Faculty Bibliography

Decades of research have shown that childhood experiences interact with our genetics to change the structure and function of the brain. Within the range of normal experiences, this system enables the brain to be modified during development to adapt to various environments and cultures. Experiences with and attachment to the caregiver appear particularly important, and recent research suggests this may be due, in part, to the attachment circuitry within the brain. Children have brain circuitry to ensure attachment to their caregivers. Attachment depends on the offspring learning about the caregiver in a process that begins prenatally and continues through most of early life. This attachment serves two basic functions. First, attachment ensures the infant remain in the proximity of the caregiver to procure resources for survival and protection. Second, attachment "quality programs" the brain. This programming impacts immediate behaviors, as well as behaviors that emerge later in development. Animal research has uncovered segments of the attachment circuitry within the brain and has highlighted rapid, robust learning to support this attachment. A child attaches to the caregiver regardless of the quality of care received, even if the caregiver is abusive and neglectful. While a neural system that ensures attachment regardless of the quality of care has immediate benefits, this attachment comes with a high cost. Traumatic experiences interact with genetics to change the structure and function of the brain, compromising emotional and cognitive development and initiating a pathway to pathology. Neurobiological research on animals suggests that trauma during attachment is processed differently by the brain, with maternal presence dramatically attenuating the fear center of the brain (amygdala). Thus, the immaturity of the brain combined with the unique processing of trauma may underlie the enduring effects of abuse, which remain largely hidden in early life but emerge as mental health issues in periadolescence.

Stress is a powerful modulator of brain structure and function. While stress is beneficial for survival, inappropriate stress dramatically increases the risk of physical and mental health problems, particularly when experienced during early developmental periods. Here we focus on the neurobiology of the infant rat's odor learning system that enables neonates to learn and approach the maternal odor and describe the unique role of the stress hormone corticosterone in modulating this odor approach learning across development. During the first nine postnatal days, this odor approach learning of infant rats is supported by a wide range of sensory stimuli and ensures attachment to the mother's odor, even when interactions with her are occasionally associated with pain. With maturation and the emergence of a stress- or pain-induced corticosterone response, this odor approach learning terminates and a more adult-like amygdala-dependent fear/avoidance learning emerges. Strikingly, the odor approach and attenuated fear learning of older pups can be re-established by the presence of the mother, due to her ability to suppress her pups' corticosterone release and amygdala activity. This suggests that developmental changes in stress responsiveness and the stimuli that produce a stress response might be critically involved in optimally adapting the pup's attachment system to its respective ecological niche.

Abuse during early life, especially from the caregiver, increases vulnerability to develop later-life psychopathologies such as depression. Although signs of depression are typically not expressed until later life, signs of dysfunctional social behavior have been found earlier. How infant abuse alters the trajectory of brain development to produce pathways to pathology is not completely understood. Here we address this question using two different but complementary rat models of early-life abuse from postnatal day 8 (P8) to P12: a naturalistic paradigm, where the mother is provided with insufficient bedding for nest building; and a more controlled paradigm, where infants undergo olfactory classical conditioning. Amygdala neural assessment (c-Fos), as well as social behavior and forced swim tests were performed at preweaning (P20) and adolescence (P45). Our results show that both models of early-life abuse induce deficits in social behavior, even during the preweaning period; however, depressive-like behaviors were observed only during adolescence. Adolescent depressive-like behavior corresponds with an increase in amygdala neural activity in response to forced swim test. A causal relationship between the amygdala and depressive-like behavior was suggested through amygdala temporary deactivation (muscimol infusions), which rescued the depressive-like behavior in the forced swim test. Our results indicate that social behavior deficits in infancy could serve as an early marker for later psychopathology. Moreover, the implication of the amygdala in the ontogeny of depressive-like behaviors in infant abused animals is an important step toward understanding the underlying mechanisms of later-life mental disease associated with early-life abuse.

Survival of altricial infants depends on attachment to the caregiver - a process that requires infants to identify, learn, remember, and approach their attachment figure. Here we review the neurobiology of attachment in infant rats where learning about the caregiver is supported by a specialized attachment neural circuitry to promote the infant-caregiver relationship. Specifically, the attachment circuit relies on infants acquiring learned preferences to the maternal odor, and this behavior is supported by the hyperfunctioning locus coeruleus and generous amounts of norepinephrine to produce experience-induced changes in the olfactory bulb and anterior piriform cortex. Infants also possess a reduced ability to acquire learned aversions or fear, and this behavior is facilitated through attenuated amygdala plasticity to block fear learning. Presumably, this attachment circuitry constrains the infant animal to express only learned preferences regardless of the quality of care received. As pups mature, and begin to travel in and out of the nest, the specialized attachment learning becomes contextually confined to when pups are with the mother. Thus, when outside the nest, these older pups show learning more typical of adult learning, presumably to prepare for independent life outside the nest. The quality of attachment can alter this circuitry, with early life stress prematurely terminating the pups' access to the attachment system through premature functional activation of the amygdala. Overall, the attachment circuit appears to have a dual function: to keep pups close to the caregiver but also to shape pups' behavior to match the environment and define long-term emotion and cognition.

Background and Objectives: Maltreatment from the caregiver induces vulnerability to later life psychopathology. Animal models of early life stress suggest this is due to disruption of neural development of long-distance circuits linking amygdala to prefrontal cortex. Methods: We used a rat model of early life maltreatment to examine amygdala connectivity using resting-state functional magnetic resonance imaging (R-fMRI). Rat pups were reared by a mother provided with insufficient bedding for nest building or by one with abundant bedding from postnatal days (PND) 8 to 12. In adolescence (at PND 45) and in early adulthood (at PND 60), R-fMRI sessions were conducted under light (*1%) isofluorane anesthesia. Behavioral tests were obtained in animals reared under identical conditions to model negative affectivity, including the Forced Swim Test, Sucrose Preference Test, and Social Behavior Test. Results: Behaviors reflecting negative affectivity were seen in both adolescent and adult animals. Amygdala functional connectivity (FC) with frontal, parietal, and basal ganglia, including thalamus, increased significantly with increased age. By contrast, local amygdala FC decreased significantly with age. Additionally, we detected significant interactions between abuse condition and age. Local amygdala FC decreased between PND 45 and 60 in control rats, but increased significantly in abused rats. The reverse pattern was observed for amygdala FC with medial frontal cortex and parietal cortex. Conclusions: Translation of an in vivo longitudinal imaging approach to a rodent model of early caregiver maltreatment revealed enduring evidence of differences in brain functional connectivity in adulthood that likely underlies negative affectivity and vulnerability to internalizing psychopathology in humans

Antidepressant drugs and psychotherapy combined are more effective in treating mood disorders than either treatment alone, but the neurobiological basis of this interaction is unknown. To investigate how antidepressants influence the response of mood-related systems to behavioral experience, we used a fear-conditioning and extinction paradigm in mice. Combining extinction training with chronic fluoxetine, but neither treatment alone, induced an enduring loss of conditioned fear memory in adult animals. Fluoxetine treatment increased synaptic plasticity, converted the fear memory circuitry to a more immature state, and acted through local brain-derived neurotrophic factor. Fluoxetine-induced plasticity may allow fear erasure by extinction-guided remodeling of the memory circuitry. Thus, the pharmacological effects of antidepressants need to be combined with psychological rehabilitation to reorganize networks rendered more plastic by the drug treatment.