Upon entering the cerebral cortex sensory information spreads through six different horizontal neuronal layers that are interconnected by vertical axonal projections. It is believed that through these projections layers can influence each other’s response to sensory stimuli, yet the specific role played by each layer in cortical processing is still poorly understood. Here we show that layer 6 in the primary visual cortex of the mouse plays a crucial role in controlling the gain of visually evoked activity in neurons of the upper layers without, however, changing their tuning to orientation. This gain modulation results from the coordinated action of layer 6 projections to superficial layers and deep projections to the thalamus, with a substantial role of the former circuit. This study thus establishes L6 as a major mediator of cortical gain modulation and suggests it could be a node through which convergent inputs from several brain areas can regulate the earliest steps of cortical visual processing.

SUMMARYOlfactory signals are transduced by a large family of odorant receptor proteins, each of which corresponds to a unique glomerulus in the first olfactory relay of the brain. Cross-talk between glomeruli has been proposed to be important in olfactory processing, but it is not clear how these interactions shape the odor responses of second-order neurons. In the Drosophila antennal lobe (a region analogous to the vertebrate olfactory bulb), we selectively remove most inter-glomerular input to identified second-order olfactory neurons. We find this broadens the odor tuning of these neurons, implying that inter-glomerular inhibition dominates over inter-glomerular excitation. The strength of this inhibitory signal scales with total feedforward input to the entire antennal lobe, and has similar tuning in different glomeruli. A substantial portion of this inter-glomerular inhibition acts at a presynaptic locus, and our results imply this is mediated by both GABA A and GABA B receptors on the same nerve terminal.A sensory stimulus generally triggers activity in multiple neural processing channels, each of which carries information about some feature of that stimulus. The concept of a processing channel has a particularly clear anatomical basis in the first relay of the olfactory system, which is typically divided into glomerular compartments. Each glomerulus receives input from many first-order olfactory receptor neurons (ORNs), all of which express the same odorant receptor. Each second-order neuron receives direct ORN input from a single glomerulus, and thus all the first-and second-order neurons corresponding to a glomerulus constitute a discrete processing channel. An odorant typically triggers activity in multiple glomeruli, and local interneurons that interconnect glomeruli provide a substrate for cross-talk between channels.The Drosophila antennal lobe is a favored model for investigating olfactory processing because it contains only ~50 glomeruli 1 , each of which corresponds to an identified type of ORN and an identified type of postsynaptic projection neuron (PN) 2-5. Several recent studies of the Drosophila antennal lobe have produced divergent views of the relative importance of interglomerular connections. One model proposes that PN odor responses are almost completely determined by feedforward excitation6 , 7. This model ascribes little importance to cross-talk between glomerular processing channels. An alternative model proposes that inter-glomerular connections make an important contribution to shaping PN odor responses8 -12 . However, thisCorrespondence and requests for materials should be addressed to R.I.W. (rachel_wilson@hms.harvard.edu). Full Methods are available in the online version of the paper at www.nature.com/nature.Supplementary Information is linked to the online version of the paper at www.nature.com/nature. A figure summarizing the main result of this paper is available in Supplementary Information. . This could reflect a purely intra-glomerular nonlinear process, such as short-term...

Highlights d Two network models of the mouse primary visual cortex are developed and released d One uses compartmental-neuron models and the other pointneuron models d The models recapitulate observations from in vivo experimental data d Simulations identify experimentally testable predictions about cortex circuitry

In many regions of the visual system, the activity of a neuron is normalized by the activity of other neurons in the same region. Here we show that a similar normalization occurs during olfactory processing in the Drosophila antennal lobe. We exploit the orderly anatomy of this circuit to independently manipulate feedforward and lateral input to second-order projection neurons (PNs). Lateral inhibition increases the level of feedforward input needed to drive PNs to saturation, and this normalization scales with the total activity of the olfactory receptor neuron (ORN) population. Increasing total ORN activity also makes PN responses more transient. Strikingly, a model with just two variables (feedforward and total ORN activity) accurately predicts PN odor responses. Finally, we show that discrimination by a linear decoder is facilitated by two complementary transformations: the saturating transformation intrinsic to each processing channel boosts weak signals, while normalization helps equalize responses to different stimuli.