The DOI matches its Crossref record; 83 of the 83 references it cites were found in a registry or an index; 7 of the 65 sources its claims cite were checked for support.
Regulation of autism-relevant behaviors by cerebellar-prefrontal cortical circuits
Open accessAbstract
Cerebellar dysfunction has been demonstrated in autism spectrum disorders (ASDs); however, the circuits underlying cerebellar contributions to ASD-relevant behaviors remain unknown. In this study, we demonstrated functional connectivity between the cerebellum and the medial prefrontal cortex (mPFC) in mice; showed that the mPFC mediates cerebellum-regulated social and repetitive/inflexible behaviors; and showed disruptions in connectivity between these regions in multiple mouse models of ASD-linked genes and in individuals with ASD. We delineated a circuit from cerebellar cortical areas Right crus 1 (Rcrus1) and posterior vermis through the cerebellar nuclei and ventromedial thalamus and culminating in the mPFC. Modulation of this circuit induced social deficits and repetitive behaviors, whereas activation of Purkinje cells (PCs) in Rcrus1 and posterior vermis improved social preference impairments and repetitive/inflexible behaviors, respectively, in male PC-Tsc1 mutant mice. These data raise the possibility that these circuits might provide neuromodulatory targets for the treatment of ASD. Kelly et al. describe two cerebellum–thalamus–mPFC pathways in mice that regulate social and repetitive behavior. PC activation in Rcrus1 and posterior vermis improved social and reduced repetitive behaviors, respectively, in PC-Tsc1 mutant mice.
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TL;DR
This study delineates cerebellar–prefrontal circuits in mice through which Rcrus1 and posterior vermis Purkinje cell output converges on ventromedial thalamus–medial prefrontal cortex projections to regulate autism-relevant social and repetitive/inflexible behaviors. It also reports disrupted cerebellar–mPFC connectivity in multiple ASD-linked mouse models and in individuals with ASD, and shows that circuit modulation can rescue behaviors in adult PC-Tsc1 mutant mice.
Key findings
- Cerebellar Purkinje cell dysfunction or chemogenetic inhibition of Rcrus1 or posterior vermis increased left prelimbic mPFC single-unit firing; inhibiting left mPFC rescued social deficits and repetitive grooming in PC-Tsc1 mutant mice.
- A polysynaptic circuit was delineated from Rcrus1 and posterior vermis through cerebellar nuclei (lateral nucleus and medial/fastigial nucleus) and ventromedial thalamus to left prelimbic mPFC; optogenetic activation of VM thalamic terminals in mPFC induced social deficits and repetitive grooming, while optogenetic silencing rescued both in PC-Tsc1 mutants.
- Distinct cerebellar domains regulated different behaviors: Rcrus1/lateral nucleus modulation rescued social behaviors but not repetitive behaviors, whereas posterior vermis Purkinje cell stimulation selectively reduced repetitive grooming and improved water Y-maze flexibility without improving social preference in PC-Tsc1 mutants.
- Connectivity was disrupted in ASD models and humans: structural covariance between Rcrus1 and left PRL mPFC was altered across 94 ASD-linked mouse lines (FDR q = 0.0191), with 30 of 94 models showing significant volume changes (binomial P = 2.02 × 10−18; combined q < 0.0001); human POND structural covariance showed Rcrus1–left rectus gyrus disruption (P = 0.012) that did not survive multiple corrections (q > 0.05); human resting-state fMRI in 8 ASD vs 8 TD males showed mPFC/Rcrus1–Rcrus2 alterations (P < 0.001, FDR q < 0.05) and reduced seed-to-voxel functional connectivity (P < 0.001, k > 50).
Methods
- Mice: PC-Tsc1 mutants (PCCre;Tsc1flox/flox) and littermate controls, aged 5–12 weeks; only male animals were used for behavioral experiments and electrophysiological recordings. Methods included stereotaxic viral injections, chemogenetic and optogenetic modulation, in vivo single-unit recordings, acute slice electrophysiology, viral tracing, and behavioral assays (three-chamber social approach/novelty, social olfaction, grooming, water T/Y-maze reversal, open field, elevated plus maze, rotarod).
- MRI/connectivity: mouse structural covariance MRI across 94 ASD-linked gene models (2,414 mice, 67.7% male, PND 30–245), plus a subset of 30 models (n = 559 mutants, n = 1,101 controls); human structural MRI from POND and other data (902 scans, 425 ASD and 477 control, from 648 individuals, age 2–50 years, mean 13); human resting-state fMRI in 8 TD male adults (mean age 20.75 ± 1.91 years) and 8 ASD male adults (mean age 26.13 ± 9.79 years).
- Analysis: structural covariance modeled with sex and sex interaction covariates, two-sided t-tests, Benjamini–Hochberg FDR q values; behavioral data analyzed with two- or three-way ANOVA and Sidak post hoc tests; electrophysiology with t-tests or Mann–Whitney tests; sample size estimated with PASS 12.
