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The Cerebellum, Sensitive Periods, and Autism

2014; Cell Press; Volume: 83; Issue: 3 Linguagem: Inglês

10.1016/j.neuron.2014.07.016

1097-4199

Samuel S.‐H. Wang, Alexander D. Kloth, Aleksandra Badura,

Neonatal and fetal brain pathology

Cerebellar research has focused principally on adult motor function. However, the cerebellum also maintains abundant connections with nonmotor brain regions throughout postnatal life. Here we review evidence that the cerebellum may guide the maturation of remote nonmotor neural circuitry and influence cognitive development, with a focus on its relationship with autism. Specific cerebellar zones influence neocortical substrates for social interaction, and we propose that sensitive-period disruption of such internal brain communication can account for autism’s key features. Cerebellar research has focused principally on adult motor function. However, the cerebellum also maintains abundant connections with nonmotor brain regions throughout postnatal life. Here we review evidence that the cerebellum may guide the maturation of remote nonmotor neural circuitry and influence cognitive development, with a focus on its relationship with autism. Specific cerebellar zones influence neocortical substrates for social interaction, and we propose that sensitive-period disruption of such internal brain communication can account for autism’s key features. In recent decades, much neuroscience research has focused narrowly on the cerebellum’s role in balance, posture, and motor control. This framework has been explored in the greatest detail in cases where input pathways convey sensory information to the cerebellum, and outputs influence motor effectors. Emerging from this program is the view that the cerebellum acts as a processor that uses a variety of inputs to guide movement. Receiving much less emphasis has been the role of the cerebellum in higher function. This idea is not new: cognitive roles for cerebellum have been discussed since the mid-19th century (reviewed in Steinlin and Wingeier, 2013Steinlin M. Wingeier K. Cerebellum and Cogniton. Springer, Dordrecht2013Google Scholar), with a resurgence of interest in recent years (D’Angelo and Casali, 2012D’Angelo E. Casali S. Seeking a unified framework for cerebellar function and dysfunction: from circuit operations to cognition.Front. Neural Circuits. 2012; 6: 116PubMed Google Scholar, Koziol et al., 2014Koziol L.F. Budding D. Andreasen N. D’Arrigo S. Bulgheroni S. Imamizu H. Ito M. Manto M. Marvel C. Parker K. et al.Consensus paper: the cerebellum’s role in movement and cognition.Cerebellum. 2014; 13: 151-177Crossref PubMed Scopus (3) Google Scholar, Mariën et al., 2014Mariën P. Ackermann H. Adamaszek M. Barwood C.H. Beaton A. Desmond J. De Witte E. Fawcett A.J. Hertrich I. Küper M. et al.Consensus paper: Language and the cerebellum: an ongoing enigma.Cerebellum. 2014; 13: 386-410Crossref PubMed Scopus (1) Google Scholar). Evidence for cerebellar lesions leading to nonmotor deficits has come from adult cases showing subtle cognitive and affective changes (Stoodley et al., 2012Stoodley C.J. Valera E.M. Schmahmann J.D. Functional topography of the cerebellum for motor and cognitive tasks: an fMRI study.Neuroimage. 2012; 59: 1560-1570Crossref PubMed Scopus (66) Google Scholar) and congenital cerebellar defects, where deficits are much more pronounced (Basson and Wingate, 2013Basson M.A. Wingate R.J. Congenital hypoplasia of the cerebellum: developmental causes and behavioral consequences.Front. Neuroanat. 2013; 7: 29Crossref PubMed Scopus (3) Google Scholar, Steinlin and Wingeier, 2013Steinlin M. Wingeier K. Cerebellum and Cogniton. Springer, Dordrecht2013Google Scholar). Two facts have stood in the way of wider recognition of the nonmotor aspects of cerebellar function. First, the most prominent deficits in acute cerebellar injury in adults are of a motor nature. Monitoring the short-term results of injury does not capture long-term consequences that can accumulate over time. The consequences of cerebellar deficit are highly dependent on when the outcome is assessed. Second, cerebellar connectivity is highly differentiated, and focal injury typically leads to focal deficits (Romaniella and Borgatti, 2012Romaniella R. Borgatti R. Cerebellar agenesis.in: Manto M. Schmahmann J.D. Rossi F. Koibuchi N. Handbook of the Cerebellum and Cerebellar Disorders. Springer, Dordrecht2012: 1855-1872Google Scholar). While some cerebellar regions project predominantly to sensorimotor cortex, homologous connections project to cognitive and affective regions and comprise a large fraction of cerebellar connectivity (Strick et al., 2009Strick P.L. Dum R.P. Fiez J.A. Cerebellum and nonmotor function.Annu. Rev. Neurosci. 