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Cited by 766Memory and Neural MechanismsNeuroscience and Neuropharmacology ResearchNeurotransmitter Receptor Influence on Behavior

Resolving the neural circuits of anxiety

Open access
Calhoon, Gwendolyn G, Tye, Kay M·2015·Nature Neuroscience
DOI 10.1038/nn.4101PMC PMC7575249
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Abstract

Although anxiety disorders represent a major societal problem demanding new therapeutic targets, these efforts have languished in the absence of a mechanistic understanding of this subjective emotional state. While it is impossible to know with certainty the subjective experience of a rodent, rodent models hold promise in dissecting well-conserved limbic circuits. The application of modern approaches in neuroscience has already begun to unmask the neural circuit intricacies underlying anxiety by allowing direct examination of hypotheses drawn from existing psychological concepts. This information points toward an updated conceptual model for what neural circuit perturbations could give rise to pathological anxiety and thereby provides a roadmap for future therapeutic development.

AI snapshot

Written from the paper’s full text.

TL;DR

This review proposes that anxiety arises from distributed, highly interconnected corticolimbic circuits that assign emotional value to stimuli ("interpretation") and weigh threats against learned associations and competing drives ("evaluation"), with perturbations anywhere in the system producing pathological anxiety. It argues that circuit-level approaches, particularly optogenetics, have shifted the field from region-specific lesion studies toward a network model with therapeutic implications.

Key findings

  • Anxiety disorders are common and undertreated: prevalence is estimated at 18% among adults with lifetime prevalence over 28%, yet since the 1950s FDA-approved new molecular entities with primary anxiety indications have been limited to benzodiazepines and the atypical anxiolytics buspirone, meprobamate and hydroxyzine pamoate.
  • The authors propose a four-step framework — detection, interpretation, evaluation, response initiation — in which the amygdala (notably the BLA) assigns valence, while the mPFC and motivational circuits (NAc, mesocorticolimbic dopamine) evaluate whether threat interpretations are appropriately weighted.
  • Projection-defined populations within the same region can have opposing behavioral effects: photoactivation of BLA somata increases innate anxiety, whereas targeted photostimulation of BLA inputs to CeL is anxiolytic; BLA projections to NAc versus CeM oppositely encode positive and negative valence.
  • Oscillatory synchrony reflects internal state: vHPC theta (4–12 Hz) entrains mPFC and conveys an anxiogenic signal, whereas mPFC-originating theta provides a safety signal to BLA; theta coherence among infralimbic cortex, CA1 and lateral amygdala is greater in serotonin receptor 1A knockout mice (a trait-anxiety model) than in wild-type controls.

Methods

  • Narrative review synthesizing rodent circuit-level literature on fear and anxiety, with emphasis on optogenetic, pharmacological, electrophysiological and lesion studies.
  • Organizes evidence around macrocircuit nodes (amygdala, BNST, vHPC, mPFC) and their reciprocal projections, plus microcircuit-level findings (e.g., CeL PKCδ-positive and -negative populations, SOM-positive CeL neurons).
  • Reviews rodent behavioral assays (EPM, elevated zero maze, OFT, light-dark box, staircase, elevated alley, hole board, shock-probe and marble burying, hyponeophagia, social interaction, ultrasonic vocalizations) and physiological measures, noting validity considerations.

Limitations

  • The paper states no formal limitations section; it acknowledges that whether animals experience emotions as humans do is controversial, and that the review focuses on rodent 'state' anxiety rather than the clinical 'trait' anxiety of the literature.
  • Evident from the text: the proposed interpretation/evaluation model is a conceptual framework rather than a directly tested hypothesis, and the authors note that a comprehensive understanding of dynamic interactions within these distributed networks is still needed before circuit-based interventions such as neural circuit reprogramming become reality.
  • Evident from the text: several cited findings conflict (e.g., direct photostimulation of ventral dentate gyrus granule cells suppresses anxiety-like behavior, apparently at odds with BLA-to-vHPC results), and the authors offer only a tentative reconciliation via feedforward inhibition of CA3 pyramidal cells.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/nn.4101

Cites

149 of 149 references verified0 citation errors · 0 not checkable

Statistics

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Claims the paper makes

0 of 154 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Exploration-based tasks cannot distinguish a reduced anxiety phenotype from increased novelty-seeking, exploration or impulsive approach behavior.

    “A further confound of exploration-based tasks is that they cannot distinguish a reduced anxiety phenotype from increased novelty-seeking, exploration or impulsive approach behavior23.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [23] Cryan, J.F. & Holmes, A. The ascent of mouse: advances in modelling human depression and anxiety. Nat. Rev. Drug Discov. 4, 775–790 (2005). source

      Not checked in the free run.

  • Premisecitation

    Since the 1950s, new molecular entities approved by the FDA with primary indications for anxiety have been limited to benzodiazepines and the atypical anxiolytics buspirone, meprobamate and hydroxyzine pamoate.

    “Since the 1950s, new molecular entities approved by the US Food and Drug Administration (FDA) with primary indications for anxiety have been limited to benzodiazepines and the atypical anxiolytics buspirone, meprobamate and hydroxyzine pamoate18.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Kinch, M.S., Haynesworth, A., Kinch, S.L. & Hoyer, D. An overview of FDA-approved new molecular entities: 1827–2013. Drug Discov. Today 19, 1033–1039 (2014). source

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  • Premisecitation

    The neural systems implicated in anxiety by rodent studies are consistent with those identified in human patients.

    “This contrast notwithstanding, the neural systems implicated in anxiety by rodent studies are consistent with those identified in human patients26-34, underscoring the utility and translatability of these rodent studies.”
    Quote in the paperSubstantial claim0 of 9 sources checked
    • cites [26] Adhikari, A. Distributed circuits underlying anxiety. Front. Behav. Neurosci. 8, 112 (2014). source

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    • cites [27] Degroot, A. & Treit, D. Anxiety is functionally segregated within the septo-hippocampal system. Brain Res. 1001, 60–71 (2004). source

      Not checked in the free run.

