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Cited by 6Genetics and Neurodevelopmental DisordersSchizophrenia research and treatmentNeuroscience and Neuropharmacology Research

Linking haploinsufficiency of the autism- and schizophrenia-associated gene Cyfip1 with striatal-limbic-cortical network dysfunction and cognitive inflexibility

Open access
Haddon, Josephine E., Titherage, Daniel, Heckenast, Julia R., Carter, Jennifer, Owen, Michael J., Hall, Jeremy, Wilkinson, Lawrence S., Jones, Matthew W.·2024·Translational Psychiatry
DOI 10.1038/s41398-024-02969-xPMC PMC11178837
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Abstract

Impaired behavioural flexibility is a core feature of neuropsychiatric disorders and is associated with underlying dysfunction of fronto-striatal circuitry. Reduced dosage of Cyfip1 is a risk factor for neuropsychiatric disorder, as evidenced by its involvement in the 15q11.2 (BP1–BP2) copy number variant: deletion carriers are haploinsufficient for CYFIP1 and exhibit a two- to four-fold increased risk of schizophrenia, autism and/or intellectual disability. Here, we model the contributions of Cyfip1 to behavioural flexibility and related fronto-striatal neural network function using a recently developed haploinsufficient, heterozygous knockout rat line. Using multi-site local field potential (LFP) recordings during resting state, we show that Cyfip1 heterozygous rats (Cyfip1+/−) harbor disrupted network activity spanning medial prefrontal cortex, hippocampal CA1 and ventral striatum. In particular, Cyfip1+/− rats showed reduced influence of nucleus accumbens and increased dominance of prefrontal and hippocampal inputs, compared to wildtype controls. Adult Cyfip1+/− rats were able to learn a single cue-response association, yet unable to learn a conditional discrimination task that engages fronto-striatal interactions during flexible pairing of different levers and cue combinations. Together, these results implicate Cyfip1 in development or maintenance of cortico-limbic-striatal network integrity, further supporting the hypothesis that alterations in this circuitry contribute to behavioural inflexibility observed in neuropsychiatric diseases including schizophrenia and autism.

AI snapshot

Written from the paper’s full text.

TL;DR

Cyfip1 haploinsufficient rats show disrupted resting-state cortico-limbic-striatal network dynamics and a selective inability to learn a conditional discrimination requiring flexible cue-response pairing. The findings link reduced Cyfip1 dosage to fronto-striatal network dysfunction and cognitive inflexibility relevant to 15q11.2 CNV-associated neuropsychiatric risk.

Key findings

  • Resting-state LFP showed disrupted network directionality: WT rats had stronger Granger causality from nucleus accumbens core to NAc shell (W = 1636, p < 0.001) and infralimbic cortex (W = 1882, p < 0.01), whereas Cyfip1+/− rats had stronger drive from prelimbic cortex to dCA1 (W = 3717, p < 0.01) and IL (W = 3570, p < 0.05), from dCA1 to NAc shell (W = 3605, p < 0.05), and from vCA1 to dCA1 (W = 3678, p < 0.01); six pairings survived FDR correction.
  • Cyfip1+/− rats were impaired on the auditory biconditional discrimination: significant GENOTYPE × SESSION × LEVER interaction, F(7, 126) = 2.560, p = 0.017; at session 8, GENOTYPE × LEVER interaction F(1, 144) = 16.637, p < 0.001, with Cyfip1+/− rats producing fewer correct-lever responses than WT rats, F(1, 288) = 9.246, p = 0.003.
  • On the final training session, WT rats responded correctly to both cues, while Cyfip1+/− rats responded correctly only to the Clicker: GENOTYPE × LEVER interaction F(1, 18) = 7.266, p = 0.015; LEVER effect in WT F(1, 18) = 29.870, p < 0.001, but not in Cyfip1+/− F(1, 18) = 2.733, p = 0.116.
  • A stricter discrimination ratio confirmed impaired biconditional learning in Cyfip1+/− rats, F(1, 18) = 5.403, p = 0.032; no genotype differences were observed during pretraining, magazine entries, or rewards earned.

Methods

  • Used 49 adult male Long Evans rats (25 Cyfip1+/−, 24 WT); 27 rats (14 WT, 13 Cyfip1+/−) underwent multisite LFP implantation, with final electrophysiology n = 14 WT and 11 Cyfip1+/− after exclusions; 22 rats (10 WT, 12 Cyfip1+/−) entered behavioral training, with final n = 9 WT and 11 Cyfip1+/−.
  • Resting-state LFP was recorded from prelimbic cortex, infralimbic cortex, nucleus accumbens core and shell, and dorsal/ventral hippocampal CA1; 10 min of quiet wakefulness was analyzed using multivariate Granger causality across 0–100 Hz, with band-limited and broadband Wilcoxon rank-sum comparisons and FDR correction.
  • Behavioral testing used an auditory biconditional discrimination: Tone and Clicker cues required different lever-press responses for food reward, trained for 8 days, 24 trials/session, with reinforcement on an RI15 schedule; performance was analyzed with mixed ANOVA.

Limitations

  • The paper states that stability of fronto-striatal integrity was not quantified and that longitudinal studies across days and neurodevelopmental timepoints would be useful next steps.
  • The paper notes that other functional impairments, such as auditory perception or motor responding, could contribute to behavior, though no pretraining motor/magazine differences were observed and no consistent hearing/perception deficits are reported in 15q11.2del.
  • The paper states that training was blind to genotype for 8 days and that some Cyfip1+/− rats might learn the full conditional discrimination with extensive training or more salient cues; it also notes that age- and region-restricted knockdown would help disentangle causal circuit mechanisms. Evident from the text: only adult male rats were studied, and the design is correlational rather than a direct causal manipulation of the recorded circuits.

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

Integrity signals

Registry

Crossref · 10.1038/s41398-024-02969-x

Cites

99 of 99 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

78 of 125 cited sources checked · 43 supported · 1 flagged · accuracy not yet measured

  • Premisecitation

    The 15q11.2(BP1-BP2) deletion contains four genes: NIPA1, NIPA2, CYFIP1 and TUBGCP5.

    “The deletion contains four genes: non-imprinted in Prader–Willi/Angelman syndrome 1 (NIPA1) and 2 (NIPA2) genes, CYFIP1 and tubulin gamma complex associated protein 5 gene (TUBGCP5) [6].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [6] Chai JH, Locke DP, Greally JM, Knoll JH, Ohta T, Dunai J, et al. Identification of four highly conserved genes between breakpoint hotspots BP1 and BP2 of the Prader-Willi/Angelman syndromes deletion region that have undergone evolutionary transposition mediated by flanking duplicons. Am J Hum Genet. 2003;73:898–925. source
  • Premisecitation

    Deficits in flexible updating are consistently linked to fronto-striatal dysfunction in patients.

