Traumatic Brain Injury–Induced Fear Generalization in Mice Involves Hippocampal Memory Trace Dysfunction and Is Alleviated by (R,S)-Ketamine

McGowan, Josephine C.; Ladner, Liliana; Tapia, Juliana; LaGamma, Christina T; Anqueira-González, Amanda; DeFrancesco, Ariana; Chen, Briana K.; Hunsberger, Holly C.; E, Sydnor; Logan, Ryan W.; Yu, Tzong-Shiue; Kernie, Steven G.; Denny, Christine A.

doi:10.1016/j.biopsych.2023.06.030

Cited by 2 publications

(1 citation statement)

References 49 publications

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“…Furthermore, besides psychological stress, the physical injuries that occur in TBI are also associated with an increased risk for comorbid PTSD (Stein et al, 2019;Yurgil et al, 2014), anxiety disorders (Mallya et al, 2015), and fear of symptoms known as fear avoidance (e.g., withdrawal from environments that trigger symptoms) that can contribute to persistent symptoms (Silverberg et al, 2018). Preclinical models of TBI also support heightened and prolonged defensive behaviors (Almeida-Suhett et al, 2014;Jones et al, 2008;Reger et al, 2012), increased sensory sensitivity that promotes exaggerated fear learning (Hoffman et al, , 2020, and increased fear generalization (Hoffman, Watson, et al, 2022;McGowan et al, 2024). Significant stressors, trauma exposure, traumatic injuries, and prior close calls with a predator have a profound impact on subsequent responses and appraisal of threat and potential threat cues.…”

Section: Stress and Trauma-related Disordersmentioning

confidence: 99%

Fear, defense, and emotion: A neuroethological understanding of the negative valence research domain criteria.

Fanselow,

Hoffman

2024

American Psychologist

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We describe the close correspondence between predatory imminence continuum theory (PICT) and the National Institute of Mental Health's Research Domain Criteria (RDoC) for negative valence. RDoC's negative valence constructs relate aversively motivated behavioral reactions to various levels of threat. PICT divides defensive responses into distinct modes that vary along a continuum of the psychological closeness of predatory threat. While there is a close correspondence between PICT modes and negative valence threat constructs, based on PICT, we describe some potential elaborations of RDoC constructs. Both have consonant views of fear and anxiety and provide explicit distinctions between these emotional states, relating them to specific defensive behaviors and functions. We describe recent data that causally implicate human subjective emotional states with amygdala activity, which is also critical for defensive behavior. We conclude that attention to neuroethological views of defense can advance our understanding of the etiology and treatment of anxiety and stress disorders. Public Significance StatementThe National Institute of Mental Health's Research Domain Criteria (RDoC) for negative valence aims to connect clinical observations relevant to anxiety disorders to their underlying biology. RDoC's negative valence constructs relate aversively motivated behavioral reactions to various levels of threat. We describe the correspondence between predatory imminence theory, which divides defensive responses into distinct modes that vary along a continuum of the psychological closeness of predatory threat and RDoC.

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Section: Stress and Trauma-related Disordersmentioning

confidence: 99%

Fear, defense, and emotion: A neuroethological understanding of the negative valence research domain criteria.

Fanselow,

Hoffman

2024

American Psychologist

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An infralimbic cortex neuronal ensemble encoded during learning attenuates fear generalization expression

Subramanian,

Bauman,

Carpenter

et al. 2024

Preprint

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Generalization expands learned experiences to flexible guide behavior when conditions change. A basic physical unit of memory storage and expression in the brain are sparse, distributed groups of neurons known as ensembles (i.e., the engram). The infralimbic (IL) subregion of the ventral medial prefrontal cortex plays a key role in modulating conditioned defensive responses. How IL neuronal ensembles established during learning contribute to generalized responses is unknown. In this set of experiments, generalization was tested in male and female mice by presenting a novel, ambiguous, tone generalization stimulus following Pavlovian defensive (fear) conditioning. The first experiment was designed to test a role for IL in generalization using chemogenetic manipulations. Results show IL bidirectionally regulates defensive behavior. IL silencing promotes a switch in defensive state from vigilant scanning to generalized freezing, while IL stimulation reduced freezing in favor of scanning. Leveraging activity-dependent tagging technology (ArcCreERT2 x eYFP system), a neuronal ensemble, preferentially located in IL superficial layer 2/3, was associated with the generalization stimulus. Remarkably, in the identical discrete location, fewer reactivated neurons were associated with the generalization stimulus at the remote timepoint (30 days) following learning. When an IL neuronal ensemble established during learning was selectively chemogenetically silenced, generalization increased. Conversely, IL neuronal ensemble stimulation reduced generalization. Overall, these data identify a crucial role for IL in suppressing generalized responses. Further, we uncovered an IL neuronal ensemble, formed during learning, functions to later attenuate the expression of generalization in the presence of ambiguous threat stimuli.

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Traumatic Brain Injury–Induced Fear Generalization in Mice Involves Hippocampal Memory Trace Dysfunction and Is Alleviated by (R,S)-Ketamine

Cited by 2 publications

References 49 publications

Fear, defense, and emotion: A neuroethological understanding of the negative valence research domain criteria.

Fear, defense, and emotion: A neuroethological understanding of the negative valence research domain criteria.

An infralimbic cortex neuronal ensemble encoded during learning attenuates fear generalization expression

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