2009; 32: 413-434Crossref PubMed Scopus (333) Google Scholar). Recently, the extension of this parcellated mapping to nonmotor brain structures has become clearer using modern methods (Buckner et al., 2011Buckner 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. 2011; 106: 2322-2345Crossref PubMed Scopus (110) Google Scholar, Strick et al., 2009Strick P.L. Dum R.P. Fiez J.A. Cerebellum and nonmotor function.Annu. Rev. Neurosci. 2009; 32: 413-434Crossref PubMed Scopus (333) Google Scholar). The cerebellar cortex and nuclei have a distinctive circuit structure that is repeated in a modular fashion throughout the cerebellum and is highly conserved among vertebrates (Apps and Hawkes, 2009Apps R. Hawkes R. Cerebellar cortical organization: a one-map hypothesis.Nat. Rev. Neurosci. 2009; 10: 670-681Crossref PubMed Scopus (110) Google Scholar). This has led to the proposal that the cerebellum performs a common algorithm upon a variety of inputs, whether sensory, motor, cognitive, or affective. In this Perspective, we outline a development-based framework for understanding the nonmotor roles of cerebellum. A variety of observations can be explained by the following unified hypothesis: in addition to its role in the mature brain, the cerebellum acts in early life to shape the function of other brain regions, especially those relating to cognition and affect. We propose that the cerebellum takes an early role in processing external sensory and internally generated information to influence neocortical circuit refinement during developmental sensitive periods. We end by describing how new methods for imaging, mapping, and perturbing neural circuits can be used to explore the complex role of the cerebellum in guiding nonmotor function. As part of this framework, we propose that cerebellar dysfunction may disrupt the maturation of distant neocortical circuits. To summarize the concept of developmental influence between brain regions, we use the term developmental diaschisis. Diaschisis (∖dī-as’-kə-səs∖; Gr. dia: across, schisis: break) is an existing neurological term indicating a sharp inhibition in activity at a site that is distant from a site of injury but is anatomically connected with it through fiber tracts. For example, prefrontal injury has been shown to lead to abrupt decreases in blood flow to the contralateral cerebellum and vice versa. In the same way, we define developmental diaschisis as a phenomenon in which disruptions in activity in a particular brain area, such as the cerebellum, can affect the organization and function of other, remote brain sites over developmental time. As a central example, we will focus on autism spectrum disorder (ASD), for which the developmental diaschisis hypothesis can resolve some longstanding puzzles regarding the cerebellum’s role. ASD, one of the most strongly heritable major neurodevelopmental disorders (Abrahams and Geschwind, 2008Abrahams B.S. Geschwind D.H. Advances in autism genetics: on the threshold of a new neurobiology.Nat. Rev. Genet. 2008; 9: 341-355Crossref PubMed Scopus (689) Google Scholar), has attracted tremendous research interest. Usually diagnosable by the age of 2 (http://cdc.gov/ncbddd/autism/data.html and reviewed in Daniels et al., 2014Daniels A.M. Halladay A.K. Shih A. Elder L.M. Dawson G. Approaches to enhancing the early detection of autism spectrum disorders: a systematic review of the literature.J. Am. Acad. Child Adolesc. Psychiatry. 2014; 53: 141-152Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar), ASD is highly heterogeneous and encompasses a wide range of deficits including social impairment, communication difficulties, and repetitive and stereotyped behaviors. A Web of Science literature search reveals over 34,000 scientific publications mentioning autism since Kanner’s original description (Kanner, 1943Kanner L. Autistic disturbances of affective contact.Nervous Child. 1943; 2: 217-250Google Scholar), more than half of which have been published since 2008. Generally speaking, fetal brain development is guided by a genetic program that can be driven off track by genetic or environmental perturbations. One theme emerging from the considerable autism research literature is the idea that fetal brain development can be perturbed by any of hundreds of autism risk alleles (SFARI GENE; https://gene.sfari.org). Inherited genetic variation accounts for ∼40% of the risk for ASD (Stein et al., 2013Stein J.L. Parikshak N.N. Geschwind D.H. Rare inherited variation in autism: beginning to see the forest and a few trees.Neuron. 2013; 77: 209-211Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar), with each allele contributing a small fraction to the total risk. In most cases, each allele is a variant of an essential gene, and its presence most often leads to normal-range function (Leblond et al., 2012Leblond C.S. Heinrich J. Delorme R. Proepper C. Betancur C. Huguet G. Konyukh M. Chaste P. Ey E. Rastam M. et al.Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders.PLoS Genet. 2012; 8: e1002521Crossref PubMed Scopus (75) Google Scholar, O’Roak et al., 2011O’Roak B.J. Deriziotis P. Lee C. Vives L. Schwartz J.J. Girirajan S. Karakoc E. Mackenzie A.P. Ng S.B. Baker C. et al.Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations.Nat. Genet. 2011; 43: 585-589Crossref PubMed Scopus (321) Google Scholar). Thus, most autistic children have two neurotypical parents. First-degree relatives of persons with ASD often show distinctive mental traits, including unusual social and emotional characteristics (Sasson et al., 2013Sasson N.J. Lam K.S. Parlier M. Daniels J.L. Piven J. Autism and the broad autism phenotype: familial patterns and intergenerational transmission.J. Neurodev. Disord. 2013; 5: 11Crossref PubMed Scopus (1) Google Scholar) and an interest in technical subjects (Baron-Cohen et al., 1998Baron-Cohen S. Bolton P. Wheelwright S. Scahill V. Short L. Mead G. Smith A. Does autism occur more often in families of physicists, engineers, and mathematicians?.Autism. 1998; 2: 296-301Crossref Google Scholar, Campbell and Wang, 2012Campbell B.C. Wang S.S.-H. Familial linkage between neuropsychiatric disorders and intellectual interests.PLoS ONE. 2012; 7: e30405Crossref PubMed Google Scholar), indicating that ASD risk genes may drive variations of outcome within the normal range. In this sense, development is robust, and combinations of genes are likely to work together to trigger ASD. However, despite this booming literature, it is not yet established how genetic risks drive specific missteps in the maturation of brain circuitry. Three recent computational studies have used aggregated gene expression patterns to ask when and where ASD genes are expressed (Figure 1A; Menashe et al., 2013Menashe I. Grange P. Larsen E.C. Banerjee-Basu S. Mitra P.P. Co-expression profiling of autism genes in the mouse brain.PLoS Comput. Biol. 2013; 9: e1003128Crossref PubMed Scopus (3) Google Scholar, Parikshak et al., 2013Parikshak N.N. Luo R. Zhang A. Won H. Lowe J.K. Chandran V. Horvath S. Geschwind D.H. Integrative functional genomic analyses implicate specific molecular pathways and circuits in autism.Cell. 2013; 155: 1008-1021Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, Willsey et al., 2013Willsey A.J. Sanders S.J. Li M. Dong S. Tebbenkamp A.T. Muhle R.A. Reilly S.K. Lin L. Fertuzinhos S. Miller J.A. et al.Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism.Cell. 2013; 155: 997-1007Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar). Some ASD susceptibility genes show a high degree of coexpression with one another in mouse and human brain, allowing the identification of specific gene networks or “cliques” (Menashe et al., 2013Menashe I. Grange P. Larsen E.C. Banerjee-Basu S. Mitra P.P. Co-expression profiling of autism genes in the mouse brain.PLoS Comput. Biol. 2013; 9: e1003128Crossref PubMed Scopus (3) Google Scholar). ASD-related coexpression networks have been found during two distinct periods of development. First, during human gestational weeks 10–24 and mouse postnatal days 0–10 (P0–P10), expression occurs in a broadly defined somato-motor-frontal region (Willsey et al., 2013Willsey A.J. Sanders S.J. Li M. Dong S. Tebbenkamp A.T. Muhle R.A. Reilly S.K. Lin L. Fertuzinhos S. Miller J.A. et al.Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism.Cell. 2013; 155: 997-1007Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar) especially in layer 5/6 cortical projection neurons (Parikshak et al., 2013Parikshak N.N. Luo R. Zhang A. Won H. Lowe J.K. Chandran V. Horvath S. Geschwind D.H. Integrative functional genomic analyses implicate specific molecular pathways and circuits in autism.Cell. 2013; 155: 1008-1021Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, Willsey et al., 2013Willsey A.J. Sanders S.J. Li M. Dong S. Tebbenkamp A.T. Muhle R.A. Reilly S.K. Lin L. Fertuzinhos S. Miller J.A. et al.Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism.Cell. 2013; 155: 997-1007Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar) and other layers (Parikshak et al., 2013Parikshak N.N. Luo R. Zhang A. Won H. Lowe J.K. Chandran V. Horvath S. Geschwind D.H. Integrative functional genomic analyses implicate specific molecular pathways and circuits in autism.Cell. 2013; 155: 1008-1021Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar). Second, in humans from neonatal to age 6, cerebellar network expression is strong (Willsey et al., 2013Willsey A.J. Sanders S.J. Li M. Dong S. Tebbenkamp A.T. Muhle R.A. Reilly S.K. Lin L. Fertuzinhos S. Miller J.A. et al.Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism.Cell. 2013; 155: 997-1007Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar), particularly in the cerebellar granule cell layer (Menashe et al., 2013Menashe I. Grange P. Larsen E.C. Banerjee-Basu S. Mitra P.P. Co-expression profiling of autism genes in the mouse brain.PLoS Comput. Biol. 2013; 9: e1003128Crossref PubMed Scopus (3) Google Scholar). The third recent study examining aggregated gene coexpression patterns did not examine cerebellum (Parikshak et al., 2013Parikshak N.N. Luo R. Zhang A. Won H. Lowe J.K. Chandran V. Horvath S. Geschwind D.H. Integrative functional genomic analyses implicate specific molecular pathways and circuits in autism.Cell. 2013; 155: 1008-1021Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar). Taken together, these patterns identify two regions where genetically driven ASD-related developmental programs can go off track: the second-trimester frontal/somatomotor neocortex and the perinatal/postnatal cerebellar cortex. Based on gene ontology classification, many of the coexpressed ASD susceptibility genes are involved in synaptic plasticity, development, and neuronal differentiation (Parikshak et al., 2013Parikshak N.N. Luo R. Zhang A. Won H. Lowe J.K. Chandran V. Horvath S. Geschwind D.H. Integrative functional genomic analyses implicate specific molecular pathways and circuits in autism.Cell. 2013; 155: 1008-1021Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar), indicating disruptions in neural circuit formation and plasticity as targets for investigation. The diverse body of autism research provides an opportunity to quantify the contribution of a wide range of risks, with the goal of identifying putative neural substrates and mechanisms. Just as there are two major periods of ASD gene coexpression, epidemiological and clinical literature reveal two major time windows for environmental risk. These time windows, identified independently from the gene expression analysis, suggest a postnatal period when the cerebellum might influence ASD-like outcomes. To illustrate both genetic and environmental risk factors for autism in quantitative perspective, we show a variety of associated risk ratios in Figure 1B. The highest risk ratio is found for identical twins with a substantially lower risk for fraternal twins, a finding that formed the original basis for the idea of genetic causation. Yet, ASD is also affected by environmental factors occurring before birth, demonstrating the potential of environmental risk factors to impede the maturation of social function. A large body of research has investigated the hypothesis that the developing brain may be particularly vulnerable to maternal stress and other environmental insults before, at, and after birth (McEwen, 2007McEwen B.S. Physiology and neurobiology of stress and adaptation: central role of the brain.Physiol. Rev. 2007; 87: 873-904Crossref PubMed Scopus (1014) Google Scholar, Kinney et al., 2008bKinney D.K. Munir K.M. Crowley D.J. Miller A.M. Prenatal stress and risk for autism.Neurosci. Biobehav. Rev. 2008; 32: 1519-1532Crossref PubMed Scopus (97) Google Scholar). The effects of maternal infection during pregnancy, especially the second and third trimester (Atladóttir et al., 2010Atladóttir H.O. Thorsen P. Østergaard L. Schendel D.E. Lemcke S. Abdallah M. Parner E.T. Maternal infection requiring hospitalization during pregnancy and autism spectrum disorders.J. Autism Dev. 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Neonatal corticosterone administration impairs adult eyeblink conditioning and decreases glucocorticoid receptor expression in the cerebellar interpositus nucleus.Neuroscience. 2011; 177: 56-65Crossref PubMed Scopus (1) Google Scholar). Speculatively, in the case of ASD such mechanisms might underlie the effects of premature birth (Moster et al., 2008Moster D. Lie R.T. Markestad T. Long-term medical and social consequences of preterm birth.N. Engl. J. Med. 2008; 359: 262-273Crossref PubMed Scopus (335) Google Scholar), elective cesarean section (Glasson et al., 2004Glasson E.J. Bower C. Petterson B. de Klerk N. Chaney G. Hallmayer J.F. Perinatal factors and the development of autism: a population study.Arch. Gen. Psychiatry. 2004; 61: 618-627Crossref PubMed Scopus (204) Google Scholar), being born to mothers caught in a hurricane strike zone (Kinney et al., 2008aKinney D.K. Miller A.M. Crowley D.J. Huang E. Gerber E. 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All of these autism risks are larger than the risk associated with advanced maternal or paternal age and suggest a period of stress sensitivity that starts before birth. All of the nongenetic ASD factors shown are associated with risk ratios between 2 and 7, with one notable exception: injury to the cerebellum. Early disruption of the cerebellar circuitry has been shown to be positively correlated with autism (Beversdorf et al., 2005Beversdorf D.Q. Manning S.E. Hillier A. Anderson S.L. Nordgren R.E. Walters S.E. Nagaraja H.N. Cooley W.C. Gaelic S.E. Bauman M.L. Timing of prenatal stressors and autism.J. Autism Dev. Disord. 