Balanced Enhancements of Synaptic Excitation and Inhibition Underlie Developmental Maturation of Receptive Fields in the Mouse Visual Cortex.

Neurons in the developing visual cortex undergo progressive functional maturation as indicated by the refinement of their visual feature selectivity. However, changes of the synaptic architecture underlying the maturation of spatial visual receptive fields (RFs) per se remain largely unclear. Here, loose-patch as well as single-unit recordings in layer 4 of mouse primary visual cortex (V1) of both sexes revealed that RF development following an eye-opening period is marked by an increased proportion of cortical neurons with spatially defined RFs, together with the increased signal-to-noise ratio of spiking responses. By exploring excitatory and inhibitory synaptic RFs with whole-cell voltage-clamp recordings, we observed a balanced enhancement of both synaptic excitation and inhibition, and while the excitatory subfield size remains relatively constant during development, the inhibitory subfield is broadened. This balanced developmental strengthening of excitatory and inhibitory synaptic inputs results in enhanced visual responses, and with a reduction of spontaneous firing rate, contributes to the maturation of visual cortical RFs. Visual deprivation by dark rearing impedes the normal strengthening of excitatory inputs but leaves the apparently normal enhancement of inhibition while preventing the broadening of the inhibitory subfield, leading to weakened RF responses and a reduced fraction of neurons exhibiting a clear RF, compared with normally reared animals. Our data demonstrate that an experience-dependent and coordinated maturation of excitatory and inhibitory circuits underlie the functional development of visual cortical RFs.SIGNIFICANCE STATEMENT The organization of synaptic RFs is a fundamental determinant of feature selectivity functions in the cortex. However, how changes of excitatory and inhibitory synaptic inputs lead to the functional maturation of visual RFs during cortical development remains not well understood. In layer 4 of mouse V1, we show that a coordinated, balanced enhancement of synaptic excitation and inhibition contributes to the developmental maturation of spatially defined visual RFs. Visual deprivation by dark rearing partially interferes with this process, resulting in a relatively more dominant inhibitory tone and a reduced fraction of neurons exhibiting clear RFs at the spike level. These data provide an unprecedented understanding of the functional development of visual cortical RFs at the synaptic level.

Hydrogen Bond Strength-Mediated Self-Assembly of Supramolecular Nanogels for Selective and Effective Cancer Treatment.

This study provides a significant contribution to the development of multiple hydrogen-bonded supramolecular nanocarrier systems by demonstrating that controlling the hydrogen bond strength within supramolecular polymers represents a crucial factor to tailor the drug delivery performance and enhance the effectiveness of cancer therapy. Herein, we successfully developed two kinds of poly(ethylene glycol)-based telechelic polymers Cy-PEG and UrCy-PEG having self-constituted double and quadruple hydrogen-bonding cytosine (Cy) and ureido-cytosine (UrCy) end-capped groups, respectively, which directly assemble into spherical nanogels with a number of interesting physical characteristics in aqueous solutions. The UrCy-PEG nanogels containing quadruple hydrogen-bonded UrCy dimers exhibited excellent long-term structural stability in a serum-containing biological medium, whereas the double hydrogen-bonded Cy moieties could not maintain the structural integrity of the Cy-PEG nanogels. More importantly, after the drug encapsulation process, a series of in vitro experiments clearly confirmed that drug-loaded UrCy-PEG nanogels induced selective apoptotic cell death in cancer cells without causing significant cytotoxicity to healthy cells, while drug-loaded Cy-PEG nanogels exerted nonselective cytotoxicity toward both cancer and normal cells, indicating that increasing the strength of hydrogen bonds in nanogels plays a key role in enhancing the selective cellular uptake and cytotoxicity of drugs and the subsequent induction of apoptosis in cancer cells.

Spatial Asymmetry and Short-Term Suppression Underlie Direction Selectivity of Synaptic Excitation in the Mouse Visual Cortex.

Direction selectivity (DS) of neuronal responses is fundamental for motion detection. With in vivo whole-cell voltage-clamp recordings from layer (L)4 neurons in the mouse visual cortex, we observed a strong correlation between DS and spatial asymmetry in the distribution of excitatory input strengths. This raises an interesting possibility that the latter may contribute to DS. The preferred direction of excitatory input was found from the stronger to weaker side of its spatial receptive field. A simple linear summation of asymmetrically distributed excitatory responses to stationary flash stimuli however failed to predict the correct directionality: it at best resulted in weak DS with preferred direction opposite to what was observed experimentally. Further studies with sequential 2 flash-bar stimulation revealed a short-term suppression of excitatory input evoked by the late bar. More importantly, the level of the suppression positively correlated with the relative amplitude of the early-bar response. Implementing this amplitude-dependent suppressive interaction can successfully predict DS of excitatory input. Our results suggest that via nonlinear temporal interactions, the spatial asymmetry can be transformed into differential temporal integration of inputs under opposite directional movements. This mechanism may contribute to the DS of excitatory inputs to L4 neurons.