Limitations
- Stated: the human structural covariance finding between Rcrus1 and left rectus gyrus did not survive multiple corrections (q > 0.05); the human resting-state fMRI cohort was small; the precise function of these regions/circuits during social interactions and the broader cerebellar–cerebro cortical network map require future research; additional cortical and subcortical regions/routes may contribute; mPFC is a less accessible target for noninvasive neuromodulation.
- Evident from the text: behavioral and electrophysiological experiments used only male mice, limiting generalization to females; mice were of mixed genetic backgrounds; some human imaging analyses involved small samples or did not survive correction.
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Claims the paper makes
81 Own result · 36 Not checked yet · 26 Own interpretation · 21 Own method · 3 Partly supported · 1 Supported · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“disruptions in cerebellar–mPFC connectivity have been demonstrated in ASD20.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Main
What the sources say
- Partly supportedcites [20] Gilbert, S. J., Bird, G., Brindley, R., Frith, C. D. & Burgess, P. W. Atypical recruitment of medial prefrontal cortex in autism spectrum disorders: an fMRI study of two executive function tasks. Neuropsychologia 46, 2281–2291 (2008). sourceExperimental — accuracy not yet measured
The Results (fMRI results: alphabet task) report ASD–control differences in activity in both medial PFC and the cerebellum. The Discussion (task-specific abnormalities in executive function) also reports cerebellar differences in the random-generation task. Neither passage demonstrates disrupted connectivity between the cerebellum and mPFC; the paper’s discussion of underconnectivity concerns modulation of sensory areas, not this specific connection. (LLM, conf=0.84)
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“in mouse models of cerebellar PC loss, and in genetic mouse models of ASD17,18.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Main
What the sources say
- Partly supportedcites [17] Rogers, T. D. et al. Connecting the dots of the cerebro-cerebellar role in cognitive function: neuronal pathways for cerebellar modulation of dopamine release in the prefrontal cortex. Synapse 65, 1204–1212 (2011). sourceExperimental — accuracy not yet measured
The Introduction (page unavailable) reports that lurcher mice with near-total Purkinje cell loss show mPFC dopamine release dependent on functional Purkinje cell output. That supports a cerebellar–mPFC functional link, but the paper does not identify a measured change in functional connectivity in those mice or report such a finding in a genetic mouse model of ASD. The Conclusions describe reduced connectivity as a hypothesis and propose further experiments on Purkinje cell loss. (LLM, conf=0.84)
- Supportedcites [18] Rogers, T. D. et al. Reorganization of circuits underlying cerebellar modulation of prefrontal cortical dopamine in mouse models of autism spectrum disorder. Cerebellum 12, 547–556 (2013). source
The Introduction identifies the two models as Lurcher mice, which lose cerebellar Purkinje cells, and Fmr1-knockout mice, a genetic model of fragile X syndrome. The Discussion reports altered cerebellar modulation of mPFC dopamine and a functional shift between the VTA and thalamic pathways in both mutants. The claim's ‘functional connectivity’ is supported in this specific circuitry sense. (LLM, conf=0.94)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“We and others previously demonstrated connectivity between the left mPFC and Rcrus1 in humans and primates8,9,10.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Results > Rcrus1 and left mPFC connections are disrupted in mouse models of ASD-linked genes and in ASD
What the sources say
- Partly supportedcites [8] Stoodley, C. J. et al. Altered cerebellar connectivity in autism and cerebellar-mediated rescue of autism-related behaviors in mice. Nat. Neurosci. 20, 1744–1751 (2017). sourceExperimental — accuracy not yet measured
The section ‘RCrusI is functionally connected to multiple whole-brain networks in neurotypical adults’ (page unavailable) reports functional connectivity between right Crus I and predominantly left-lateralized regions including medial frontal cortex in humans. It does not specifically identify the left mPFC or demonstrate this connection in nonhuman primates; the paper’s animal connectivity experiments concern mice. (LLM, conf=0.85)
- Partly supportedcites [9] Krienen, F. M. & Buckner, R. L. Segregated fronto-cerebellar circuits revealed by intrinsic functional connectivity. Cereb. Cortex 19, 2485–2497 (2009). sourceExperimental — accuracy not yet measured
The Results (Table 3) identify right Crus I as preferentially correlated with MPFC, and the Methods (Table 1) show that left MPFC was among the human seed regions. The paper does not establish this specific left-MPFC–right-Crus-I connection in nonhuman primates; the Discussion says the human prefrontal–cerebellar circuits it identifies may lack monkey homologues. (LLM, conf=0.88)
- Partly supportedcites [10] Middleton, F. A. & Strick, P. L. Cerebellar projections to the prefrontal cortex of the primate. J. Neurosci. 21, 700–712 (2001). sourceExperimental — accuracy not yet measured
The ‘Labeling in cerebellar output nuclei’ section reports that injections into medial prefrontal area 9 in monkeys labeled dentate neurons predominantly on the opposite side, supporting a contralateral cerebellar–medial prefrontal connection in primates. The paper does not identify that connection specifically as left mPFC to right Crus I or demonstrate it in humans. (LLM, conf=0.88)
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“we demonstrated functional connectivity between the cerebellum and the medial prefrontal cortex (mPFC) in mice”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Abstract
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“showed that the mPFC mediates cerebellum-regulated social and repetitive/inflexible behaviors”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We delineated a circuit from cerebellar cortical areas Right crus 1 (Rcrus1) and posterior vermis through the cerebellar nuclei and ventromedial thalamus and culminating in the mPFC.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“showed disruptions in connectivity between these regions in multiple mouse models of ASD-linked genes and in individuals with ASD”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“activation of Purkinje cells (PCs) in Rcrus1 and posterior vermis improved social preference impairments and repetitive/inflexible behaviors, respectively, in male PC-Tsc1 mutant mice.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“activation of Purkinje cells (PCs) in Rcrus1 and posterior vermis improved social preference impairments and repetitive/inflexible behaviors, respectively, in male PC-Tsc1 mutant mice.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Modulation of this circuit induced social deficits and repetitive behaviors”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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- Probably not a substantial claim. 32
- It may state two separate claims as one. 36
- The quote only partly states this claim. 2
Every source the paper cites for this claim was checked and supports it.
