Tania Roth - US grants

Prenatal exposure to morphine affects both neurological development and behavior of infants. Both rat pups and human infants born after prenatal exposure to morphine exhibit withdrawal and abnormal behavior, indicating that morphine affects development of the central nervous system (CNS). Mechanisms of mother-infant attachment in both species involve associative learning mediated by the CNS. Rat pups exhibit a sensitive period for learning these associations, dependent upon norepinephrine. Also, endogenous opioids are involved in early associative learning. The extent of interaction of both endogenous opioids and norepinephrine is not known. Are these two learning systems independent of one another, or is input necessary from both systems for early associative learning? The specific aims of this proposal are to determine the role of opioids in early olfactory associative learning and to determine the extent of the interaction between these two learning systems. Overall, a better understanding of the role of opioids in early learning would aid in the understanding of the consequences of prenatal exposure to morphine, which affects both learning systems, on the development of the CNS and mother-infant attachment.

Making adaptive changes in behavior in response to environmental change is essential to survival and therefore is likely to be mediated by complex interactions within a network of distributed neural circuits. One brain region that has been implicated in behavioral flexibility is the medial prefrontal cortex (mPFC). Damage to this region causes impairments in executive function, planning, and working memory, which are all important components of behavioral flexibility. Recording studies have shown that single mPFC neurons show elevated firing rates during the delay period of tasks that require the retention of information over a temporal gap, such as delayed-match/nonmatch-to-sample, suggesting that mPFC neurons are involved in working memory. Other studies have shown that mPFC activity shows anticipatory increases in firing rate prior to the execution of a response, suggesting its role in planning imminent actions. The goal ofthe current proposal is to dissociate mPFC involvement in working memory from other functions by comparing the effects of mPFC lesions and the firing patterns of mPFC single neurons between two similar tasks: one that requires working memory and one that does not. Additionally, reversal of these tasks will reveal the role of the mPFC in behavioral flexibility. Finally, we will investigate the interaction between the hippocampus and mPFC by inactivating the hippocampus and concurrently recording mPFC single neurons during task acquisition, performance and reversal. The results will aid in developing a better understanding ofthe role of the mPFC in adaptive behavior, both alone and in conjunction with the hippocampus.

? DESCRIPTION (provided by applicant): Caregiver experiences during early development profoundly affect development of the brain and behavior. Caregiver maltreatment imparts risk for later cognitive dysfunction and psychiatric disorders. An emerging idea is that epigenetic marking of the genome may underlie the genesis of these outcomes. However, this is based largely on correlational evidence and a causal relationship has not been established. Using a rodent model that we developed, we have shown that caregiver maltreatment induces aberrant methylation of DNA associated with the Brain-derived neurotrophic factor (Bdnf) gene within the prefrontal cortex (hypermethylation), amygdala (hypomethylation), and hippocampus (hypermethylation) of female rats. We have also shown that females when adult exhibit more anxiety-like behavior during gestation and mistreat their own offspring. Finally, we have shown that aberrant cortical Bdnf gene expression and DNA methylation patterns (hypermethylation) induced by caregiver maltreatment are reversible in adulthood by pharmacological manipulation of DNA methylation. The present project will utilize our rodent model to explore the central hypothesis that epigenetic gene changes are a basis for parenting behavior associated with caregiver maltreatment. The goal of the first aim is to determine whether pharmacological manipulation of DNA methylation improves behavior of maltreated-females. The goal of the second aim is to determine whether treatment of females with a demethylating agent at the time of maltreatment can prevent the emergence of aberrant methylation and maternal behavior. Finally, the goal of the third aim is to characterize gene-specific DNA methylation patterns in maltreated-females in brain regions associated with maternal behavior. These studies provide an innovative and informative approach for understanding the epigenetic consequences of exposure to an adverse caregiving environment. Furthermore, data generated from these studies will be the first to empirically establish a causal link between maltreatment-induced DNA methylation alterations and parenting behavior.