Early life experience can alter adult emotionality and stress responsiveness, but only limited research has examined how experience shapes the development of central neural circuits. We predict that manipulation of early life experience will alter the functional organization of central visceral circuits, and that altered neuroanatomy will correspond with altered behavioral, physiological, and neural responses to stressful events. The proposed research will test this prediction by performing experiments in adult male and female rats with a developmental history of having been handled briefly for daily maternal separation of either 15 min (MS15) or 3 hr (MS180) during the first two postnatal weeks. Non-separated (MS0) rats will serve as controls. As young adults, all rats will be screened for behavioral differences in the elevated plus maze, and blood samples will be collected to document restraint stress-evoked excursions in plasma corticosterone. Subsequent experiments in Aims 1 and 2 will be performed in behaviorally- and hormonally-screened adult rats.
Aim 1 experiments will test the hypothesis that early maternal care (manipulated via MS15 and MS180) interacts with sex to differentially alter the anatomical features of central visceral circuits. Retrograde transneuronal transport of pseudorabies virus will be used to probe for differences in central autonomic circuits in rats with different developmental histories. In the second experiment, experience-dependent alterations in noradrenergic (NA) sensory pathways will be examined. For this, a unique lentivirus vector that expresses enhanced green fluorescent protein under the control of a dopamine beta hydroxylase promoter will be microinjected into the caudal medulla to label the axonal arbors of transfected NA neurons that project to the hypothalamus and limbic forebrain.
Aim 2 experiments will test the hypothesis that early maternal care interacts with sex to differentially alter stressor-induced neural Fos activation in central visceral circuit nodes. Rats will be perfused with fixative after restraint, LiCl treatment, predator odor exposure, or matched control treatment for analyses of stimulus-induced Fos expression in medullary NA neurons and in their central projection fields. NA terminal immunolabeling density and CRF/CRH labeling also will be quantified to determine whether sex and/or MS group differences interact. Data will be analyzed and interpreted within the context of behavioral and hormonal responses in the screening tests, with attention paid to predicted effects of early postnatal experience and sex on anatomical and physiological outcomes. The proposed work will advance our understanding of how early maternal care can alter the developmental trajectory of central visceral circuits in males and females, and will provide new insights regarding the impact of early experience on adult emotionality and stress responsiveness.

Public Health Relevance

Interactions between infants and their mother (or primary caregiver) are critical for normal growth and development, and perturbations can disrupt physiological and behavioral functions in the offspring. The proposed research will use anatomical and physiological methods in rats to test the hypothesis that the influence of early life events on later responses to stress and emotional events is linked to developmental plasticity of circuits that provide visceral sensory feedback to the brain and generate emotional expression.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Neurobiology of Motivated Behavior Study Section (NMB)
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Simmons, Janine M
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University of Pittsburgh
Schools of Arts and Sciences
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Kojima, Sayuri; Catavero, Christina; Rinaman, Linda (2016) Maternal high-fat diet increases independent feeding in pre-weanling rat pups. Physiol Behav 157:237-45
Zheng, Huiyuan; Rinaman, Linda (2016) Simplified CLARITY for visualizing immunofluorescence labeling in the developing rat brain. Brain Struct Funct 221:2375-83
Maniscalco, James W; Kreisler, Alison D; Rinaman, Linda (2012) Satiation and stress-induced hypophagia: examining the role of hindbrain neurons expressing prolactin-releasing Peptide or glucagon-like Peptide 1. Front Neurosci 6:199
Rinaman, Linda; Banihashemi, Layla; Koehnle, Thomas J (2011) Early life experience shapes the functional organization of stress-responsive visceral circuits. Physiol Behav 104:632-40
Banihashemi, L; O'Neill, E J; Rinaman, L (2011) Central neural responses to restraint stress are altered in rats with an early life history of repeated brief maternal separation. Neuroscience 192:413-28
Rinaman, Linda (2011) Hindbrain noradrenergic A2 neurons: diverse roles in autonomic, endocrine, cognitive, and behavioral functions. Am J Physiol Regul Integr Comp Physiol 300:R222-35
Koehnle, Thomas J; Rinaman, Linda (2010) Early experience alters limbic forebrain Fos responses to a stressful interoceptive stimulus in young adult rats. Physiol Behav 100:105-15
Banihashemi, L; Rinaman, L (2010) Repeated brief postnatal maternal separation enhances hypothalamic gastric autonomic circuits in juvenile rats. Neuroscience 165:265-77
Rinaman, Linda (2010) Ascending projections from the caudal visceral nucleus of the solitary tract to brain regions involved in food intake and energy expenditure. Brain Res 1350:18-34
Rinaman, Linda; Saboury, Mitra; Litvina, Elizabeth (2009) Ondansetron blocks LiCl-induced conditioned place avoidance but not conditioned taste/flavor avoidance in rats. Physiol Behav 98:381-5

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