    “and are consistently linked to fronto-striatal dysfunction in patients [17, 28, 31–33].”
    Quote in the paperSubstantial claim4 of 5 sources checked
    • cites [17] Cadena EJ, White DM, Kraguljac NV, Reid MA, Lahti AC. Evaluation of fronto-striatal networks during cognitive control in unmedicated patients with schizophrenia and the effect of antipsychotic medication. NPJ Schizophr. 2018;4:8. source

      The Introduction (page unavailable) says fronto-striatal dysfunction is widely reported in schizophrenia. The Abstract and Stroop task methods (pages unavailable) link reduced activity in these networks to cognitive control, but the study uses a Stroop color-naming task and does not establish a specific link to deficits in flexible updating. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [28] Vaghi MM, Vértes PE, Kitzbichler MG, Apergis-Schoute AM, van der Flier FE, Fineberg NA, et al. Specific frontostriatal circuits for impaired cognitive flexibility and goal-directed planning in obsessive compulsive disorder: evidence from resting-state functional connectivity. Biol Psychiatry. 2017;81:708–17. source
    • cites [31] Cools R, Barker RA, Sahakian BJ, Robbins TW. Enhanced or impaired cognitive function in Parkinson’s disease as a function of dopaminergic medication and task demands. Cereb Cortex. 2001;11:1136–43. source
    • cites [32] Gruszka A, Hampshire A, Barker RA, Owen AM. Normal aging and Parkinson’s disease are associated with the functional decline of distinct frontal-striatal circuits. Cortex. 2017;93:178–92. source

      The Discussion (‘The neural basis of set-shifting deficits in PD’; page not provided) links attentional set-shifting impairments in Parkinson’s disease to reduced activity in frontal regions and the caudate nucleus. That supports a link between a form of cognitive flexibility and fronto-striatal dysfunction, but the paper does not establish the broader claim about flexible updating consistently across patients. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [33] Quidé Y, Morris RW, Shepherd AM, Rowland JE, Green MJ. Task-related fronto-striatal functional connectivity during working memory performance in schizophrenia. Schizophr Res. 2013;150:468–75. source

      The Discussion (page unavailable) links poor working-memory performance in schizophrenia to reduced putamen–VLPFC connectivity and aberrant striatal activity. It discusses selection of information during memory retrieval, but does not establish a specific deficit in flexible updating or that such deficits are consistently linked to fronto-striatal dysfunction. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
  • Premisecitation

    Deletion of 15q11.2(BP1-BP2) leads to a two- to fourfold increase in the risk for schizophrenia, autism and intellectual disability.

    “Deletion of 15q11.2(BP1–BP2) leads to a two to fourfold increase in the risk for schizophrenia, autism and intellectual disability [1–5].”
    Quote in the paperSubstantial claim4 of 5 sources checked
    • cites [1] Stefansson H, Rujescu D, Cichon S, Pietiläinen OP, Ingason A, Steinberg S, et al. Large recurrent microdeletions associated with schizophrenia. Nature. 2008;455:232–6. source

      The paper’s 15q11.2 passage (section labeled Abstract; page unavailable) reports the deletion in 0.55% of schizophrenia and related-psychosis cases versus 0.19% of controls, consistent with an approximately threefold association. It discusses autism and intellectual impairment in particular syndromes or a previously reported case, but does not establish a two- to fourfold risk increase for autism or intellectual disability from this deletion. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [2] Pathania M, Davenport EC, Muir J, Sheehan DF, López-Doménech G, Kittler JT. The autism and schizophrenia associated gene CYFIP1 is critical for the maintenance of dendritic complexity and the stabilization of mature spines. Transl Psychiatry. 2014;4:e423. source
    • cites [3] Cox DM, Butler MG. The 15q11.2 BP1-BP2 microdeletion syndrome: a review. Int J Mol Sci. 2015;16:4068–82. source

      The Abstract reports a two- to fourfold higher prevalence of the deletion among patients presenting for microarray analysis than among controls; it does not give a two- to fourfold increase in risk for each named condition. Sections 2.3 and 2.4 discuss intellectual disability, an association with schizophrenia, and a modest autism risk, but do not assign that magnitude to those outcomes. (LLM, conf=0.91)

      Experimental — accuracy not yet measured
    • cites [4] Butler MG. Clinical and genetic aspects of the 15q11.2 BP1-BP2 microdeletion disorder. J Intellect Disabil Res. 2017;61:568–79. source

      The Introduction (Clinical Description; page not provided) estimates a two- to fourfold higher prevalence of the deletion compared with controls, and the Results and Discussion (Genetic Services and Genetic Counseling; page not provided) lists schizophrenia, autism and intellectual disability among findings in affected individuals. It does not give a two- to fourfold risk increase for each of those three conditions; it also describes low penetrance, so “leads to” overstates the relationship. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [5] Ulfarsson MO, Walters GB, Gustafsson O, Steinberg S, Silva A, Doyle OM, et al. 15q11.2 CNV affects cognitive, structural and functional correlates of dyslexia and dyscalculia. Transl Psychiatry. 2017;7:e1109. source

      The Results (Neuropsychology; page not provided) associate the 15q11.2(BP1–BP2) deletion with schizophrenia. They mention autism and intellectual disability as possible phenotypes of neuropsychiatric CNVs generally, but do not give a two- to fourfold risk increase for the three named conditions. The reported odds ratios concern dyslexia and dyscalculia instead. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
  • Premisecitation

    CYFIP1 haploinsufficiency is likely to be a significant contributor to the 15q11.2(BP1-BP2)del psychiatric phenotype.

    “CYFIP1 haploinsufficiency is likely to be a significant contributor to the 15q11.2(BP1–BP2)del psychiatric phenotype due to its known involvement in several key brain plasticity-related functions such as dendritic spine morphology and branching [7, 8], and the interaction between CYFIP1 and fragile X mental retardation 1 (FMR1) [9].”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [7] De Rubeis S, Pasciuto E, Li KW, Fernández E, Di Marino D, Buzzi A, et al. CYFIP1 coordinates mRNA translation and cytoskeleton remodeling to ensure proper dendritic spine formation. Neuron. 2013;79:1169–82. source

      The Introduction (page unavailable) links deletions of the 15q11.2 region containing CYFIP1 to cognitive disabilities and autism. The Results section on spine morphology (page unavailable) shows altered spines in Cyfip1+/− mice. These findings make the proposed contribution plausible, but the paper does not establish that CYFIP1 haploinsufficiency is a significant contributor to the psychiatric phenotype of the BP1–BP2 deletion specifically. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [8] Davenport EC, Szulc BR, Drew J, Taylor J, Morgan T, Higgs N, et al. Autism and schizophrenia—associated CYFIP1 regulates the balance of synaptic excitation and inhibition. Cell Rep. 2019;26:2037–51. source

      The Introduction and Discussion (page unavailable) link altered CYFIP1 dosage to synaptic changes and suggest that CYFIP1 deletion could contribute to cognitive changes in people with 15q11.2 microdeletions. The paper does not establish that CYFIP1 haploinsufficiency is likely to be a significant contributor to the deletion’s psychiatric phenotype; its conclusion is more tentative. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [9] Clifton NE, Thomas KL, Wilkinson LS, Hall J, Trent S. FMRP and CYFIP1 at the synapse and their role in psychiatric vulnerability. Complex Psychiatry. 2020;6:5–19. source
  • Premisecitation

    In the Cyfip1 rat model, inability to respond flexibly was linked to white matter changes observed using DTI.

