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      Normal cognitive and social development require posterior cerebellar activity

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          Abstract

          Cognitive and social capacities require postnatal experience, yet the pathways by which experience guides development are unknown. Here we show that the normal development of motor and nonmotor capacities requires cerebellar activity. Using chemogenetic perturbation of molecular layer interneurons to attenuate cerebellar output in mice, we found that activity of posterior regions in juvenile life modulates adult expression of eyeblink conditioning (paravermal lobule VI, crus I), reversal learning (lobule VI), persistive behavior and novelty-seeking (lobule VII), and social preference (crus I/II). Perturbation in adult life altered only a subset of phenotypes. Both adult and juvenile disruption left gait metrics largely unaffected. Contributions to phenotypes increased with the amount of lobule inactivated. Using an anterograde transsynaptic tracer, we found that posterior cerebellum made strong connections with prelimbic, orbitofrontal, and anterior cingulate cortex. These findings provide anatomical substrates for the clinical observation that cerebellar injury increases the risk of autism.

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          Most cited references53

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          A mesoscale connectome of the mouse brain.

          Comprehensive knowledge of the brain's wiring diagram is fundamental for understanding how the nervous system processes information at both local and global scales. However, with the singular exception of the C. elegans microscale connectome, there are no complete connectivity data sets in other species. Here we report a brain-wide, cellular-level, mesoscale connectome for the mouse. The Allen Mouse Brain Connectivity Atlas uses enhanced green fluorescent protein (EGFP)-expressing adeno-associated viral vectors to trace axonal projections from defined regions and cell types, and high-throughput serial two-photon tomography to image the EGFP-labelled axons throughout the brain. This systematic and standardized approach allows spatial registration of individual experiments into a common three dimensional (3D) reference space, resulting in a whole-brain connectivity matrix. A computational model yields insights into connectional strength distribution, symmetry and other network properties. Virtual tractography illustrates 3D topography among interconnected regions. Cortico-thalamic pathway analysis demonstrates segregation and integration of parallel pathways. The Allen Mouse Brain Connectivity Atlas is a freely available, foundational resource for structural and functional investigations into the neural circuits that support behavioural and cognitive processes in health and disease.
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            • Article: not found

            The adolescent brain and age-related behavioral manifestations.

            L Spear (2000)
            To successfully negotiate the developmental transition between youth and adulthood, adolescents must maneuver this often stressful period while acquiring skills necessary for independence. Certain behavioral features, including age-related increases in social behavior and risk-taking/novelty-seeking, are common among adolescents of diverse mammalian species and may aid in this process. Reduced positive incentive values from stimuli may lead adolescents to pursue new appetitive reinforcers through drug use and other risk-taking behaviors, with their relative insensitivity to drugs supporting comparatively greater per occasion use. Pubertal increases in gonadal hormones are a hallmark of adolescence, although there is little evidence for a simple association of these hormones with behavioral change during adolescence. Prominent developmental transformations are seen in prefrontal cortex and limbic brain regions of adolescents across a variety of species, alterations that include an apparent shift in the balance between mesocortical and mesolimbic dopamine systems. Developmental changes in these stressor-sensitive regions, which are critical for attributing incentive salience to drugs and other stimuli, likely contribute to the unique characteristics of adolescence.
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              Contributions of anterior cingulate cortex to behaviour

