Distinct subtypes of inhibitory interneuron are known to shape diverse rhythmic activities in the cortex, but how they interact to orchestrate specific band activity remains largely unknown. By recording optogenetically tagged interneurons of specific subtypes in the primary visual cortex of behaving mice, we show that spiking of somatostatin (SOM)- and parvalbumin (PV)-expressing interneurons preferentially correlates with cortical beta and gamma band oscillations, respectively. Suppression of SOM cell spiking reduces the spontaneous low-frequency band (<30-Hz) oscillations and selectively reduces visually induced enhancement of beta oscillation. In comparison, suppressing PV cell activity elevates the synchronization of spontaneous activity across a broad frequency range and further precludes visually induced changes in beta and gamma oscillations. Rhythmic activation of SOM and PV cells in the local circuit entrains resonant activity in the narrow 5- to 30-Hz band and the wide 20- to 80-Hz band, respectively. Together, these findings reveal differential and cooperative roles of SOM and PV inhibitory neurons in orchestrating specific cortical oscillations.

The lengths of von Willebrand factor (VWF) concatamers correlate with hemostatic potency. After secretion in plasma, length is regulated by hydrodynamic shear force-dependent unfolding of the A2 domain, which is then cleaved by a specific protease. The 1.9-Å crystal structure of the A2 domain demonstrates evolutionary adaptations to this shear sensor function. Unique among VWF A (VWA) domains, A2 contains a loop in place of the ␣4 helix, and a cis-proline. The central ␤4-strand is poorly packed, with multiple side-chain rotamers. The Tyr-Met cleavage site is buried in the ␤4-strand in the central hydrophobic core, and the Tyr structurally links to the C-terminal ␣6-helix. The ␣6-helix ends in 2 Cys residues that are linked by an unusual vicinal disulfide bond that is buried in a hydrophobic pocket. These features may narrow the force range over which unfolding occurs and may also slow refolding. Von Willebrand disease mutations, which presumably lower the force at which A2 unfolds, are illuminated by the structure. Although there is great interest in the use of mechanical force to unfold protein domains and gain insights into the structural factors that govern mechanical stability, there are, as yet, few structural studies on domains that have evolved to unfold in the course of normal physiology and serve as biological force sensors (1). Von Willebrand factor (VWF) senses the high vascular flow rates (shear) found at sites of arterial bleeding and cross-links platelets to plug vessels in hemostasis. High shear activates binding of the A1 domain in VWF to platelet GPIb, and facilitates binding of VWF through its A3 domain to subendothelial collagen exposed at sites of vessel injury. The force-sensing A2 domain is located in between the A1 and A3 domains (2, 3).Hemostatic potential greatly increases with VWF length, which is tightly regulated in vivo (2, 3). The 240,000-Mr VWF monomer is dimerized through disulfide bonds at its C terminus (COC) and then concatenated through specific disulfide bonds at its N terminus (NON) into multimers up to Ϸ50 ϫ 10 6 Mr (Fig. 1A). VWF is stored in granules in endothelial cells in an ultralarge form (ULVWF) that is secreted in response to thrombogenic stimuli. Within 2 hours after release into the circulation, ULVWF is converted by ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) to smaller multimers with a wide range of lengths that are characteristic of the circulating pool of VWF (4). Cleavage depends on hydrodynamic shear force, and occurs within the A2 domain at its Tyr 1605 -Met 1606 bond. Genetic or acquired deficiency of ADAMTS13 causes thrombotic thrombocytopenic purpura, a life-threatening disease in which microvascular thrombi form in arterioles and capillaries. Conversely, mutations in the A2 domain cause a bleeding disorder, type 2A von Willebrand disease (VWD), in which VWF multimers are smaller in size than in healthy individuals and have less hemostatic potential (2, 5, 6).Models of the A2 domain suggest that the ADAMTS...

