Faculty Bibliography

Long tolerated as a rite of passage into adulthood, bullying is now recognized as a major and preventable public health problem. The consequences of bullying-for those who are bullied, the perpetrators of bullying, and the witnesses-include poor physical health, anxiety, depression, increased risk for suicide, poor school performance, and future delinquent and aggressive behavior. Despite ongoing efforts to address bullying at the law, policy, and programmatic levels, there is still much to learn about the consequences of bullying and the effectiveness of various responses. In 2016, the National Academies of Sciences, Engineering, and Medicine published a report entitled Preventing Bullying Through Science, Policy and Practice, which examined the evidence on bullying, its impact, and responses to date. This article summarizes the report's key findings and recommendations related to bullying prevention.

Disrupted social behavior is a core symptom of multiple psychiatric and neurodevelopmental disorders. Many of these disorders are exacerbated by adverse infant experiences, including maltreatment and abuse, which negatively affect amygdala development. Although a link between impaired social behavior, abnormal amygdala function and depressive-like behavior following early adversity has been demonstrated in humans and animal models, the developmental emergence of maltreatment-related social deficits and associated amygdala neural activity are unknown. We used a naturalistic rodent model of maternal maltreatment during a sensitive period, postnatal days 8-12 (PN8-12), which produces social behavior deficits that precede adolescent depressive-like behavior and amygdala dysfunction, to examine social behavior in infancy, periweaning and adolescence. Neural activity in response to the social behavior test was assessed via c-Fos immunohistochemistry at these ages. A separate group of animals was tested for adult depressive-like behavior in the forced swim test. Maltreatment spared infant (PN16-18) social behavior but disrupted periweaning (PN20-22) and adolescent (PN42-48) social behavior. Maltreated rats exhibited blunted neural activation in the amygdala and other areas implicated in social functioning, including the medial prefrontal cortex and nucleus accumbens, at these ages and increased adult depressive-like behavior. These findings may suggest corticolimbic involvement in the emergence of maltreatment-induced social deficits that are linked to adult depressive-like behavior, thereby highlighting potential targets for therapeutic intervention. Understanding how infant experiences influence social behavior and age-specific expression across development may provide insights into basic neural mechanisms of social behaviors and disease-relevant social dysfunction exacerbated by early-life stress.

As altricial infants gradually transition to adults, their proximate environment changes. In three short weeks, pups transition from a small world with the caregiver and siblings to a complex milieu rich in dangers as their environment expands. Such contrasting environments require different learning abilities and lead to distinct responses throughout development. Here, we will review some of the learned fear conditioned responses to threats in rats during their ontogeny, including behavioral and physiological measures that permit the assessment of learning and its supporting neurobiology from infancy through adulthood. In adulthood, odor-shock conditioning produces robust fear learning to the odor that depends upon the amygdala and related circuitry. Paradoxically, this conditioning in young pups fails to support fear learning and supports approach learning to the odor previously paired with shock. This approach learning is mediated by the infant attachment network that does not include the amygdala. During the age range when pups transition from the infant to the adult circuit (10-15 d old), pups have access to both networks: odor-shock conditioning in maternal presence uses the attachment circuit but the adult amygdala-dependent circuit when alone. However, throughout development (as young as 5 d old) the attachment associated learning can be overridden and amygdala-dependent fear learning supported, if the mother expresses fear in the presence of the pup. This social modulation of the fear permits the expression of defense reactions in life threatening situations informed by the caregiver but prevents the learning of the caregiver itself as a threat.

Objectives: During infancy, rapid learning associated with attachment and orientation to a caregiver is essential to survival. This developmental period also prevents the acquisition of avoidance learning. In rodent models, this developmental time window occurs prior to post-natal day 10 (PND 10), during which pups display heightened preference learning accompanied by decreased aversion learning. PND 10 rats presented with odor-shock pairings fail to avoid the odor associated with shock, and show a preference for the paired odor. Older pups (PND 12) given odorshock pairings develop an aversion to the odor at subsequent test. One key developmental mechanism that appears to direct the change from a preference for the odor associated with shock to an aversion, involves the activation of the amygdala by corticosterone. Corticosterone is low in pups during the sensitive period and increases at PND 10. We investigated synaptic markers which may be important for establishing the avoidance memory and that are likely activated by corticosterone. Protein kinase M zeta (PKMzeta), which is important for late-phase LTP and long-term memory, is also upregulated during stress (Sebastian et al 2013, PLoS One, vol 8, e79077). Therefore, we investigated the role of PKMzeta in avoidance vs preference learning in rat pups using the paired odor-0.5mA shock fear-conditioning paradigm. Methods: PND 8 and PND 12 pups were given either paired (simultaneous odor and shock) or unpaired (shock 2 min after odor) training and tested 24hr later on a Y maze with one arm containing the conditioned stimulus (CS) odor and the other a familiar odor. Immediately after Y maze test, pups were sacrificed and amygdalae were harvested. The tissues were separated into cytosolic and synaptic cellular fractions. Each fraction was analyzed by Western blots. Results: Pups in the unpaired condition showed no preference for either arm. PND 8 pups in the paired condition preferred the CS odor and PND 12 pups in the paired condition avoided the CS odor (p<0.01). PND 12 in the paired condition had higher cytosolic PKMzeta in the amygdala compared to unpaired pups (p<0.05) with no change in synaptic PKMzeta. PN8 paired did not show any changes in cytosolic or synaptic PKMzeta Conclusions: Increased PKMzeta expression following the sensitive period plays a role in the activation process of the amygdala and the formation of aversive memories

