Functional Role of Cortical Circuits in Sensory-Guided Behaviors

Comprised of six distinct layers, the neocortex is a key brain structure for many of our advanced cognitive abilities, ranging from sensation to decision making to movement. Each layer contains distinct cell types differing in their genes, biophysical properties, and connectivity with other parts of the brain. Yet how these diverse cortical layers and cell types contribute to any given behavior remains unresolved. Because sensory cortical areas have stereotyped anatomies and the six cortical layer organization is highly conserved across all mammals, understanding computations in one cortical area, such as the mouse barrel cortex within the primary somatosensory cortex, may inform us of computations being performed by similar microcircuits across the neocortex. This thesis is an investigation of cortical circuit function as it pertains to (1) distinct functional role of cortical layers in sensory discrimination, (2) increased cortical connectivity enhancing sensation, (3) a cautionary tale of selecting appropriate transgenic mouse lines for in vivo manipulations, (4) and the role of proprioception in the establishment of long-term visuospatial memory. Investigating layer-specific function first requires a cortex-dependent task. Yet, despite our extensive understanding of cortical anatomy and physiology, the contributions of different cortical layers to behaviors remain unknown. We developed a two-alternative forced choice paradigm in which head-fixed mice use a single whisker to either discriminate textures of parametrically varied roughness or detect the same textured surfaces. Lesioning barrel cortex revealed that texture discrimination, but not detection, was cortex-dependent. Paralyzing the whisker pad demonstrated that passive can rival active perception and cortical dependence is not movement-related. Transgenic Cre lines were used to target inhibitory opsins to excitatory cortical neurons of specific layers for selective perturbations. Discrimination required all layers, but deep layers (layers 5/6) were critical for accumulation of sensory evidence whereas superficial layers (layers 2-4) appeared to provide top-down motor input. This thesis shows that superficial layers contextually interpret sensory evidence to modify the deep layer output in behaviorally appropriate ways. Having identified distinct functional roles of deep and superficial layers through perturbation experiments, we next sought to enhance texture task performance by selectively activating texture-encoding neurons. However, given that all layers are involved in the task and the technical difficulties of targeting stimulus-selective cells, we turned to humanized mouse model (SRGAP2C) that exhibits increased local and long-range cortico-cortical connections and increased response selectivity to whisker stimulations in layer 2/3 pyramidal neurons in the barrel cortex. This thesis demonstrates that the increased cortico-cortical connectivity not only improved sensory coding accuracy in SRGAP2C mice, but the humanized animals trained on the texture discrimination task displayed increased learning rate and were more likely to learn the task compared to control. Next, we provide a cautionary tale of selecting appropriate mouse lines for in vivo experiments. Advances in optogenetics and transgenic Cre mouse lines enable us to probe the function of genetically defined neuronal populations, but transgene expression can adversely affect cell health and cause neural and behavioral abnormalities. We discovered learning impairments specific to cortex-dependent sensory discrimination behaviors in Emx1-Cre animals that express inhibitory opsins in excitatory cortical neurons. We suggest Nex1-Cre line as a more reliable and robust alternative to Emx1-Cre animals. The thesis highlights the importance of characterizing and selecting appropriate transgenic lines for in vivo optogenetic experiments. In addition to touch, the primary somatosensory cortex processes other tactile information including temperature, pain, and proprioception. Creating a spatially accurate representation of the visual world requires transforming spatially inaccurate visual information coming from a constantly moving retina into a representation that can be used for accurate perception and action. This thesis shows that the dysgranular zone, the proprioceptive region of the primary somatosensory cortex, is required to establish long-term visuospatial memory