Overexpressing Corticotropin-Releasing Factor in the Primate Amygdala Increases Anxious Temperament and Alters Its Neural Circuit

Kalin, Ned H.; Fox, Andrew S.; Kovner, Rothem; Riedel, Marissa K.; Fekete, Éva; Roseboom, Patrick H.; Tromp, Do; Grabow, Benjamin P.; Olsen, Miles; Brodsky, Ethan K.; McFarlin, Daniel R.; Alexander, Andrew L.; Emborg, Marina E.; Block, Walter F.; Fudge, Julie L.; Oler, Jonathan A.

doi:10.1016/j.biopsych.2016.01.010

Cited by 71 publications

(70 citation statements)

References 94 publications

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“…Although the molecular underpinnings of dispositional negativity and its neural substrates remain poorly understood (Bastiaansen et al, 2014; Bogdan, Pagliaccio, Baranger, & Hariri, 2016; Christian et al, 2009), some promising candidates have recently been identified in humans (Buckholtz et al, 2008; Okbay et al, in press ), monkeys (Alisch et al, 2014; A. S. Fox et al, 2012; Kalin et al, in press ; Oler et al, 2009; Rogers et al, 2013; Roseboom et al, 2014), and rodents (Turner, Clinton, Thompson, Watson, & Akil, 2011). …”

Section: The Nature and Consequences Of Elevated Dispositional Negatimentioning

confidence: 99%

“…Reduced BST activity has also been found in humans with OFC damage (Motzkin, Philippi, Oler, et al, 2015), suggesting that this circuit is conserved across primate species. Interestingly, viral vector manipulations that increase metabolic activity in the Ce—the other major component of the central extended amygdala—are associated with elevated metabolic activity in the OFC, increased functional connectivity between the Ce and OFC, and heightened signs of fear and anxiety during prolonged exposure to threat (Kalin et al, in press ). Conversely, Ce lesions are associated with reduced metabolic activity in the OFC (Machado et al, 2008).…”

Section: The Psychophysiology and Neurobiology Of Dispositional Negatmentioning

confidence: 99%

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Dispositional negativity: An integrative psychological and neurobiological perspective.

Shackman¹,

Tromp²,

Stockbridge³

et al. 2016

Psychological Bulletin

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Dispositional negativity—the propensity to experience and express more frequent, intense, or enduring negative affect—is a fundamental dimension of childhood temperament and adult personality. Elevated levels of dispositional negativity can have profound consequences for health, wealth, and happiness, drawing the attention of clinicians, researchers, and policy makers. Here, we highlight recent advances in our understanding of the psychological and neurobiological processes linking stable individual differences in dispositional negativity to momentary emotional states. Self-report data suggest that three key pathways—increased stressor reactivity, tonic increases in negative affect, and increased stressor exposure—explain most of the heightened negative affect that characterizes individuals with a more negative disposition. Of these three pathways, tonically elevated, indiscriminate negative affect appears to be most central to daily life and most relevant to the development of psychopathology. New behavioral and biological data provide insights into the neural systems underlying these three pathways and motivate the hypothesis that seemingly ‘tonic’ increases in negative affect may actually reflect increased reactivity to stressors that are remote, uncertain, or diffuse. Research focused on humans, monkeys, and rodents suggests that this indiscriminate negative affect reflects trait-like variation in the activity and connectivity of several key brain regions, including the central extended amygdala and parts of the prefrontal cortex. Collectively, these observations provide an integrative psychobiological framework for understanding the dynamic cascade of processes that bind emotional traits to emotional states and, ultimately, to emotional disorders and other kinds of adverse outcomes.

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Section: The Nature and Consequences Of Elevated Dispositional Negatimentioning

confidence: 99%

Section: The Psychophysiology and Neurobiology Of Dispositional Negatmentioning

confidence: 99%

Dispositional negativity: An integrative psychological and neurobiological perspective.

