| Summary: | <p>Information processing in the mammalian cortex is achieved via a precise arrangement of synaptic connections between different neuronal subtypes. The excitatory neurons of the cortex are arranged in a laminar manner across six layers and form specific intralaminar and translaminar connections with one another. In addition, these excitatory neurons interact with a series of inhibitory interneuron subtypes, such that the relative levels and timing of excitatory and inhibitory synaptic transmission determine how information is processed by the cortical network. This thesis examines the translaminar signaling from layer 5 (L5) to layer 2/3 (L2/3) of cortex. Considered the principal output layer, L5 is populated by intratelencephalic (IT) and pyramidal tract (PT) pyramidal neurons, which form long-range projections to other cortical and subcortical regions, respectively. These long-range axons of L5 pyramidal neurons also branch locally and form ascending collaterals that extend to more superficial layers, including L2/3. An unanswered question in the field, is what sorts of translaminar signals do these local collaterals deliver.</p>
<p>I have used the mouse somatosensory cortex in order to address this question. In the first series of experiments, transgenic mice expressing the optogenetic activator, channelrhodopsin-2 (ChR2), were used to stimulate a non-specific population of L5 pyramidal neurons. This was shown to elicit both monosynaptic excitation and disynaptic inhibition within L2/3, and to modulate the action potential activity of L2/3 pyramidal neurons in vitro and in vivo. I then used retrograde labelling strategies in order to distinguish between IT and PT L5 pyramidal neurons, revealing that the long-range target of the L5 neuron is associated with morphological differences in its local ascending collaterals. To investigate whether the functional consequences, I used a retrograde viral system to deliver ChR2 to each of the projection-defined L5 subtypes. Patch clamp recordings revealed that IT L5 neurons evoked robust excitation but little inhibition within L2/3. In contrast, PT L5 neurons elicited significant levels of synaptic inhibition, which was shown to result from the selective targeting of L2/3 parvalbumin-expressing interneurons. Finally, I was able to demonstrate that this differential recruitment of excitation and inhibition by the L5 subtypes results in opposing modulatory effects upon L2/3 pyramidal neuron activity in vitro and during sensory-driven input in vivo.</p>
<p>The work supports growing evidence that L5 plays a significant role in modulating ongoing local cortical activity. It also suggests that projection-defined L5 subpopulations provide opposing translaminar signals to L2/3, which could be important for sensory processing, sensory-motor integration and synaptic plasticity.</p>
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