Early sensory experience instructs the maturation of neural circuitry in cortex 1,2. This has been extensively studied in the primary visual cortex where loss of vision to one eye permanently degrades cortical responsiveness to that eye 3,4, a phenomenon known as ocular dominance plasticity (ODP). Cortical inhibition mediates this process 4-6, but the precise role of specific classes of inhibitory neurons in ODP is controversial. Here we report that evoked firing rates of binocular excitatory neurons in primary visual cortex immediately drop by half when vision is restricted to one eye, but gradually return to normal over the following 24 hours, despite the fact that vision remains restricted to one eye. This restoration of binocular-like excitatory firing rates following monocular deprivation results from a rapid, though transient reduction in the firing rates of fast-spiking, parvalbumin-positive (PV) interneurons, which in turn can be attributed to a decrease in local excitatory circuit input onto PV interneurons. This reduction in PV cell evoked responses following monocular lid suture is restricted to the critical period for ODP and appears to be necessary for subsequent shifts in excitatory ODP. Pharmacologically enhancing inhibition at the time of sight deprivation blocks ODP and, conversely, pharmaco-genetic reduction of PV cell firing rates can extend the critical period for ODP. These findings define the microcircuit changes initiating competitive plasticity during critical periods of cortical development. Moreover, they show that the restoration of evoked firing rates of L2/3 pyramidal neurons by PV-specific disinhibition is a key step in the progression of ocular dominance plasticity.

The primary visual cortex of higher mammals is organized into two-dimensional maps, where the preference of cells for stimulus parameters is arranged regularly on the cortical surface. In contrast, the preference of neurons in the rodent appears to be arranged randomly, in what is termed a salt-and-pepper map. Here we revisited the spatial organization of receptive fields in mouse primary visual cortex by measuring the tuning of pyramidal neurons in the joint orientation and spatial frequency domain. We found that the similarity of tuning decreases as a function of cortical distance, revealing a weak but statistically significant spatial clustering. Clustering was also observed across different cortical depths, consistent with a columnar organization. Thus, the mouse visual cortex is not strictly a salt-and-pepper map. At least on a local scale, it resembles a degraded version of the organization seen in higher mammals, hinting at a possible common origin.

Key pointsr Using functional mapping assays, we conducted a quantitative assessment of both excitatory and inhibitory synaptic laminar connections to excitatory neurons in layers 2/3-6 of the mouse visual cortex (V1).r Laminar-specific synaptic wiring diagrams of excitatory neurons were constructed on the basis of circuit mapping.r The present study reveals that that excitatory and inhibitory synaptic connectivity is spatially balanced across excitatory neuronal networks in V1. AbstractIn the mammalian neocortex, excitatory neurons provide excitation in both columnar and laminar dimensions, which is modulated further by inhibitory neurons. However, our understanding of intracortical excitatory and inhibitory synaptic inputs in relation to principal excitatory neurons remains incomplete, and it is unclear how local excitatory and inhibitory synaptic connections to excitatory neurons are spatially organized on a layer-by-layer basis. In the present study, we combined whole cell recordings with laser scanning photostimulation via glutamate uncaging to map excitatory and inhibitory synaptic inputs to single excitatory neurons throughout cortical layers 2/3-6 in the mouse primary visual cortex (V1). We find that synaptic input sources of excitatory neurons span the radial columns of laminar microcircuits, and excitatory neurons in different V1 laminae exhibit distinct patterns of layer-specific organization of excitatory inputs. Remarkably, the spatial extent of inhibitory inputs of excitatory neurons for a given layer closely mirrors that of their excitatory input sources, indicating that excitatory and inhibitory synaptic connectivity is spatially balanced across excitatory neuronal networks. Strong interlaminar inhibitory inputs are found, particularly for excitatory neurons in layers 2/3 and 5. This differs from earlier studies reporting that inhibitory cortical connections to excitatory neurons are generally localized within the same cortical layer. On the basis of the functional mapping assays, we conducted a quantitative assessment of both excitatory and inhibitory synaptic laminar connections to excitatory cells at single cell resolution, establishing precise layer-by-layer synaptic wiring diagrams of excitatory neurons in the visual cortex. Abbreviations aCSF, artificial cerebrospinal fluid; DAPI, 4 -6-diamidino-2-phenylindole; LSPS, laser scanning photostimulation; V1, primary visual cortex.

The development of modern neuroscience tools is critical for deciphering brain circuit organization and function. An important aspect for technical development is to enhance each technique's advantages and compensate for limitations. We developed a high-precision and fast functional mapping technique in brain slices that incorporates the spatial precision of activation that can be achieved by laser-scanning photostimulation with rapid and high-temporal resolution assessment of evoked network activity that can be achieved by voltage-sensitive dye imaging. Unlike combination of whole cell recordings with photostimulation for mapping local circuit inputs to individually recorded neurons, this innovation is a new photostimulation-based technique to map cortical circuit output and functional connections at the level of neuronal populations. Here we report on this novel technique in detail and show its effective applications in mapping functional connections and circuit dynamics in mouse primary visual cortex and hippocampus. Given that this innovation enables rapid mapping and precise evaluation of cortical organization and function, it can have broad impacts in the field of cortical circuitry.

Key pointsr Melanin-concentrating hormone (MCH) neurons express histamine-3 receptor (H3R) mRNA but not histamine-1 (H1R) or histamine-2 (H2R) receptor mRNA.r Histamine inhibits MCH neurons by activating postsynaptic H3R. This effect is mediated through G protein-dependent inwardly rectifying potassium (GIRK) channels.r Histamine may function to silence MCH neurons during wakefulness.Abstract Melanin-concentrating hormone (MCH)-producing neurons are known to regulate a wide variety of physiological functions such as feeding, metabolism, anxiety and depression, and reward. Recent studies have revealed that MCH neurons receive projections from several wake-promoting brain regions and are integral to the regulation of rapid eye movement (REM) sleep. Here, we provide evidence in both rats and mice that MCH neurons express histamine-3 receptors (H3R), but not histamine-1 (H1R) or histamine-2 (H2R) receptors. Electrophysiological recordings in brain slices from a novel line of transgenic mice that specifically express the reporter ZsGreen in MCH neurons show that histamine strongly inhibits MCH neurons, an effect which is TTX insensitive, and blocked by the intracellular presence of GDP-β-S. A specific H3R agonist, α-methylhistamine, mimicks the inhibitory effects of histamine, and a specific neutral H3R antagonist, VUF 5681, blocks this effect. Tertiapin Q (TPQ), a G protein-dependent inwardly rectifying potassium (GIRK) channel inhibitor, abolishes histaminergic inhibition of MCH neurons. These results indicate that histamine directly inhibits MCH neurons through H3R by activating GIRK channels and suggest that that inhibition of the MCH system by wake-active histaminergic neurons may be responsible for silencing MCH neurons during wakefulness and thus may be directly involved in the regulation of sleep and arousal.