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Decades-old material now available for de novo research

The Department of Neuroscience at Yale University is home to a unique resource (MacBrainResource) of non-human primate brain tissue derived from the anatomic studies of Dr. Pasko Rakic and the late Dr. Patricia Goldman-Rakic. Both ran (and Dr. Rakic still runs) large, productive laboratories directed toward understanding the primate brain, its prenatal and postnatal maturation, connectivity, response to lesion, and function. Early in their careers, they recognized that the non-human primate brain, because of its close resemblance to the human brain, is an excellent model system to address fundamental issues in neurobiology and neurodevelopment that would have direct relevance to the human condition.

Dr. Rakic has been at the forefront of developmental neuroscience research for over four decades. He began his quest to understand human brain development while a Fulbright Fellow and later faculty member at Harvard University. There he initiated a series of studies to address one of the basic tenets of neurodevelopment: where and when neurons are generated (See Collection 1). These pioneering studies of neurogenesis utilized an approach that was novel at the time: tritiated thymidine injections in pregnant monkeys to locate newly born neurons. After recruitment to Yale in 1978 to become founder and chairman of the Section of Neuroanatomy (now Department of Neuroscience), Dr. Rakic continued these studies throughout the 1980’s. In the ensuing years and continuing to the present time, this collection of archived brain slides has been used to probe contemporary issues in neurodevelopment, with publication of these data in top rated journals.

Dr. Goldman-Rakic was one of the most influential women in neuroscience before her tragic death in 2003. She dedicated her life to understanding the biologic mechanisms underlying the executive functions of the prefrontal cortex. In her endeavors to probe the workings of the prefrontal cortex, she utilized a multidisciplinary approach that spanned the fields of neuroanatomy, neurophysiology, neurochemistry, and neuroimaging. Dr. Goldman-Rakic’s neuroanatomical studies are a centerpiece of her legacy. Having trained with Walle Nauta in the 1970’s, she mastered the relatively new technique of tracer autoradiography and was a pioneerin the injection of anterogradely transported tritiated amino acids to trace connections between brain areas. One of her first studies revealed the presence of columnar terminal labeling in the prefrontal cortex, establishing the biologic similarity between primary sensory cortical areas and higher associative areas of the brain. In 1979, she joined Dr. Rakic in the Department of Neurobiology at Yale where she continued to study brain connectivity and amassed a large collection of brains histologically processed to reveal brain pathways (See Collection 2).

While together at Yale, the professional partnership of Drs Rakic and Goldman-Rakic blossomed even as each became world renowned in their respective fields. As accomplished surgeons, they used ablation techniques to examine the consequences of removal of brain areas at different developmental stages. The prenatal lesions required temporary removal and replacement of the fetus from the mother’s uterus in order to perform delicate surgical procedures. Yale is one of the only research facilities in the world to undertake prenatal surgical manipulation of the developing brain, in large measure due to their highly skilled surgical prowess. Prenatal and postnatal brain lesions comprise Collection 3 of this Resource.

In 1989, Drs. Rakic and Goldman-Rakic began an ambitious undertaking to create a neurodevelopmental model of prefrontal cortical dysfunction in schizophrenia. Fetal exposure to x-irradiation was used to curtail neurogenesis either in the upper layers of cortex (exposure in midgestation) or in subcortical structures such as the thalamus (exposure in early gestation). Controls include both non-irradiated and fetally sham-irradiated monkeys. These brains were celloidin embedded and processed in such a manner to optimize stereological analysis (Collection 4). As most of the animals were adults at the time of sacrifice, these brains provide a unique opportunity to examine the adult manifestation of a prenatal perturbation, notably at considerable cost incurred by housing non-human primates for upwards of 5 years. In addition, a cohort of early gestationally irradiated and control animals was structurally imaged in vivo with MRI and imaged ex vivo with DTI as well. The availability of brain scans and histological sections from the same animals allows for novel combinations of methodologies, as for example the transfer of cytoarchitectonic boundaries of cortical areas to the MRI scans in order to assess volume, surface area, and cortical thickness in the undistorted, un-shrunken living state.

One of the most important questions in neurodevelopmental biology is that of the timing of formation of synaptic connections between brain regions. In the 1980’s, Drs. Rakic and Goldman-Rakic addressed this question by launching a comprehensive study of synaptogenesis in multiple regions of the non-human primate brain based on quantitative analysis of synapses at the ultrastructural level. These landmark studies demonstrated that synapses, like neurons and axons, are overproduced during development of the non-human primate cortex and subsequently reduced to adult numbers; a similar pattern of overproduction and elimination of synapses has been described in the human cortex. These studies were based on plastic-embedded electron microscopy (EM) blocks of the visual, sensorimotor, prefrontal cortices and the dentate gyrus of the hippocampus from 25 non-human primates ranging in age from E47 to 20 years of age. EM blocks from these studies, as well as from many of the cases in Collection 1 comprise Collection 5.