Shaping the Developing Brain: Prenatal through Early Childhood Fifth Annual Aspen Brain Forum

Abstracts

Day 2 — November 12, 2014

Keynote Address

How Will We Map Neurodevelopment?
Thomas R. Insel, MD, National Institute of Mental Health, Bethesda, Maryland, United States

The diversity of factors that shape brain development is just coming into focus. While genetic programming and environmental exposures have been known, the complexity of neurodevelopment now includes immune and microbial factors, as well as interactions that have yet to be defined. In mapping this complexity, we are challenged by tools that are not yet up to the task. Some of the most precise molecular and cellular tools we have for studying development in zebrafish and drosophila are not yet available for mammals. And the tools for humans are limited to the macro-connectome, orders of magnitude away from the level of resolution needed to map neurodevelopment. How will we fill in this gap between the micro-level studies in model systems and the macro-level data from human infants? New investments through the BRAIN (Brain Research through Advancing Innovative Neurotechnologies) initiative may give us the tools we will need to create a “meso” level understanding of human brain development. This presentation will share some of the new opportunities for mapping the complexity of neurodevelopment.
 

Session I: Overview Lectures on Neural and Cognitive Development

Mechanisms of Critical Period Brain Development
Takao K. Hensch, PhD, Harvard University, Cambridge, Massachusetts, United States

The potency of the environment to shape brain function changes dramatically across the lifespan. Neural circuits exhibit profound plasticity during early life and are later stabilized. The cellular and molecular bases of these developmental trajectories have recently begun to unravel. Two important concepts have emerged from the study of critical periods in sensory cortex: (1) excitatory–inhibitory (E-I) circuit balance is a trigger; and (2) molecular “brakes” limit adult plasticity. Targeting these mechanisms using pharmacological or genetic approaches are so powerful that animals of identical chronological age may be at the peak, before, or past their plastic window. Thus, critical period timing per se is plastic. One of the outcomes of normal development is to then stabilize the neural networks initially sculpted by experience. Rather than being passively lost, the brain’s intrinsic potential for plasticity is actively dampened to limit excessive circuit rewiring beyond the critical period. Understanding why so many regulators exist, how they interact and, ultimately, how to lift them in non-invasive ways, may hold the key to understanding mental illnesses, novel therapies and lifelong learning.
 

Transcriptional Landscape of the Developing Human Brain
Ed S. Lein, PhD, Allen Institute for Brain Science, Seattle, Washington, United States

How the genome provides the fundamental code for brain development is still poorly understood, as is our understanding of which features of brain development are conserved across all mammals versus specific to human. To chart this landscape we have created a series of transcriptional atlases of the developing human, non-human primate and mouse brain, marrying classical neuroanatomy with cutting edge modern transcriptomics. These data allow a systematic analysis of transcriptional dynamics during brain development, and a comparison between species to understand which features are unique to human. The vast majority of genes are active during brain development and vary tremendously across brain region and developmental stages, particularly in prenatal and early postnatal stages. Furthermore, we have observed many differences between human and mouse, the dominant experimental model organism for biomedical research, indicating that altered gene regulation underlies many of the differences in brain structure and function between species. These atlases provide a valuable community resource for understanding how genes function in shaping the brain, and clues to the locus of action for genes associated with neurodevelopmental diseases.
 

New Tools to Investigate Brain Development
Serena J. Counsell, PhD, Gareth Ball, PhD, and A. David Edwards, FRCP, Centre for the Developing Brain, King’s College London, London, England

Magnetic Resonance (MR) imaging during the neonatal period has become widely employed to provide detailed images of the developing brain, assess patterns of brain injury, and provide prognostic information. In addition to providing a highly detailed qualitative assessment of brain development, advanced MR approaches such as deformation based morphometry (DBM), diffusion MRI (d-MRI), and Blood Oxygen Level Dependent (BOLD) functional MRI (fMRI), can provide quantitative assessments of morphology, tissue structure, and functional activity. This talk focuses on recently published MR studies, particularly those using d-MRI, fMRI, and morphometric techniques that have (i) improved our understanding of the underlying neural mechanisms associated with disrupted brain development or (ii) demonstrated the potential of MR imaging to provide objective biomarkers of cerebral injury that relate to subsequent neurodevelopmental performance.
 