    • cites [28] Eden, A.S. et al. Emotion regulation and trait anxiety are predicted by the microstructure of fibers between amygdala and prefrontal cortex. J. Neurosci. 35, 6020–6027 (2015). source

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    • cites [29] Etkin, A., Prater, K.E., Schatzberg, A.F., Menon, V. & Greicius, M.D. Disrupted amygdalar subregion functional connectivity and evidence of a compensatory network in generalized anxiety disorder. Arch. Gen. Psychiatry 66, 1361–1372 (2009). source

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    • cites [30] Irle, E. et al. Reduced amygdalar and hippocampal size in adults with generalized social phobia. J. Psychiatry Neurosci. 35, 126–131 (2010). source

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    • cites [31] Kim, S.-Y. et al. Diverging neural pathways assemble a behavioural state from separable features in anxiety. Nature 496, 219–223 (2013). First study to provide causal evidence that separate circuits control the behavioral and physiological features of anxiety. source

      Not checked in the free run.

    • cites [32] Likhtik, E., Stujenske, J.M., Topiwala, M.A., Harris, A.Z. & Gordon, J.A. Prefrontal entrainment of amygdala activity signals safety in learned fear and innate anxiety. Nat. Neurosci. 17, 106–113 (2014). Identifies a macrocircuit-level mechanism to discern safety from threat, whereby BLA firing is tuned to mPFC oscillatory activity. source

      Not checked in the free run.

    • cites [33] Tye, K.M. et al. Amygdala circuitry mediating reversible and bidirectional control of anxiety. Nature 471, 358–362 (2011). Original optogenetic dissection of the control of anxiety by separate aspects of the BLA microcircuit and first study to employ projection-specific optogenetic manipulations of behavior. source

      Not checked in the free run.

    • cites [34] Yassa, M.A., Hazlett, R.L., Stark, C.E.L. & Hoehn-Saric, R. Functional MRI of the amygdala and bed nucleus of the stria terminalis during conditions of uncertainty in generalized anxiety disorder. J. Psychiatr. Res. 46, 1045–1052 (2012). source

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  • Premisecitation

    In the elevated zero maze, anxious mice prefer the walled quadrants to the open ones.

    “The ambiguous center of the EPM is eliminated in the elevated zero maze; however, the task resembles the EPM otherwise in that anxious mice prefer the walled quadrants to the open ones36.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] Shepherd, J.K., Grewal, S.S., Fletcher, A., Bill, D.J. & Dourish, C.T. Behavioural and pharmacological characterisation of the elevated 'zero-maze' as an animal model of anxiety. Psychopharmacology (Berl.) 116, 56–64 (1994). source

      Not checked in the free run.

  • Premisecitation

    In the elevated plus maze, anxious mice avoid the open arms of the maze in favor of the walled arms.

    “In the elevated plus maze (EPM), anxious mice avoid the open arms of the maze in favor of the walled arms35.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Pellow, S., Chopin, P., File, S.E. & Briley, M. Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J. Neurosci. Methods 14, 149–167 (1985). source

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  • Classified as probably not a substantial claim. 31
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    Premisecitation

    In all cases of pathological anxiety, the somatic, cognitive and behavioral manifestations interfere with normal functioning and lead to substantial economic and personal burdens.

    “The precipitating stimuli differ among these diagnoses; however, in all cases, the somatic, cognitive and behavioral manifestations of anxiety interfere with normal functioning and lead to substantial economic and personal burdens9-11.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [9] Bereza, B.G., Machado, M. & Einarson, T.R. Systematic review and quality assessment of economic evaluations and quality-of-life studies related to generalized anxiety disorder. Clin. Ther. 31, 1279–1308 (2009). source

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    • cites [10] Mondin, T.C. et al. Anxiety disorders in young people: a population-based study. Rev. Bras. Psiquiatr. 35, 347–352 (2013). source

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    • cites [11] Pagotto, L.F. et al. The impact of posttraumatic symptoms and comorbid mental disorders on the health-related quality of life in treatment-seeking PTSD patients. Compr. Psychiatry 58, 68–73 (2015). source

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    Premisecitation

    Fear occurs acutely in response to a real or perceived imminent threat and dissipates on removal of the eliciting stimulus.

    “By contrast, the related emotional state of fear occurs acutely in response to a real or perceived imminent threat and dissipates on removal of the eliciting stimulus7.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] Davis, M., Walker, D.L., Miles, L. & Grillon, C. Phasic vs sustained fear in rats and humans: role of the extended amygdala in fear vs anxiety. Neuropsychopharmacology 35, 105–135 (2010). source

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  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Computations in corticolimbic circuits resulting in the interpretation of environmental threat subsequently drive an observable anxiety-like response.

    “Moreover, we suggest that computations in corticolimbic circuits resulting in the interpretation of environmental threat subsequently drive an observable anxiety-like response.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Premisecitation

    For a truly mechanistic understanding of the neural underpinnings of anxiety, the ability to manipulate specific circuit components is required, demanding the use of next-generation technologies in model organisms.

    “For a truly mechanistic understanding of the neural underpinnings of anxiety, the ability to manipulate specific circuit components is required, demanding the use of next-generation technologies in model organisms21.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Allsop, S.A., Vander Weele, C.M., Wichmann, R. & Tye, K.M. Optogenetic insights on the relationship between anxiety-related behaviors and social deficits. Front. Behav. Neurosci. 8, 241 (2014). source

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    Premisecitation

    To provide insights about the pathophysiology of anxiety disorders, measurements of anxiety-like behaviors in animals must meet the essential criterion of validity.

    “To provide insights about the pathophysiology of anxiety disorders, measurements of anxiety-like behaviors in animals must meet the essential criterion of validity (see Box 1) (refs. 22,23).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [22] Belzung, C. & Griebel, G. Measuring normal and pathological anxiety-like behaviour in mice: a review. Behav. Brain Res. 125, 141–149 (2001). source

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    • cites [23] Cryan, J.F. & Holmes, A. The ascent of mouse: advances in modelling human depression and anxiety. Nat. Rev. Drug Discov. 4, 775–790 (2005). source

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    Premisecitation

    DSM-5 divides pathological anxiety into three main categories: obsessive-compulsive and related disorders, trauma- and stressor-related disorders, and anxiety disorders.

    “The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition divides pathological anxiety into three main categories of disorders, including obsessive-compulsive and related disorders, trauma- and stressor-related disorders, and anxiety disorders8.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 5th edn., http://dsm.psychiatryonline.org/doi/book/10.1176/appi.books.9780890425596 (American Psychiatric Association, 2013). source

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    Interpretationreasoning

    Perturbations anywhere in these circuits disrupt balance in the entire system, resulting in a fundamental misinterpretation of neutral sensory information as threatening and leading to the inappropriate emotional and behavioral responses seen in anxiety disorders and other psychiatric disease states.

