This project aims to elucidate the interactive neurobiological and immunological effects of early life stress (ELS) in an animal model. The overarching goal of these studies is to prevent behavioral deficits later in life by intervening during an early and critical period. The results could potentially translate to techniques for identifying which ELS-exposed individuals are vulnerable to psychiatric disorders, and which might benefit from prophylactic therapies. We have exciting preliminary data in rats that shows ELS leads to the loss of parvalbumin (PVB)- expressing interneurons in the prefrontal cortex (PFC) and cognitive deficits during adolescence, which are key features of several psychiatric disorders. Moreover, these effects of ELS are preventable with pre-adolescent inhibition of neuroinflammatory activity. Neuroinflammatory damage occurs largely through the actions of cytokines and glutamate. We recently showed that both circulating cytokines and glutamatergic receptors are altered in ELS-exposed adolescents. Therefore, the proposed experiments will determine how ELS derails the healthy developmental trajectory of immune signals and glutamatergic receptors in the PFC to cause deleterious changes later in life. These studies accomplish two specific aims. First, we will examine potential immunological biomarkers that could predict later effects of ELS. We will use a highly sensitive assay to measure circulating cytokines in young rats exposed to varied time-courses of ELS. Collaboration with an expert on immunological measurements will allow us to assay multiple cytokines from small blood samples. The comparison of effects from different ELS time-courses will also help clarify existing inconsistencies in the literature. We will assess the predictive value of circulating cytokines by correlating early levels with later changes in PVB and behavior. Second, we will localize a mechanistic cause of cellular and behavioral dysfunction by investigating the role of glutamatergic receptors in ELS effects. In one experiment, we will target the NMDA receptor subunit NR2A, which we have shown is over-expressed in ELS adolescents. During the pre-adolescent window, we will microinject the cell-permeable peptide TAT2A into the PFC in order to uncouple NR2A from the intracellular machinery. We will determine whether blocking the effects of NR2A overexpression will help protect ELS-exposed animals from PVB loss and behavioral dysfunction. In another experiment, we will investigate whether ELS-induced neuroinflammation produces the same deleterious changes in AMPA receptors as other inflammatory events have been shown to produce. Taken together, we will test the following hypothesis: ELS increases inflammatory signaling that interacts with altered PFC glutamatergic receptor development to cause behavioral and neural dysfunction in adolescence.
Exposure to early life stress is associated with vulnerabilities to psychiatric illnesses, which often do not emerge until adolescence or early adulthood. We aim here to identify biomarkers of risk after early life stress, and to provide mechanistic framework for preventative interventions to help protect a vulnerable population from psychiatric illness.
|Brenhouse, Heather C; Schwarz, Jaclyn M (2016) Immunoadolescence: Neuroimmune development and adolescent behavior. Neurosci Biobehav Rev 70:288-299|
|Grassi-Oliveira, Rodrigo; Honeycutt, Jennifer A; Holland, Freedom H et al. (2016) Cognitive impairment effects of early life stress in adolescents can be predicted with early biomarkers: Impacts of sex, experience, and cytokines. Psychoneuroendocrinology 71:19-30|
|do Prado, Carine H; Narahari, Tanya; Holland, Freedom H et al. (2016) Effects of early adolescent environmental enrichment on cognitive dysfunction, prefrontal cortex development, and inflammatory cytokines after early life stress. Dev Psychobiol 58:482-91|
|Ganguly, Prabarna; Brenhouse, Heather C (2015) Broken or maladaptive? Altered trajectories in neuroinflammation and behavior after early life adversity. Dev Cogn Neurosci 11:18-30|
|Ganguly, Prabarna; Holland, Freedom H; Brenhouse, Heather C (2015) Functional Uncoupling NMDAR NR2A Subunit from PSD-95 in the Prefrontal Cortex: Effects on Behavioral Dysfunction and Parvalbumin Loss after Early-Life Stress. Neuropsychopharmacology 40:2666-75|
|Holland, Freedom H; Ganguly, Prabarna; Potter, David N et al. (2014) Early life stress disrupts social behavior and prefrontal cortex parvalbumin interneurons at an earlier time-point in females than in males. Neurosci Lett 566:131-6|