Effects of gene dosage and development on subcortical nuclei volumes in individuals with 22q11.2 copy number variations.

The 22q11.2 locus contains genes critical for brain development. Reciprocal Copy Number Variations (CNVs) at this locus impact risk for neurodevelopmental and psychiatric disorders. Both 22q11.2 deletions (22qDel) and duplications (22qDup) are associated with autism, but 22qDel uniquely elevates schizophrenia risk. Understanding brain phenotypes associated with these highly penetrant CNVs can provide insights into genetic pathways underlying neuropsychiatric disorders. Human neuroimaging and animal models indicate subcortical brain alterations in 22qDel, yet little is known about developmental differences across specific nuclei between reciprocal 22q11.2 CNV carriers and typically developing (TD) controls. We conducted a longitudinal MRI study in a total of 385 scans from 22qDel (n = 96, scans = 191, 53.1% female), 22qDup (n = 37, scans = 64, 45.9% female), and TD controls (n = 80, scans = 130, 51.2% female), across a wide age range (5.5-49.5 years). Volumes of the thalamus, hippocampus, amygdala, and anatomical subregions were estimated using FreeSurfer, and the linear effects of 22q11.2 gene dosage and non-linear effects of age were characterized with generalized additive mixed models (GAMMs). Positive gene dosage effects (volume increasing with copy number) were observed for total intracranial and whole hippocampus volumes, but not whole thalamus or amygdala volumes. Several amygdala subregions exhibited similar positive effects, with bi-directional effects found across thalamic nuclei. Distinct age-related trajectories were observed across the three groups. Notably, both 22qDel and 22qDup carriers exhibited flattened development of hippocampal CA2/3 subfields relative to TD controls. This study provides novel insights into the impact of 22q11.2 CNVs on subcortical brain structures and their developmental trajectories.

Spatiotemporal molecular dynamics of the developing human thalamus.

The thalamus plays a central coordinating role in the brain. Thalamic neurons are organized into spatially distinct nuclei, but the molecular architecture of thalamic development is poorly understood, especially in humans. To begin to delineate the molecular trajectories of cell fate specification and organization in the developing human thalamus, we used single-cell and multiplexed spatial transcriptomics. We show that molecularly defined thalamic neurons differentiate in the second trimester of human development and that these neurons organize into spatially and molecularly distinct nuclei. We identified major subtypes of glutamatergic neuron subtypes that are differentially enriched in anatomically distinct nuclei and six subtypes of γ-aminobutyric acid-mediated (GABAergic) neurons that are shared and distinct across thalamic nuclei.

Development of thalamus mediates paternal age effect on offspring reading: A preliminary investigation.

The importance of (inherited) genetic impact in reading development is well established. De novo mutation is another important contributor that is recently gathering interest as a major liability of neurodevelopmental disorders, but has been neglected in reading research to date. Paternal age at childbirth (PatAGE) is known as the most prominent risk factor for de novo mutation, which has been repeatedly shown by molecular genetic studies. As one of the first efforts, we performed a preliminary investigation of the relationship between PatAGE, offspring's reading, and brain structure in a longitudinal neuroimaging study following 51 children from kindergarten through third grade. The results showed that greater PatAGE was significantly associated with worse reading, explaining an additional 9.5% of the variance after controlling for a number of confounds-including familial factors and cognitive-linguistic reading precursors. Moreover, this effect was mediated by volumetric maturation of the left posterior thalamus from ages 5 to 8. Complementary analyses indicated the PatAGE-related thalamic region was most likely located in the pulvinar nuclei and related to the dorsal attention network by using brain atlases, public datasets, and offspring's diffusion imaging data. Altogether, these findings provide novel insights into neurocognitive mechanisms underlying the PatAGE effect on reading acquisition during its earliest phase and suggest promising areas of future research.

Development of Auditory Cortex Circuits.

