Grant Number: 5P50MH045156-170002
Project Title: ORGANIZATION AND DEVELOPMENT OF PREFRONTAL CORTICAL CIRCUITRY IN SCHIZOPHRENIA
PI Information: PROFESSOR DAVID A. LEWIS, lewisda@upmc.edu

Abstract: Based on our findings during the current period of funding, this renewal application for a Conte Center for the Neuroscience of Mental Disorders posits that understanding the neurobiology of schizophrenia requires a focus on the abnormalities in cognitive processing that are present in this disorder, on the components of the dorsolateral prefrontal cortex (DLPFC) and its extrinsic connections that are likely to mediate these processes, and on the developmental events that may make these neural systems vulnerable in schizophrenia. In particular, deciphering the cascade of pathophysiological events that produces the clinical features of schizophrenia depends upon investigations that examine 1) the normal molecular, structural and functional features of DLPFC circuitry, 2) the effects of alterations in one component of the system on other elements of the circuitry, and 3) the normal development of this circuitry and the impact of genetic factors on these developmental trajectories. Moreover, the success of such an endeavor depends upon the creative blending of clinical and basic studies, each of which is guided by and informs a common central hypothesis. Consequently, in the seven integrated programs of research proposed by Center investigators, we will test complementary aspects of the following central hypothesis: Certain critical disturbances in the regulation of cognition in schizophrenia reflect functional abnormalities both in the intrinsic circuitry of the DLPFC and in its interconnections with other cortical and subcortical regions. These functional disturbances arise during postnatal development as a consequence of alterations in the molecular signals and structural elements that determine synaptic efficacy in the affected circuits. The convergent tests of this hypothesis will be conducted in a highly interactive scientific environment that integrates the basic and clinical research activities of multiple investigators from the University of Pittsburgh, in concert with faculty at the adjacent Carnegie Mellon University and with accomplished senior scientists at Princeton and Vanderbilt Universities. Collectively, our Center represents a broad array of expertise that spans molecular, developmental, systems, cognitive and clinical neuroscience. Our extensive interactions enable us to conduct a translational research program in schizophrenia that effectively transfers information from the clinic to the laboratory and back to the clinic in a truly bidirectional fashion.

Thesaurus Terms:
central neural pathway /tract, developmental neurobiology, neuroanatomy, prefrontal lobe /cortex, schizophrenia
animal puberty, antipsychotic agent, disease /disorder model, dopamine, neuropathology, neuropharmacology, pyramidal cell, stimulus /response, synapse
Macaca fascicularis, Macaca mulatta, human subject, immunocytochemistry, postmortem

Institution: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
350 THACKERAY HALL
PITTSBURGH, PA 15260
Fiscal Year: 2006
Department:
Project Start:
Project End:
ICD: NATIONAL INSTITUTE OF MENTAL HEALTH
IRG:

The Journal of Neuroscience, March 21, 2007, 27(12):3295-3304

Amygdala Gene Expression Correlates of Social Behavior in Monkeys Experiencing Maternal Separation

Michael J. Sabatini,^1,3 Philip Ebert,^7,8 David A. Lewis,^1,2 Pat Levitt,^1,7,8 Judy L. Cameron,^1,4,5 and Károly Mirnics^1,6,8

Departments of ¹Psychiatry, ²Neuroscience, and ³Neurobiology, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, ⁴Departments of Physiology and Pharmacology and Behavioral Neuroscience, Oregon Health & Science University, Portland, Oregon 97239-3098, ⁵Oregon National Primate Research Center, Beaverton, Oregon 97006-3448, and Departments of ⁶Psychiatry and ⁷Pharmacology and ⁸Vanderbilt Kennedy Center for Human Development, Vanderbilt University, Nashville, Tennessee 37203

Maternal separation paradigm
A total of 12 female rhesus monkeys born in the breeding colony at the University of Pittsburgh Primate Research Laboratory were used for these studies. At birth, each monkey was arbitrarily selected to enter the "1 week separated," "1 month separated," or "control" experimental groups (n = 4 per group). All monkeys in this study spent the first week of life in a single cage with their mother. During this initial period, monkeys were housed in cages in temperature-controlled (24 ± 2°C) communal rooms with artificial lighting from 7:00 A.M. to 7:00 P.M., Purina Monkey Chow was provided once daily (number 5045; Ralston Purina, St. Louis, MO), and water was available ad libitum. After the first week of life, the animals were handled differently depending on experimental group assignment. At 1 week of age, monkeys designated as 1 week separated were removed from their mothers and placed in a single cage immediately adjacent to a group-rearing pen that they would ultimately join. After a 5–7 d period of learning to bottle feed (ad libitum Similac with Iron baby formula; Abbott Laboratories, Columbus OH), these monkeys were introduced into the group-rearing environment. One week separated monkeys spent weeks 3–12 in the group-rearing environment. Conversely, at 1 week of age, monkeys designated as 1 month separated were introduced into a group-rearing pen with their mothers. One month separated monkeys spent weeks 2–4 in the group-rearing environment with their mothers. At 4 weeks of age, 1 month separated monkeys' mothers were removed from the group-rearing environment, and the infants were placed in the single cage positioned identically as described for the 1 week separated group. After a 5–7 d period of learning to bottle-feed, these monkeys were reintroduced into the group-rearing environment. One month separated infants again spent weeks 6–12 in the group-rearing environment. Monkeys from both separation groups were provided a soft-cotton stuffed toy when they were in the single cage learning to bottle feed. This toy could be held to provide contact comfort. Control monkeys were introduced into the group-rearing pen at 1 week of age with their mother, and they remained there with their mother for the study's entirety, weeks 2–12. The group-rearing pen consisted of 4–5 monkeys of varying ages, with no monkey more dominant than the adult female mother (when present). An adolescent female was always present in the social rearing groups because they have been shown to be particularly attentive to infants. The group-rearing pen, measuring 14 x 11 x 12 feet, was cement block construction with a several inch bed of wood shavings on the floor, four perches at various heights, and a chain-link penfront. A "nursery chamber", measuring 2 x 2 x 3 feet, was placed in each pen and accessible only to infants. Infants had access to bottles of standard human artificial formula that were replaced three times each day. Other monkeys were fed one meal per day between 9:00 and 10:00 A.M. of Purina high-protein monkey chow supplemented several times a week with fresh fruit and seeds strewn in the bedding to encourage foraging. Water was available ad libitum. Artificial lighting in the hallways was on from 7:00 A.M. to 7:00 P.M. each day, and sky lights above each pen admitted natural light. Temperature was maintained at 24 ± 2°C. The infant monkeys were weighed weekly, and all animals, regardless of maternal separation status, reported a comparable weight gain over time (supplemental material 1, available at www.jneurosci.org ).

Behavioral assays
Behavioral assessments were initially made at the time of separation and again during the third month of life and will be described briefly below.
Acute separation behaviors. At the time of maternal separation, each monkey (four 1 week separated and four 1 month separated) was videotaped in the single nursery cage setting for 10 min per focal session. This occurred two to four times per day for the first 3 d after maternal separation, and every other day thereafter, until the infant was transferred to the group-rearing pen. All behaviors displayed by the focal monkeys in the acute separation cage (Table 1)
Table 1. Acute separation behaviors