This is a competing renewal to study the structure and function of the prefrontal cortex in nonhuman primates. The proposed research has the long- range goal of understanding cognitive processes in the human brain through animal models. Its focus is on the principal sulcus (PS) (Walkers'area 46) of the macaque dorsolateral prefrontal cortex; this region of the primate cortex is essential for the process of working memory. Our specific goal in this grant is to provide a neurobiological foundation for understanding the memory functions of the PS at the areal, network, column and single cell levels. A series of anatomical studies will combine pathway tracing and electrophysiology and, in some instances immunocytochemistry, to examine selected visual, motor and intrinsic connections of prefrontal columns upon which memory functions are mapped. In complementary studies, a battery of functional approaches, e.g. intracortical injections of bicucculine for temporary disruption of function (Specific Aim #2), single- and double-label 2-deoxyglucose (Specific Aims #3 and #4) and finally single cell recording studies (Specific Aim #5) conducted in animals trained to perform memory-guided and sensory-guided oculomotor delayed response tasks are designed to provide a comprehensive analysis of the topography and dynamics of working memory in prefrontal cortex. These studies will also test the hypothesis that areas anatomically interconnected with the PS and parietal cortex are likewise dedicated to spatial cognition, each making a distinctive contribution within a distributed network defined by circuitry. The 2-deoxyglucose metabolic mapping technique allows visualization of metabolic activity in all areas of the brain during a given behavioral condition; and the double-label version of this method, developed in this laboratory, can address the long-standing issue of the cortical column as the functional unit of the cerebral cortex by examining the same cortical columns under two behavioral conditions in the very same animal. The columnar basis of working memory at the cellular level will be addressed by combined anatomical tracing and single cell recording studies. The proposed studies should advance our understanding of the circuit and cellular basis of cognitive functions and their breakdown in mental disease.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Method to Extend Research in Time (MERIT) Award (R37)
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Neurosciences Research Review Committee (BPN)
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Yale University
Schools of Medicine
New Haven
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Negyessy, Laszlo; Bergson, Clare; Garab, Sandor et al. (2008) Ultrastructural localization of calcyon in the primate cortico-basal ganglia-thalamocortical loop. Neurosci Lett 440:59-62
Leung, H-C; Gore, J C; Goldman-Rakic, P S (2005) Differential anterior prefrontal activation during the recognition stage of a spatial working memory task. Cereb Cortex 15:1742-9
Tanibuchi, Ikuo; Goldman-Rakic, Patricia S (2005) Comparison of oculomotor neuronal activity in paralaminar and mediodorsal thalamus in the rhesus monkey. J Neurophysiol 93:614-9
Negyessy, L; Goldman-Rakic, P S (2005) Morphometric characterization of synapses in the primate prefrontal cortex formed by afferents from the mediodorsal thalamic nucleus. Exp Brain Res 164:148-54
Negyessy, Laszlo; Goldman-Rakic, Patricia S (2005) Subcellular localization of the dopamine D2 receptor and coexistence with the calcium-binding protein neuronal calcium sensor-1 in the primate prefrontal cortex. J Comp Neurol 488:464-75
Koos, Tibor; Tepper, James M; Wilson, Charles J (2004) Comparison of IPSCs evoked by spiny and fast-spiking neurons in the neostriatum. J Neurosci 24:7916-22
Leung, Hoi-Chung; Seelig, David; Gore, John C (2004) The effect of memory load on cortical activity in the spatial working memory circuit. Cogn Affect Behav Neurosci 4:553-63
Compte, Albert; Constantinidis, Christos; Tegner, Jesper et al. (2003) Temporally irregular mnemonic persistent activity in prefrontal neurons of monkeys during a delayed response task. J Neurophysiol 90:3441-54
Gao, Wen-Jun; Goldman-Rakic, Patricia S (2003) Selective modulation of excitatory and inhibitory microcircuits by dopamine. Proc Natl Acad Sci U S A 100:2836-41
Gao, Wen-Jun; Wang, Yun; Goldman-Rakic, Patricia S (2003) Dopamine modulation of perisomatic and peridendritic inhibition in prefrontal cortex. J Neurosci 23:1622-30

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