Session II: Social and Environmental Influences on Brain Development

Language and the Developing Brain
Patricia K. Kuhl, PhD, Institute for Learning & Brain Sciences, University of Washington, Seattle, Washington, United States

Advances in neuroscience have opened a new door with regard to understanding human development. In my laboratory, we are using both structural and functional brain measures to chart development of an individual infant’s brain, relating physical brain changes to environmental factors thought to enhance or impede early learning, and identifying measures that predict future learning. In the arena of language development, we employ magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), electrophysiology (EEG), and magnetoencephalography (MEG) to reveal links between brain development, the young child’s environment, and development of the early skills related to language and literacy that are critical to success in school and in life. Our most recent studies use MEG brain measures to produce “movies” of activity patterns across the entire brain as the child listens to sounds or words. We demonstrated that when young infants hear speech, the brain’s auditory areas are active, as we expected, but also that activity occurs in brain areas responsible for motor action as well. Apparently, when we talk to children, their brains activate the machinery they need to talk back, a surprising new finding. Future studies will examine how genes that affect brain development interact with the timing of environmental stimulation. Developmental neuroscience will deeply affect our understanding of the extraordinary human capacity to learn, helping all children, including those with developmental disabilities, reach their potential.
 

Early Attachment, Emotional Development and Differential Susceptibility to Environmental Influences
Jay Belsky, PhD, University of California, Davis, Davis, California, United States

It is widely assumed that developmental experiences and environmental exposures early in life shape human development across the life course. Perhaps nowhere is this view more evident than in attachment theory. And, to a degree, there is an abundance of evidence that indicates that the quality of care experienced in the first years of life influence whether a child develops a secure or insecure attachment with his/her caregivers. Moreover, related evidence reveals that security is predictive of somewhat better functioning in the future, including the ability to cope with stress, than does an early history of insecurity. At the same time, however, the effects of parenting on and the developmental legacy of early attachment security prove to be less powerful than often presumed by theory. Why is that? One reason may be that individuals, including children, vary in their susceptibility to environmental influences, with some proving more and some less developmentally plastic or malleable. Evolutionary theory leads to this expectation, and ever more evidence is consistent with it. This new understanding of variation in developmental plasticity may have important implications for science, policy, and practice.
 

Infant Neural Mirroring Mechanisms and Developing Social Cognition
Andrew N. Meltzoff, PhD, Institute for Learning & Brain Sciences, University of Washington, Seattle, Washington, United States

The mechanisms underlying infant imitation require a close mapping between action perception and production. The mapping can be described at both the psychological level, and increasingly at the neural level. In this talk I will describe the “Like-Me” framework as a foundation for human social cognition. It proposes that one of the infant’s first and most basic psychological acts is the recognition of others who act, move, and behave like the self. This theoretical framework, based on behavioral studies, is aligned with emerging findings in developmental social neuroscience, especially results using the infant EEG to measure the sensorimotor mu rhythm. After introducing new data relating brain and behavioral measures in infancy, I will focus discussion on the initial state of infants’ mapping between self and other, the role of experience — both exogenous and self-generated — in altering this initial state, and the impact of early self-other mapping on later social-cognitive developments. The talk seeks to build specific bridges between developmental behavioral science, cognitive neuroscience, and social psychology.
 