The ability to process and perceive sensory stimuli is an essential function for animals. Among the sensory modalities, audition is crucial for communication, pleasure, care for the young, and perceiving threats. The auditory cortex (ACtx) is a key sound processing region that combines ascending signals from the auditory periphery and inputs from other sensory and non-sensory regions. The development of ACtx is a protracted process starting prenatally and requires the complex interplay of molecular programs, spontaneous activity, and sensory experience. Here, we review the development of thalamic and cortical auditory circuits during pre- and early post-natal periods.

Dual midbrain and forebrain origins of thalamic inhibitory interneurons.

The ubiquitous presence of inhibitory interneurons in the thalamus of primates contrasts with the sparsity of interneurons reported in mice. Here, we identify a larger than expected complexity and distribution of interneurons across the mouse thalamus, where all thalamic interneurons can be traced back to two developmental programmes: one specified in the midbrain and the other in the forebrain. Interneurons migrate to functionally distinct thalamocortical nuclei depending on their origin: the abundant, midbrain-derived class populates the first and higher order sensory thalamus while the rarer, forebrain-generated class is restricted to some higher order associative regions. We also observe that markers for the midbrain-born class are abundantly expressed throughout the thalamus of the New World monkey marmoset. These data therefore reveal that, despite the broad variability in interneuron density across mammalian species, the blueprint of the ontogenetic organisation of thalamic interneurons of larger-brained mammals exists and can be studied in mice.

Increased wiring cost during development is driven by long-range cortical, but not subcortical connections.

The brain undergoes a protracted, metabolically expensive maturation process from childhood to adulthood. Therefore, it is crucial to understand how network cost is distributed among different brain systems as the brain matures. To address this issue, here we examined developmental changes in wiring cost and brain network topology using resting-state functional magnetic resonance imaging (rsfMRI) data longitudinally collected in awake rats from the juvenile age to adulthood. We found that the wiring cost increased in the vast majority of cortical connections but decreased in most subcortico-subcortical connections. Importantly, the developmental increase in wiring cost was dominantly driven by long-range cortical, but not subcortical connections, which was consistent with more pronounced increase in network integration in the cortical network. These results collectively indicate that there is a non-uniform distribution of network cost as the brain matures, and network resource is dominantly consumed for the development of the cortex, but not subcortex from the juvenile age to adulthood.

LacZ-reporter mapping of Dlx5/6 expression and genoarchitectural analysis of the postnatal mouse prethalamus.

We present here a thorough and complete analysis of mouse P0-P140 prethalamic histogenetic subdivisions and corresponding nuclear derivatives, in the context of local tract landmarks. The study used as fundamental material brains from a transgenic mouse line that expresses LacZ under the control of an intragenic enhancer of Dlx5 and Dlx6 (Dlx5/6-LacZ). Subtle shadings of LacZ signal, jointly with pan-DLX immunoreaction, and several other ancillary protein or RNA markers, including Calb2 and Nkx2.2 ISH (for the prethalamic eminence, and derivatives of the rostral zona limitans shell domain, respectively) were mapped across the prethalamus. The resulting model of the prethalamic region postulates tetrapartite rostrocaudal and dorsoventral subdivisions, as well as a tripartite radial stratification, each cell population showing a characteristic molecular profile. Some novel nuclei are proposed, and some instances of potential tangential cell migration were noted.

Preterm birth leads to impaired rich-club organization and fronto-paralimbic/limbic structural connectivity in newborns.

