Accurate perception of the environment is a constructive process that requires integration of external bottom-up sensory signals with internally-generated top-down information reflecting past experiences and current aims. Decades of work have elucidated how sensory neocortex processes physical stimulus features. In contrast, examining how memory-related-top-down information is encoded and integrated with bottom-up signals has long been challenging. Here, I will discuss our recent work pinpointing the outermost layer 1 of neocortex as a central hotspot for processing of experience-dependent top-down information threat during perception, one of the most fundamentally important forms of sensation.

Transcriptomics has revealed that cortical inhibitory neurons exhibit a great diversity of fine molecular subtypes, but it is not known whether these subtypes have correspondingly diverse activity patterns in the living brain. We show that inhibitory subtypes in primary visual cortex (V1) have diverse correlates with brain state, but that this diversity is organized by a single factor: position along their main axis of transcriptomic variation. We combined in vivo 2-photon calcium imaging of mouse V1 with a novel transcriptomic method to identify mRNAs for 72 selected genes in ex vivo slices. We classified inhibitory neurons imaged in layers 1-3 into a three-level hierarchy of 5 Subclasses, 11 Types, and 35 Subtypes using previously-defined transcriptomic clusters. Responses to visual stimuli differed significantly only across Subclasses, suppressing cells in the Sncg Subclass while driving cells in the other Subclasses. Modulation by brain state differed at all hierarchical levels but could be largely predicted from the first transcriptomic principal component, which also predicted correlations with simultaneously recorded cells. Inhibitory Subtypes that fired more in resting, oscillatory brain states have less axon in layer 1, narrower spikes, lower input resistance and weaker adaptation as determined in vitro and express more inhibitory cholinergic receptors. Subtypes firing more during arousal had the opposite properties. Thus, a simple principle may largely explain how diverse inhibitory V1 Subtypes shape state-dependent cortical processing.

Arguably one of the biggest mysteries in neuroscience is how the brain stores long-term memories. The major challenge for investigating the neural circuit underlying memory formation in the neocortex is the distributed nature of the resulting memory trace throughout the cortex. Here, we used a new behavioral paradigm that enabled us to generate memory traces in a specific cortical location and to specifically examine the mechanisms of memory formation in that region. We found that medial-temporal inputs arrive in neocortical layer 1 where the apical dendrites of cortical pyramidal neurons predominate. These dendrites have active properties that make them sensitive to contextual inputs from other areas that also send axons to layer 1 around the cortex. Blocking the influence of these medial-temporal inputs prevented learning and suppressed resulting dendritic activity. We conclude that layer 1 is the locus for hippocampal-dependent memory formation in the neocortex and propose that this process enhances the sensitivity of the tuft dendrites to contextual inputs.