Coauthor: Peter J. Marshall, PhD, Temple University, Philadelphia, Pennsylvania, United States
 

Session II: Social and Environmental Influences on Brain Development

Maternal Stress Programming of Neurodevelopment: Placental Mechanisms
Tracy L. Bale, PhD, and Christopher Howerton, PhD, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Neurodevelopmental disorders including autism and schizophrenia have been highly associated with prenatal factors, including maternal stress. The mechanisms through which these influences may contribute to disease development are not well understood, though likely involve complex interactions between the maternal milieu and the developing placenta. We have identified a sensitive period of early gestation where maternal stress (EPS) produces sex-specific epigenetic programming effects on offspring stress pathway neurodevelopment. In this mouse model, we identified O-linked N-acetylglucosamine transferase (OGT) as a sex-specific and stress-sensitive placental biomarker of maternal stress. OGT, an X-linked gene and key intracellular glycotransferase, has great potential to have broad impact on chromatin state and key cellular functions within the placenta. OGT was similarly regulated in human placental tissue supporting its translational potential. In our model, chromatin immunoprecipitation and deep sequencing analyses identified a reduced association with the histone transcriptional activational mark, H3K4me3, at key loci important in regulating steroid biosynthesis within the placenta. Biochemical analyses confirmed a significant reduction in steroid hormone production in male EPS placentas. To confirm a role for placental OGT in programming of the developing hypothalamus, we generated mice with placental-specific targeting of this gene. Adult mice with a targeted reduction of placental OGT recapitulated key features of our EPS phenotype, with male mice demonstrating a dysregulated HPA stress axis, reduced post-weaning body weight and growth, and significant mitochondrial dysfunction. These studies provide valuable insight into novel placental contributions to sex-biased disease vulnerability following maternal stress exposure impacting the developing brain.
 

Role of Early Experience in Neuro-Affective Development
Nim Tottenham, PhD, Columbia University, New York, New York, United States

Strong evidence indicates that reciprocal connections between the amygdala and medial prefrontal cortex (mPFC) support fundamental aspects of emotional behavior. Despite the central role that this circuitry plays in regulating emotions in adulthood, little is known regarding human amygdala-mPFC development. In this talk, I will present developmental functional magnetic resonance imaging data describing age-related changes in amygdala-mPFC circuitry throughout childhood and adolescence and how they relate to emergent emotion regulation. I will focus on both typical development as well as development following maternal deprivation (e.g., orphanage care), showing that maternal deprivation may accelerate development of this circuitry, perhaps as an ontogenetic adaptation in response to amygdala hyperreactivity. The findings presented are highly consistent with the animal literature showing both large changes in amygdala-mPFC circuitry throughout childhood/adolescence, as well as the large influence of maternal care in shaping this neural circuitry. These age-related changes will be discussed in terms of potential developmental sensitive periods for environmental influence.
 

Impact of Poverty on the Developing Brain
Martha J. Farah, PhD, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Decades of research have demonstrated psychological correlates of socioeconomic status (SES) in general, and poverty in particular, with childhood poverty shown to exert a lifelong effect on intellectual and emotional functioning. Neuroscience methods have recently been brought to bear on the problem of how and why poverty shapes life trajectories though its effects on the developing brain. In this talk I will review what is known about the effects of childhood poverty on brain development, drawing on behavioral, electrophysiological, and imaging studies in humans and relevant animal models. I will share preliminary conclusions and open questions (the latter far outnumbering the former!) concerning the causal pathways by which the many correlated but distinct facets of poverty impact brain development, and thence lifelong psychological functioning.
 

Windows of Opportunity and Vulnerability: The First Years of Life
Charles A. Nelson III, PhD, Harvard Medical School/Boston Children’s Hospital, Harvard Graduate School of Education, Harvard Center on the Developing Child, Cambridge, Massachusetts, United States

There is mounting evidence that exposure to significant adversity early in life can exert a profound impact on the course of development that extends well beyond childhood. In this talk I will begin by briefly talking about the role of experience in brain development, focusing in particular on the concepts of neural plasticity and critical periods. To illustrate these concepts, I will next turn my attention to two separate literatures: exposure to so-called “toxic stress” and then to the effects of early, profound deprivation on brain-behavioral development. I will conclude my talk by summarizing the main take home messages that emerge from the literature on early adversity.
 

