The neocortex constitutes the largest component of the brain in mammals and is the primary site of mental functions. Crucial to its functionality are the interactions between distinct neuronal networks within the cortex. No unitary theory of how the cortex works exists, although it is clear that understanding its microcircuit is necessary to discern its computational capabilities. Anatomical and physiological studies have suggested that the connectivity of the cortical microcircuitry is complex, but not random. It is clear that inhibitory neurons target their connections extremely specifically. Less is known about the pyramidal-pyramidal connections that constitutes the `skeleton' of the cortex. A variety of anatomical and physiological experiments have highlighted the fact that there is heterogeneity among pyramidal cells in both their morphologies and response properties. It is conceivable that their interconnections are also precise and that the neocortex, like the retina, may be composed of dozens or hundreds of classes of neurons with specialized circuit functions. A major limitation of past work using traditional in vivo and in vitro recording techniques is the difficulty in revealing functional connections in large numbers. Furthermore, it is difficult to know with a high degree of certainty what type of neuron is being recorded from, for instance; is it a local circuit neuron or is it a cortical-fugal neuron? Finally, it is difficult to determine what network a specific neuron is incorporated within. These limitations have slowed our understanding of the connectivity patterns of the cortical microcircuit. To overcome these limitations fluorescent beads will be retrogradely transported back to independent networks of pyramidal cells located in layer VI of the primary somatosensory cortex, following injections into the ipsilateral motor cortex and/or the ventral posterior nucleus of the thalamus of mice. Fluorescent optics will facilitate the targeting of specific classes of neurons. Thalamocortical slices will be prepared from these animals for electrophysiological recordings and optical imaging of network activity using calcium indicators. By combining optical, fluorescent and electrophysiological techniques we will be able to both image the activity of an entire local circuit as well as record the activity of individual elements in the circuit during ongoing and stimulus driven network activity. The results of this study will further our understanding of the different classes of pyramidal cells and how they are connected as well as how the circuits anatomical connectivity affects is functionality. Gaining insight into the functioning of the cortical circuit can pave the way towards an understanding of fundamental physiological processes involved in information processing and how the disruption of the microcircuit by pathophysiological processes (e.g. schizophrenia) works, and thus possibly lead towards the development of new therapeutic interventions.
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