    “Finally, we posit that perturbations anywhere in these circuits disrupt balance in the entire system, resulting in a fundamental misinterpretation of neutral sensory information as threatening and leading to the inappropriate emotional—and thereby behavioral—responses seen in anxiety disorders, as well as other psychiatric disease states.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In the light-dark box, anxiety-related behavior is measured as a propensity to remain in the darkened portion of the chamber.

    “whereas in the light-dark box, anxiety-related behavior is measured as a propensity to remain in the darkened portion of the chamber38.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Ambrogi Lorenzini, C., Bucherelli, C. & Giachetti, A. Passive and active avoidance behavior in the light-dark box test. Physiol. Behav. 32, 687–689 (1984). source

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    Premisecitation

    Rodents will bury an electrified probe after having received shocks from the probe and will spontaneously bury marbles introduced as a novelty into their home cages.

    “Rodents will bury an electrified probe after having received shocks from the probe43 and will even spontaneously bury marbles introduced as a novelty into their home cages44.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [43] Degroot, A. & Nomikos, G.G. Genetic deletion and pharmacological blockade of CB1 receptors modulates anxiety in the shock-probe burying test. Eur. J. Neurosci. 20, 1059–1064 (2004). source

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    • cites [44] Njung'e, K. & Handley, S.L. Evaluation of marble-burying behavior as a model of anxiety. Pharmacol. Biochem. Behav. 38, 63–67 (1991). source

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    Premisecitation

    More recently, the label indications for antidepressants such as certain tricyclic antidepressants, SSRIs and SNRIs have been extended by the FDA to include anxiety.

    “More recently, the label indications for antidepressants such as certain tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) have been extended by the FDA to include anxiety19.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] U.S. Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm .

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  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based). May combine two claims.

    Interpretationnone given

    Information processing in distributed, interlinked nodes results in the assignment of emotional value to environmental stimuli (interpretation) and the weighing of potential threats against previously learned associations and competing motivational needs (evaluation).

    “We propose that information processing in distributed, interlinked nodes results in the assignment of emotional value to environmental stimuli, operationalized here as “interpretation,” as well as the weighing of potential threats against previously learned associations and competing motivational needs, referred to here as “evaluation.””
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Premisecitation

    To improve treatment strategies for anxiety, a thorough understanding of the neural circuits governing this emotional state in health and disorder is needed.

    “To improve treatment strategies for anxiety, a thorough understanding of the neural circuits governing this emotional state in health and disorder is needed20.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Tye, K.M. Neural circuit reprogramming: a new paradigm for treating neuropsychiatric disease? Neuron 83, 1259–1261 (2014). source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Anxiety represents a state of high arousal and negative valence and results in enhanced vigilance in the absence of an immediate threat.

    “Anxiety represents a state of high arousal and negative valence6 and results in enhanced vigilance in the absence of an immediate threat7.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [6] Russell, J.A. A circumplex model of affect. J. Pers. Soc. Psychol. 39, 1161–1178 (1980). source

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    • cites [7] Davis, M., Walker, D.L., Miles, L. & Grillon, C. Phasic vs sustained fear in rats and humans: role of the extended amygdala in fear vs anxiety. Neuropsychopharmacology 35, 105–135 (2010). source

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  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Anxiety disorders arise from disruptions in the highly interconnected circuits normally serving to process the stream of stimuli detected by our brains from the outside world.

    “Here we review the state of our field and postulate that anxiety disorders arise from disruptions in the highly interconnected circuits normally serving to process the stream of stimuli detected by our brains from the outside world.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Anxiety disorders represent a major societal problem demanding new therapeutic targets.
    • Rests on an assumption: Efforts to develop new therapeutic targets for anxiety have languished in the absence of a mechanistic understanding of this subjective emotional state.

  • May combine two claims.

    Interpretationnone given

    In the macrocircuit, sensory information regarding potential threats flows along circular loops, transmitted forward from the amygdala to the BNST, vHPC and mPFC and downstream effector nuclei, and backward from the mPFC and vHPC to the amygdala and BNST.

    “In this macrocircuit, sensory information regarding potential threats flows along circular loops in which it is transmitted both forward (from the amygdala onward to the BNST, vHPC and medial PFC (mPFC), and consequently to downstream effector nuclei) and backward (from the mPFC and vHPC back to the amygdala and BNST).”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Inhibition of PKCδ-positive CeLOFF cells by PKCδ-negative CeLON cells results in disinhibition of CeM output neurons, consequently driving freezing behavior and changes in heart rate via CeM projections to the periaqueductal gray and dorsal vagal complex.

    “Inhibition of the latter population by the former results in the disinhibition of CeM output neurons, consequently driving freezing behavior and changes in heart rate via CeM projections to the periaqueductal gray and dorsal vagal complex, respectively52 (Fig. 3).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52] Viviani, D. et al. Oxytocin selectively gates fear responses through distinct outputs from the central amygdala. Science 333, 104–107 (2011). Identification of discrete CeA efferent pathways separately regulating behavioral and physiological fear responses. source

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  • May combine two claims.

    Premisecitation

    BLA inputs to the anterodorsal BNST promote behavioral and physiological anxiolysis; local inhibition of anterodorsal BNST by the oval nucleus of the BNST is anxiogenic.

    “BLA inputs to the anterodorsal BNST promote behavioral and physiological anxiolysis; local inhibition of anterodorsal BNST by the oval nucleus of the BNST is anxiogenic31.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Kim, S.-Y. et al. Diverging neural pathways assemble a behavioural state from separable features in anxiety. Nature 496, 219–223 (2013). First study to provide causal evidence that separate circuits control the behavioral and physiological features of anxiety. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Photoactivation of BLA somata increases measures of innate anxiety, as well as learned inhibitory avoidance.

    “Moreover, photoactivation of BLA somata increases measures of innate anxiety33, as well as learned inhibitory avoidance80.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [33] Tye, K.M. et al. Amygdala circuitry mediating reversible and bidirectional control of anxiety. Nature 471, 358–362 (2011). Original optogenetic dissection of the control of anxiety by separate aspects of the BLA microcircuit and first study to employ projection-specific optogenetic manipulations of behavior. source

      Not checked in the free run.

