Brain c-fos expression patterns induced by emotional stressors differing in nature and intensity

Úbeda-Contreras, Jesús; Marín-Blasco, Ignacio; Nadal, Roser; Armario, Antonio

doi:10.1007/s00429-018-1624-2

Cited by 20 publications

(15 citation statements)

References 73 publications

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“…Weaker RSFC between the nLOT and ACC can reduce ACC’s control over predator scent-triggered defense reaction in low-freezing animals. In addition, the NAc-amygdala circuit mediates avoidance behaviors 28 , and decreased NAc connectivity was consistent with report of the inverse association between NAc activity and the intensity of emotional stress response 24 , which might also be related to goal-directed motor behavior 29 . Furthermore, lower connectivity in ZI circuits (i.e.…”

Section: Resultssupporting

confidence: 88%

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Individual variability in behavior and functional networks predicts vulnerability using a predator scent model of PTSD

Dopfel

Verbitsky

et al. 2018

Preprint

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30Only a minority of individuals who experience traumatic event(s) subsequently 31 develop post-traumatic stress disorder (PTSD). However, whether differences in 32 vulnerability to PTSD result from predisposition or a consequence of trauma exposure 33 remains unclear. A major challenge in differentiating these possibilities is that clinical 34 studies focus on individuals already exposed to traumatic experiences, and do not take 35 into account pre-trauma conditions. Here using the predator scent model of PTSD in rats 36 and a longitudinal design, we measured pre-trauma brain-wide neural circuit functional 37 connectivity (FC), behavioral and corticosterone responses to trauma exposure, and post-38 trauma anxiety. Individual differences in freezing responses to predator scent exposure 39 correlated with differences in pre-trauma FC in a set of neural circuits, especially in 40 olfactory and stress-related systems, indicating that pre-existing function in these circuits 41 could predispose animals to differential fearful responses to threats. Counterintuitively, 42 rats with the lowest freezing showed more avoidance of the predator scent, a prolonged 43 corticosterone response, and higher anxiety long after exposure. This study provides a 44 comprehensive framework of pre-existing circuit function that determines threat response 45 strategy, which might be directly related to the development of PTSD-like behaviors. 46 47 91 awake rat rsfMRI approach established in our lab [17][18][19][20] . Awake rat rsfMRI avoids 92 confounding factors from anesthetics and permits correlation with behavior 21-23 . We 93 5 found that individual differences in behavior and neural circuit function prior to trauma 94 exposure predicted animals' susceptibility to developing PTSD-like behaviors. This 95 suggests that pre-existing traits such as anterior olfactory nucleus (AON)-amygdala 96 connectivity may be critical for determining individual resilience/susceptibility to 97 developing PTSD. 98 99 Results 100The experimental schedule was summarized in Fig. 1a. Rats were first scanned 101 using rsfMRI, then exposed to fox urine, and then given an anxiety test approximately 102 one week after exposure. 103Freezing responses to fox urine were highly variable across animals 104 A total of 87 Long-Evans (LE) rats were exposed to a predator scent stressor in 105 the form of a compressed cotton pad sprayed with fox urine in an inescapable cage for 106 10 min. Freezing and location within the cage were quantified with behavioral tracking 107 software (ANY-maze, Stoelting Co., Reston, VA). Compared to control animals that were 108 exposed to a clean cotton pad, the group exposed to predator scent showed increased 109 freezing (t-test, t87 = 3.660, p = 0.00044, Fig. 1b, left), and maintained a significantly 110 greater distance from the cotton pad (t-test, t87 = 3.568, p = 0.00060, Fig. 1b, right). These 111 data confirm that predator scent exposed animals displayed a significantly greater stress 112 response compared to controls. 113Clos...