    “This inability to respond flexibly was linked to white matter changes observed using diffusion tensor imaging (DTI), that were similar to those seen in 15q11.2(BP1–2)del CNV carriers [12] and Cyfip1-deficient mice [13].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [12] Silva AI, Ulfarsson MO, Stefansson H, Gustafsson O, Walters GB, Linden DEJ, et al. Reciprocal white matter changes associated with copy number variation at 15q11.2 BP1-BP2: a diffusion tensor imaging study. Biol Psychiatry. 2019;85:563–72. source
    • cites [13] Domínguez-Iturza N, Lo AC, Shah D, Armendáriz M, Vannelli A, Mercaldo V, et al. The autism- and schizophrenia-associated protein CYFIP1 regulates bilateral brain connectivity and behaviour. Nat Commun. 2019;10:3454. source
  • Classified as probably not a substantial claim. 34
  • May combine two claims. 22

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

    Premisecitation

    White matter abnormalities in frontostriatal loops have been associated with severity in schizophrenia.

    “White matter abnormalities in frontostriatal loops have been associated with severity in schizophrenia [15].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [15] Quan M, Lee SH, Kubicki M, Kikinis Z, Rathi Y, Seidman LJ, et al. White matter tract abnormalities between rostral middle frontal gyrus, inferior frontal gyrus and striatum in first-episode schizophrenia. Schizophr Res. 2013;145:1–10. source

      The Discussion reports no significant correlation between frontostriatal white matter integrity and symptom severity measured by BPRS. It instead links disrupted integrity to worse executive function in patients with first-episode schizophrenia. (LLM, conf=0.90)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    Performance on conditional discrimination tasks is dependent upon the intact functioning of the nucleus accumbens.

    “Previous animal studies have revealed that performance on conditional discrimination tasks is dependent upon the intact functioning of the nucleus accumbens [64, 65].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [64] Ambroggi F, Ghazizadeh A, Nicola SM, Fields HL. Roles of nucleus accumbens core and shell in incentive-cue responding and behavioral inhibition. J Neurosci. 2011;31:6820–30. source

      The Discussion reports that inactivating the nucleus accumbens core impaired reward-cue responding in a rat discriminative-stimulus task, while shell inactivation increased responses to an unrewarded cue. The broader claim that performance on conditional discrimination tasks depends on an intact nucleus accumbens is not fully supported: the Discussion also says that inactivating the entire nucleus accumbens did not decrease correct responding in that task. No page numbers are available in our copy. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [65] Bossert JM, Stern AL, Theberge FR, Marchant NJ, Wang HL, Morales M, et al. Role of projections from ventral medial prefrontal cortex to nucleus accumbens shell in context-induced reinstatement of heroin seeking. J Neurosci. 2012;32:4982–91. source

      The Introduction and Results address the accumbens shell’s role in context-induced reinstatement of heroin seeking, not performance on conditional discrimination tasks. Searches for “conditional discrimination tasks” and “nucleus accumbens lesions conditional discrimination performance” found no passage in our copy addressing the claimed task dependence; page numbers were not available. (LLM, conf=0.73)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Fronto-striatal fMRI activity has been linked to cognition in healthy populations, patients with schizophrenia, and individuals with genetic high risk for schizophrenia.

    “Fronto-striatal fMRI activity has been linked to cognition in healthy populations [16], patients with schizophrenia [17], and individuals with genetic high risk for schizophrenia [18].”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [16] de Wit S, Watson P, Harsay HA, Cohen MX, van de Vijver I, Ridderinkhof KR. Corticostriatal connectivity underlies individual differences in the balance between habitual and goal-directed action control. J Neurosci. 2012;32:12066–75. source
    • cites [17] Cadena EJ, White DM, Kraguljac NV, Reid MA, Lahti AC. Evaluation of fronto-striatal networks during cognitive control in unmedicated patients with schizophrenia and the effect of antipsychotic medication. NPJ Schizophr. 2018;4:8. source
    • cites [18] Ma X, Zheng W, Li C, Li Z, Tang J, Yuan L, et al. Decreased regional homogeneity and increased functional connectivity of default network correlated with neurocognitive deficits in subjects with genetic high-risk for schizophrenia: A resting-state fMRI study. Psychiatry Res. 2019;281:112603. source

  • Classified as probably not a substantial claim.

    Premisecitation

    Extensive research in rodents and non-human primates emphasises major roles of fronto-striatal circuits in the ability to respond flexibly.

    “Extensive research in rodents and non-human primates emphasises the major roles of fronto-striatal circuits in the ability to respond flexibly [34–42].”
    Quote in the paperSubstantial claim2 of 9 sources checked
    • cites [34] Ragozzino ME. The contribution of the medial prefrontal cortex, orbitofrontal cortex, and dorsomedial striatum to behavioral flexibility. Ann N Y Acad Sci. 2007;1121:355–75. source
    • cites [35] McDonald RJ, King AL, Foong N, Rizos Z, Hong NS. Neurotoxic lesions of the medial prefrontal cortex or medial striatum impair multiple-location place learning in the water task: evidence for neural structures with complementary roles in behavioural flexibility. Exp Brain Res. 2008;187:419–27. source
    • cites [36] Floresco SB, Zhang Y, Enomoto T. Neural circuits subserving behavioural flexibility and their relevance to schizophrenia. Behav Brain Res. 2009;204:396–409. source
    • cites [37] George DN, Duffaud AM, Pothuizen HH, Haddon JE, Killcross S. Lesions to the ventral, but not the dorsal, medial prefrontal cortex enhance latent inhibition. Eur J Neurosci. 2010;31:1474–82. source
    • cites [38] Lindgren HS, Wickens R, Tait DS, Brown VJ, Dunnett SB. Lesions of the dorsomedial striatum impair formation of attentional set in rats. Neuropharmacology. 2013;71:148–53. source
    • cites [39] Hamilton DA, Brigman JL. Behavioral flexibility in rats and mice: contributions of distinct frontocortical regions. Genes Brain Behav. 2015;14:4–21. source

      The Introduction says that rodent and non-human-primate research has investigated neural circuits underlying behavioral flexibility. The section on extradimensional set-shifting reports that disconnecting rat medial frontal cortex from the nucleus accumbens impaired flexible responding, supporting a fronto-striatal role in rodents. The review focuses on frontocortical regions, however, and the passages do not establish a major fronto-striatal role in non-human primates. Our copy provides section labels but no page numbers. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [40] Izquierdo A, Brigman JL, Radke AK, Rudebeck PH, Holmes A. The neural basis of reversal learning: an updated perspective. Neuroscience. 2017;345:12–26. source
    • cites [41] Fitoussi A, Renault P, Le Moine C, Coutureau E, Cador M, Dellu-Hagedorn F. Inter-individual differences in decision-making, flexible and goal-directed behaviors: novel insights within the prefronto-striatal networks. Brain Struct Funct. 2018;223:897–912. source
    • cites [42] Mansouri FA, Buckley MJ. Context-dependent adjustments in executive control of goal-directed behaviour: contribution of frontal brain areas to conflict-induced behavioural adjustments in primates. Adv Neurobiol. 2018;21:71–83. source

  • Classified as probably not a substantial claim.