17-(Allylamino)-17-Demethoxygeldanamycin Enhances Etoposide-Induced Cytotoxicity via the Downregulation of Xeroderma Pigmentosum Complementation Group C Expression in Human Lung Squamous Cell Carcinoma Cells.

Etoposide (VP16) is a topoisomerase II inhibitor and has been used for the treatment of non-small cell lung cancer (NSCLC). Xeroderma pigmentosum complementation group C (XPC) protein is a DNA damage recognition factor in nucleotide excision repair and involved in regulating NSCLC cell proliferation and viability. Heat shock protein 90 (Hsp90) is a ubiquitous molecular chaperone that is responsible for the stabilization and maturation of many oncogenic proteins. In this study, we report whether Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) enhanced etoposide-induced cytotoxicity in NSCLC cells through modulating the XPC expression. We found that etoposide increased XPC expression in an AKT activation manner in 2 squamous cell carcinoma H1703 and H520 cells. Knockdown of XPC using siRNA or inactivation of AKT by pharmacological inhibitor PI3K inhibitor (LY294002) enhanced the cytotoxic effects of etoposide. In contrast, enforced expression of XPC cDNA or AKT-CA (a constitutively active form of AKT) reduced the cytotoxicity and cell growth inhibition of etoposide. Hsp90 inhibitor 17-AAG enhanced cytotoxicity and cell growth inhibition of etoposide in NSCLC cells, which were associated with the downregulation of XPC expression and inactivation of AKT. Our findings suggested that the Hsp90 inhibition induced XPC downregulation involved in enhancing the etoposide-induced cytotoxicity in H1703 and H520 cells.

Excess incidence and risk factors for recurrent pneumonia in bipolar disorder.

AIM: Patients with bipolar disorder (BD) tend to have poorer outcomes after pneumonia and could have a higher risk for recurrence of pneumonia. We aimed to investigate the incidence and risk factors of recurrent pneumonia in patients with BD. METHODS: In a nationwide cohort of BD patients (derived from the National Health Insurance Research Database in Taiwan) who were hospitalized for pneumonia between 1996 and 2012, we identified 188 patients who developed recurrent pneumonia after a baseline pneumonia episode. Applying risk-set sampling at a 1:2 ratio, 353 matched controls were selected from the study cohort. We used multivariate conditional logistic regression analysis to explore the association between recurrent pneumonia and physical illness, concomitant medications, and psychotropic drugs. RESULTS: The findings showed that the incidence of recurrent pneumonia in BD was 6.60 cases per 100 person-years, which was higher than that in the general population. About 10% (9.24%) of cases with recurrent pneumonia died within 30 days of hospitalization. Patients had increased risk of recurrent pneumonia if they had hypertension, diabetes mellitus, cancer, or asthma. Conversely, psychotropic drugs, both first- and second-generation antipsychotics, which are known to increase susceptibility to baseline pneumonia, were not associated with risk of pneumonia recurrence. CONCLUSION: We found an excess incidence of recurring pneumonia in patients with BD, and this risk was associated with pre-existing medical conditions but not psychotropic agents. Physicians should carefully consider the comorbid medical conditions of patients with BD that could lead to recurrent pneumonia.

Antipsychotic drugs and risk of newly diagnosed tuberculosis in schizophrenia.

AIM: Patients with schizophrenia have a higher incidence of tuberculosis than do people in the general population. Information is limited regarding the association between antipsychotic agents and the risk of tuberculosis in patients with schizophrenia. This exploratory study assessed the risk of tuberculosis among patients with schizophrenia on antipsychotic therapy. METHODS: Among a nationwide schizophrenia cohort derived from the National Health Insurance Research Database in Taiwan (n = 32 399), we identified 284 patients who had developed newly diagnosed tuberculosis after their first psychiatric admission. Ten or fewer matched controls were selected randomly from the cohort for each patient based on risk-set sampling. We categorized exposure to antipsychotic medications by type and defined daily dose. Using multivariate methods, we explored individual antipsychotic agents for the risk of tuberculosis and employed a propensity-scoring method in sensitivity analyses to validate any associations. RESULTS: Among the antipsychotic agents studied and after adjustment for covariates, current use of clozapine was the only antipsychotic agent associated with a 63% increased risk of tuberculosis (adjusted risk ratio = 1.63, P = 0.014). In addition, the association did not show a clear dose-dependent relationship. Clozapine combined with other antipsychotic agents showed a potential synergistic risk for tuberculosis (adjusted risk ratio = 2.30, P = 0.044). CONCLUSION: This exploratory study suggests the potential risk of clozapine on the risk of tuberculosis, especially for those on clozapine in combination with other antipsychotics. Future studies are needed to verify the association.

