Cortical Circuits of Interhemispheric Communication

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PROJECT SUMMARY/ABSTRACT Auditory interhemispheric communication remains a neurobiological mystery. Processing of auditory signals at cortical level requires coordination of sensory input between the two hemispheres. Abnormal circuitry underlying interhemispheric communication may explain deficits in communication and social behavior observed in autism spectrum disorders (ASD) and auditory verbal hallucinations (AVH), one of the most prominent symptoms in schizophrenia, affecting approximately 70% of patients. However, the organization and functionality of these circuits remain unclear. The inferior colliculus (IC) is a major processing center in the auditory pathways. Particularly, IC is a major center for processing of information used in localizing sound sources in space. Importantly, a subset of neurons, in the layer 5 of the auditory cortex (AC), project to the IC (CCol neurons) and to the contralateral AC (CCort neurons). Callosal projections to layer 5 cells originate in layer 2/3 and layer 5 of AC. Determining the functional effects and connectivity of layer 2/3 and layer 5 callosal projections onto these neurons is critical for understanding auditory processing at both cortical and subcortical levels. The objective of this proposal is to dissect if both layers have a similar effect on the contralateral cortex. In particular, both layers could excite CCol and inhibit CCort neurons. Alternatively, layer-specific stimulation could have differing effects on layer 5 neurons, and a different balance of input to CCol and CCort neurons contributing to different responses of these neurons. Our findings will establish a new framework for understanding the roles of layer 2/3 and layer 5 callosal projections in the modulation of cortical and subcortical auditory processing required for the continuity of sensory input between the two hemispheres. The aims of this proposal are (1) Determine the synaptic organization of layer 2/3 and layer 5 callosal projections onto CCort and CCol neurons in AC. (2) Establish the synaptic mechanism of callosal disynaptic inhibition onto CCort and CCol neurons in AC. (3) Determine tone-evoked responses in AC during optogenetic stimulation of layer 2/3 and layer 5 callosal projections. The approach for addressing these aims will use the mouse as the experimental model, retrograde and optogenetic labeling, specific opto-physiological recordings of synaptic connectivity in defined pathways, and in vivo electrophysiology to quantify the excitatory and inhibitory component of the interlaminar, intralaminar, and the subclass projection specificity of the neurons recruited during photoactivation of the callosal projections. Discoveries from this work will be significant because they will provide foundational knowledge regarding circuit and functional aspects of AC neurons contributing to interhemispheric communication which is clinically relevant to cortical neuropathologies.