publications

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“…In the procedure, three auditory cues predict unique foot shock probabilities: danger ( p = 1.00), uncertainty ( p = .375) and safety ( p = .00). Using conditioned suppression of rewarded nose poking as our dependent measure, we have previously found excellent discriminative fear in male and female rats: high to danger, intermediate to uncertainty, and low to safety (Berg et al., ; DiLeo, Wright, & McDannald, ; Ray, Hanlon, & McDannald, ; Walker et al., ; Wright et al., ). Theoretically, +PEs provide an updating mechanism that would permit fear to uncertainty to remain at an intermediate level.…”

Section: Resultsmentioning

confidence: 99%

“…Nevertheless, excessive threat processing is not limited to disorders of anxiety. Adults maltreated as children show exaggerated neural responses to threatening stimuli despite the lack of any clinical diagnosis (Dannlowski et al., ), and our laboratory has shown that early adolescent adversity inflates fear to uncertainty in rodents (Walker et al., ; Wright et al., ). While speculative, the current results offer a potential mechanism by which exaggerated +PE activity in vlPAG neurons could drive excessive fear to ambiguous, threatening cues.…”

Section: Discussionmentioning

confidence: 99%

“…In two experiments, we sought to uncover a relationship between vlPAG +PE activity and fear updating. We employed a fear discrimination procedure in which a danger cue predicted shock deterministically and an uncertainty cue predicted shock probabilistically (Berg, Schoenbaum, & McDannald, 2014;Walker, Andreansky, Ray, & McDannald, 2018;Wright, DiLeo, & McDannald, 2015). In experiment 1, we recorded vlPAG single-units during ongoing fear discrimination, focusing on activity around predicted (danger) and surprising (uncertainty) foot shock delivery.…”

Section: Introductionmentioning

confidence: 99%

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The ventrolateral periaqueductal grey updates fear via positive prediction error

Walker

Wright

Jhou

et al. 2019

Eur J of Neuroscience

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Aversive, positive prediction error (+PE) provides a mechanism to update and increase future fear to uncertain threat predictors. The ventrolateral periaqueductal grey (vlPAG) has been offered as a neural locus for +PE computation. Yet, a causal demonstration of vlPAG +PE activity to update fear remains elusive. We devised a fear discrimination procedure in which a danger cue predicts shock deterministically and an uncertainty cue predicts shock probabilistically, requiring prediction errors to achieve an appropriate fear response. Recording vlPAG single‐unit activity during fear discrimination in Long‐Evans rats, we reveal activity related to shock is consistent with +PE and updates subsequent fear to uncertainty at the trial level. We further demonstrate that vlPAG inhibition during shock selectively decreases future fear to uncertainty, but not danger, and temporal emergence of this effect is consistent with single‐unit activity. These findings provide causal evidence that vlPAG +PE is necessary for fear updating.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The ventrolateral periaqueductal grey updates fear via positive prediction error

Walker

Wright

Jhou

et al. 2019

Eur J of Neuroscience

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“…Stimuli can be heard or downloaded at http://mcdannaldlab.org/resources/ardbark. Previous studies have found these stimuli to be equally salient, yet highly discriminable (Berg et al, 2014;Wright et al, 2015;DiLeo et al, 2016;Ray et al, 2018). The 42-min pre-exposure sessions consisted of four presentations of each cue (12 total presentations) with a mean inter-trial interval (ITI) of 3.5 min.…”

Section: Pre-exposurementioning

confidence: 99%

The nucleus accumbens core is necessary to scale fear to degree of threat

Ray

Russ

Walker

et al. 2020

Preprint

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AbstractFear is adaptive when the level of the response rapidly scales to degree of threat. Using a discrimination procedure consisting of danger, uncertainty and safety cues, we have found rapid fear scaling (within two seconds of cue presentation) in male rats. Here we examined a possible role for the nucleus accumbens core (NAcc) in the acquisition and expression of fear scaling. In experiment 1, male Long Evans rats received bilateral sham or neurotoxic NAcc lesions, recovered and underwent fear discrimination. NAcc-lesioned rats were generally impaired in scaling fear to degree of threat, and specifically impaired in rapid uncertainty-safety discrimination. In experiment 2, male Long Evans rats received NAcc transduction with halorhodopsin or a control fluorophore. After fear scaling was established, the NAcc was illuminated during cue or control periods. NAcc-halorhodopsin rats receiving cue illumination were specifically impaired in rapid uncertainty-safety discrimination. The results reveal a general role for the NAcc in scaling fear to degree of threat, and a specific role in rapid discrimination of uncertain threat and safety.Significance StatementRapidly discriminating cues for threat and safety is essential for survival and impaired threat-safety discrimination is a hallmark of stress and anxiety disorders. In two experiments, we induced nucleus accumbens core (NAcc) dysfunction in rats receiving fear discrimination consisting of cues for danger, uncertainty and safety. Permanent NAcc dysfunction, via neurotoxic lesion, generally disrupted the ability to scale fear to degree of threat, and specifically impaired one component of scaling: rapid discrimination of uncertain threat and safety. Reversible NAcc dysfunction, via optogenetic inhibition, specifically impaired rapid discrimination of uncertain threat and safety. The results reveal that the NAcc is essential to scale fear to degree of threat, and is a plausible source of dysfunction in stress and anxiety disorders.

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“…Clinical studies demonstrate a strong correlation between early-life experiences and cognitive outcomes later in life. Early-life adversity has been linked to increased risk for AD 12 , PTSD 13 and other adult-onset learning and memory impairments 14 . Rodent models allow for the study of causation; indeed, early-life stress in rats and mice lead to structural atrophy of dendrites, attenuated long-term potentiation, and impaired hippocampus-dependent memory in adulthood [15][16][17] .…”

Section: Introductionmentioning

confidence: 99%

A Unique Mouse Model of Early Life Exercise Enables Hippocampal Memory and Synaptic Plasticity

Ivy

Kramár³

et al. 2019

Preprint

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Exercise is a powerful modulator of learning and memory function in humans. The cognitive benefits of aerobic physical activity, as well as underlying molecular mechanisms, are well documented in studies on adult rodents. For example, voluntary running wheel activity in adult mice allows for the formation of long term, hippocampus-dependent memory of typically subthreshold learning events 1 . One of the primary mechanisms by which exercise enables long term memory is via the regulation of the brain-derived neurotrophic factor (BDNF), a molecule critical for hippocampal-dependent learning and memory formation in adult rodents. Less is known about the short and long-term consequences of early life exercise (ELE) on hippocampal-dependent memory and synaptic plasticity, specifically if the exercise is taking place during periods of postnatal hippocampal maturation. We hypothesize that ELE during one week (postnatal days P21-27) or three weeks (P21-41) can enable long term spatial memory formation in adolescent mice. To address this hypothesis, we tested spatial memory formation in the Object Location Memory task, which is hippocampus-dependent. Further, we test for changes in hippocampal synaptic plasticity after these two periods of ELE with electrophysiological studies. Our results suggest early-exercise has a lasting impact on hippocampal memory and synaptic plasticity when occurring during periods of postnatal hippocampal maturation.

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Early adversity disrupts the adult use of aversive prediction errors to reduce fear in uncertainty

Cited by 27 publications

References 46 publications

The ventrolateral periaqueductal grey updates fear via positive prediction error

The ventrolateral periaqueductal grey updates fear via positive prediction error

The nucleus accumbens core is necessary to scale fear to degree of threat

A Unique Mouse Model of Early Life Exercise Enables Hippocampal Memory and Synaptic Plasticity

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