Understanding how cortical activity generates sensory perceptions requires a detailed dissection of the function of cortical layers. Despite our relatively extensive knowledge of their anatomy and wiring, we have a limited grasp of what each layer contributes to cortical computation. We need to develop a theory of cortical function that is rooted solidly in each layer’s component cell types and fine circuit architecture and produces predictions that can be validated by specific perturbations. Here we briefly review the progress toward such a theory and suggest an experimental road map toward this goal. We discuss new methods for the all-optical interrogation of cortical layers, for correlating in vivo function with precise identification of transcriptional cell type, and for mapping local and long-range activity in vivo with synaptic resolution. The new technologies that can crack the function of cortical layers are finally on the immediate horizon.

Main Text

“At present we have no direct evidence on how the cortex transforms the incoming visual information. Ideally, one should determine the properties of a cortical cell, and then examine one by one the receptive fields of all the afferents projecting upon that cell.”– Hubel and Wiesel, 1962, Journal of Physiology

A primary goal of cortical physiology is to explain how the cortex transforms incoming information to generate perceptions. More than half a century has passed since the above statement was made, but a detailed understanding of the mechanisms that mediate cortical transformations across the cortical layers remains remarkably incomplete. However, recent technological advances finally allow execution of the experiment that Hubel and Wiesel prescribed, as well as many other sophisticated assays that can overcome this conceptual challenge. First, we briefly review how existing data have motivated the available theories regarding the function of cortical layers, primarily with respect to sensory transformations. Next, we highlight the key data we lack that could confirm or invalidate these models or motivate new ones. Finally, we propose the new technologies and experiments that are needed to obtain the data that will allow us to arrive at a much more mechanistic, circuit-driven theory for the unique contributions of layer-specific circuits in sensory perception.

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Shepherd G.M. The neocortical circuit: themes and variations. More recently, the canonical circuit has been conceptualized less in terms of layers and more in terms of cell types that occupy specific layers and are connected by cell type-specific pathways (). Although layer and cell type are closely intertwined, this is an important distinction. A layer-centric view implicitly assumes that at least some basic cortical computations can be understood mechanistically by analyzing the activity of neurons in just one layer; the cell type-centered view assumes that we cannot achieve a satisfactory understanding of any computation without taking into account coordinated activity across multiple layers. Although we retain layer as an organizing concept for the purposes of this perspective, we note that the experimental approaches we outline below apply equally well to cracking the function of cortical sublaminae or cortical cell types. Nevertheless, we argue that the cortical literature regarding layers supports the notion that, in a specific set of contexts, ensembles of neurons located in just one layer are sufficient to mediate key cortical computations, such as fast sensorimotor transformations. However, under most conditions, such as those involved in generating conscious sensory percepts, the basic unit of cortical computation is a neuronal ensemble spread across multiple layers or spread across multiple layers and cortical areas.

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Svoboda K. The subcellular organization of neocortical excitatory connections. We suspect that neural ensembles composed of co-active neurons distributed across layers are the major substrate of cortical computation. However, the selective effects of the perturbation experiments described above imply that, under certain circumstances, layers can have specific and identifiable effects on their local cortical circuit and even on behavioral output. These studies raise the possibility that, for particular computations or behaviors, only one cortical layer, or even a specific subtype within a single cortical layer, might be sufficient to execute the task based on its afferent input and its long-range output. This is surely possible from an anatomical perspective. Principal neurons across all layers receive bottom-up thalamic inputs, most receive top-down cortical input from higher cortical areas, and many project a long-range axon out of the cortex. If any of their long-range input pathways are sufficiently strong (or strong when provided in combination), many cortical neurons could operate independently of their local circuits. There is evidence to support this notion. A recent study identified a compact long-range circuit from the whisker to the barrel cortex in which a subset of L5 PCs projects directly back to pre-motor spinal trigeminal neurons that control whisker retraction (). Because L5 neurons can be driven directly by the thalamus () or through the conjunction of bottom-up and top-down motor cortical input (), under specific conditions, motor control of certain features of whisking (e.g., touch-induced pumps;) might only require activation of these specific L5 PCs. If so, it would represent a complete sensorimotor behavior that could be cortically dependent but does not require activity of superficial layers at all. In a similar vein, because other projection subtypes of L5 PCs target various sub-cortical nuclei, we suspect that there might exist a suite of reflex-like sensorimotor behaviors that require minimal local processing within the primary sensory cortex and that, instead, rely exclusively on the integration of various long-range pathways to specific subtypes of L5 PCs. Conversely, because L2/3 PCs across species receive direct thalamic input and project to downstream cortical areas (), various types of sensory computations in L2/3 could also be executed with limited involvement of L4–L6. Taken together, this suggests that there may be specific behaviors and cortical computations that can depend on a single layer or even a single cell type within one layer.