In the paper
“earlier findings that decreasing mPFC excitatory activity can rescue social deficits in an ASD mouse model24”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Results > Inhibition of mPFC improves social deficits and repetitive/inflexible behaviors in PC-Tsc1 mutant mice
What the sources say
- Supportedcites [24] Selimbeyoglu, A. et al. Modulation of prefrontal cortex excitation/inhibition balance rescues social behavior in CNTNAP2-deficient mice. Sci. Transl. Med. 9, eaah6733 (2017). source
The Results describe decreasing the excitability of excitatory pyramidal neurons in the mPFC of CNTNAP2 knockout mice. The Discussion reports that reducing pyramidal-neuron excitability rescued social behavior deficits in this autism-like mouse model. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
- Supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Motor learning, locomotor and anxiety behaviors were unaffected in PC-Tsc1 mutants and not altered by mPFC chemogenetic inhibition”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Results > Inhibition of mPFC improves social deficits and repetitive/inflexible behaviors in PC-Tsc1 mutant mice
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“without altering unit firing frequency in the motor cortex or in the right PRL”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Results > Rcrus1 and left mPFC connections are disrupted in mouse models of ASD-linked genes and in ASD
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“CNO-injected Gi/GFP mice demonstrated impairments in these behaviors as well as in social odor preference”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Results > Inhibition of mPFC improves social deficits and repetitive/inflexible behaviors induced by inhibition of Rcrus1 PCs
boosteddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“VEH-injected Gi/Gi and Gi/GFP mice exhibited significant social preference and social novelty preference, consistent with their control background.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Results > Inhibition of mPFC improves social deficits and repetitive/inflexible behaviors induced by inhibition of Rcrus1 PCs
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Downstream thalamic and cortical areas identified are consistent with previously published results”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Results > Optogenetic activation of ventromedial thalamic terminals in the mPFC induces ASD-related behaviors
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“GFP-control and light-OFF Arch-expressing PC-Tsc1 mutants showed social impairments consistent with their mutant backgrounds.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Results > Optogenetic silencing of VM thalamic terminals in the left PRL mPFC reduces ASD-relevant behaviors in PC-Tsc1 mutants
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The photo-inhibition did not induce any change in locomotion, motor learning or anxiety”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Results > Optogenetic silencing of VM thalamic terminals in the left PRL mPFC reduces ASD-relevant behaviors in PC-Tsc1 mutants
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We did not observe any effects of laser stimulation on locomotor behavior, motor learning or anxiety measures that would affect the interpretation of the social or grooming behaviors”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Results > Optogenetic activation of ventromedial thalamic terminals in the mPFC induces ASD-related behaviors
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These cells also have terminals in the left PRL mPFC in the same area (layer 1) receiving input from the LN”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Results > A polysynaptic circuit connects cerebellar vermis with mPFC via VM thalamus
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Rests on an assumption: Inhibitory PC output emerges from the cerebellum via cerebellar nuclei.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Stimulation of posterior vermis PCs had no significant effect on locomotion, motor learning or anxiety”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Results > Posterior vermis function is necessary for normal social and grooming/flexible behaviors, and modulation is sufficient to rescue repetitive behaviors
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“and improved behavioral flexibility in the water Y-maze”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Results > Posterior vermis function is necessary for normal social and grooming/flexible behaviors, and modulation is sufficient to rescue repetitive behaviors
plaindirect- Asserted: passes — The authors put it forward as true.