Prematurity disrupts brain development during a critical period of brain growth and organization and is known to be associated with an increased risk of neurodevelopmental impairments. Investigating whole-brain structural connectivity alterations accompanying preterm birth may provide a better comprehension of the neurobiological mechanisms related to the later neurocognitive deficits observed in this population. Using a connectome approach, we aimed to study the impact of prematurity on neonatal whole-brain structural network organization at term-equivalent age. In this cohort study, twenty-four very preterm infants at term-equivalent age (VPT-TEA) and fourteen full-term (FT) newborns underwent a brain MRI exam at term age, comprising T2-weighted imaging and diffusion MRI, used to reconstruct brain connectomes by applying probabilistic constrained spherical deconvolution whole-brain tractography. The topological properties of brain networks were quantified through a graph-theoretical approach. Furthermore, edge-wise connectivity strength was compared between groups. Overall, VPT-TEA infants' brain networks evidenced increased segregation and decreased integration capacity, revealed by an increased clustering coefficient, increased modularity, increased characteristic path length, decreased global efficiency and diminished rich-club coefficient. Furthermore, in comparison to FT, VPT-TEA infants had decreased connectivity strength in various cortico-cortical, cortico-subcortical and intra-subcortical networks, the majority of them being intra-hemispheric fronto-paralimbic and fronto-limbic. Inter-hemispheric connectivity was also decreased in VPT-TEA infants, namely through connections linking to the left precuneus or left dorsal cingulate gyrus - two regions that were found to be hubs in FT but not in VPT-TEA infants. Moreover, posterior regions from Default-Mode-Network (DMN), namely precuneus and posterior cingulate gyrus, had decreased structural connectivity in VPT-TEA group. Our finding that VPT-TEA infants' brain networks displayed increased modularity, weakened rich-club connectivity and diminished global efficiency compared to FT infants suggests a delayed transition from a local architecture, focused on short-range connections, to a more distributed architecture with efficient long-range connections in those infants. The disruption of connectivity in fronto-paralimbic/limbic and posterior DMN regions might underlie the behavioral and social cognition difficulties previously reported in the preterm population.

Association of early skin breaks and neonatal thalamic maturation: A modifiable risk?

OBJECTIVE: To test the hypothesis that a strategy of prolonged arterial line (AL) and central venous line (CVL) use is associated with reduced neonatal invasive procedures and improved growth of the thalamus in extremely preterm neonates (<28 weeks' gestation). METHODS: Two international cohorts of very preterm neonates (n = 143) with prolonged (≥14 days) or restricted (<14 days) use of AL/CVL were scanned serially with MRI. General linear models were used to determine the association between skin breaks and thalamic volumes, accounting for clinical confounders and site differences. Children were assessed at preschool age on standardized tests of motor and cognitive function. Outcome scores were assessed in relation to neonatal thalamic growth. RESULTS: Prolonged AL/CVL use in neonates (n = 86) was associated with fewer skin breaks (median 34) during the hospital stay compared to restricted AL/CVL use (n = 57, median 91, 95% confidence interval [CI] 60.35-84.89). Neonates with prolonged AL/CVL use with fewer skin breaks had significantly larger thalamic volumes early in life compared to neonates with restricted line use (B = 121.8, p = 0.001, 95% CI 48.48-195.11). Neonatal thalamic growth predicted preschool-age cognitive (B = 0.001, 95% CI 0.0003-0.001, p = 0.002) and motor scores (B = 0.01, 95% CI 0.001-0.10, p = 0.02). Prolonged AL/CVL use was not associated with greater incidence of sepsis or multiple infections. CONCLUSIONS: Prolonged AL/CVL use in preterm neonates may provide an unprecedented opportunity to reduce invasive procedures in preterm neonates. Pain reduction in very preterm neonates is associated with optimal thalamic growth and neurodevelopment.

Functional topography of the thalamo-cortical system during development and its relation to cognition.