    Premisecitation

    Deficits in the ability to flexibly update behaviour are manifest in a wide range of neurological and psychiatric disorders, including autism, obsessive-compulsive disorder, major depressive disorder and schizophrenia.

    “Deficits in the ability to flexibly update behaviour are manifest in a wide range of neurological and psychiatric disorders, including autism, obsessive–compulsive disorder, major depressive disorder and schizophrenia [23–30]”
    Quote in the paperSubstantial claim6 of 8 sources checked
    • cites [23] Chamberlain SR, Fineberg NA, Blackwell AD, Robbins TW, Sahakian BJ. Motor inhibition and cognitive flexibility in obsessive-compulsive disorder and trichotillomania. Am J Psychiatry. 2006;163:1282–4. source
    • cites [24] Verdejo-García A, Bechara A, Recknor EC, Pérez-García M. Executive dysfunction in substance dependent individuals during drug use and abstinence: an examination of the behavioral, cognitive and emotional correlates of addiction. J Int Neuropsychol Soc. 2006;12:405–15. source
    • cites [25] Ceaser AE, Goldberg TE, Egan MF, McMahon RP, Weinberger DR, Gold JM. Set-shifting ability and schizophrenia: a marker of clinical illness or an intermediate phenotype? Biol Psychiatry. 2008;64:782–8. source
    • cites [26] Yerys BE, Wallace GL, Harrison B, Celano MJ, Giedd JN, Kenworthy LE. Set-shifting in children with autism spectrum disorders: reversal shifting deficits on the intradimensional/extradimensional shift test correlate with repetitive behaviors. Autism. 2009;13:523–38. source

      The Abstract reports significantly more errors on a set-shifting task in high-functioning children with autism spectrum disorders, supporting the autism portion of the sentence. The paper does not address comparable deficits in obsessive-compulsive disorder, major depressive disorder, or schizophrenia, so it does not support the full list attributed to the citation range. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [27] Gruner P, Pittenger C. Cognitive inflexibility in obsessive-compulsive disorder. Neuroscience. 2017;345:243–55. source
    • cites [28] Vaghi MM, Vértes PE, Kitzbichler MG, Apergis-Schoute AM, van der Flier FE, Fineberg NA, et al. Specific frontostriatal circuits for impaired cognitive flexibility and goal-directed planning in obsessive compulsive disorder: evidence from resting-state functional connectivity. Biol Psychiatry. 2017;81:708–17. source

      The Results (Cognitive Flexibility and Frontostriatal Connectivity; page unavailable) report impaired attentional shifting in patients with obsessive-compulsive disorder. The paper does not establish the claimed deficits in autism, major depressive disorder, or schizophrenia, so it supports only the OCD part of the sentence. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [29] Waltz JA. The neural underpinnings of cognitive flexibility and their disruption in psychotic illness. Neuroscience. 2017;345:203–17. source

      The Introduction describes cognitive-flexibility deficits in schizophrenia, and the General Conclusions describe excessive rigidity in obsessive–compulsive disorder and atypical switching in major depressive disorder. Our copy does not address autism, so it does not support that example in the cited sentence (searched: autism). (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [30] Lima IMM, Peckham AD, Johnson SL. Cognitive deficits in bipolar disorders: implications for emotion. Clin Psychol Rev. 2018;59:126–36. source

      The Abstract and “Cognitive deficits in bipolar disorder” section discuss cognitive flexibility and deficits in bipolar disorder. Searches for autism, obsessive-compulsive disorder, major depressive disorder, and schizophrenia did not find a passage establishing the claimed deficits across those conditions; references to some of them do not establish that point. (LLM, conf=0.73)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Nucleus accumbens dysfunction has been heavily implicated in schizophrenia.

    “In ventral striatum, nucleus accumbens (NAc) dysfunction has been heavily implicated in schizophrenia [19, 20].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [19] Goto Y, Grace AA. Limbic and cortical information processing in the nucleus accumbens. Trends Neurosci. 2008;31:552–8. source
    • cites [20] Deserno L, Schlagenhauf F, Heinz A. Striatal dopamine, reward, and decision making in schizophrenia. Dialog Clin Neurosci. 2016;18:77–89. source

      The Reward anticipation section reports replicated reductions in ventral striatal activation in unmedicated and medication-naive patients with schizophrenia, supporting the broader ventral-striatum claim. It does not specifically identify nucleus accumbens dysfunction in those patients, and it notes that the reduction was not observed in patients taking second-generation antipsychotics. Page numbers are unavailable in our copy. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    Conditional discrimination tasks have been suggested as a useful translational paradigm for assessing the cognitive inflexibility observed in neuropsychiatric disease.

    “Conditional discrimination tasks have been suggested as a useful translational paradigm for assessing the cognitive inflexibility observed in neuropsychiatric disease [43].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [43] Koychev I, Barkus E, Ettinger U, Killcross S, Roiser JP, Wilkinson L, et al. Evaluation of state and trait biomarkers in healthy volunteers for the development of novel drug treatments in schizophrenia. J Psychopharmacol. 2011;25:1207–25. source

      The Biconditional learning section (p. 9) says conditional discrimination tasks assess how task-setting cues control performance and links difficulty applying such cues to cognitive deficits in schizophrenia. It describes human and animal versions, but notes that few human studies exist and that animal drug effects have not yet been shown to reproduce in humans. The claim extends this schizophrenia-focused discussion to neuropsychiatric disease generally and presents the task’s translational usefulness more broadly than the paper establishes. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Maternally inherited Cyfip1 haploinsufficient mice have reduced Cyfip1 gene expression in the nucleus accumbens and an increase in compulsive-like behaviours.

    “In animals, Babbs et al. [75] found that maternally inherited Cyfip1 haploinsufficient mice have reduced Cyfip1 gene expression in the nucleus accumbens and an increase in compulsive-like behaviours.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [75] Babbs RK, Beierle JA, Ruan QT, Kelliher JC, Chen MM, Feng AX. Cyfip1 haploinsufficiency increases compulsive-like behavior and modulates palatable food intake in mice: dependence on Cyfip2 genetic background. Parent-of Origin, and Sex. G3 (Bethesda). 2019;9:3009–22. source

  • Classified as probably not a substantial claim.

    Premisecitation

    Increased integrity of white matter in the corpus callosum and internal capsule is positively associated with activation in the nucleus accumbens.