Synaptic Basis for Differential Orientation Selectivity between Complex and Simple Cells in Mouse Visual Cortex.

In the primary visual cortex (V1), orientation-selective neurons can be categorized into simple and complex cells primarily based on their receptive field (RF) structures. In mouse V1, although previous studies have examined the excitatory/inhibitory interplay underlying orientation selectivity (OS) of simple cells, the synaptic bases for that of complex cells have remained obscure. Here, by combining in vivo loose-patch and whole-cell recordings, we found that complex cells, identified by their overlapping on/off subfields, had significantly weaker OS than simple cells at both spiking and subthreshold membrane potential response levels. Voltage-clamp recordings further revealed that although excitatory inputs to complex and simple cells exhibited a similar degree of OS, inhibition in complex cells was more narrowly tuned than excitation, whereas in simple cells inhibition was more broadly tuned than excitation. The differential inhibitory tuning can primarily account for the difference in OS between complex and simple cells. Interestingly, the differential synaptic tuning correlated well with the spatial organization of synaptic input: the inhibitory visual RF in complex cells was more elongated in shape than its excitatory counterpart and also was more elongated than that in simple cells. Together, our results demonstrate that OS of complex and simple cells is differentially shaped by cortical inhibition based on its orientation tuning profile relative to excitation, which is contributed at least partially by the spatial organization of RFs of presynaptic inhibitory neurons. SIGNIFICANCE STATEMENT: Simple and complex cells, two classes of principal neurons in the primary visual cortex (V1), are generally thought to be equally selective for orientation. In mouse V1, we report that complex cells, identified by their overlapping on/off subfields, has significantly weaker orientation selectivity (OS) than simple cells. This can be primarily attributed to the differential tuning selectivity of inhibitory synaptic input: inhibition in complex cells is more narrowly tuned than excitation, whereas in simple cells inhibition is more broadly tuned than excitation. In addition, there is a good correlation between inhibitory tuning selectivity and the spatial organization of inhibitory inputs. These complex and simple cells with differential degree of OS may provide functionally distinct signals to different downstream targets.

Topochemical Nitridation with Anion Vacancy-Assisted N(3-)/O(2-) Exchange.

We present how the introduction of anion vacancies in oxyhydrides enables a route to access new oxynitrides, by conducting ammonolysis of perovskite oxyhydride EuTiO3-xHx (x ∼ 0.18). At 400 °C, similar to our studies on BaTiO3-xHx, hydride lability enables a low temperature direct ammonolysis of EuTi(3.82+)O2.82H0.18, leading to the N(3-)/H(-)-exchanged product EuTi(4+)O2.82N0.12□0.06. When the ammonolysis temperature was increased up to 800 °C, we observed a further nitridation involving N(3-)/O(2-) exchange, yielding a fully oxidized Eu(3+)Ti(4+)O2N with the GdFeO3-type distortion (Pnma) as a metastable phase, instead of pyrochlore structure. Interestingly, the same reactions using the oxide EuTiO3 proceeded through a 1:1 exchange of N(3-) with O(2-) only above 600 °C and resulted in incomplete nitridation to EuTiO2.25N0.75, indicating that anion vacancies created during the initial nitridation process of EuTiO2.82H0.18 play a crucial role in promoting anion (N(3-)/O(2-)) exchange at high temperatures. Hence, by using (hydride-induced) anion-deficient precursors, we should be able to expand the accessible anion composition of perovskite oxynitrides.

Strengthening of Direction Selectivity by Broadly Tuned and Spatiotemporally Slightly Offset Inhibition in Mouse Visual Cortex.

Direction selectivity (DS) of neuronal responses is fundamental for motion detection. How the integration of synaptic excitation and inhibition contributes to DS however remains not well-understood. Here, in vivo whole-cell voltage-clamp recordings in mouse primary visual cortex (V1) revealed that layer 4 simple cells received direction-tuned excitatory inputs but barely tuned inhibitory inputs under drifting-bar stimulation. Excitation and inhibition exhibited differential temporal offsets under movements of opposite directions: excitation peaked earlier than inhibition at the preferred direction, and vice versa at the null direction. This could be attributed to a small spatial mismatch between overlapping excitatory and inhibitory receptive fields: the distribution of excitatory input strengths was skewed and the skewness was strongly correlated with the DS of excitatory input, whereas that of inhibitory input strengths was spatially symmetric. Neural modeling revealed that the relatively stronger inhibition under null directional movements, as well as the specific spatial-temporal offsets between excitation and inhibition, allowed inhibition to enhance the DS of output responses by suppressing the null response more effectively than the preferred response. Our data demonstrate that while tuned excitatory input provides the basis for DS in mouse V1, the largely untuned and spatiotemporally offset inhibition contributes importantly to sharpening of DS.