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The quote only partly states this claim.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In this study, we showed that cerebellar PC dysfunction and targeted inhibition of Rcrus1 or the posterior vermis resulted in increased mPFC activity”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Discussion
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Voxel-to-voxel functional connectivity maps thresholded at P < 0.001, FDR cluster corrected P < 0.05 yielded significant clusters in the medial prefrontal cortex (peak coordinates (x, y, z): 4, 38, −24; k = 260) and Rcrus 1 and Rcrus2 of the cerebellum (peak coordinates (x, y, z): 34, −82, −40; k = 18).”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Methods > Human functional MRI
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Thirty models with P < 0.05 in both the left mPFC and the cerebellar regions were identified, and structural covariance analysis on these models (n = 559) and controls (n = 1,101) was also performed”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Methods > Mouse MRI
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
In the paper
“PC-specific deletion of Tsc1 is sufficient to generate ASD-relevant social impairment and repetitive/inflexible behaviors in mice5.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Main
What the sources say
- Not checked yetcites [5] Tsai, P. T. et al. Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice. Nature 488, 647–651 (2012). source
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Many studies have detailed volumetric changes in the posterior cerebellar vermis and in Rcrus1 in children with ASD”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Main
What the sources say
- Not checked yetcites [6] Pierce, K. & Courchesne, E. Evidence for a cerebellar role in reduced exploration and stereotyped behavior in autism. Biol. Psychiatry 49, 655–664 (2001). source
- Not checked yetcites [7] D’Mello, A. M., Crocetti, D., Mostofsky, S. H. & Stoodley, C. J. Cerebellar gray matter and lobular volumes correlate with core autism symptoms. Neuroimage Clin. 7, 631–639 (2015). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“We recently demonstrated that inhibition of Rcrus1 PCs could generate both social impairments and repetitive behaviors”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Main
What the sources say
- Not checked yetcites [8] Stoodley, C. J. et al. Altered cerebellar connectivity in autism and cerebellar-mediated rescue of autism-related behaviors in mice. Nat. Neurosci. 20, 1744–1751 (2017). source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Taken together, these data demonstrate that inhibition of mPFC was sufficient to enhance social behavior and reduce repetitive grooming in PC-Tsc1 mutants.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Results > Inhibition of mPFC improves social deficits and repetitive/inflexible behaviors in PC-Tsc1 mutant mice
boosteddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Sex and interaction with sex were included as covariates in the structural covariance model.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Results > Rcrus1 and left mPFC connections are disrupted in mouse models of ASD-linked genes and in ASD
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Together, these data point to disruptions in connectivity between the mPFC and Rcrus1 both in mouse models and in humans with ASD.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Results > Rcrus1 and left mPFC connections are disrupted in mouse models of ASD-linked genes and in ASD
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“A regression model tested covariates for scanner, age at scan and sex.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Results > Rcrus1 and left mPFC connections are disrupted in mouse models of ASD-linked genes and in ASD
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Taken together, these data indicate that reduction of mPFC activity is sufficient to rescue both social deficits and repetitive/inflexible behaviors induced by Rcrus1 PC inhibition”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Results > Inhibition of mPFC improves social deficits and repetitive/inflexible behaviors induced by inhibition of Rcrus1 PCs
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In contrast, modulation of Rcrus1 or LN rescued only the social preference behaviors but did not affect grooming.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Results > A polysynaptic circuit connects cerebellar vermis with mPFC via VM thalamus
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We have demonstrated that inhibition of the PRL mPFC itself or its inputs from the VM thalamus both reduces repetitive grooming and increases social preference in PC-Tsc1 mutant mice.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Results > A polysynaptic circuit connects cerebellar vermis with mPFC via VM thalamus
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Taken together, photo-activation of VM terminals in the left PRL mPFC was sufficient to induce social deficits and repetitive grooming.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Results > Optogenetic activation of ventromedial thalamic terminals in the mPFC induces ASD-related behaviors
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These results demonstrate that inhibition of VM thalamus–PRL mPFC projections was sufficient to rescue both social impairments and repetitive grooming in PC-Tsc1 mutant mice.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Results > Optogenetic silencing of VM thalamic terminals in the left PRL mPFC reduces ASD-relevant behaviors in PC-Tsc1 mutants
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“these data suggest that cerebellar outputs from Rcrus1 and posterior vermis converge on VM thalamus–mPFC projections to regulate social preference and behavioral flexibility, respectively”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Results > Posterior vermis function is necessary for normal social and grooming/flexible behaviors, and modulation is sufficient to rescue repetitive behaviors
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Inhibitory PC output emerges from the cerebellum via cerebellar nuclei.