    “Increased integrity of white matter in the corpus callosum and internal capsule has been found to be positively associated with activation in the nucleus accumbens [84].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [84] Koch K, Wagner G, Schachtzabel C, Schultz CC, Güllmar D, Reichenbach JR, et al. Association between white matter fiber structure and reward-related reactivity of the ventral striatum. Hum Brain Mapp. 2014;35:1469–76. source

  • May combine two claims.

    Premisecitation

    15q11.2 CNV deletion carriers show dysfunctional connectivity in fronto-striatal circuitry and widespread differences in brain morphology throughout the cortex, including the frontal and cingulate cortices.

    “Dysfunctional connectivity in fronto-striatal circuitry is supported by evidence in 15q11.2 CNV deletion carriers with widespread differences in brain morphology seen throughout the cortex, including the frontal and cingulate cortices.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [72] Sønderby IE, Ching CRK, Thomopoulos SI, van der Meer D, Sun D, Villalon-Reina JE, et al. Effects of copy number variations on brain structure and risk for psychiatric illness: Large-scale studies from the ENIGMA working groups on CNVs. Hum Brain Mapp. 2022;43:300–28. source

      The “Other CNVs” section reports widespread differences in cortical surface area and thickness in 15q11.2 deletion carriers, particularly in the frontal lobe and anterior cingulate (page unavailable). It does not report dysfunctional fronto-striatal connectivity in those carriers; its mention of white-matter alterations does not establish that specific claim. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [73] Writing Committee for the ENIGMA-CNV Working Group, van der Meer D, et al. Association of copy number variation of the 15q11.2 BP1-BP2 region with cortical and subcortical morphology and cognition. JAMA Psychiatry. 2020;77:420–30. source

      The Regional Cortical Morphology section (page not provided) reports widespread structural differences in deletion carriers, particularly in the frontal lobe and anterior cingulate. The paper does not report dysfunctional connectivity in fronto-striatal circuitry; its imaging analyses concern brain morphology, not functional connectivity. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    The ability of the hippocampus to promote response strategies is proposed to be partly supported via projections from the hippocampus to the NAc shell.

    “The ability of the hippocampus to promote response strategies is proposed to be partly supported via projections from the hippocampus to the NAc shell [81].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [81] Barker JM, Bryant KG, Chandler LJ. Inactivation of ventral hippocampus projections promotes sensitivity to changes in contingency. Learn Mem. 2018;26:1–8. source

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

    Interpretationcitation

    Broadly, these findings are consistent with reports in neuropsychiatric disorders of brain network dysconnectivity and failures of neural integration.

    “Broadly, these findings are consistent with reports in neuropsychiatric disorders of brain network dysconnectivity and failures of neural integration [57–59]”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [57] Dong D, Wang Y, Chang X, Luo C, Yao D. Dysfunction of large-scale brain networks in schizophrenia: a meta-analysis of resting-state functional connectivity. Schizophr Bull. 2018;44:168–81. source
    • cites [58] Friston K, Brown HR, Siemerkus J, Stephan KE. The dysconnection hypothesis. Schizophr Res. 2016;176:83–94. source
    • cites [59] Hull JV, Dokovna LB, Jacokes ZJ, Torgerson CM, Irimia A, Van Horn JD. Resting-state functional connectivity in autism spectrum disorders: a review. Front Psychiatry. 2017;7:205. source

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

    Study design and conductcitation

    These sample sizes were utilised on the basis of previous published research and pilot studies.

    “These sample sizes were utilised on the basis of previous published research [11, 44, 45] and pilot studies.”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [11] Silva AI, Haddon JE, Ahmed Syed Y, Trent S, Lin TE, Patel Y, et al. Cyfip1 haploinsufficient rats show white matter changes, myelin thinning, abnormal oligodendrocytes and behavioural inflexibility. Nat Commun. 2019;10:3455. source
    • cites [44] George DN, Jenkins TA, Killcross S. Dissociation of prefrontal cortex and nucleus accumbens dopaminergic systems in conditional learning in rats. Behav Brain Res. 2011;225:47–55. source
    • cites [45] Barnett L, Barrett AB, Seth AK. Solved problems for Granger causality in neuroscience: a response to Stokes and Purdon. Neuroimage.2018;178:744–8. https://doi.org/10.1016/j.neuroimage.2018.05.067. source

  • Classified as probably not a substantial claim.

    Premisecitation

    Hippocampal neurogenesis-mediated inhibition has been proposed as a mechanism to reduce memory interference-enabling cognitive flexibility in tasks such as reversal learning.

    “Hippocampal neurogenesis-mediated inhibition has been proposed as a mechanism to reduce memory interference—enabling cognitive flexibility in tasks such as reversal learning [76], which we have previously shown is sensitive to reductions of Cyfip1 in the rat [11].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [76] Anacker C, Hen R. Adult hippocampal neurogenesis and cognitive flexibility—linking memory and mood. Nat Rev Neurosci. 2017;18:335–46. source

  • May combine two claims.

    Premisecitation

    The Cyfip1 rat model was created using CRISPR-Cas9 targeting, implementing a 4 base-pair deletion in exon 7 of CYFIP1 on one chromosome, causing a premature stop codon leading to reduced CYFIP1 mRNA and protein in the brain.

    “The Cyfip1 rat model was created by Cardiff University in collaboration with Horizon Discovery (St Louis, USA) using CRISPR–Cas9 targeting. CRISPR/Cas9 engineering of exon 7 implemented a 4 base-pair deletion in DNA of the CYFIP1 gene on one of the chromosomes, causing a premature stop codon leading to reduced CYFIP1 mRNA and CYFIP1 protein in the brain, mimicking the human situation in the 15q11.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [11] Silva AI, Haddon JE, Ahmed Syed Y, Trent S, Lin TE, Patel Y, et al. Cyfip1 haploinsufficient rats show white matter changes, myelin thinning, abnormal oligodendrocytes and behavioural inflexibility. Nat Commun. 2019;10:3455. source

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

    Premisecitation

    Aberrant brain connectivity has been observed using resting-state MEG in adults with a wide range of neurodevelopmental CNVs including 15q11.2, although primary abnormalities involved decreased connectivity between occipital, temporal, and parietal areas and were only measured in 7 15q11.2 deletion carriers.

    “Aberrant brain connectivity has been observed using resting-state MEG in adults with a wide range of neurodevelopmental CNVs including 15q11.2 [74], although primary abnormalities involved decreased connectivity between occipital, temporal, and parietal areas and were only measured in 7 15q11.2 deletion carriers.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [74] Dima DC, Adams R, Linden SC, et al. Electrophysiological network alterations in adults with copy number variants associated with high neurodevelopmental risk. Transl Psychiatry. 2020;10:324. source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

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

    Premisecitation

    Many studies have indicated cortico-striatal network dysregulation is linked to psychotic symptoms, symptom severity, and response to antipsychotic treatment.