    • cites [80] Huff, M.L., Miller, R.L., Deisseroth, K., Moorman, D.E. & LaLumiere, R.T. Posttraining optogenetic manipulations of basolateral amygdala activity modulate consolidation of inhibitory avoidance memory in rats. Proc. Natl. Acad. Sci. USA 110, 3597–3602 (2013). source

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    Premisecitation

    Targeted photostimulation of BLA inputs to CeL is anxiolytic, presumably via enhanced inhibitory influence over CeM projection neurons.

    “Targeted photostimulation of BLA inputs to CeL, by contrast, is anxiolytic, presumably via enhanced inhibitory influence over CeM projection neurons55.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [55] McDonald, A.J. Cortical pathways to the mammalian amygdala. Prog. Neurobiol. 55, 257–332 (1998). source

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    Premisecitation

    In the absence of a functional BLA, the BNST acts as a compensatory site in the acquisition of fear memories, although this BLA-independent fear learning requires more training.

    “For example, in the absence of a functional BLA, the BNST acts as a compensatory site in the acquisition of fear memories, although this BLA-independent fear learning requires more training84.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [84] Poulos, A.M., Ponnusamy, R., Dong, H.-W. & Fanselow, M.S. Compensation in the neural circuitry of fear conditioning awakens learning circuits in the bed nuclei of the stria terminalis. Proc. Natl. Acad. Sci. USA 107, 14881–14886 (2010). source

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    Premisecitation

    When removed from their mothers, pups emit ultrasonic vocalizations in the frequency range associated with fear and anxiety-like responses, and such stress-induced vocalizations are reduced by anxiolytics.

    “When removed from their mothers, pups emit ultrasonic vocalizations in the frequency range associated with fear and anxiety-like responses, and such stress-induced vocalizations are reduced by anxiolytics50.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [50] Gardner, C.R. Distress vocalization in rat pups. A simple screening method for anxiolytic drugs. J. Pharmacol. Methods 14, 181–187 (1985). source

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  • May combine two claims.

    Interpretationreasoning

    Threats are detected and interpreted as worthy of enhanced vigilance in the forward direction, and this initial interpretation is evaluated in the backward direction.

    “Threats are detected and interpreted as worthy of enhanced vigilance in the forward direction, and this initial interpretation is evaluated in the backward direction.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Lateral amygdala cells develop robust responses to shock-predictive cues, corresponding to freezing behavior when the cues are presented.

    “These cells develop robust responses to shock-predictive cues, corresponding to freezing behavior when the cues are presented71.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [71] Quirk, G.J., Repa, C. & LeDoux, J.E. Fear conditioning enhances short-latency auditory responses of lateral amygdala neurons: parallel recordings in the freely behaving rat. Neuron 15, 1029–1039 (1995). source

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    Premisereasoning

    Cues predicting threat are themselves recognized as threatening, and cues predicting reward themselves become rewarding.

    “In this way, cues predicting threat are themselves recognized as threatening60 and, likewise, those predicting reward themselves become rewarding61,62.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [60] LeDoux, J.E. Emotion circuits in the brain. Annu. Rev. Neurosci. 23, 155–184 (2000). source

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    • cites [61] Tye, K.M. & Janak, P.H. Amygdala neurons differentially encode motivation and reinforcement. J. Neurosci. 27, 3937–3945 (2007). source

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    • cites [62] Tye, K.M., Stuber, G.D., de Ridder, B., Bonci, A. & Janak, P.H. Rapid strengthening of thalamo-amygdala synapses mediates cue-reward learning. Nature 453, 1253–1257 (2008). source

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  • May combine two claims.

    Premisecitation

    Effects on the innate anxiety state are mediated via projections from the anterodorsal BNST to the VTA, lateral hypothalamus and parabrachial nucleus, which independently regulate subjective preference, risk avoidance in the EPM and OFT, and respiration rate, respectively.

    “These effects on the innate anxiety state are mediated via projections from the anterodorsal BNST to the ventral tegmental area (VTA), lateral hypothalamus and parabrachial nucleus, which independently regulate subjective preference, risk avoidance in the EPM and OFT, and respiration rate, respectively31.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Kim, S.-Y. et al. Diverging neural pathways assemble a behavioural state from separable features in anxiety. Nature 496, 219–223 (2013). First study to provide causal evidence that separate circuits control the behavioral and physiological features of anxiety. source

      Not checked in the free run.

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    Premisecitation

    Burying behavior is quantifiable and sensitive to anxiolytics.

    “This burying behavior is quantifiable and sensitive to anxiolytics45,46.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [45] Nicolas, L.B., Kolb, Y. & Prinssen, E.P.M. A combined marble burying-locomotor activity test in mice: a practical screening test with sensitivity to different classes of anxiolytics and antidepressants. Eur. J. Pharmacol. 547, 106–115 (2006). source

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    • cites [46] Treit, D., Pinel, J.P.J. & Fibiger, H.C. Conditioned defensive burying: A new paradigm for the study of anxiolytic agents. Pharmacol. Biochem. Behav. 15, 619–626 (1981). source

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  • May combine two claims.

    Premisecitation

    Initiation of fear and sustained anxiety responses requires the recruitment of the BNST, which occurs partly as a result of direct innervation by BLA afferents, as well as through dense glutamatergic input from the hippocampus, mPFC, entorhinal cortex and insular cortex.

    “Initiation of fear and sustained anxiety responses requires the recruitment of the BNST7, which occurs partly as a result of direct innervation by BLA afferents, as well as through dense glutamatergic input from the hippocampus81,82, mPFC, entorhinal cortex and insular cortex55,83.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [7] Davis, M., Walker, D.L., Miles, L. & Grillon, C. Phasic vs sustained fear in rats and humans: role of the extended amygdala in fear vs anxiety. Neuropsychopharmacology 35, 105–135 (2010). source

      Not checked in the free run.

    • cites [81] Cullinan, W.E., Herman, J.P. & Watson, S.J. Ventral subicular interaction with the hypothalamic paraventricular nucleus: evidence for a relay in the bed nucleus of the stria terminalis. J. Comp. Neurol. 332, 1–20 (1993). source

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    • cites [82] Dong, H.W., Petrovich, G.D. & Swanson, L.W. Topography of projections from amygdala to bed nuclei of the stria terminalis. Brain Res. Brain Res. Rev. 38, 192–246 (2001). source

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    Premisecitation

    Principal neurons and interneurons in the BLA receive monosynaptic input from the mPFC and vHPC, and send reciprocal projections to both of these regions.