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Section: Resultssupporting

confidence: 88%

“…vulnerable) animals caused disinhibition of BNST activity, which led to a stronger stress response and heightened long-lasting anxiety. Conversely, LS mediated activity, possibly again driven by olfactory inputs 24 , can potentiate BNST activity in these animals, and generate stronger stress responses and heightened anxiety.…”

Section: Discussionmentioning

confidence: 94%

Individual variability in behavior and functional networks predicts vulnerability using a predator scent model of PTSD

Dopfel

Verbitsky

et al. 2018

Preprint

View full text Add to dashboard Cite

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“…Additionally, the LS-BNST projection might underlie stronger predator scent-induced stress response in low-freezing animals. In support of this, both the LS and BNST are activated by predator odor 24,25 , and the BNST is actively involved in sustained fear response to diffuse threat 26 . Stronger functional connectivity within the stress system can also contribute to higher stress response and anxiety in low-freezing animals.…”

Section: Resultsmentioning

confidence: 78%

Individual variability in behavior and functional networks predicts vulnerability using an animal model of PTSD

et al. 2019

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Only a minority of individuals experiencing trauma subsequently develop post-traumatic stress disorder (PTSD). However, whether differences in vulnerability to PTSD result from a predisposition or trauma exposure remains unclear. A major challenge in differentiating these possibilities is that clinical studies focus on individuals already exposed to trauma without pre-trauma conditions. Here, using the predator scent model of PTSD in rats and a longitudinal design, we measure pre-trauma brain-wide neural circuit functional connectivity, behavioral and corticosterone responses to trauma exposure, and post-trauma anxiety. Freezing during predator scent exposure correlates with functional connectivity in a set of neural circuits, indicating pre-existing circuit function can predispose animals to differential fearful responses to threats. Counterintuitively, rats with lower freezing show more avoidance of the predator scent, a prolonged corticosterone response, and higher anxiety long after exposure. This study provides a framework of pre-existing circuit function that determines threat responses, which might directly relate to PTSD-like behaviors.

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“…This is supported by a recent finding that stressors varying in intensity, such as open field, cat odor, or immobilization stress, elicit differential patterns of Fos activation throughout the brain. Úbeda-Contreras et al (2018) identified unique patterns of cfos expression that, in some cases, exhibited either a positive or negative relationship with the intensity of the stressor, as assessed by plasma adrenocorticotropic hormone (ACTH) levels, or, in other cases, showed patterns of expression that were independent of stressor intensity. Recognizing which activation responses generalize across stressors and which are stressor-specific is important when interpreting studies aimed at defining neurocircuitry that contributes to stressor-induced relapse.…”

Section: Stress-associated Neurocircuitry: Evidence From Fos Imagingmentioning

confidence: 99%

What does the Fos say? Using Fos-based approaches to understand the contribution of stress to substance use disorders

McReynolds

Christianson

Blacktop

et al. 2018

Neurobiology of Stress

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Despite extensive research efforts, drug addiction persists as a largely unmet medical need. Perhaps the biggest challenge for treating addiction is the high rate of recidivism. While many factors can promote relapse in abstinent drug users, the contribution of stress is particularly problematic, as stress is uncontrollable and pervasive in the lives of those struggling with addiction. Thus, understanding the neurocircuitry that underlies the influence of stress on drug seeking is critical for guiding treatment. Preclinical research aimed at defining this neurocircuitry has, in part, relied upon the use of experimental approaches that allow visualization of cellular and circuit activity that corresponds to stressor-induced drug seeking in rodent relapse models. Much of what we have learned about the mechanisms that mediate stressor-induced relapse has been informed by studies that have used the expression of the immediate early gene, cfos, or its protein product, Fos, as post-mortem activity markers. In this review we provide an overview of the rodent models used to study stressor-induced relapse and briefly summarize what is known about the underlying neurocircuitry before describing the use of cfos/Fos-based approaches. In addition to reviewing findings obtained using this approach, its advantages and limitations are considered. Moreover, new techniques that leverage the expression profile of cfos to tag and manipulate cells based on their activity patterns are discussed. The intent of the review is to guide the interpretation of old and design of new studies that utilize cfos/Fos-based strategies to study the neurocircuitry that contributes to stress-related drug use.

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Brain c-fos expression patterns induced by emotional stressors differing in nature and intensity

Cited by 20 publications

References 73 publications

Individual variability in behavior and functional networks predicts vulnerability using a predator scent model of PTSD

Individual variability in behavior and functional networks predicts vulnerability using a predator scent model of PTSD

Individual variability in behavior and functional networks predicts vulnerability using an animal model of PTSD

What does the Fos say? Using Fos-based approaches to understand the contribution of stress to substance use disorders

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