The thalamus has complex connections with the cortex and is involved in various cognitive processes. However, little is known about the age-related changes of thalamo-cortical connections and their relation to cognitive abilities. The present study analyzed resting-state functional connectivity between the thalamus and nine cortical functional networks (default mode network (DMN), posterior DMN, left/right executive, dorsal attention, salience, motor, visual and auditory network) in a healthy human sample (N = 95, aged 5-25 years). Cognitive abilities, including processing speed, selective attention, and cognitive flexibility were assessed using neuropsychological tests. All nine cortical resting-state networks showed functional connections to the thalamus at rest, with no effect for sex (p > 0.05). For the motor, visual, auditory, DMN, posterior DMN, salience and dorsal attention network, we found mainly bilateral thalamic projections in the mediodorsal nucleus, pulvinar and in nuclei of the lateral group. For the right and left lateralized executive network, corresponding lateralized thalamic projections were found. Thalamo-cortical connectivity strength showed significant age-related changes from distinct sub-nuclei of the thalamus to different cortical networks including the visual, DMN, salience and dorsal attention network. Further, connectivity strength of thalamo-cortical networks was associated with cognitive abilities, including processing speed, selective attention and cognitive flexibility. Better cognitive abilities were associated with increased thalamo-cortical connectivity in the pulvinar, mediodorsal nucleus, intralaminar nucleus, and nuclei from the lateral group. Alterations in the integrity of the thalamo-cortical system seem to be crucial for the development of cognitive abilities during brain maturation.

The enigmatic fetal subplate compartment forms an early tangential cortical nexus and provides the framework for construction of cortical connectivity.

The most prominent transient compartment of the primate fetal cortex is the deep, cell-sparse, synapse-containing subplate compartment (SPC). The developmental role of the SPC and its extraordinary size in humans remain enigmatic. This paper evaluates evidence on the development and connectivity of the SPC and discusses its role in the pathogenesis of neurodevelopmental disorders. A synthesis of data shows that the subplate becomes a prominent compartment by its expansion from the deep cortical plate (CP), appearing well-delineated on MR scans and forming a tangential nexus across the hemisphere, consisting of an extracellular matrix, randomly distributed postmigratory neurons, multiple branches of thalamic and long corticocortical axons. The SPC generates early spontaneous non-synaptic and synaptic activity and mediates cortical response upon thalamic stimulation. The subplate nexus provides large-scale interareal connectivity possibly underlying fMR resting-state activity, before corticocortical pathways are established. In late fetal phase, when synapses appear within the CP, transient the SPC coexists with permanent circuitry. The histogenetic role of the SPC is to provide interactive milieu and capacity for guidance, sorting, "waiting" and target selection of thalamocortical and corticocortical pathways. The new evolutionary role of the SPC and its remnant white matter neurons is linked to the increasing number of associative pathways in the human neocortex. These roles attributed to the SPC are regulated using a spatiotemporal gene expression during critical periods, when pathogenic factors may disturb vulnerable circuitry of the SPC, causing neurodevelopmental cognitive circuitry disorders.

Circuitry Underlying Experience-Dependent Plasticity in the Mouse Visual System.

Since the discovery of ocular dominance plasticity, neuroscientists have understood that changes in visual experience during a discrete developmental time, the critical period, trigger robust changes in the visual cortex. State-of-the-art tools used to probe connectivity with cell-type-specific resolution have expanded the understanding of circuit changes underlying experience-dependent plasticity. Here, we review the visual circuitry of the mouse, describing projections from retina to thalamus, between thalamus and cortex, and within cortex. We discuss how visual circuit development leads to precise connectivity and identify synaptic loci, which can be altered by activity or experience. Plasticity extends to visual features beyond ocular dominance, involving subcortical and cortical regions, and connections between cortical inhibitory interneurons. Experience-dependent plasticity contributes to the alignment of networks spanning retina to thalamus to cortex. Disruption of this plasticity may underlie aberrant sensory processing in some neurodevelopmental disorders.

Cumulative Blood Pressure Exposure, Basal Ganglia, and Thalamic Morphology in Midlife.