    “principal neurons and interneurons in the BLA have been shown to receive monosynaptic input from mPFC and vHPC, and send reciprocal projections to both of these regions66-68.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [66] Felix-Ortiz, A.C. et al. BLA to vHPC inputs modulate anxiety-related behaviors. Neuron 79, 658–664 (2013). Provides the first direct evidence of bidirectional control of anxiety via the BLA projection to vHPC. source

      Not checked in the free run.

    • cites [67] Herry, C. et al. Switching on and off fear by distinct neuronal circuits. Nature 454, 600–606 (2008). source

      Not checked in the free run.

    • cites [68] Hübner, C., Bosch, D., Gall, A., Lüthi, A. & Ehrlich, I. Ex vivo dissection of optogenetically activated mPFC and hippocampal inputs to neurons in the basolateral amygdala: implications for fear and emotional memory. Front. Behav. Neurosci. 8, 64 (2014).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A population of cells in the BLA projecting directly to the CeM shows evidence of potentiation following fear conditioning, and photoinhibition of these neurons inhibits the acquisition of the fear association.

    “Furthermore, a population of cells in the BLA projecting directly to the CeM shows evidence of potentiation following fear conditioning, and photoinhibition of these neurons inhibits the acquisition of the fear association63.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [63] Namburi, P. et al. A circuit mechanism for differentiating positive and negative associations. Nature 520, 675–678 (2015). First evidence of largely non-overlapping, projection target–defined populations of neurons in the BLA oppositely encoding valence in fear and reward learning. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Activity in pathways from the mPFC and vHPC to the BLA can both directly invigorate the anxiety response and influence the likelihood of a threat appraisal.

    “Activity in these pathways can both directly invigorate the anxiety response (for example, through projections of the vHPC to the lateral septum and hypothalamic nuclei; see below), as well as influence the likelihood of a threat appraisal (for example, through fear-memory retrieval via mPFC projections to the amygdala; see below and ref. 69).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [69] Herry, C. & Johansen, J.P. Encoding of fear learning and memory in distributed neuronal circuits. Nat. Neurosci. 17, 1644–1654 (2014). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    The amygdala, BNST, vHPC and PFC are highly interconnected, with multiple reciprocal projections facilitating macrocircuit-level interactions that initiate vigilance and defensive behaviors through recruitment of brainstem and hypothalamic nuclei.

    “These structures are highly interconnected, with multiple reciprocal projections facilitating macrocircuit-level interactions, which subsequently initiate vigilance and defensive behaviors through the recruitment of brainstem and hypothalamic nuclei.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    BLA inputs to the ventrolateral BNST promote freezing during uncontrollable stress and subsequent reduction in social interaction, both of which responses are reduced by inhibition of ventrolateral BNST.

    “BLA inputs to the ventrolateral BNST promote freezing during uncontrollable stress and subsequent reduction in social interaction, both of which responses are reduced by inhibition of ventrolateral BNST86.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [86] Christianson, J.P. et al. Safety signals mitigate the consequences of uncontrollable stress via a circuit involving the sensory insular cortex and bed nucleus of the stria terminalis. Biol. Psychiatry 70, 458–464 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Activity in glutamatergic ventral BNST neurons projecting to the VTA produces anxiety-like behaviors, whereas GABAergic neurons in the ventral BNST exert anxiolysis via a parallel pathway.

    “activity in glutamatergic ventral BNST neurons projecting to the VTA produces anxiety-like behaviors, whereas GABAergic neurons in the ventral BNST exert anxiolysis via a parallel pathway85.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [85] Jennings, J.H. et al. Distinct extended amygdala circuits for divergent motivational states. Nature 496, 224–228 (2013)Presents causal evidence of functionally opposed, neurochemically defined populations of projection neurons within a single efferent pathway. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Activation of CRFR type 2-expressing GABAergic projection neurons in the lateral septum results in inhibition of cells in the anterior hypothalamic area, which themselves inhibit the paraventricular nucleus of the hypothalamus and periaqueductal gray.

    “Activation of these neurons results in inhibition of cells in the anterior hypothalamic area, which themselves inhibit the paraventricular nucleus of the hypothalamus and periaqueductal gray.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [97] Anthony, T.E. et al. Control of stress-induced persistent anxiety by an extra-amygdala septohypothalamic circuit. Cell 156, 522–536 (2014)First optogenetic interrogation of the septohippocampal system in anxiety, which has not been otherwise evaluated using modern tools. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Prelimbic cortical inputs to the amygdala facilitate responses to threatening stimuli, whereas infralimbic cortex inputs to the amygdala suppress them.

    “Taken together, these findings indicate that prelimbic cortical inputs to the amygdala facilitate responses to threatening stimuli, whereas infralimbic cortex inputs to the amygdala suppress them.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The mPFC can be parsed into distinct subregions on the basis of their cytoarchitectures, which are consistent with divergent functions among these regions.

    “The mPFC can be parsed into distinct subregions on the basis of their cytoarchitectures, which are consistent with divergent functions among these regions100.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [100] Van De Werd, H.J.J.M. & Uylings, H.B.M. Comparison of (stereotactic) parcellations in mouse prefrontal cortex. Brain Struct. Funct. 219, 433–459 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Glutamatergic terminals of BLA fibers onto pyramidal neurons in the CA1 region of the vHPC bidirectionally control innate anxiety-related behaviors in the EPM and OFT, such that increased activity in this projection enhances anxiety-like behavior and inactivation reduces anxiety-like behavior.

    “Furthermore, glutamatergic terminals of BLA fibers onto pyramidal neurons in the CA1 region of the vHPC bidirectionally control innate anxiety-related behaviors in the EPM and OFT66, such that increased activity in this projection enhances anxiety-like behavior and inactivation of this pathway reduces anxiety-like behavior27,66.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [27] Degroot, A. & Treit, D. Anxiety is functionally segregated within the septo-hippocampal system. Brain Res. 1001, 60–71 (2004). source

      Not checked in the free run.