Shackman¹,

Tromp²,

Stockbridge³

et al. 2016

Psychological Bulletin

Self Cite

210

208

View full text Add to dashboard Cite

show abstract

“…However, this tendency is itself the result of biological and environmental factors. The experience of frequent anxious states is assumed to feed back into biological factors through neuroplasticity (105) and epigenetic changes (106, 107), thereby opening a pathway for the effect of early stressful life events on biological vulnerability to the development of anxiety disorders (108–110). Biological vulnerabilities are assumed to affect environment factors directly by increasing attention to environmental threats, as described in the section, “Trait Anxiety: Targets for Computational Studies” [for other ways in which trait vulnerabilities might promote aversive experiences, see Ref.…”

Section: State Anxiety Trait Anxiety and Anxiety Disordersmentioning

confidence: 99%

Modeling Trait Anxiety: From Computational Processes to Personality

2017

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Computational methods are increasingly being applied to the study of psychiatric disorders. Often, this involves fitting models to the behavior of individuals with subclinical character traits that are known vulnerability factors for the development of psychiatric conditions. Anxiety disorders can be examined with reference to the behavior of individuals high in “trait” anxiety, which is a known vulnerability factor for the development of anxiety and mood disorders. However, it is not clear how this self-report measure relates to neural and behavioral processes captured by computational models. This paper reviews emerging computational approaches to the study of trait anxiety, specifying how interacting processes susceptible to analysis using computational models could drive a tendency to experience frequent anxious states and promote vulnerability to the development of clinical disorders. Existing computational studies are described in the light of this perspective and appropriate targets for future studies are discussed.

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“…The increase in anxious temperament correlated directly with increased fluorodeoxyglucose metabolism (by PET) and fMRI functional connectivity within a circuit that included the dorsal amygdala, orbital proisocortex/anterior insula and hippocampus (Kalin et al 2016). …”

Section: Recent Genetic and Molecular Findings In Humansmentioning

confidence: 99%

Don’t stress about CRF: assessing the translational failures of CRF1antagonists

2017

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BACKGROUND Dr. Athina Markou sought treatments for a common neural substrate shared by depression and drug dependence. Antagonists of corticotropin-releasing factor (CRF) receptors, a target of interest to her, have not reached the clinic despite strong preclinical rationale and sustained translational efforts. METHODS We explore potential causes for the failure of CRF1 antagonists and review recent findings concerning CRF-CRF1 systems in psychopathology. RESULTS Potential causes for negative outcomes include: 1) poor safety and efficacy of initial drug candidates due to bad pharmacokinetic and physicochemical properties 2) specificity problems with preclinical screens, 3) the acute nature of screens vs late-presenting patients, 4.) positive preclinical results were limited to certain models and conditions with dynamic CRF-CRF1 activation not homologous to tested patients, 5) repeated CRF1 activation-induced plasticity that reduces the importance of ongoing CRF1 agonist stimulation, 6) therapeutic silencing may need to address CRF2 receptor or CRF-BP molecules, constitutive CRF1 activity, or molecules that influence agonist-independent activity or to target structural regions other than the allosteric site bound by all drug candidates We describe potential markers of activation towards individualized treatment, human genetic and functional data that still implicate CRF1 systems in emotional disturbance, sex differences, and suggestive clinical findings for CRF1 antagonists in food craving and CRF-driven HPA-axis overactivation. CONCLUSION The therapeutic scope of selective CRF1 antagonists now appears narrower than had been hoped. Yet, much remains to be learned about CRF’s role in the neurobiology of dysphoria and addiction and the potential for novel anti-CRF therapies therein.

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Overexpressing Corticotropin-Releasing Factor in the Primate Amygdala Increases Anxious Temperament and Alters Its Neural Circuit

Cited by 71 publications

References 94 publications

Dispositional negativity: An integrative psychological and neurobiological perspective.

Dispositional negativity: An integrative psychological and neurobiological perspective.

Modeling Trait Anxiety: From Computational Processes to Personality

Don’t stress about CRF: assessing the translational failures of CRF1antagonists

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