    “insofar as many studies have indicated cortico-striatal network dysregulation is linked to psychotic symptoms [60], symptom severity [61], and response to antipsychotic treatment [62].”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [60] Xu T, Gu Q, Zhao Q, Wang P, Liu Q, Fan Q, et al. Impaired cortico-striatal functional connectivity is related to trait impulsivity in unmedicated patients with obsessive-compulsive disorder. J Affect Disord. 2021;281:899–907. source
    • cites [61] Fornito A, Harrison BJ, Goodby E, Dean A, Ooi C, Nathan PJ, et al. Functional dysconnectivity of corticostriatal circuitry as a risk phenotype for psychosis. JAMA Psychiatry. 2013;70:1143–51. source
    • cites [62] Sarpal DK, Argyelan M, Robinson DG, Szeszko PR, Karlsgodt KH, John M. Baseline striatal functional connectivity as a predictor of response to antipsychotic drug treatment. Am J Psychiatry. 2016;173:69–77. source

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

    Premisecitation

    Fragile X syndrome is caused by mutations of FMR1 and is associated with intellectual disability and a variety of psychiatric symptoms.

    “Fragile X syndrome is caused by mutations of FMR1 and is associated with intellectual disability and a variety of psychiatric symptoms [10].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [10] Lozano R, Rosero CA, Hagerman RJ. Fragile X spectrum disorders. Intractable Rare Dis. Res. 2014;3:134–46. source

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

    Premisecitation

    The striatum has been highlighted as playing an important role in the pathogenesis of the cognitive symptoms of schizophrenia.

    “Moreover, the striatum has been highlighted as playing an important role in the pathogenesis of the cognitive symptoms of schizophrenia [63].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [63] Simpson EH, Kellendonk C, Kandel E. A possible role for the striatum in the pathogenesis of the cognitive symptoms of schizophrenia. Neuron. 2010;11:585–96. source

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

    Premisecitation

    Previous research has reported changes to white matter in the low dosage Cyfip1 rat model, most prominently in corpus callosum.

    “Previous research has reported changes to white matter in the low dosage Cyfip1 rat model, most prominently in corpus callosum [11]”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [11] Silva AI, Haddon JE, Ahmed Syed Y, Trent S, Lin TE, Patel Y, et al. Cyfip1 haploinsufficient rats show white matter changes, myelin thinning, abnormal oligodendrocytes and behavioural inflexibility. Nat Commun. 2019;10:3455. source

  • May combine two claims.

    Premisecitation

    Loss of Cyfip1 may drive overactive NMDAR signalling, hippocampal hyperactivity and aberrant drive of dopamine release; behavioural deficits in the Cyfip1 knockout and overexpressing lines could be ameliorated by pharmacological treatment with NMDAR antagonists and agonists, respectively.

    “Moreover, this loss of Cyfip1 may drive overactive NMDAR signalling, hippocampal hyperactivity and aberrant drive of dopamine release; behavioural deficits in the Cyfip1 knockout and overexpressing lines could be ameliorated by pharmacological treatment with NMDAR antagonists and agonists, respectively.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [98] Kim NS, Ringeling FR, Zhou Y, Nguyen HN, Temme SJ, Lin YT, et al. CYFIP1 dosages exhibit divergent behavioral impact via diametric regulation of NMDA receptor complex translation in mouse models of psychiatric disorders. Biol Psychiatry. 2022;92:815–26. source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

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

    Premisecitation

    Converging evidence suggests a crucial role for dopamine in the aetiology of neurodevelopmental disorders such as schizophrenia.

    “Converging evidence suggests a crucial role for dopamine in the aetiology of neurodevelopmental disorders such as schizophrenia [92, 93].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [92] Howes OD, Kapur S. The dopamine hypothesis of schizophrenia: version III–the final common pathway. Schizophr Bull. 2009;35:549–62. source
    • cites [93] Tost H, Alam T, Meyer-Lindenberg A. Dopamine and psychosis: theory, pathomechanisms and intermediate phenotypes. Neurosci. Biobehav. Rev. 2010;34:689–700. source

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

    Premisecitation

    Some Cyfip1+/− rats were able to complete a reversal learning task in which performance to criteria rather than number of sessions of training dictated how long animals were trained for.

    “For example, some Cyfip1+/− were able to complete a reversal learning task in which performance to criteria rather than number of sessions of training dictated how long animals were trained for [11].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [11] Silva AI, Haddon JE, Ahmed Syed Y, Trent S, Lin TE, Patel Y, et al. Cyfip1 haploinsufficient rats show white matter changes, myelin thinning, abnormal oligodendrocytes and behavioural inflexibility. Nat Commun. 2019;10:3455. source

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

    Premisecitation

    Cortico-striatal synchrony is disrupted by treatment with phencyclidine.

    “Moreover, cortico-striatal synchrony is disrupted by treatment with phencyclidine [96], and anti-psychotic drugs that act on dopamine also alter the functional connectivity between these regions and the hippocampus [97].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [96] Bolding MS, White DM, Hadley JA, Weiler M, Holcomb HH, Lahti AC. Antipsychotic drugs alter functional connectivity between the medial frontal cortex, hippocampus, and nucleus accumbens as measured by H215O PET. Front Psychiatry. 2012;3:105. source

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

    Premisecitation

    Anti-psychotic drugs that act on dopamine alter the functional connectivity between cortico-striatal regions and the hippocampus.

    “Moreover, cortico-striatal synchrony is disrupted by treatment with phencyclidine [96], and anti-psychotic drugs that act on dopamine also alter the functional connectivity between these regions and the hippocampus [97].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [97] Asif-Malik A, Dautan D, Young AMJ, Gerdjikov TV. Altered cortico-striatal crosstalk underlies object recognition memory deficits in the sub-chronic phencyclidine model of schizophrenia. Brain Struct Funct. 2017;222:3179–90. source

  • May combine two claims.

    Findingown data

    Cyfip1 heterozygous rats showed a selective deficit in responding flexibly during the conditional discrimination task, being able to respond correctly during only one of the cue types and responding incorrectly when the other cue was presented.

    “Cyfip1 heterozygous rats showed a selective deficit in responding flexibly during the conditional discrimination task - being able to respond correctly during only one of the cue types, responding incorrectly when the other cue was presented.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    WT rats responded more to the correct lever than the incorrect lever, but Cyfip1+/− rats did not.

    “Simple effects analysis revealed an effect of LEVER for WT [F(1,18) = 29.870, p < 0.001] but not Cyfip1+/− rats [F(1,18) = 2.733, p = 0.116, n.s.], such that WT rats responded more to the correct lever than the incorrect lever.”
    Quote in the paperSubstantial claim

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

    Findingown data

    Both WT and Cyfip1+/− rats produced more correct than incorrect responses during the last session of training.

    “An effect of LEVER was observed in both WT [F(1, 144) = 68.393, p < 0.001] and Cyfip1+/− rats [F(1, 144) = 6.258, p = 0.014] such that all animals produced more correct than incorrect responses during the last session of training.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Cyfip1+/− rats only appeared to respond correctly to the Clicker, responding equally on the correct and incorrect levers to the Tone.