    • cites [66] Felix-Ortiz, A.C. et al. BLA to vHPC inputs modulate anxiety-related behaviors. Neuron 79, 658–664 (2013). Provides the first direct evidence of bidirectional control of anxiety via the BLA projection to vHPC. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Rodent mPFC subdivisions receive inputs from midline thalamic nuclei, the BLA and the hippocampus, and send reciprocal projections to BLA and efferent projections to the striatum.

    “These receive inputs from midline thalamic nuclei, the BLA and the hippocampus, and send reciprocal projections to BLA, as well as efferent projections to the striatum101.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [101] Groenewegen, H.J., Wright, C.I. & Uylings, H.B. The anatomical relationships of the prefrontal cortex with limbic structures and the basal ganglia. J. Psychopharmacol. 11, 99–106 (1997). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Neighboring cells in the basal amygdala that are innervated by PFC afferents fire in response to extinguished conditioned stimuli and project reciprocally to the PFC.

    “Neighboring cells in the basal amygdala that are innervated by PFC afferents fire in response to conditioned stimuli that have been extinguished, and they project reciprocally to the PFC67.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [67] Herry, C. et al. Switching on and off fear by distinct neuronal circuits. Nature 454, 600–606 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    The mPFC is an integral source of evaluation for threat interpretations and regulates subcortical responses to threatening stimuli.

    “An integral source of evaluation for threat interpretations is the mPFC, which regulates subcortical responses to threatening stimuli.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The primary subdivisions of the mPFC in rodents include the prelimbic and infralimbic cortices.

    “The primary subdivisions of the mPFC in rodents include the prelimbic and infralimbic cortices.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [101] Groenewegen, H.J., Wright, C.I. & Uylings, H.B. The anatomical relationships of the prefrontal cortex with limbic structures and the basal ganglia. J. Psychopharmacol. 11, 99–106 (1997). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ipsilateral projections from vHPC to lateral septum convey an anxiety signal; bilateral blockade of activity in either structure using muscimol increases open-arm exploration in the EPM, as does disconnection of the two using pharmacological inactivation of vHPC in one hemisphere and concurrent inactivation of the contralateral lateral septum.

    “Ipsilateral projections from vHPC to lateral septum convey an anxiety signal; bilateral blockade of activity in either structure using muscimol increases open-arm exploration in the EPM, as does disconnection of the two using pharmacological inactivation of vHPC in one hemisphere and concurrent inactivation of the contralateral lateral septum95.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [95] Trent, N.L. & Menard, J.L. The ventral hippocampus and the lateral septum work in tandem to regulate rats' open-arm exploration in the elevated plus-maze. Physiol. Behav. 101, 141–152 (2010). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning

    The dominant source of theta activity may dynamically shift between the vHPC and mPFC in periods of relative threat and security to aid in the interpretation and evaluation of environmental events and support circuit-level activity promoting defensive or exploratory behaviors.

    “The dominant source of theta activity may dynamically shift between the vHPC and mPFC in periods of relative threat and security to aid in the interpretation and evaluation of environmental events and support circuit-level activity promoting defensive or exploratory behaviors.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Limbic circuits are loops, rather than one-way streams of information flow.

    “We emphasize that limbic circuits are loops, rather than one-way streams of information flow.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    For interpretation to occur, an organism must first detect that the stimuli exist through its sensory systems.

    “For this interpretation to occur, an organism must first detect that the stimuli exist through its sensory systems.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Interpretation is in part dictated by the individual's previous experience and includes the assignment of valence to the stimulus via BLA circuits.

    “This interpretation is in part dictated by the individual’s previous experience and includes the assignment of valence to the stimulus via BLA circuits56.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [56] Janak, P.H. & Tye, K.M. From circuits to behaviour in the amygdala. Nature 517, 284–292 (2015). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Coordinated processing of potentially threatening stimuli must occur to elicit a well-defined behavioral response.

    “However, coordinated processing of potentially threatening stimuli must occur to elicit a well-defined behavioral response.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Synchronization of local field potentials provides a mechanism whereby the timing of activity in distributed regions could be orchestrated.

    “Synchronization of local field potentials (LFPs) provides a mechanism whereby the timing of activity in these distributed regions could be orchestrated.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    The combined actions of distributed neural circuits emerging from the amygdala, BNST, vHPC and mPFC result in the interpretation and evaluation of the emotional value of environmental stimuli.

    “The combined actions of distributed neural circuits emerging from the amygdala, BNST, vHPC and mPFC result in the interpretation and evaluation of the emotional value of environmental stimuli.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Approach-avoidance conflict resulting from the incongruence between the animal's needs and the interpretation of threat promotes vigilance and apprehension, which serve a protective function and produce behaviors measurable as anxiety.

    “In fact, this approach-avoidance conflict resulting from the incongruence between the animal’s needs and the interpretation of threat promotes vigilance and apprehension, which serve a protective function for the animal and produce behaviors we can measure as anxiety (see above).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Disconnection of LFP coherence by unilateral administration of gap junction blockers in contralateral vHPC and mPFC reduces theta activity in both regions, as well as innate anxiety-like behaviors in ethological tasks.

    “disconnection of LFP coherence by unilateral administration of gap junction blockers in contralateral vHPC and mPFC reduces theta activity in both regions, as well as innate anxiety-like behaviors in ethological tasks135.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [135] Schoenfeld, T.J. et al. Gap junctions in the ventral hippocampal-medial prefrontal pathway are involved in anxiety regulation. J. Neurosci. 34, 15679–15688 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Once potential threats are detected, the highly interconnected circuits interpret the meaning of those stimuli and determine whether they portend danger.

    “Once potential threats are detected, the highly interconnected circuits described here ‘interpret’ the meaning of those stimuli and determine whether they portend danger.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In the threatening zones of the elevated plus maze and open field test, theta activity has been observed in the mPFC, which is entrained to vHPC theta.

    “in the threatening zones of the EPM and OFT (open arms and center, respectively), theta activity has been observed in the mPFC, which is entrained to vHPC theta129.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [129] Adhikari, A., Topiwala, M.A. & Gordon, J.A. Synchronized activity between the ventral hippocampus and the medial prefrontal cortex during anxiety. Neuron 65, 257–269 (2010). Early demonstration that vHPC (but not dorsal HPC) theta rhythm synchrony with mPFC increases during anxiety. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    mPFC theta rhythms originate as a result of phasic inhibition of parvalbumin interneurons residing there, which mediates local theta-rhythm phase resetting.

