Bilateral widefield calcium imaging reveals circuit asymmetries and lateralized functional activation of the mouse auditory cortex

Significance

Coordinated functioning of the two cortical hemispheres is crucial for perception, and neurodevelopmental disorders are associated with altered functional connectivity. The human auditory cortex shows functional lateralization, but the origin of lateralization is unknown. We developed a widefield microscope enabling bilateral calcium imaging on large areas of both temporal lobes in mice. Our results show that while auditory cortex topography is highly symmetrical, higher-order area A2 shows functional lateralization to high-frequency tones and adult vocalizations. Functional circuit analysis shows that A2 has lower and asymmetric hemispheric functional connections, which might underlie the functional lateralization. Lack of sound experiences prevents the development of asymmetric connections. Therefore, altered interhemispheric connections should be considered when treating developmental sensory disorders such as congenital deafness.

Abstract

Coordinated functioning of the two cortical hemispheres is crucial for perception. The human auditory cortex (ACx) shows functional lateralization with the left hemisphere specialized for processing speech, whereas the right analyzes spectral content. In mice, virgin females demonstrate a left-hemisphere response bias to pup vocalizations that strengthens with motherhood. However, how this lateralized function is established is unclear. We developed a widefield imaging microscope to simultaneously image both hemispheres of mice to bilaterally monitor functional responses. We found that global ACx topography is symmetrical and stereotyped. In both male and virgin female mice, the secondary auditory cortex (A2) in the left hemisphere shows larger responses than right to high-frequency tones and adult vocalizations; however, only virgin female mice show a left-hemisphere bias in A2 in response to adult pain calls. These results indicate hemispheric bias with both sex-independent and -dependent aspects. Analyzing cross-hemispheric functional correlations showed that asymmetries exist in the strength of correlations between DM-AAF and A2-AAF, while other ACx areas showed smaller differences. We found that A2 showed lower cross-hemisphere correlation than other cortical areas, consistent with the lateralized functional activation of A2. Cross-hemispheric activity correlations are lower in deaf, otoferlin knockout (OTOF ^−/−) mice, indicating that the development of functional cross-hemispheric connections is experience dependent. Together, our results reveal that ACx is topographically symmetric at the macroscopic scale but that higher-order A2 shows sex-dependent and independent lateralized responses due to asymmetric intercortical functional connections. Moreover, our results suggest that sensory experience is required to establish functional cross-hemispheric connectivity.