Survival of altricial infants, including humans and rats, depends on attachment to the caregiver -a process that requires infants to recognize, learn, and remember their attachment figure. The demands of a dynamic environment combined with a maturing organism requires frequent neurobehavioral reorganization. This restructuring of behavior and its supporting neural circuitry can be viewed through the unique lens of attachment learning in rats in which preference learning is enhanced and aversion learning is attenuated. Behavioral restructuring is well adapted to securing the crucial infantcaregiver relationship regardless of the quality of care. With maturation and the end of the infantcaregiver attachment learning period, the complex interplay of neural structures, hormones, and social behavior coordinates the developing rat' s eventual transition to life outside of the nest. Nevertheless, early-life environmental and physiological stressors can alter the resilient nature of this system, particularly in respect to the amygdala, and these changes may provide important clues to understanding the lasting effects of early stress."…development is essentially a dynamic process that promotes reorganization and adaptation across time" (S. Levine, 1982) The maturing organism has the daunting task of frequently reorganizing behavior to meet not only the demands of a changing environment, but also those of physiological and neural maturation. The myriad processes by which an organism reorganizes its behavior are not well understood, but are thought to include complex interactions between experience, learning, as well as genetic and neural changes. Of course, each reorganization is likely to involve unique processes and can occur either rapidly or gradually. These periods of reorganization, which are also referred to as developmental transitions, are believed to represent periods of vulnerability and have received more experimental attention in recent years (for review see: Adriani and Laviola, 2004;Crews et al. 2007;Hensch, 2004;Hofer and Sullivan, 2008;Rice and Barone, 2000;Sullivan et al., 2009). However, Levine and others have long highlighted the importance of these transitions and the critical role of proper reorganization for normal development (Bell and Denenberg, 1962;Denenberg, 1963;Levine, 1982 Levine, , 2000. Correspondence: Regina M. Sullivan, Emotional Brain Institute, The Nathan S. Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, Orangeburg, NY 10962, Office: 845-398-5511, lab: 845-398-6692, fax: 845-398-2193, regina.sullivan@nyumc.org. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal dis...

The hippocampus is a part of the limbic system and is important for the formation of associative memories, such as acquiring information about the context (e.g. the place where an experience occurred) during emotional learning (e.g. fear conditioning). Here, we assess whether the hippocampus is responsible for pups’ newly emerging context learning. In all experiments, postnatal day (PN) 21 and PN24 rat pups received 10 pairings of odor-0.5mA shock or control unpaired odor-shock, odor only and shock only. Some pups were used for context, cue or odor avoidance tests, while the remaining pups were used for c-Fos immunohistochemistry to assess hippocampal activity during acquisition. Our results show that cue and odor avoidance learning were similar at both ages, while contextual fear learning and learning-associated hippocampal (CA1, CA3 and dentate gyrus) activity (c-Fos) only occurred in PN24 paired pups. To assess a causal relationship between the hippocampus and context conditioning, we infused muscimol into the hippocampus, which blocked acquisition of context fear learning in the PN24 pups. Muscimol or vehicle infusions did not affect cue learning or aversion to the odor at PN21 or PN24. The results suggest that the newly emerging contextual learning exhibited by PN24 pups is supported by the hippocampus.

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The contribution of the early postnatal environment to the pervasive effects of prenatal alcohol exposure (PAE) is poorly understood. Moreover, PAE often carries increased risk of exposure to adversity/stress during early life. Dysregulation of immune function may play a role in how pre- and/or postnatal adversity/stress alters brain development. Here, we combine two animal models to examine whether PAE differentially increases vulnerability to immune dysregulation in response to early-life adversity. PAE and control litters were exposed to either limited bedding (postnatal day [PN] 8–12) to model early-life adversity or normal bedding, and maternal behavior and pup vocalizations were recorded. Peripheral (serum) and central (amygdala) immune (cytokines and C-reactive protein - CRP) responses of PAE animals to early-life adversity were evaluated at PN12. Insufficient bedding increased negative maternal behavior in both groups. Early-life adversity increased vocalization in all animals; however, PAE pups vocalized less than controls. Early-life adversity reduced serum TNF-α, KC/GRO, and IL-10 levels in control but not PAE animals. PAE increased serum CRP, and levels were even higher in pups exposed to adversity. Finally, PAE reduced KC/GRO and increased IL-10 levels in the amygdala. Our results indicate that PAE alters immune system development and both behavioral and immune responses to early-life adversity, which could have subsequent consequences for brain development and later life health.

Social behavior deficits resulting from prenatal alcohol exposure (PAE) emerge early in life and become more pronounced across development. Maturational changes associated with adolescence, including pubertal onset, can have significant consequences for social behavior development, making adolescence a unique period of increased vulnerability to social behavior dysfunction. Unfortunately, little is known about the underlying neurobiology supporting PAE-related social behavior impairments, particularly in the context of adolescence, when the transition to a more complex social environment may exacerbate existing deficits in social behavior function. Here we perform a comprehensive evaluation of social behavior development in PAE animals during two different periods in adolescence using three separate but related tests of social behavior in increasingly complex social contexts: the social interaction test, the social recognition memory test (i.e. habituation-dishabituation test), and the social discrimination test. Additionally, we investigated the underlying neurobiology of the oxytocin (OT) and vasopressin (AVP) systems following PAE, given their well-documented role in mediating social behavior. Our results demonstrate that compared to controls, early adolescent PAE animals showed impairments on the social recognition memory test and increased OT receptor binding in limbic networks, while late adolescent PAE animals exhibited impairments on the social discrimination test and increased OTR binding in forebrain reward systems. Taken together, these data indicate that PAE impairs adolescent social behavior - especially with increasing complexity of the social context - and that impairments are associated with altered development of the OT but not the AVP system.