In the paper
“The cerebellum provides an important source of inhibitory tone, as its output emerges solely via inhibitory PCs41.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Discussion
What the sources say
- Not checked yetcites [41] Mouginot, D. & Gahwiler, B. H. Characterization of synaptic connections between cortex and deep nuclei of the rat cerebellum in vitro. Neuroscience 64, 699–712 (1995). source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Neural circuit manipulation in combination with neural recordings provide direct evidence that elevated mPFC activity results in ASD-related phenotypes, whereas decreasing mPFC activity is sufficient to rescue abnormal behaviors in ASD models22,23,24.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Discussion
What the sources say
- Not checked yetcites [22] Kobayashi, M., Hayashi, Y., Fujimoto, Y. & Matsuoka, I. Decreased parvalbumin and somatostatin neurons in medial prefrontal cortex in BRINP1-KO mice. Neurosci. Lett. 683, 82–88 (2018). source
- Not checked yetcites [23] Yizhar, O. et al. Neocortical excitation/inhibition balance in information processing and social dysfunction. Nature 477, 171–178 (2011). source
- Not checked yetcites [24] Selimbeyoglu, A. et al. Modulation of prefrontal cortex excitation/inhibition balance rescues social behavior in CNTNAP2-deficient mice. Sci. Transl. Med. 9, eaah6733 (2017). source
boosteddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“One prominent hypothesis is that excitation/inhibition (E/I) imbalance contributes to ASD37.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Discussion
What the sources say
- Not checked yetcites [37] Rubenstein, J. L. & Merzenich, M. M. Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav. 2, 255–267 (2003). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“synaptic abnormalities resulting in neuronal hyperactivity and altered brain connectivity39”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Discussion
What the sources say
- Not checked yetcites [39] Contractor, A., Klyachko, V. A. & Portera-Cailliau, C. Altered neuronal and circuit excitability in fragile X syndrome. Neuron 87, 699–715 (2015). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These results support our hypothesis that the posterior cerebellar vermis regulates social behaviors and behavioral flexibility.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Results > Posterior vermis function is necessary for normal social and grooming/flexible behaviors, and modulation is sufficient to rescue repetitive behaviors
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our data further demonstrate that distinct cerebellar regions regulate specific behaviors, with Rcrus1 stimulation sufficient to ameliorate social behaviors, whereas posterior vermis stimulation is sufficient to improve repetitive/inflexible behaviors.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Discussion
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“from these models, disruption in these delineated circuits that connect the cerebellum and mPFC would be predicted to result in disruption in the ability to generate predictions, validate timing and update those parameters, which, all told, would be expected to have a detrimental effect on social interaction.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“However, precise targeting of human mPFC circuits presents a therapeutic challenge owing to the dense processing occurring in the mPFC and because the mPFC offers a less accessible target for noninvasive neuromodulation46.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Discussion
What the sources say
- Not checked yetcites [46] Carmi, L. et al. Clinical and electrophysiological outcomes of deep TMS over the medial prefrontal and anterior cingulate cortices in OCD patients. Brain Stimulation 11, 158–165 (2018). source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“These models involve closed-loop interactions between the cortex and cerebellum19.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Discussion
What the sources say
- Not checked yetcites [19] Buckner, R. L., Krienen, F. M., Castellanos, A., Diaz, J. C. & Yeo, B. T. The organization of the human cerebellum estimated by intrinsic functional connectivity. J. Neurophysiol. 106, 2322–2345 (2011). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“the mPFC has been demonstrated to have key roles in socio-emotional processing44 and to have critical roles in executive control of behavior.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Discussion
What the sources say
- Not checked yetcites [44] Bicks, L. K., Koike, H., Akbarian, S. & Morishita, H. Prefrontal cortex and social cognition in mouse and man. Front. Psychol. 6, 1805 (2015). source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
In the paper
“Alternatively, the cerebellum, a more accessible anatomic area, might offer similar, if not greater, therapeutic value for neuropsychiatric disorders47.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Discussion
What the sources say
- Not checked yetcites [47] van Dun, K., Bodranghien, F., Manto, M. & Marien, P. Targeting the cerebellum by noninvasive neurostimulation: a review. Cerebellum 16, 695–741 (2017). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: unclear — It is unclear whether it could be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“This output is negatively affected in ASD owing to significant PC loss and decreased cerebellar activity2,5,42.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Discussion
What the sources say
- Not checked yetcites [2] Fatemi, S. H. et al. Consensus paper: pathological role of the cerebellum in autism. Cerebellum 11, 777–807 (2012). source
- Not checked yetcites [5] Tsai, P. T. et al. Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice. Nature 488, 647–651 (2012). source
- Not checked yetcites [42] Ryu, Y. H. et al. Perfusion impairments in infantile autism on technetium-99m ethyl cysteinate dimer brain single-photon emission tomography: comparison with findings on magnetic resonance imaging. Eur. J. Nucl. Med. 26, 253–259 (1999). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our results further understanding of the roles that the cerebellum plays in the modulation and execution of complex behaviors”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“it is likely that additional cortical, including the clinically implicated right-sided prefrontal cortices20, and other sub-cortical regions might also be regulated by the cerebellum to contribute to ASD-relevant behaviors19.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Discussion
What the sources say
- Not checked yetcites [20] Gilbert, S. J., Bird, G., Brindley, R., Frith, C. D. & Burgess, P. W. Atypical recruitment of medial prefrontal cortex in autism spectrum disorders: an fMRI study of two executive function tasks. Neuropsychologia 46, 2281–2291 (2008). source
