Symposium 7: THE IMPACT OF ELA ON THE DEVELOPING BRAIN: CLARIFYING SPATIOTEMPORAL CASCADES

Chair:

Jennifer Silvers, PhD,  Associate Professor of Psychology, University of California, Los Angeles, United States

Presenters:

Tallie Z. Baram, MD, PhD., Distinguished & Bren Professor, University of California- Irvine, United States

Dylan Gee, PhD, Associate Professor of Psychology, Yale University, New Haven, United Stats

Jennifer Silvers, PhD,  Associate Professor of Psychology, University of California, Los Angeles, United States, Session Chair

Heather Brenhouse, PhD, Professor of Psychology, Northeastern University

Symposium Description: 

The statistical link between exposure to early life adversity (ELA) in infancy and childhood and alteration of motivated behaviors later in life, including those characteristic of cognitive and mental illnesses, is exceptionally strong. However, in human studies alone it is difficult to prove causality and establish the specific neural mechanisms and the temporal cascades that unfold after ELA exposure. In this symposium, we first ask where in the brain is ELA encoded, and whether the neurons and node encoding ELA contribute to ELA-induced alterations of reward behaviors (Dr. Baram), capitalizing on animal models. Next we address, in children and adolescents, several of the circuits whose developmental maturation is impacted by ELA, and the consequent behavioral problems (Dr. Gee). We then center on ambiguity perception and learning, core features of both typical emotional and cognitive development as well as anxiety – a common outcome of ELA – across development (Dr. Silvers). Again, leveraging an animal model, we discuss how neuronal populations responsive to ELA are reactivated when encoding risky behaviors in the face of ambiguous punishment (Dr. Brenhouse).  Collectively, this symposium will delineate the spatiotemporal cascade between encoding of infant/childhood ELA to alteration of circuit maturation, to the impact of ELA on fundamental brain processes such as ambiguity perception, which typify ELA-associated outcomes in the real world.  Consistent with the ISDP mission, this symposium will integrate research across species and different developmental stages, and the use of diverse, inter-disciplinary technologies.

List of abstracts and presenters: 

Where in the Brain is early-life adversity encoded? and why is this important, Tallie Z. Baram, MD, PhD., Distinguished & Bren Professor, University of California- Irvine

Experiences encountered early in life play an outsize role in determining our reactions and spontaneous behaviors, likely by influencing the maturation of important high-order networks. Whereas much is known about the networks involved in encoding memories later in life, and specifically the hippocampus, there are gaps in our understanding how salient experiences, including early-life adversity (ELA) are encoded in the infant and child’s brain before the hippocampal memory system becomes operational .

In a transgenic mouse engineered to enable permanent labeling of neurons activated at a specific time-point (TRAP mice), we mapped brain regions activated by adverse or typical early-life experiences. Surprisingly, permanently tagged neurons resided robustly and almost exclusively in the thalamic paraventricular nucleus (PVT).  Quantitative analyses showed that PVT was the only analyzed region that distinguished ELA from typical early-life experiences.  Remarkably, PVT cells activated by early-life experiences contributed to aberrant reward behaviors later in life, as silencing them using chemogenetic technology normalized the aberrant adult behavioral phenotype. Collaborative studies are now mapping the functional connectivity of the PVT in both humans and rodents and delineating the trajectory of PVT-network development from childhood to the adult.

In conclusion, in experimental models, the PVT is a novel key node for encoding salient early-life emotional memories and their influence on future behaviors. These discoveries provide strong impetus for studying the human PVT and its interconnected circuitry.

How adversity alters corticolimbic development and affective behavior in humans, Dylan Gee, Ph.D., Associate Professor of Psychology, Yale University

Early-life adversity can have lasting consequences on behavior and mental health. Delineating the neurobiological mechanisms linking adversity with behavior is critical to understanding risk and resilience. Leveraging data from large-scale consortium studies as well as community-based samples exposed to adversity, the studies presented will examine how adversity alters connections between the hippocampus, amygdala, and prefrontal cortex to shape affective behavior during human development. In a sample of over 4,000 youth, we used resting-state fMRI to identify patterns of hippocampal-frontoamygdala circuitry that linked adversity exposure with risk for internalizing psychopathology. We then examined how adversity exposure related to specific affective behavior in a sample of youth who completed an fMRI task of threat and safety learning. Youth with adversity exposure showed altered amygdala activation and age-related differences in hippocampal activation and functional connectivity during safety learning, which in turn related to symptoms of post-traumatic stress disorder. These data will be discussed in the context of developmental timing and the multilevel socioecological contexts in which youth develop. Together, the findings illustrate how adversity experienced early in life can shape the development of corticolimbic circuitry in ways that may promote adaptation to adverse environments but may also confer risk for mental health disorders.

IMPACTS OF ELA ON AMBIGUITY PROCESSING DURING LATE ADOLESCENCE, Jennifer Silvers, Ph.D., Associate Professor of Psychology, University of California, Los Angeles

Emerging work suggests that ELA may bias ambiguity processing in the brain and in behavior. To test this, I will present data from two studies of individuals in late adolescence. The first study involved a community sample of individuals with variable ELA histories who underwent fMRI scanning while they viewed negative (angry), positive (happy), and ambiguous (surprised) facial expressions. Representational similarity analyses revealed that across a host of brain regions involved in appraising affective stimuli (amygdala, ventral striatum, anterior insula, ventromedial prefrontal cortex), individuals exposed to ELA were more likely to represent ambiguous stimuli as threatening. The second study investigated decision making behavior in older adolescents and young adults with variable exposure to ELA, aimed at dissociating the effects of ELA on processing novelty vs. uncertainty, both of which are important for representing ambiguity. More childhood abuse or neglect exposure was negatively associated with less self-reported tolerance for uncertainty, but positively associated with their behavioral tolerance for uncertainty. Individuals who reported more uncertainty during childhood exhibited slightly more novelty seeking behavior. Together, these data suggest that ELA differentially impacts the way adversity, uncertainty, and novelty uncertainty are processed at the level of brain and behavior.   

Contribution of ELA-responsive neural ensembles to heightened adolescent risk-taking, Heather Brenhouse, Ph.D., Professor of Psychology, Northeastern University

Early life adversity (ELA) heightens adolescent vulnerability to risk-taking, driving a range of maladaptive health outcomes. ELA can alter the developmental trajectory of neuronal activity in regions controlling risk assessment, including the basolateral amygdala (BLA), nucleus accumbens, and prefrontal cortex. The BLA is particularly poised to control risk-related behaviors and is also vulnerable to long-term changes induced by ELA. Examining ELA-induced activity changes in the BLA may uncover a targetable mechanism underpinning adolescent maladaptive behavior. In the studies presented, BLA cells activated by maternal separation were tagged during late infancy with an activity- dependent cFos-tTa viral vector. Animals then were tested in the risky decision-making test (RDT) during the adolescent period, where they demonstrated a higher probability to choose a risky reward under increasing likelihoods of risk. cFos expression in response to the risk-taking task was then measured in the BLA, accumbens, and prefrontal cortex. In the BLA, the percent overlap of risk-activated cFos+ cells and tagged ELA-responsive cFos+ cells was quantified to identify ensembles that were encoded by ELA and activated during the RDT. These findings will be discussed in the context of ELA encoding and consequential changes to the perception of ambiguity, risk and reward.