Elucidating the role of inhibition in the circuit basis of spatial working memory (Extracellular recording)

'Working memory' refers to that component of memory that is responsible for holding information that is active and relevant for only a short period of time. Considerable evidence accumulated over many years has pointed to the prefrontal cortex as an important anatomical substrate for working memory. Pioneering studies conducted over 60 years ago revealed that monkeys with extensive bilateral prefrontal lobe lesions had difficulties performing a delayed response task, the classical experimental paradigm for testing working memory. More recent studies have established that subsets of neurons recorded within the primate dorsolateral prefrontal cortex (dPFC) possess both directionally-selective mnemonic and sensorimotor activity when the monkey is tested with a spatial delayed response task. The goal of this thesis was to elucidate the role that inhibition plays in the generation of such tuned activity in the dPFC.; Extracellular recordings were made in the left dPFC of two rhesus monkeys performing a spatial working memory task, and inhibitory interneurons were segregated from pyramidal cells based on action potential width. An analysis of tuning direction and strength in these populations revealed that both neuronal classes share similar tuning properties. Further, analysis of the tuning relationships between simultaneously recorded pairs of neurons revealed that the neurons constituting such pairs generally share similar tuning directions. These data support a functional microcolumnar organization in the dPFC similar to that suggested in other cortical areas.; To further elucidate local circuit mechanisms, microiontophoresis of receptor-specific agents was employed. The importance of GABAA mediated inhibition in supporting the spatial tuning of prefrontal neurons was demonstrated by the finding that the microiontophoresis of an antagonist at this receptor site onto prefrontal units destroyed previously extant tuning in the vast majority of cases. Further, the actions of 5-HT2 receptor selective agents on the tuning of pyramidal neurons demonstrated the importance of serotonergic mechanisms in working memory function and further supported the finding that local inhibition is primarily iso-directionally oriented. Thus, taken as a whole, this work demonstrates the importance of spatially-tuned inhibition in working memory function and supports a hypothesis of a functional microcolumnar organization in the dPFC.