- Not checked yetcites [19] Buckner, R. L., Krienen, F. M., Castellanos, A., Diaz, J. C. & Yeo, B. T. The organization of the human cerebellum estimated by intrinsic functional connectivity. J. Neurophysiol. 106, 2322–2345 (2011). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Pyramidal neurons were distinguished from interneurons by their shape, spiking pattern and action potential. In addition, their identity was confirmed by their large apical dendrites, which were visualized by using Neurobiotin staining.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Methods > Electrophysiology in acute slices
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In fact, stimulation of the cerebellum has been shown to positively alter behaviors while affecting downstream prefrontal cortex function in preclinical studies of schizophrenia48,49.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Discussion
What the sources say
- Not checked yetcites [48] Parker, K. L. et al. Delta-frequency stimulation of cerebellar projections can compensate for schizophrenia-related medial frontal dysfunction. Mol. Psychiatry 22, 647–655 (2017). source
- Not checked yetcites [49] Brady, R. O., Jr. et al. Cerebellar-prefrontal network connectivity and negative symptoms in schizophrenia. Am. J. Psychiatry 176, 512–520 (2019). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Littermate controls were used for all behavioral experiments.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Methods > Mice
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Mice were randomly assigned to groups for viral injection type.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Methods > Behavioral analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Mice were randomly assigned to treatment groups.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Methods > Mouse in vivo electrophysiology
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Given that the MRI scanning, registration and volume measurements were an automated process, the experimenters were not blinded to genotype.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Methods > Mouse MRI
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“After quality control, 902 scans (425 ASD and 477 control) from 648 individuals (285 ASD and 368 control) were considered for analysis.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Methods > Human structural MRI
plainn = 648- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“P values were corrected for multiple comparisons using the Benjamini–Hochberg procedure; these FDR-corrected P values are herein referred to as q values.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Methods > Statistical analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Starting treatment was randomly assigned and then alternated between VEH and CNO treatments.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Methods > Behavioral analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Recordings were included only when a GΩ seal formed before whole-cell access.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Methods > Electrophysiology in acute slices
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“To ensure that our brain volume covarying strategy did not unduly influence the results, we repeated the analyses using log regressions as in ref. 75. The results were largely identical.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Methods > Human structural MRI
What the sources say
- Not checked yetcites [75] Reardon, P. K. et al. Normative brain size variation and brain shape diversity in humans. Science 360, 1222–1227 (2018). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Our previous findings have suggested that there is a sensitive period for social behavior that extends into adulthood, whereas the sensitive period for repetitive behaviors closes before adulthood50.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Discussion
What the sources say
- Not checked yetcites [50] Tsai, P. T. et al. Sensitive periods for cerebellar-mediated autistic-like behaviors. Cell Rep. 25, 357–367 (2018). source
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Recording locations were verified post hoc via electrolytic lesions and histologic analysis of 50-μm coronal sections.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Methods > In vivo awake recordings
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“The sample size estimate was performed based on a repeated-measures ANOVA design (mixed-model ANOVA with covariance structure of compound symmetry) using PASS 12 to estimate sample size5,8.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Methods > Statistics
What the sources say
- Not checked yetcites [5] Tsai, P. T. et al. Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice. Nature 488, 647–651 (2012). source
- Not checked yetcites [8] Stoodley, C. J. et al. Altered cerebellar connectivity in autism and cerebellar-mediated rescue of autism-related behaviors in mice. Nat. Neurosci. 20, 1744–1751 (2017). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“To minimize previous exposure to the task, repeated testing in a specific behavioral paradigm was separated by 1 week.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Methods > Behavioral analysis
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All behavioral assays were performed by examiners blinded to genotype.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Methods > Behavioral analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Outlier tests were also conducted using the robust regression outlier test in the Prism software suite to determine if data should be excluded.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Methods > Statistics
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Electrophysiological data were analyzed with Prism software and tested for normality of distribution with a one-tailed Kolmogorov–Smirnov test.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Methods > Statistics
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Six datum were found to be outliers across all mini EPSC/IPSC recordings and were excluded.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Methods > Statistics
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“For rotarod and water maze testing, which were performed in the weeks after the above testing, mice were randomly assigned to one treatment group (either VEH or CNO), and no repeat testing was performed owing to the learning component involved in these tests.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Methods > Behavioral analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Chemogenetic studies involved the following controls: GFP infection (VEH and CNO) and designer receptors exclusively activated by designer drugs (DREADD) infection (VEH and CNO) for all behavioral studies to control for DREADD activation and potential effects of VEH and to control for CNO off-target effects76.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Methods > Behavioral analysis
What the sources say
- Not checked yetcites [76] Roth, B. L. DREADDs for neuroscientists. Neuron 89, 683–694 (2016). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
The paper relies on this without support.