    “These theta rhythms originate in the mPFC as a result of phasic inhibition of parvalbumin interneurons residing there, which mediates local theta-rhythm phase resetting107.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [107] Courtin, J. et al. Prefrontal parvalbumin interneurons shape neuronal activity to drive fear expression. Nature 505, 92–96 (2014)Original causal demonstration that mPFC microcircuit dynamics locally produce the mPFC theta rhythm to control the timing of fear behaviors. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The hippocampal theta rhythm entrains single-unit activity in both pyramidal cells and interneurons of the PFC, as well as PFC gamma-band activity (40-120 Hz).

    “This hippocampal theta rhythm has been shown to entrain single-unit activity in both pyramidal cells and interneurons of the PFC, as well as PFC gamma-band activity (40–120 Hz)132.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [132] Sirota, A. et al. Entrainment of neocortical neurons and gamma oscillations by the hippocampal theta rhythm. Neuron 60, 683–697 (2008). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    The process of CBT almost certainly occurs through plastic changes in the interpretation circuits described here.

    “a process that almost certainly occurs through plastic changes in the interpretation circuits described here.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The best intervention so far available for the treatment of anxiety disorders is cognitive-behavioral therapy (CBT).

    “the best intervention so far available for the treatment of anxiety disorders is cognitive-behavioral therapy (CBT)149”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [149] Butler, A.C., Chapman, J.E., Forman, E.M. & Beck, A.T. The empirical status of cognitive-behavioral therapy: a review of meta-analyses. Clin. Psychol. Rev. 26, 17–31 (2006). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationnone given

    The proposed model builds on existing models within a framework of four steps: detection, interpretation, evaluation and response initiation.

    “The model that we propose builds on existing models, within a framework of four steps: detection, interpretation, evaluation and response initiation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Dopamine inputs to the striatum push the animal toward obtaining maximum reward, a process that must take into account possible dangers.

    “dopamine inputs to the striatum push the animal toward obtaining maximum reward, a process that must take into account possible dangers.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [145] Houk, J.C., Adams, J.L. & Barto, A.G. in Models of Information Processing in the Basal Ganglia (eds. Houk, J.C., Davis, J.L. & Beiser, D.G.) 249–270 (MIT Press, 1995). source

      Not checked in the free run.

    • cites [146] Joel, D., Niv, Y. & Ruppin, E. Actor-critic models of the basal ganglia: new anatomical and computational perspectives. Neural Netw. 15, 535–547 (2002). source

      Not checked in the free run.

    • cites [147] Sugrue, L.P., Corrado, G.S. & Newsome, W.T. Choosing the greater of two goods: neural currencies for valuation and decision making. Nat. Rev. Neurosci. 6, 363–375 (2005). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning

    Bias toward threat interpretation may be the outcome of a disruption to homeostatic mechanisms that normally maintain balance between circuits supporting defensive versus exploratory behaviors, particularly in persistent anxiety.

    “or may be the outcome of a disruption to homeostatic mechanisms that normally maintain balance between circuits supporting defensive versus exploratory behaviors (particularly in persistent anxiety, such as generalized anxiety disorder).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Action is taken as a result of increased activity in the basal ganglia, which serve as the limbic-motor interface and facilitate the initiation of motor responses following upstream processing in the interpretation system.

    “This action is taken as a result of increased activity in the basal ganglia, which serve as the limbic-motor interface140 and facilitate the initiation of motor responses following upstream processing in the interpretation system.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [140] Mogenson, G.J., Jones, D.L. & Yim, C.Y. From motivation to action: functional interface between the limbic system and the motor system. Prog. Neurobiol. 14, 69–97 (1980). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    In cases of pathological anxiety, excessive apprehension occurs in response to minimally threatening stimuli or even in the absence of provocation.

    “In cases of pathological anxiety, excessive apprehension occurs in response to minimally threatening stimuli or even in the absence of provocation”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Disruption to any one part of a highly interconnected system results in changes to the whole.

    “Because disruption to any one part of a highly interconnected system results in changes to the whole”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Top-down suppression of attention to ambiguous stimuli may reduce the anxiety response.

    “top-down suppression of attention to ambiguous stimuli may reduce the anxiety response.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    CBT aims to replace maladaptive interpretations of events with more helpful ones.

    “which aims to replace maladaptive interpretations of events with more helpful ones”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [149] Butler, A.C., Chapman, J.E., Forman, E.M. & Beck, A.T. The empirical status of cognitive-behavioral therapy: a review of meta-analyses. Clin. Psychol. Rev. 26, 17–31 (2006). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    To select appropriate behavioral responses in a given environmental context, an animal must weigh potential rewards against potential risks.

    “To select appropriate behavioral responses in a given environmental context, an animal must weigh potential rewards against potential risks.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Bias of the system toward rendering a threat interpretation in the absence of probable danger may result from undue Hebbian plasticity in limbic pathways, particularly in cued anxiety disorders.

    “Bias of the system toward rendering a threat interpretation in the absence of probable danger may result from undue Hebbian plasticity in limbic pathways (particularly in cued anxiety disorders, such as social anxiety disorder and specific phobias)”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Effective solutions require interventions that consider the dynamics of the entire system.

    “effective solutions require interventions that consider the dynamics of the entire system.”
    Quote in the paperNot a substantial claim
68 of 68

  • The paper relies on this without support.

    Anxiety disorders represent a major societal problem demanding new therapeutic targets.

    “Although anxiety disorders represent a major societal problem demanding new therapeutic targets, these efforts have languished in the absence of a mechanistic understanding of this subjective emotional state.”

  • The paper relies on this without support.

    Efforts to develop new therapeutic targets for anxiety have languished in the absence of a mechanistic understanding of this subjective emotional state.

    “Although anxiety disorders represent a major societal problem demanding new therapeutic targets, these efforts have languished in the absence of a mechanistic understanding of this subjective emotional state.”

  • The paper relies on this without support.

    Rodent models hold promise in dissecting well-conserved limbic circuits relevant to anxiety.

    “While it is impossible to know with certainty the subjective experience of a rodent, rodent models hold promise in dissecting well-conserved limbic circuits.”

  • The paper relies on this without support.