The surface of the cornea consists of a unique type of non-keratinized epithelial cells arranged in an orderly fashion, and this is essential for vision by maintaining transparency for light transmission. Cornea epithelial cells (CECs) undergo continuous renewal from limbal stem or progenitor cells (LSCs)1,2, and deficiency in LSCs or corneal epithelium—which turns cornea into a non-transparent, keratinized skin-like epithelium—causes corneal surface disease that leads to blindness in millions of people worldwide3. How LSCs are maintained and differentiated into corneal epithelium in healthy individuals and which key molecular events are defective in patients have been largely unknown. Here we report establishment of an in vitro feeder-cell-free LSC expansion and three-dimensional corneal differentiation protocol in which we found that the transcription factors p63 (tumour protein 63) and PAX6 (paired box protein PAX6) act together to specify LSCs, and WNT7A controls corneal epithelium differentiation through PAX6. Loss of WNT7A or PAX6 induces LSCs into skin-like epithelium, a critical defect tightly linked to common human corneal diseases. Notably, transduction of PAX6 in skin epithelial stem cells is sufficient to convert them to LSC-like cells, and upon transplantation onto eyes in a rabbit corneal injury model, these reprogrammed cells are able to replenish CECs and repair damaged corneal surface. These findings suggest a central role of the WNT7A–PAX6 axis in corneal epithelial cell fate determination, and point to a new strategy for treating corneal surface diseases.

In vivo induction of non-neuronal cells into neurons by transcription factors offers

Highlights d Functionally distinct neuronal ensembles exist within a single memory engram d Fosand Npas4-dependent ensembles undergo distinct synaptic modifications after CFC d Fosand Npas4-dependent ensembles drive memoryguided behaviors in opposite directions d Memory generalization and discrimination, respectively, require MEC and CCK + interneurons

Lateral and medial parts of entorhinal cortex (EC) convey nonspatial 'what' and spatial 'where' information, respectively, into hippocampal CA1, via both the indirect EC layer 2→ hippocampal dentate gyrus→CA3→CA1 and the direct EC layer 3→CA1 paths. However, it remains elusive how the direct path transfers distinct information and contributes to hippocampal learning functions. Here we report that lateral EC projection neurons selectively form direct excitatory synapses onto a subpopulation of morphologically complex, calbindin-expressing pyramidal cells (PCs) in the dorsal CA1 (dCA1), while medial EC neurons uniformly innervate all dCA1 PCs. Optogenetically inactivating the distinct lateral EC-dCA1 connections or the postsynaptic dCA1 calbindin-expressing PC activity slows olfactory associative learning. Moreover, optetrode recordings reveal that dCA1 calbindin-expressing PCs develop more selective spiking responses to odor cues during learning. Thus, our results identify a direct lateral EC→dCA1 circuit that is required for olfactory associative learning.

Mutations in the X-linked gene encoding the transcriptional modulator methyl-CpG-binding protein 2 (MeCP2) impair postnatal development of the brain. Here we use neuronal-type specific gene deletion in mice to show that conditional Mecp2 deletion in GABAergic parvalbumin-expressing (PV) cells (PV-Mecp2 À /y ) does not cause most Rett-syndrome-like behaviours, but completely abolishes experience-dependent critical period plasticity of primary visual cortex (V1) that develops normal visual functions. However, selective loss of Mecp2 in GABAergic somatostatin-expressing cells or glutamatergic pyramidal cells does not affect the critical period plasticity. MeCP2-deficient PV cells exhibit high intrinsic excitability, selectively reduced efficacy of recurrent excitatory synapses in V1 layer 4 circuits, and decreased evoked visual responses in vivo. Enhancing cortical gamma-aminobutyric acid (GABA) inhibition with diazepam infusion can restore critical period plasticity in both young and adult PV-Mecp2 À /y mice. Thus, MeCP2 expression in inhibitory PV cells during the critical period is essential for local circuit functions underlying experiencedependent cortical plasticity.

The basolateral amygdala (BLA) and ventral hippocampal CA1 (vCA1) are cellularly and functionally diverse along their anterior-posterior and superficial-deep axes. Here, we find that anterior BLA (aBLA) and posterior BLA (pBLA) innervate deep-layer calbindin1-negative (Calb1−) and superficial-layer calbindin1-positive neurons (Calb1+) in vCA1, respectively. Photostimulation of pBLA-vCA1 inputs has an anxiolytic effect in mice, promoting approach behaviours during conflict exploratory tasks. By contrast, stimulating aBLA-vCA1 inputs induces anxiety-like behaviour resulting in fewer approaches. During conflict stages of the elevated plus maze task vCA1 Calb1+ neurons are preferentially activated at the open-to-closed arm transition, and photostimulation of vCA1 Calb1+ neurons at decision-making zones promotes approach with fewer retreats. In the APP/PS1 mouse model of Alzheimer's disease, which shows anxiety-like behaviour, photostimulating the pBLA-vCA1 Calb1+ circuit ameliorates the anxiety in a Calb1-dependent manner. These findings suggest the pBLA-vCA1 Calb1+ circuit from heterogeneous BLA-vCA1 connections drives approach behaviour to reduce anxiety-like behaviour.