The circuits connecting the cerebellum to other brain areas to orchestrate complex behaviors such as those altered in ASDs remain unknown.
“Additionally, the circuits connecting the cerebellum to other brain areas to orchestrate complex behaviors such as those altered in ASDs remain unknown.”
The paper relies on this without support.
Inhibitory PC output emerges from the cerebellum via cerebellar nuclei.
“Because inhibitory PC output emerges from the cerebellum via cerebellar nuclei (CN), we identified the CN receiving Rcrus1 PC output.”
The paper relies on this without support.
Cerebellar-prefrontal circuits and their regulation of ASD-relevant behaviors are conserved between mice and humans.
“Our findings provide critical insights into how the cerebellum regulates ASD-relevant behaviors, while also offering important preclinical evidence to support a potential cerebellar therapeutic target of neuromodulation through which the therapeutic benefits of mPFC modulation could be leveraged to benefit ASD behaviors.”
The authors state this as an assumption.
For all other data, the data distribution was assumed to be normal, but this was not formally tested.
“For all other data, data distribution was assumed to be normal, but this was not formally tested.”
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?
In the citing paper
“these results suggest that previous reports implicating the cerebellum in the pathogenesis of social impairments in the Tsc1 KO model of ASD (Kelly et al., 2020; Tsai et al., 2012) do not generalize across ASD”
From Parallel social information processing circuits are differentially impacted in autism (2020) · cites this paper as Kelly et al., 2020
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.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Results > Inhibition of mPFC improves social deficits and repetitive/inflexible behaviors induced by inhibition of Rcrus1 PCs
“CNO-injected Gi/GFP mice showed increased repetitive grooming and impaired performance on the water T-maze reversal task, consistent with our previous studies (Fig. 2j,k)8.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Results > Inhibition of mPFC improves social deficits and repetitive/inflexible behaviors induced by inhibition of Rcrus1 PCs
“In contrast, CNO-treated Gi/Gi mice demonstrated no abnormal grooming nor impairments in reversal learning in the water Y-maze (Fig. 2j,k).”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Methods > Mice
“Only male animals were used for behavioral experiments and electrophysiological recordings.”
§ Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits > Methods > Mouse in vivo electrophysiology
“Male and female mice were used for in vivo anesthetized extracellular single-unit recordings.”
Citations
Cites
Shrestha, S., & Offer, S. M. (2016) · Medical Epigenetics · doi:10.1159/000444713 · Cited by 8,951
The organization of the human cerebellum estimated by intrinsic functional connectivity
Buckner, R. L., Krienen, F. M., Castellanos, A., Diaz, J. C., & Yeo, B. T. T. (2011) · Journal of Neurophysiology · doi:10.1152/jn.00339.2011 · Cited by 7,304
A robust and high-throughput Cre reporting and characterization system for the whole mouse brain
Madisen, L., Zwingman, T. A., Sunkin, S. M., Oh, S. W., Zariwala, H. A., Gu, H., Ng, L. L., Palmiter, R. D., Hawrylycz, M. J., Jones, A. R., et al. (2010) · Nature Neuroscience · doi:10.1038/nn.2467 · Cited by 6,907
Model of autism: increased ratio of excitation/inhibition in key neural systems
Rubenstein, J. L. R., & Merzenich, M. M. (2003) · Genes, Brain and Behavior · doi:10.1034/j.1601-183x.2003.00037.x · Cited by 2,768
Parvalbumin neurons and gamma rhythms enhance cortical circuit performance
Sohal, V. S., Zhang, F., Yizhar, O., & Deisseroth, K. (2009) · Nature · doi:10.1038/nature07991 · Cited by 2,606
Neocortical excitation/inhibition balance in information processing and social dysfunction
Yizhar, O., Fenno, L. E., Prigge, M., Schneider, F., Davidson, T. J., O’Shea, D. J., Sohal, V. S., Goshen, I., Finkelstein, J., Paz, J. T., et al. (2011) · Nature · doi:10.1038/nature10360 · Cited by 2,454
Armbruster, B. N., Li, X., Pausch, M. H., Herlitze, S., & Roth, B. L. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0700293104 · Cited by 2,046
Roth, B. L. (2016) · Neuron · doi:10.1016/j.neuron.2016.01.040 · Cited by 1,742
Optogenetics: 10 years of microbial opsins in neuroscience
Deisseroth, K. A. (2015) · Nature Neuroscience · doi:10.1038/nn.4091 · Cited by 1,335
Early brain development in infants at high risk for autism spectrum disorder
The IBIS Network, Hazlett, H. C., Gu, H., Munsell, B. C., Kim, S. H., Styner, M., Wolff, J. J., Elison, J. T., Swanson, M. R., Zhu, H., et al. (2017) · Nature · doi:10.1038/nature21369 · Cited by 1,128
Research works printed but not linked: 2
- Paxinos, G. & Franklin, K. Paxinos and Franklin’s the Mouse Brain in Stereotaxic Coordinates 4th edn (Academic Press, 2012).