High blood pressure (BP) negatively affects brain structure and function. Hypertension is associated with white matter hyperintensities, cognitive and mobility impairment in late-life. However, the impact of BP exposure from young adulthood on brain structure and function in mid-life is unclear. Identifying early brain structural changes associated with BP exposure, before clinical onset of cognitive dysfunction and mobility impairment, is essential for understanding mechanisms and developing interventions. We examined the effect of cumulative BP exposure from young adulthood on brain structure in a substudy of 144 (61 female) individuals from the CARDIA (Coronary Artery Risk Development in Young Adults) study. At year 30 (Y30, ninth visit), participants (56±4 years old) completed brain magnetic resonance imaging and gait measures (pace, rhythm, and postural control). Cumulative systolic and diastolic BP (cumulative systolic blood pressure, cDBP) over 9 visits were calculated, multiplying mean values between 2 consecutive visits by years between visits. Surface-based analysis of basal ganglia and thalamus was achieved using FreeSurfer-initiated Large Deformation Diffeomorphic Metric Mapping. Morphometric changes were regressed onto cumulative BP to localize regions of shape variation. Y30 white matter hyperintensity volumes were small and positively correlated with cumulative BP but not gait. Negative morphometric associations with cumulative systolic blood pressure were seen in the caudate, putamen, nucleus accumbens, pallidum, and thalamus. A concave right medial putamen shape mediated the relationship between cumulative systolic blood pressure and stride width. Basal ganglia and thalamic morphometric changes, rather than volumes, may be earlier manifestation of gray matter structural signatures of BP exposure that impact midlife gait.

Progressive alignment of inhibitory and excitatory delay may drive a rapid developmental switch in cortical network dynamics.

Nervous system maturation occurs on multiple levels-synaptic, circuit, and network-at divergent timescales. For example, many synaptic properties mature gradually, whereas emergent network dynamics can change abruptly. Here we combine experimental and theoretical approaches to investigate a sudden transition in spontaneous and sensory evoked thalamocortical activity necessary for the development of vision. Inspired by in vivo measurements of timescales and amplitudes of synaptic currents, we extend the Wilson and Cowan model to take into account the relative onset timing and amplitudes of inhibitory and excitatory neural population responses. We study this system as these parameters are varied within amplitudes and timescales consistent with developmental observations to identify the bifurcations of the dynamics that might explain the network behaviors in vivo. Our findings indicate that the inhibitory timing is a critical determinant of thalamocortical activity maturation; a gradual decay of the ratio of inhibitory to excitatory onset time drives the system through a bifurcation that leads to a sudden switch of the network spontaneous activity from high-amplitude oscillations to a nonoscillatory active state. This switch also drives a change from a threshold bursting to linear response to transient stimuli, also consistent with in vivo observation. Thus we show that inhibitory timing is likely critical to the development of network dynamics and may underlie rapid changes in activity without similarly rapid changes in the underlying synaptic and cellular parameters.NEW & NOTEWORTHY Relying on a generalization of the Wilson-Cowan model, which allows a solid analytic foundation for the understanding of the link between maturation of inhibition and network dynamics, we propose a potential explanation for the role of developing excitatory/inhibitory synaptic delays in mediating a sudden switch in thalamocortical visual activity preceding vision onset.

Basal ganglia and thalamic tract connectivity in very preterm and full-term children; associations with 7-year neurodevelopment.

BACKGROUND: Altered basal ganglia and thalamic connectivity may be critical for cognitive, motor and behavioural impairments common to very preterm (<32 weeks' gestational age) children. This study aims to (1) compare corticostriatal and thalamocortical tract connectivity between very preterm and term-born children at 7 years of age; (2) explore tract connectivity associations with 7-year neurodevelopmental outcomes, and whether these relationships differed between groups. METHODS: Eighty-three very preterm and 19 term-born (≥37 weeks' gestational age) children underwent structural and diffusion magnetic resonance imaging and had a neuropsychological assessment at 7 years. Corticostriatal and thalamocortical tracts were reconstructed and white matter connectivity was estimated with apparent fibre density. RESULTS: Compared with term-born controls, very preterm children had decreased connectivity in tracts linking the caudate to right motor areas (-10%, p = 0.03) and the thalamus with left motor areas (-5.7%, p = 0.03). Reduced connectivity in corticostriatal and thalamocortical tracts was associated with adverse motor functioning in both groups (p = 0.06). Decreased connectivity of the left caudate and putamen with the lateral prefrontal cortex was associated with lower reading performance for controls (p = 0.06). CONCLUSION: Corticostriatal and thalamocortical tracts are vulnerable to very preterm birth. Poorer connectivity in these tracts may underlie the motor impairments observed in very preterm children.