              Assessments of anterior cingulate cortex in experimental animals and humans have led to unifying theories of its structural organization and contributions to mammalian behaviour. The anterior cingulate cortex forms a large region around the rostrum of the corpus callosum that is termed the anterior executive region. This region has numerous projections into motor systems, however, since these projections originate from different parts of anterior cingulate cortex and because functional studies have shown that it does not have a uniform contribution to brain functions, the anterior executive region is further subdivided into 'affect' and 'cognition' components. The affect division includes areas 25, 33 and rostral area 24, and has extensive connections with the amygdala and periaqueductal grey, and parts of it project to autonomic brainstem motor nuclei. In addition to regulating autonomic and endocrine functions, it is involved in conditioned emotional learning, vocalizations associated with expressing internal states, assessments of motivational content and assigning emotional valence to internal and external stimuli, and maternal-infant interactions. The cognition division includes caudal areas 24' and 32', the cingulate motor areas in the cingulate sulcus and nociceptive cortex. The cingulate motor areas project to the spinal cord and red nucleus and have premotor functions, while the nociceptive area is engaged in both response selection and cognitively demanding information processing. The cingulate epilepsy syndrome provides important support of experimental animal and human functional imaging studies for the role of anterior cingulate cortex in movement, affect and social behaviours. Excessive cingulate activity in cases with seizures confirmed in anterior cingulate cortex with subdural electrode recordings, can impair consciousness, alter affective state and expression, and influence skeletomotor and autonomic activity. Interictally, patients with anterior cingulate cortex epilepsy often display psychopathic or sociopathic behaviours. In other clinical examples of elevated anterior cingulate cortex activity it may contribute to tics, obsessive-compulsive behaviours, and aberrent social behaviour. Conversely, reduced cingulate activity following infarcts or surgery can contribute to behavioural disorders including akinetic mutism, diminished self-awareness and depression, motor neglect and impaired motor initiation, reduced responses to pain, and aberrent social behaviour. The role of anterior cingulate cortex in pain responsiveness is suggested by cingulumotomy results and functional imaging studies during noxious somatic stimulation. The affect division of anterior cingulate cortex modulates autonomic activity and internal emotional responses, while the cognition division is engaged in response selection associated with skeletomotor activity and responses to noxious stimuli. Overall, anterior cingulate cortex appears to play a crucial role in initiation, motivation, and goal-directed behaviours.(ABSTRACT TRUNCATED AT 400 WORDS)

                Author and article information

                Contributors
                Journal
                eLife
                Elife
                eLife
                eLife
                eLife Sciences Publications, Ltd
                2050-084X
                20 September 2018
                2018
                : 7
                : e36401
                Affiliations
                [1 ]deptPrinceton Neuroscience Institute Princeton University PrincetonUnited States
                [2 ]Netherlands Institute for Neuroscience AmsterdamThe Netherlands
                [3 ]deptDepartment of Molecular Biology Princeton University PrincetonUnited States
                [4 ]deptDepartment of Neuroscience Erasmus MC RotterdamThe Netherlands
                [5 ]Robert Wood Johnson Medical School New BrunswickUnited States
                Author information
                http://orcid.org/0000-0002-0119-5108
                http://orcid.org/0000-0003-2941-7697
                http://orcid.org/0000-0002-6380-8141
                http://orcid.org/0000-0001-9075-8365
                http://orcid.org/0000-0002-3119-7649
                http://orcid.org/0000-0002-0490-9786
                Article
                36401
                10.7554/eLife.36401
                6195348
                30226467
                2d0f08e1-0861-467d-a8b6-2c926ffdc0c3
                © 2018, Badura et al

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                : 05 March 2018
                : 15 September 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100003246, Nederlandse Organisatie voor Wetenschappelijk Onderzoek;
                Award ID: Innovational Research Incentives Scheme VENI (NWO,ZonMw)
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100007429, Nancy Lurie Marks Family Foundation;
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: R01 NS045193
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100008474, New Jersey Commission on Brain Injury Research;
                Award ID: CBIR16FEL010
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000001, National Science Foundation;
                Award ID: Graduate Research Fellowship DGE-1148900
                Award Recipient :
                Funded by: Rutgers Robert Wood Johnson Medical School-Princeton University M.D.-Ph.D. Program;
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: R01 MH115750
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: F30 MH115577
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: F31 NS089303
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Categories
                Research Article
                Neuroscience
                Custom metadata
                Social and cognitive functions require normal activity during development of the posterior cerebellum.

                Life sciences
                cerebellum,development,transsynaptic,cognitive,chemogenetic,flexible behavior,mouse
                Life sciences
                cerebellum, development, transsynaptic, cognitive, chemogenetic, flexible behavior, mouse

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