2005; 35: 471-478Crossref PubMed Scopus (105) Google Scholar, Courchesne et al., 2001Courchesne E. Karns C.M. Davis H.R. Ziccardi R. Carper R.A. Tigue Z.D. Chisum H.J. Moses P. Pierce K. 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As a point of quantitative comparison, cigarette smoking increases the risk of lung cancer by a factor of 20 to 40 (Pope et al., 2011Pope 3rd, C.A. Burnett R.T. Turner M.C. Cohen A. Krewski D. Jerrett M. Gapstur S.M. Thun M.J. Lung cancer and cardiovascular disease mortality associated with ambient air pollution and cigarette smoke: shape of the exposure-response relationships.Environ. Health Perspect. 2011; 119: 1616-1621Crossref PubMed Scopus (65) Google Scholar). These findings suggest that after birth, the cerebellum plays an essential role in the development of basic social capabilities. This idea is consistent with the fact that the cerebellum is among the most frequently disrupted brain regions in autistic patients, at both microscopic and gross levels (Courchesne et al., 2005Courchesne E. Redcay E. Morgan J.T. Kennedy D.P. Autism at the beginning: microstructural and growth abnormalities underlying the cognitive and behavioral phenotype of autism.Dev. 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In a study of children adopted from abusive Romanian orphanages into UK families, a high fraction of children who underwent long-term deprivation developed social deficits that closely resembled autism, which could be reversed by placement in a normal adoptive home (Rutter et al., 1999Rutter M. Andersen-Wood L. Beckett C. Bredenkamp D. Castle J. Groothues C. Kreppner J. Keaveney L. Lord C. O’Connor T.G. English and Romanian Adoptees (ERA) Study TeamQuasi-autistic patterns following severe early global privation.J. Child Psychol. Psychiatry. 1999; 40: 537-549Crossref PubMed Google Scholar, Smyke et al., 2009Smyke A.T. Zeanah Jr., C.H. Fox N.A. Nelson 3rd, C.A. A new model of foster care for young children: the Bucharest early intervention project.Child Adolesc. Psychiatr. Clin. N. Am. 2009; 18: 721-734Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar). The longer and later the children stayed in deprived conditions, the more severe and difficult to reverse were the behavioral changes. Thus, experience-dependent mechanisms are likely to guide the formation of social capacities during the critical first years of life. These identified risks are likely to share some common mechanisms. Genetic risks and epidemiologically identified environmental factors most likely act by influencing the developmental program of the nervous system. These risk factors are triggers that act upon as-yet-unidentified neural substrates. In this context, is early-life brain injury a general ASD risk factor, or is the cerebellum a special point of vulnerability? Because ASD arises early in development and eventually involves multiple brain structures, focal brain injury studies in early postnatal life can provide valuable information about how ASD unfolds. Although focal brain injury is not thought to be a principal cause of developmental disorders, such cases provide an approach to systems-level perturbation that deepens the significance of gene expression studies. Here we present focal perturbation data to identify candidate subsystems that may drive the maturation of brain capacities. Of particular interest for ASD are sites at which early-life injury, but not adult injury, leads to a long-term deficit; we call these developmental upstream drivers. We call sites at which adult injury leads to long-term ASD-like deficits downstream targets (Figure 2). A classical example of an upstream driver is the role of retina and thalamus in shaping the circuitry of a downstream target, the primary visual cortex. In this example and others, early-life deprivation during a sensitive period can lead to commitments that are difficult to reverse at later ages. More complex functions tend to have sensitive periods that come even later during development (Knudsen, 2004Knudsen E.I. Sensitive periods in the development of the brain and behavior.J. Cogn. Neurosci. 2004; 16: 1412-1425Crossref PubMed Scopus (239) Google Scholar), so the primary visual cortex is itself an upstream driver in the later maturation of yet more complex visual functions. In this classification scheme, many brain regions would be expected to fall into the downstream category for ASD, since cognitive and social functions engage neural substrates throughout the brain. A third category, which we call compensatable, encompasses brain regions in which an acute injury’s effects diminish over time due to plasticity mechanisms for recovering function. We will now apply this downstream/upstream/compensatable framework to ASD-lik