Sex-Based Differences in Cortical and Subcortical Development in 436 Individuals Aged 4-54 Years.

Sex-based differences in brain development have long been established in ex vivo studies. Recent in vivo studies using magnetic resonance imaging (MRI) have offered considerable insight into sex-based variations in brain maturation. However, reports of sex-based differences in cortical volumes and thickness are inconsistent. We examined brain maturation in a cross-sectional, single-site cohort of 436 individuals (201 [46%] males) aged 4-54 years (median = 16 years). Cortical thickness, cortical surface area, subcortical surface area, volumes of the cerebral cortex, white matter (WM), cortical and subcortical gray matter (GM), including the thalamic subnuclei, basal ganglia, and hippocampi were calculated using automatic segmentation pipelines. Subcortical structures demonstrated distinct curvilinear trajectories from the cortex, in both volumetric maturation and surface-area expansion in relation to age. Surface-area analysis indicated that dorsal regions of the thalamus, globus pallidus and striatum, regions demonstrating structural connectivity with frontoparietal cortices, exhibited extensive expansion with age, and were inversely related to changes seen in cortical maturation, which contracted with age. Furthermore, surface-area expansion was more robust in males in comparison to females. Age- and sex-related maturational changes may reflect alterations in dendritic and synaptic architecture known to occur during development from early childhood through to mid-adulthood.

Long-term Monocular Deprivation during Juvenile Critical Period Disrupts Binocular Integration in Mouse Visual Thalamus.

Study of the neural deficits caused by mismatched binocular vision in early childhood has predominantly focused on circuits in the primary visual cortex (V1). Recent evidence has revealed that neurons in mouse dorsolateral geniculate nucleus (dLGN) can undergo rapid ocular dominance plasticity following monocular deprivation (MD). It remains unclear, however, whether the long-lasting deficits attributed to MD during the critical period originate in the thalamus. Using in vivo two-photon Ca2+ imaging of dLGN afferents in superficial layers of V1 in female and male mice, we demonstrate that 14 d MD during the critical period leads to a chronic loss of binocular dLGN inputs while sparing response strength and spatial acuity. Importantly, MD leads to profoundly mismatched visual tuning properties in remaining binocular dLGN afferents. Furthermore, MD impairs binocular modulation, reducing facilitation of responses of both binocular and monocular dLGN inputs during binocular viewing. As predicted by our findings in thalamic inputs, Ca2+ imaging from V1 neurons revealed spared spatial acuity but impaired binocularity in L4 neurons. V1 L2/3 neurons in contrast displayed deficits in both binocularity and spatial acuity. Our data demonstrate that critical-period MD produces long-lasting disruptions in binocular integration beginning in early binocular circuits in dLGN, whereas spatial acuity deficits first arise from circuits further downstream in V1. Our findings indicate that the development of normal binocular vision and spatial acuity depend upon experience-dependent refinement of distinct stages in the mammalian visual system.SIGNIFICANCE STATEMENT Abnormal binocular vision and reduced acuity are hallmarks of amblyopia, a disorder that affects 2%-5% of the population. It is widely thought that the neural deficits underlying amblyopia begin in the circuits of primary visual cortex. Using in vivo two-photon calcium imaging of thalamocortical axons in mice, we show that depriving one eye of input during a critical period in development chronically impairs binocular integration in thalamic inputs to primary visual cortex. In contrast, visual acuity is spared in thalamic inputs. These findings shed new light on the role for developmental mechanisms in the thalamus in establishing binocular vision and may have critical implications for amblyopia.