Objectives: Human infants born prematurely experience repeated noxious medical procedures, but maternal contact can attenuate the behavioral response to these procedures. However, the mechanisms by which the mother reduces pain or the enduring impact of using the mother as an analgesic stimulus are unknown. By use of an animal model of early life pain with and without the mother, we monitored behavior at different points across the lifespan. Methods: Infant rats were given mild tail shocks (0.5 mA, 1 second every 4 minutes for 32 minutes) either with the mother present or absent for five consecutive days. Two age ranges were chosen to represent the sensitive period for pain programming (PN5-9) and the age at which maternal presence has major neurobehavioral effects, including suppression of amygdala activity (PN10-14). In infancy, neural pain responses were assessed via cFos expression in brain areas associated with pain, as well as behavioral measures related to pain response. In adulthood, pain thresholds, social behavior, and unlearned fear behavior were assessed as a function of infant pain experience. Results: Activity and ultrasonic vocalizations after treatment from PN5-9 and PN10-14 were reduced by the mother's presence during exposure to painful shock. After treatment at PN10-14 pups only, Fos expression in the periaqueductal gray and basolateral and medial amygdala was elevated by the shock alone and reduced by the mother. Adults treated at PN5-9 had reduced carrageenan-induced hyperalgesia and reduced social behavior but no changes in fear behavior if they had undergone pain-mother pairings. In contrast, when treated at PN10-14, the adult had no change in hyperalgesia and showed disruption of social behavior. Shock with or without the mother decreased unlearned fear responding only if treated at PN10-14. The social behavior deficits were normalized by 2 weeks of environmentally enriched rearing after weaning. Conclusions: Our results provide evidence that maternal presence during early life pain reduces pain responses in both infancy and adulthood, but it is also associated with long-term changes in emotionality. The results of these studies aid in our understanding of the impact of nursery procedures that are used to attenuate pain on later outcomes focused on affective behaviors and potentially provide a strategy to reduce those effects

A major component of perception is hedonic valence: perceiving stimuli as pleasant or unpleasant. Here, we used early olfactory experiences that shape odor preferences and aversions to explore developmental plasticity in circuits mediating odor hedonics. We used 2-deoxyglucose autoradiographic mapping of neural activity to identify circuits differentially activated by biologically relevant preferred and avoided odors across rat development. We then further probed this system by increasing or decreasing hedonic value. Using both region of interest and functional connectivity analyses, we identified regions within primary olfactory, amygdala/hippocampal, and prefrontal cortical networks that were activated differentially by maternal and male odors. Although some activated regions remained stable across development (postnatal days 7-23), there was a developmental emergence of others that resulted in an age-dependent elaboration of hedonic-response-specific circuitry despite stable behavioral responses (approach/avoidance) to the odors across age. Hedonic responses to these biologically important odors were modified through diet suppression of the maternal odor and co-rearing with a male. This allowed assessment of hedonic circuits in isolation of the specific odor quality and/or intensity. Early experience significantly modified odor-evoked circuitry in an age-dependent manner. For example, co-rearing with a male, which induced pup attraction to male odor, reduced activity in amygdala regions normally activated by the unfamiliar avoided male odor, making this region more consistent with maternal odor. Understanding the development of odor hedonics, particularly within the context of altered early life experience, provides insight into the development of sensory processes, food preferences, and the formation of social affiliations, among other behaviors. SIGNIFICANCE STATEMENT: Odor hedonic valence controls approach-avoidance behaviors, but also modulates ongoing behaviors ranging from food preferences and social affiliation with the caregiver to avoidance of predator odors. Experiences can shape hedonic valence. This study explored brain circuitry involved in odor hedonic encoding throughout development using maternal and predator odors and assessed the effects of early life experience on odor hedonic encoding by increasing/decreasing the hedonic value of these odors. Understanding the role of changing brain circuitry during development and its impact on behavioral function is critical for understanding sensory processing across development. These data converge with exciting literature on the brain's hedonic network and highlight the significant role of early life experience in shaping the neural networks of highly biologically relevant stimuli.

Pavlovian fear or threat conditioning, where a neutral stimulus takes on aversive properties through pairing with an aversive stimulus, has been an important tool for exploring the neurobiology of learning. In the past decades, this neurobehavioral approach has been expanded to include the developing infant. Indeed, protracted postnatal brain development permits the exploration of how incorporating the amygdala, prefrontal cortex and hippocampus into this learning system impacts the acquisition and expression of aversive conditioning. Here we review the developmental trajectory of these key brain areas involved in aversive conditioning and relate it to pups' transition to independence through weaning. Overall, the data suggests that adult-like features of threat learning emerge as the relevant brain areas become incorporated into this learning. Specifically, the developmental emergence of the amygdala permits cue learning and the emergence of the hippocampus permits context learning. We also describe unique features of learning in early life that block threat learning and enhance interaction with the mother or exploration of the environment. Finally, we describe the development of a sense of time within this learning and its involvement in creating associations. Together these data suggest that the development of threat learning is a useful tool for dissecting adult-like functioning of brain circuits, as well as providing unique insights into ecologically relevant developmental changes.