- Watson, C., Paxinos, G. & Puelles, L. The Mouse Nervous System (Academic Press, 2011).
Cited by
Sorted by citations
Signalling pathways in autism spectrum disorder: mechanisms and therapeutic implications
Jiang, C.-C., Lin, L., Long, S., Ke, X., Fukunaga, K., Lu, Y., & Han, F. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01081-0 · Cited by 295
Fujita, H., Kodama, T., & du Lac, S. (2020) · eLife · doi:10.7554/elife.58613 · Cited by 254
Self-citationWang, X., Wang, B., Wu, C., Wang, J., & Sun, M. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24031819 · Cited by 305
Neuronal circuitry for recognition memory of object and place in rodent models
Chao, O. Y.-H., Nikolaus, S., Yang, Y., & Huston, J. P. (2022) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2022.104855 · Cited by 171
Reverse-translational identification of a cerebellar satiation network
Low, A. Y. T., Goldstein, N., Gaunt, J. R., Huang, K.-P., Zainolabidin, N., Yip, A. K. K., Carty, J. R. E., Choi, J. Y., Miller, A. M., Ho, H. S. T., et al. (2021) · Nature · doi:10.1038/s41586-021-04143-5 · Cited by 135
Metadata
- Authors
- Kelly, E., Meng, F., Fujita, H., Morgado, F., Kazemi, Y., Rice, L. C., Ren, C., Escamilla, C. O., Gibson, J. M., Sajadi, S., Pendry, R. J., Tan, T., Ellegood, J., Basson, M. A., Blakely, R. D., Dindot, S. V., Golzio, C., Hahn, M. K., Katsanis, N., Robins, D. M., Silverman, J. L., Singh, K. K., Wevrick, R., Taylor, M. J., Hammill, C., Anagnostou, E., Pfeiffer, B. E., Stoodley, C. J., Lerch, J. P., du Lac, S., & Tsai, P. T.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Johns Hopkins University (US)
- University of Toronto (CA)
- American University (US)
- Hospital for Sick Children (CA)
- King's College London (GB)
- Florida Atlantic University (US)
- Texas A&M University (US)
- Centre National de la Recherche Scientifique (FR)
- Northwestern University (US)
- University of Michigan (US)
- University of California, Davis (US)
- McMaster University (CA)
- University of Alberta (CA)
- Corresponding author
- Tsai, Peter T.
- ORCID
- Kelly, Elyza
- Meng, Fantao
- Fujita, Hirofumi
- Morgado, Felipe
- Rice, Laura C.
- Escamilla, Christine Ochoa
- Tan, Tommy
- Ellegood, Jacob
- Basson, M. Albert
- Blakely, Randy D.
- Dindot, Scott V.
- Golzio, Christelle
- Hahn, Maureen K.
- Katsanis, Nicholas
- Robins, Diane M.
- Silverman, Jill L.
- Singh, Karun K.
- Wevrick, Rachel
- Taylor, Margot J.
- Hammill, Christopher
- Anagnostou, Evdokia
- Pfeiffer, Brad E.
- Stoodley, Catherine J.
- Lerch, Jason P.
- Tsai, Peter T.
- Venue
- Nature Neuroscience
- Published
- 2020-07-13
- Volume
- 23
- Issue
- 9
- Pages
- 1102-1110
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC7483861
- OpenAlex
- W3041250095
- Semantic Scholar
- 88c1b417a376de87989030480ac1dacd732efa1e
- Cited by
- 280
- References
- 83
- Citations by year
- 2026: 31 · 2025: 45 · 2024: 59 · 2023: 55 · 2022: 46 · 2021: 39 · 2020: 5
- FWCI
- 19.47
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion, cc-by-nc)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NS107004, NS095232, NS105039, NS083733)
- Autism Speaks
- Gouvernement du Canada | Instituts de Recherche en Santé du Canada | CIHR Skin Research Training Centre
- Ontario Brain Institute
- U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (MH106957, MH094268, MH116882)
- Tuberous Sclerosis Alliance
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- autism spectrum disorder, cerebellum, medial prefrontal cortex, social behavior, repetitive behavior, Purkinje cells, posterior vermis, ventromedial thalamus, cerebellar nuclei
- MeSH terms
- Autism Spectrum Disorder, Animals, Cerebellum, Male, Mice, Mutant Strains, Neural Pathways, Prefrontal Cortex, Mice
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.
A language model drew the claims from the paper on 2026-10-09, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-09 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (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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