    In health, the neural systems that underpin emotion dynamically integrate internal states and external stimuli to enable the rapid selection of situationally appropriate behaviors.

    “In health, the neural systems that underpin emotion dynamically integrate internal states and external stimuli to enable the rapid selection of situationally appropriate behaviors.”

  • The paper relies on this without support.

    The function of highly reciprocal limbic circuits is to integrate signals received by an individual and consolidate them into a singular gestalt emotional experience that directs the behavioral response.

    “The function of highly reciprocal limbic circuits is to integrate the barrage of signals received by an individual, including motivational drives1, environmental context and learned associations based on past events, and to consolidate them into a singular gestalt experience that is emotional in quality and directs the behavioral response.”

  • The paper relies on this without support.

    Occasional anxiety is a normal aspect of the emotional repertoire and aids survival by increasing awareness and enabling rapid responses to possible hazards.

    “Occasional anxiety is a normal aspect of the emotional repertoire and aids survival by increasing awareness and enabling rapid responses to possible hazards.”

  • The paper relies on this without support.

    The available therapeutic arsenal for anxiety disorders remains inadequate; available drugs do not successfully relieve anxiety in all patients, and unwanted side effects reduce compliance.

    “Despite these additions, the therapeutic arsenal for anxiety disorders remains inadequate; the available drugs do not successfully relieve anxiety in all patients, and unwanted side effects reduce compliance among those for whom they do.”

  • The paper relies on this without support.

    Rodents are well suited to model fear learning, stress and anxiety.

    “Rodents are well suited to this purpose and have historically been used in basic research and drug development to model fear learning, stress and anxiety.”

  • The paper relies on this without support.

    Most anxiety assays adapted for mice are ethologically based.

    “Most anxiety assays adapted for mice are ethologically based.”

  • The paper relies on this without support.

    These tasks capitalize on the innate, conflicting drives of rodents to explore novel spaces and to avoid open, exposed and brightly illuminated areas where they might be more vulnerable to environmental threats.

    “These tasks capitalize on the innate, conflicting drives of rodents to explore novel spaces and to avoid open, exposed and brightly illuminated areas where they might be more vulnerable to environmental threats.”

  • The paper relies on this without support.

    Generally in approach-avoidance conflict tasks, mice with an anxious phenotype tend to spend more time in enclosed or 'safe' zones of the behavioral apparatus compared to controls.

    “Generally in these approach-avoidance conflict tasks, mice with an anxious phenotype tend to spend more time in enclosed or ‘safe’ zones of the behavioral apparatus compared to controls.”

  • The paper relies on this without support.

    Use of optogenetics to manipulate behaviors in these tasks has been central in establishing causal relationships between the activity of neural circuits and anxiety.

    “For example, the use of optogenetics to manipulate behaviors in these tasks has been central in establishing causal relationships between the activity of neural circuits and anxiety.”

  • The paper relies on this without support.

    Naturalistic environments are often characterized by ambiguity, and the absolute absence of potential danger is rarely assured.

    “Naturalistic environments are often characterized by ambiguity, and the absolute absence of potential danger is rarely assured.”

  • The paper relies on this without support.

    Given sufficient motivation to seek food, to drink or to mate, an animal will engage in these appetitive behaviors despite the presence of potential dangers.

    “Given sufficient motivation to seek food, to drink or to mate, an animal will engage in these appetitive behaviors despite the presence of potential dangers.”
14 of 14

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Anxiety-related behaviors arise from distributed corticolimbic circuitry that interprets environmental stimuli.

    “Targeted manipulations in rodents have unveiled that anxiety-related behaviors arise from activity across distributed, interconnected corticolimbic circuitry, which interpret and evaluate incoming environmental stimuli (reviewed in Ref. 58).”

    From Neural mechanisms of social homeostasis (2019) · cites this paper as [58]

  • The amygdala receives inputs from thalamus, mPFC, hippocampus and modulates behavioural and physiological responses via projections from central nucleus to hypothalamus, BNST, brainstem, periaqueductal grey.

    “Specifically, the amygdala, which receives inputs e.g. from the thalamus, the medial prefrontal cortex (mPFC), and the hippocampus, modulates corresponding behavioural and physiological responses via projections that extend from its central nucleus to multiple regions, including the hypothalamus, the bed nucleus of the stria terminalis, the brainstem and the periaqueductal grey, that finally elic”

    From Novel pharmacological targets in drug development for the treatment of anxiety and anxiety-related disorders (2019) · cites this paper as Calhoon & Tye, 2015

  • The behavioral effects of RSD are indicative of enhanced fear/anxiety circuitry that is linked with anxiety and depression.

    “The behavioral effects of RSD are indicative of enhanced fear/anxiety circuitry that is linked with anxiety and depression (Calhoon and Tye, 2015).”

    From Repeated Social Defeat, Neuroinflammation, and Behavior: Monocytes Carry the Signal (2017) · cites this paper as Calhoon and Tye, 2015

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Amaral, D. & Lavenex, P. in The Hippocampus Book (eds. Anderson, P., Morris, R., Amaral, D., Bliss, T. & O'Keefe, J.) 37–114 (Oxford Univ. Press, 2007).

Cited by

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Related

Authors
Calhoon, G. G., & Tye, K. M.
Affiliations
Massachusetts Institute of Technology (US)
Corresponding author
Tye, Kay M
ORCID
Venue
Nature Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2015-09-25
Volume
18
Issue
10
Pages
1394-1404
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
DOI
10.1038/nn.4101
PMC
PMC7575249
OpenAlex
W1695265315
Semantic Scholar
53f9b4f272f4d9ec26fc1a7752f3d152df8797cc
Cited by
766
References
149
Citations by year
2026: 60 · 2025: 83 · 2024: 111 · 2023: 77 · 2022: 73 · 2021: 72 · 2020: 87 · 2019: 72 · 2018: 59 · 2017: 33 · 2016: 32 · 2015: 7
FWCI
4.29
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-sa)
Funders
  • National Institute of Mental Health (R01MH102441, R01‐MH102441‐01)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DP2-DK-102256-01, DP2DK102256)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
anxiety, neural circuits, anxiety disorders, limbic system, rodent models, anxiety-like behavior, therapeutic target, emotional state
MeSH terms
Animals, Anxiety, Brain, Disease Models, Animal, Humans, Neural Pathways

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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