    “While WT rats showed correct responding to both the Clicker and the Tone, Cyfip1+/− rats only appeared to respond correctly to the Clicker, responding equally on the correct and incorrect levers to the Tone.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Cyfip1+/− rats produced more correct than incorrect responses to the biconditional stimuli but were impaired compared to WT rats and produced fewer instrumental responses overall.

    “although they produced more correct than incorrect responses to the biconditional stimuli, they were impaired compared to WT rats and produced fewer instrumental responses overall.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    There was a significant effect of GENOTYPE on correct responses but not on incorrect lever responses.

    “A significant effect of GENOTYPE was observed on correct responses [F(1,36) = 7.528, p = 0.009] but not responses on the incorrect lever [F(1,36) = 1.431, p = 0.240, n.s.].”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    No differences were observed in motor responding (magazine entries or lever press responses) during pretraining, or magazine entries during training on the conditional task in Cyfip1+/− rats.

    “No differences, however, were observed in motor responding (magazine entries or lever press responses) during pretraining, or magazine entries during training on the conditional task.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    WT rats showed a discrimination ratio score significantly above chance, while Cyfip1+/− rats responded as if they had only learned about one cue of the biconditional discrimination task.

    “with WT rats showing a score that was significantly above chance responding and Cyfip1+/− rats responding as if they have only learned about one cue of the biconditional discrimination task.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Cyfip1+/− animals had weaker Granger causality overall, plus connectivity was more diffuse than in WTs.

    “In contrast, Cyfip1+/− animals had weaker Granger causality overall, plus connectivity was more diffuse than in WTs.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Lesions to the nucleus accumbens can produce perseverative responding, impair reversal learning, and reduce behavioural switching.

    “Lesions to the nucleus accumbens can produce perseverative responding, impair reversal learning, and reduce behavioural switching [69–71].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [69] Weiner I, Gal G, Rawlins JN, Feldon J. Differential involvement of the shell and core subterritories of the nucleus accumbens in latent inhibition and amphetamine-induced activity. Behav Brain Res. 1996;81:123–33. source
    • cites [70] Weiner I, Gal G, Feldon J. Disrupted and undisruptable latent inhibition following shell and core lesions. Ann N Y Acad Sci. 1999;877:723–7. source
    • cites [71] Haluk DM, Floresco SB. Ventral striatal dopamine modulation of different formsof behavioral flexibility. Neuropsychopharmacology. 2009;34:2041–52. source

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

    Premisecitation

    Via the nucleus accumbens, the prefrontal cortex and hippocampal formation can influence striato-pallido-thalamo-cortical circuits involving the ventral pallidum, subthalamic nucleus, ventral tegmental area, substantia nigra and thalamic areas.

    “Via the nucleus accumbens, the prefrontal cortex and hippocampal formation can influence striato-pallido-thalamo-cortical circuits involving the ventral pallidum, subthalamic nucleus, ventral tegmental area, substantia nigra and thalamic areas [21, 22].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [21] Groenewegen HJ, Berendse HW, Wolters JG, Lohman AH. The anatomical relationship of the prefrontal cortex with the striatopallidal system, the thalamus and the amygdala: evidence for a parallel organization. Prog Brain Res. 1990;85:95–116. source
    • cites [22] Thierry AM, Gioanni Y, Dégénétais E, Glowinski J. Hippocampo-prefrontal cortex pathway: anatomical and electrophysiological characteristics. Hippocampus. 2000;10:411–9. source

  • May combine two claims.

    Premisecitation

    Conditional discrimination tasks engage frontal and meso-limbic dopaminergic systems, with dopamine increased in the prefrontal cortex and reduced in the nucleus accumbens region of the striatum in wildtype rats performing this task.

    “George and colleagues [44] have demonstrated direct evidence that conditional discrimination tasks engage frontal and meso-limbic dopaminergic systems, with dopamine increased in the prefrontal cortex and reduced in the nucleus accumbens region of the striatum in wildtype rats performing this task.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] George DN, Jenkins TA, Killcross S. Dissociation of prefrontal cortex and nucleus accumbens dopaminergic systems in conditional learning in rats. Behav Brain Res. 2011;225:47–55. source

  • May combine two claims.

    Interpretationreasoning

    Reduced myelination in Cyfip1+/− rats results in impaired brain network function, which in turn leads to cognitive impairment consistent with behavioural deficits seen in neurodevelopmental disorders such as autism and schizophrenia.

    “This extends the idea that reduced myelination in Cyfip1+/− rats results in impaired brain network function, which in turn leads to cognitive impairment consistent with behavioural deficits seen in neurodevelopmental disorders such as autism and schizophrenia.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The Cyfip1+/− rat model recapitulates aspects of the human 15q11.2 BP1-BP2 deletion syndrome relevant to neuropsychiatric disease.

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

    Study design and conductreasoning

    Results for the analyses are shown for 14 WT and 11 Cyfip1+/− rats.

    “Thus, results for the analyses are shown for 14 WT and 11 Cyfip1+/− rats.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The animals were assigned to the experimental groups in a non-blinded, random manner.

    “The animals were assigned to these groups in a non-blinded, random manner.”
    Quote in the paperNot a substantial claim

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

    Study design and conductcitation

    Lesion sites were cross-checked with the Rat Brain Atlas.

    “Lesion sites were cross-checked with the Rat Brain Atlas [48], see Supplementary Fig. 1 for electrode placements.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Paxinos G, Watson C. The rat brain in stereotaxic coordinates. 6th ed. San Diego, CA: Academic Press; 2007.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Study design and conductown data

    Each VAR model had an R2 > 30% and white residuals as assessed using the Durbin-Watson test (p < 0.05) with a mean model consistency of 84%.

    “Each VAR model had an R2 > 30% and white residuals as assessed using the Durbin–Watson test (p < 0.05) with a mean model consistency of 84%.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Hippocampal projections to the NAc have been hypothesised to play a role in behavioural flexibility during latent inhibition.

    “Hippocampal projections to the NAc have also been hypothesised to play a role in behavioural flexibility during latent inhibition [82, 83].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [82] Weiner I, Feldon J. The switching model of latent inhibition: an update of neural substrates. Behav Brain Res. 1997;88:11–25. source
    • cites [83] Schmajuk NA, Cox L, Gray JA. Nucleus accumbens, entorhinal cortex and latent inhibition: a neural network model. Behav Brain Res. 2001;118:123–41. source

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

    Premisecitation

    Abnormal hyperactivity in the medial PFC combined with dysfunction in the nucleus accumbens core is associated with long term deficits in executive function in rats exposed to prolonged stress.

    “For example, Piao et al. [79] found that abnormal hyperactivity in the medial PFC combined with dysfunction in the nucleus accumbens core associated with long term deficits in executive function in rats exposed to prolonged stress.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [79] Piao C, Deng X, Wang X, Yuan Y, Liu Z, Liang J. Altered function in medial prefrontal cortex and nucleus accumbens links to stress-induced behavioral inflexibility. Beh Brain Res. 2017;317:16–26. source

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

    Study design and conductown data

    One animal was excluded from all analyses due to saturating noise during recording, and a second animal was excluded due to a mis-targeted IL electrode.