Session III: Hot Topic Talks from Submitted Abstracts

Examining the Relationships between Cortical Maturation and White Matter Myelination throughout Early Childhood
Elise C. Croteau-Chonka¹

Two important neurodevelopmental processes that occur throughout infancy and early childhood are the maturation of myelinated white matter and cortical development (including changes in thickness, surface area, gyrification, and volume).  Although prior magnetic resonance imaging studies in children have investigated white matter development independently of cortical thickness, none have yet sought to elucidate the dynamic relationship between these interrelated processes.  Moreover, few studies have investigated these processes between the ages of 2 to 5 years.  Here, we measured cortical thickness and assessed the myelination within directly adjacent white matter in a mixture of fast and slow developing brain regions (inferior temporal cortex, lingual gyrus, middle temporal cortex, postcentral gyrus, precentral gyrus, precuneus, superior frontal cortex, superior parietal cortex, and temporal pole) in a large cohort (n=186, 79 female) of healthy and typically-developing children approximately 1 to 6 years of age (363 to 2198 days corrected to a 40 week gestation).  We find that across this age range, mean cortical thickness follows a decreasing quadratic trajectory, while myelination logarithmically increases with age. In investigating the relationship between these processes in each of the 9 brain regions, we found a statistically significant (p<0.05, corrected for multiple comparisons) negative relationship, with increased myelination predicting reduced cortical thickness in adjacent regions.  These results provide the first insight into early neural network development, suggesting that the white matter maturation is closely linked to changes in cortical structure within similar networks.
 
Coauthors: Sean C. L. Deoni, PhD¹, Jonathan O’Muircheartaigh, PhD², Holly Dirks, BSc¹, and Doug C. Dean III, PhD³
1. Brown University School of Engineering, Providence, Rhode Island, United States
2. King’s College London, Institute of Psychiatry, London, United Kingdom
3. Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin, United States
 

Western Diets during Gestation and Lactation: A Novel Model for Postpartum Depression and Developmental Programming?
Jessica L. Bolton, BS¹

Maternal obesity during gestation/lactation can “program” offspring for increased obesity themselves, along with increased vulnerability to mood disorders. Emerging evidence suggests that this programming by perinatal diet is propagated via inflammatory mechanisms, specifically linked to two components that are enriched in a “Western diet”: saturated fatty acids and branched-chain amino acids (BCAAs). We placed female mice on one of 4 diets: 1) high-fat diet (HFD), 2) low-fat diet (LFD), 3) HFD supplemented with BCAA (HFD+BCAA), or 4) LFD supplemented with BCAA (LFD+BCAA) for 6 weeks prior to breeding, The combination of HFD and BCAA resulted in markedly greater weight gain in the mothers than either dietary component alone, but paradoxically, smaller birth weights for their offspring. BCAA supplementation also resulted in increased depressive-like behavior in the mothers when tested one week after birth, and BCAA offspring were smaller at weaning. RT-PCR analysis of post-partum mother and offspring brains revealed that HFD and BCAA altered expression of both serotonergic and immune genes, and further suggested that microglial colonization may be delayed in the pups, with potential consequences for overall brain development. Despite placement on a LFD at weaning, HFD and HFD+BCAA offspring exhibited increased anxiety-like behavior in adulthood. The male offspring of these groups were also hyperactive, whereas the female offspring from the same litters exhibited decreased activity, suggesting that the long-term effects of maternal nutrition are sex-specific. In sum, perinatal diet can modulate postpartum depression risk for mothers, as well as program serotonergic function, microglial development, and behavior of offspring.
 
Coauthors: Leigh Ann Simmons, PhD², Melanie Wiley, BS¹, Bailey Ryan¹, Samantha Truong¹, and Staci D. Bilbo, PhD¹
1. Duke University, Durham, North Carolina, United States;
2. Duke University School of Nursing, Durham, North Carolina, United States