Changes in the development of subcortical structures in autism spectrum disorder.

Many studies have reported abnormalities in the volume of subcortical structures in individuals with autism spectrum disorder (ASD), and many of these change with age. However, most studies that have investigated subcortical structures were cross-sectional and did not accurately segment the subcortical structures. In this study, we used volBrain, an automatic and reliable quantitative analysis tool, and a longitudinal design to examine developmental changes in the volume of subcortical structures in ASD, and quantified the relation between subcortical volume development and clinical correlates. Nineteen individuals with ASD (16 males; age: 12.53 ± 2.34 years at baseline; interval: 2.33 years) and 14 typically developing controls (TDC; 12 males; age: 13.50 ± 1.77 years at baseline; interval: 2.31 years) underwent T1-weighted MRI at two time points. Bilaterally, hippocampus volume increased from baseline to follow-up in both ASD and TDC, with no difference between groups. Left caudate and right thalamus volume decreased in ASD, but did not change in TDC. The decreases in left caudate and right thalamus volume were related to ASD social score. Right amygdala volume was larger in ASD than in TDC at baseline but not at follow-up. These results confirm previous cross-sectional findings regarding the development of subcortical structures in ASD. The association between developmental changes in left caudate and right thalamus volume and ASD social score offers an explanation for the social deficits in ASD. Results also captured the different abnormality of amygdala volume between childhood and late adolescence.

Developmental synapse remodeling in the cerebellum and visual thalamus.

Functional neural circuits of mature animals are shaped during postnatal development by eliminating early-formed redundant synapses and strengthening of necessary connections. In the nervous system of newborn animals, redundant synapses are only transient features of the circuit. During subsequent postnatal development, some synapses are strengthened whereas other redundant connections are weakened and eventually eliminated. In this review, we introduce recent studies on the mechanisms of developmental remodeling of climbing fiber-to-Purkinje cell synapses in the cerebellum and synapses from the retina to neurons in the dorsal lateral geniculate nucleus of the visual thalamus (retinogeniculate synapses). These are the two representative models of developmental synapse remodeling in the brain and they share basic principles, including dependency on neural activity. However, recent studies have disclosed that, in several respects, the two models use different molecules and strategies to establish mature synaptic connectivity. We describe similarities and differences between the two models and discuss remaining issues to be tackled in the future in order to understand the general schemes of developmental synapse remodeling.

Chronic Alcohol Drinking Slows Brain Development in Adolescent and Young Adult Nonhuman Primates.

The transition from adolescence to adulthood is associated with brain remodeling in the final stages of developmental growth. It is also a period when a large proportion of this age group engages in binge alcohol drinking (occasional consumption of four to five drinks leading to intoxication) and heavy alcohol drinking (binge drinking on ≥5 d in a month). Here we report on magnetic resonance imaging of developmental changes in the brain occurring during late adolescence and early adulthood (3.5-7.5 years of age) in a rhesus macaque model of alcohol self-administration. Monkeys were imaged prior to alcohol exposure, and following ∼6 and ∼12 months of daily (22 h/d) access to ethanol and water. The results revealed that the brain volume increases by 1 ml/1.87 years throughout the late adolescence and early adulthood in controls. Heavy alcohol drinking reduced the rate of brain growth by 0.25 ml/year per 1 g/kg daily ethanol. Cortical volume increased throughout this period with no significant effect of alcohol drinking on the cortical growth rate. In subcortical regions, age-dependent increases in the volumes of globus pallidus, thalamus, brainstem, and cerebellum were observed. Heavy drinking attenuated the growth rate of the thalamus. Thus, developmental brain volume changes in the span of late adolescence to young adulthood in macaques is altered by excessive alcohol, an insult that may be linked to the continuation of heavy drinking throughout later adult life.