Faculty Bibliography

What an animal needs to learn to survive is altered dramatically as they change from dependence on the parent for protection to independence and reliance on self-defense. This transition occurs in most altricial animals, but our understanding of the behavioral neurobiology has mostly relied on the infant rat. The transformation from dependence to independence occurs over three weeks in pups and is accompanied by complex changes in responses to both natural and learned threats and the supporting neural circuitry. Overall, in early life, the threat system is quiescent and learning is biased towards acquiring attachment related behaviors to support attachment to the caregiver and proximity seeking. Caregiver-associated cues learned in infancy have the ability to provide a sense of safety throughout lifetime. This attachment/safety system is activated by learning involving presumably pleasurable stimuli (food, warmth) but also painful stimuli (tailpinch, moderate shock). At about the midway point to independence, pups begin to have access to the adult-like amygdala-dependent threat system and amygdala-dependent responses to natural dangers such as predator odors. However, pups have the ability to switch between the infant and adult-like system, which is controlled by maternal presence and modification of stress hormones. Specifically, if the pup is alone, it will learn fear but if with the mother it will learn attachment (10-15 days of age). As pups begin to approach weaning, pups lose access to the attachment system and rely only on the amygdala-dependent threat system. However, pups learning system is complex and exhibits flexibility that enables the mother to override the control of the attachment circuit, since newborn pups may acquire threat responses from the mother expressing fear in their presence. Together, these data suggest that the development of pups' threat learning system is not only dependent upon maturation of the amygdala, but it is also exquisitely controlled by the environment. Most notably the mother can switch pup learning between attachment to threat learning in a moment's notice. This enables the mother to navigate pup's learning about the world and what is threatening and what is safe.

Social support can attenuate the behavioral and stress hormone response to threat, a phenomenon called social buffering. The mother's social buffering of the infant is one of the more robust examples, yet we understand little about the neurobiology. Using a rodent model, we explore the neurobiology of social buffering by assessing neural processing of the maternal odor, a major cue controlling social buffering in rat pups. We used pups before (Postnatal day (PN) 7) and after (PN14, PN23) the functional emergence of social buffering. Pups were injected with 14C 2-DG and presented with the maternal odor, a control preferred odor incapable of social buffering (acetophenone), or no odor. Brains were removed, processed for autoradiography and brain areas identified as important in adult social buffering were assessed, including the amygdala basolateral complex (BLA), medial prefrontal cortex (mPFC) and anterior cingulate cortex (ACC). Results suggest dramatic changes in the processing of maternal odor. PN7 pups show mPFC and ACC activation, although PN14 pups showed no activation of the mPFC, ACC or BLA. All brain areas assessed were recruited by PN23. Additional analysis suggests substantial changes in functional connectivity across development. Together, these results imply complex nonlinear transitions in the neurobiology of social buffering in early life that may provide insight into the changing role of the mother in supporting social buffering.

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

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

BACKGROUND: Trauma has neurobehavioral effects when experienced at any stage of development, but trauma experienced in early life has unique neurobehavioral outcomes related to later life psychiatric sequelae. Recent evidence has further highlighted the context of infant trauma as a critical variable in determining its immediate and enduring consequences. Trauma experienced from an attachment figure, such as occurs in cases of caregiver child maltreatment, is particularly detrimental. METHODS: Using data primarily from rodent models, we review the literature on the interaction between trauma and attachment in early life, which highlights the role of the caregiver's presence in engagement of attachment brain circuitry and suppressing threat processing by the amygdala. We then consider how trauma with and without the caregiver produces long-term changes in emotionality and behavior, and suggest that these experiences initiate distinct pathways to pathology. RESULTS: Together these data suggest that infant trauma processing and its enduring effects are impacted by both the immaturity of brain areas for processing trauma and the unique functioning of the early-life brain, which is biased toward processing information within the attachment circuitry. CONCLUSION: An understanding of developmental differences in trauma processing as well as the critical role of the caregiver in further altering early life brain processing of trauma is important for developing age-relevant treatment and interventions.

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.