    “One animal was excluded from all analyses due to saturating noise during recording (WT = 14, Cyfip1+/− = 12). A second animal was excluded due to a mis-targeted IL electrode.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The animals in the current study were trained blind to genotype for eight days on the discrimination task.

    “The animals in the current study were trained blind to genotype for eight days on the discrimination task—which we have previously shown to be long enough for WT rats to successfully acquire the discrimination [44, 49].”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    The stability of fronto-striatal integrity was not quantified in the experiments.

    “However, the stability of fronto-striatal integrity was not quantified in our experiments; longitudinal studies quantifying structural and/or functional connectivity across days and different neurodevelopmental timepoints would be one useful next step.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Accumbens neurons require activation from more than one source to reach threshold, integrating limbic and cortical innervations depending on the intensity and timing of inputs.

    “Accumbens neurons require activation from more than one source to reach threshold [87, 88] - integrating limbic and cortical innervations depending on the intensity and timing of inputs [89].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [87] DeFrance JF, Sikes RW, Chronister RB. Dopamine action in the nucleus accumbens. J Neurophysiol. 1985;54:1568–77. source
    • cites [88] Callaway CW, Hakan RL, Henriksen SJ. Distribution of amygdala input to the nucleus accumbens septi: an electrophysiological investigation. J Neural Transm Gen Sect. 1991;83:215–25. source
    • cites [89] McGinty VB, Grace AA. Timing-dependent regulation of evoked spiking in nucleus accumbens neurons by integration of limbic and prefrontal cortical inputs. J Neurophysiol. 2009;101:1823–35. source

  • Classified as probably not a substantial claim.

    Premisecitation

    The nucleus accumbens receives innervation from multiple brain regions including the prefrontal cortex and hippocampus.

    “It is well documented that the nucleus accumbens receives innervation from multiple brain regions including the prefrontal cortex and hippocampus [85, 86].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [85] Sesack SR, Deutch AY, Roth RH, Bunney BS. Topographical organization of the efferent projections of the medial prefrontal cortex in the rat: an anterograde tract-tracing study with Phaseolus vulgaris leucoagglutinin. J Comp Neurol. 1989;290:213–42. source
    • cites [86] Swanson LW, Cowan WM. Hippocampo-hypothalamic connections: origin in subicular cortex, not ammon’s horn. Science. 1975;189:303–4. source
49 of 49

  • The paper relies on this without support.

    The Cyfip1+/− rat model recapitulates aspects of the human 15q11.2 BP1-BP2 deletion syndrome relevant to neuropsychiatric disease.

    “In conclusion, we have employed a novel rat model of Cyfip1 haploinsufficiency to probe the electrophysiological and behavioural fronto-striatal mechanisms underlying the enhanced risk for neuropsychiatric disease linked to the 15q11.2 BP1-BP2 deletion.”

  • The paper relies on this without support.

    There are no consistent reports of deficits in hearing or perception in individuals with 15q11.2del.

    “It is also worth noting that there are no consistent reports of deficits in either hearing or perception in individuals with 15q11.2del.”
2 of 2

Statistics recomputed

Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.

  • Not confirmedF(1, 144) = 6.258reported p = .014 · recomputed p = .013

    “F(1, 144) = 6.258, p = .014”

  • ConsistentF(1, 144) = 16.637reported p < .001 · recomputed p < .001

    “F(1, 144) = 16.637, p < .001”

  • ConsistentF(1, 144) = 68.393reported p < .001 · recomputed p < .001

    “F(1, 144) = 68.393, p < .001”

  • ConsistentF(1, 288) = 9.246reported p = .003 · recomputed p = .003

    “F(1, 288) = 9.246, p = .003”

  • ConsistentF(1, 18) = 7.266reported p = .015 · recomputed p = .015

    “F(1,18) = 7.266, p = .015”

  • ConsistentF(1, 18) = 29.87reported p < .001 · recomputed p < .001

    “F(1,18) = 29.870, p < .001”

  • ConsistentF(1, 18) = 2.733reported p = .116 · recomputed p = .116

    “F(1,18) = 2.733, p = .116”

  • ConsistentF(1, 36) = 7.528reported p = .009 · recomputed p = .009

    “F(1,36) = 7.528, p = .009”

  • ConsistentF(1, 36) = 1.431reported p = .24 · recomputed p = .239

    “F(1,36) = 1.431, p = .240”

  • ConsistentF(1, 18) = 5.403reported p = .032 · recomputed p = .032

    “F(1, 18) = 5.403, p = .032”

10 of 10

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Phencyclidine claim points to the antipsychotic-drug reference

    Minor

    The claim about phencyclidine cites reference 96, whose listed title concerns antipsychotic drugs. The adjacent reference 97 is the one titled as a study of a phencyclidine model.

  • Median age falls outside the stated age range

    Minor

    The reported median age of 200 days cannot fall outside the stated range of 180-197 days.

  • Frontal and hippocampal connectivity is described as both weaker and stronger

    Minor

    The discussion describes connectivity involving frontal cortex and hippocampus as weaker in Cyfip1+/− rats, whereas the results report stronger connections originating from those regions in the same group.

3 of 3

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Paxinos G, Watson C. The rat brain in stereotaxic coordinates. 6th ed. San Diego, CA: Academic Press; 2007.

Cited by

Sorted by citations

Related

Authors
Haddon, J. E., Titherage, D., Heckenast, J. R., Carter, J., Owen, M. J., Hall, J., Wilkinson, L. S., & Jones, M. W.
Affiliations
  • Cardiff University (GB)
  • University of Bristol (GB)
Corresponding author
Haddon, Josephine E.
ORCID
Venue
Translational Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2024-06-14
Volume
14
Issue
1
Pages
256-256
ISSN
2158-3188 (ISSN-L)
DOI
10.1038/s41398-024-02969-x
PMC
PMC11178837
OpenAlex
W4399676481
Cited by
6
References
98
Citations by year
2026: 3 · 2025: 2 · 2024: 1
FWCI
1.42
Type
journal article
Language
en
Open access
Licence
Locations
  • Translational Psychiatry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion, cc-by)
  • PubMed Central (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Explore Bristol Research (submittedVersion, cc-by)
  • OSF Preprints (OSF Preprints) (submittedVersion, cc-by)
Funders
Wellcome Trust (100202/Z/12/Z)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
CYFIP1, haploinsufficiency, behavioral flexibility, cognitive inflexibility, frontostriatal circuits, local field potentials, nucleus accumbens, medial prefrontal cortex, hippocampal CA1, ventral striatum, conditional discrimination learning, autism spectrum disorder, schizophrenia
MeSH terms
Animals, Autistic Disorder, Behavior, Animal, Corpus Striatum, Disease Models, Animal, Male, Nerve Net, Schizophrenia, Prefrontal Cortex, Adaptor Proteins, Signal Transducing, Rats, CA1 Region, Hippocampal, Haploinsufficiency, Ventral Striatum

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 2026-10-27.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-27.

Cited sources are checked by gpt-6-sol.

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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