Theory of a microfluidic serial dilution bioreactor for growth of planktonic and biofilm populations.

We present the theory of a microfluidic bioreactor with a two-compartment growth chamber and periodic serial dilution. In the model, coexisting planktonic and biofilm populations exchange by adsorption and detachment. The criteria for coexistence and global extinction are determined by stability analysis of the global extinction state. Stability analysis yields the operating diagram in terms of the dilution and removal ratios, constrained by the plumbing action of the bioreactor. The special case of equal uptake function and logistic growth is analytically solved and explicit growth curves are plotted. The presented theory is applicable to generic microfluidic bioreactors with discrete growth chambers and periodic dilution at discrete time points. Therefore, the theory is expected to assist the design of microfluidic devices for investigating microbial competition and microbial biofilm growth under serial dilution conditions.

A feedforward inhibitory circuit mediates lateral refinement of sensory representation in upper layer 2/3 of mouse primary auditory cortex.

Sensory information undergoes ordered and coordinated processing across cortical layers. Whereas cortical layer (L) 4 faithfully acquires thalamic information, the superficial layers appear well staged for more refined processing of L4-relayed signals to generate corticocortical outputs. However, the specific role of superficial layer processing and how it is specified by local synaptic circuits remains not well understood. Here, in the mouse primary auditory cortex, we showed that upper L2/3 circuits play a crucial role in refining functional selectivity of excitatory neurons by sharpening auditory tonal receptive fields and enhancing contrast of frequency representation. This refinement is mediated by synaptic inhibition being more broadly recruited than excitation, with the inhibition predominantly originating from interneurons in the same cortical layer. By comparing the onsets of synaptic inputs as well as of spiking responses of different types of neuron, we found that the broadly tuned, fast responding inhibition observed in excitatory cells can be primarily attributed to feedforward inhibition originating from parvalbumin (PV)-positive neurons, whereas somatostatin (SOM)-positive interneurons respond much later compared with the onset of inhibitory inputs to excitatory neurons. We propose that the feedforward circuit-mediated inhibition from PV neurons, which has an analogous function to lateral inhibition, enables upper L2/3 excitatory neurons to rapidly refine auditory representation.

Synaptic mechanisms for generating temporal diversity of auditory representation in the dorsal cochlear nucleus.

In central auditory pathways, neurons exhibit a great diversity of temporal discharge patterns, which may contribute to the parallel processing of auditory signals. How such response diversity emerges in the central auditory circuits remains unclear. Here, we investigated whether synaptic mechanisms can contribute to the generation of the temporal response diversity at the first stage along the central auditory neuraxis. By in vivo whole-cell voltage-clamp recording in the dorsal cochlear nucleus of rats, we revealed excitatory and inhibitory synaptic inputs underlying three different firing patterns of fusiform/pyramidal neurons in response to auditory stimuli: "primary-like," "pauser," and "buildup" patterns. We found that primary-like neurons received strong, fast-rising excitation, whereas pauser and buildup neurons received accumulating excitation with a relatively weak fast-rising phase, followed by a slow-rising phase. Pauser neurons received stronger fast-rising excitation than buildup cells. On the other hand, inhibitory inputs to the three types of cells exhibited similar temporal patterns, all with a strong fast-rising phase. Dynamic-clamp recordings demonstrated that the differential temporal patterns of excitation could primarily account for the different discharge patterns. In addition, discharge pattern in a single neuron varied in a stimulus-dependent manner, which could be attributed to the modulation of excitation/inhibition balance by different stimuli. Further examination of excitatory inputs to vertical/tuberculoventral and cartwheel cells suggested that fast-rising and accumulating excitation might be conveyed by auditory nerve and parallel fibers, respectively. A differential summation of excitatory inputs from the two sources may thus contribute to the generation of response diversity.

Downregulation of cortical inhibition mediates ocular dominance plasticity during the critical period.

Monocular deprivation (MD) during the critical period (CP) shifts ocular dominance (OD) of cortical responsiveness toward the nondeprived eye. The synaptic mechanisms underlying MD-induced OD plasticity, in particular the contribution of cortical inhibition to the plasticity, have remained unsolved. In this study, using in vivo whole-cell voltage-clamp recordings, we revealed eye-specific excitatory and inhibitory synaptic inputs to layer 4 excitatory neurons in mouse primary visual cortex (V1) at a developmental stage close to the end of CP. We found in normally reared mice that ocular preference is primarily determined by the contralateral bias of excitatory input and that inhibition does not play an active role in shaping OD. MD results in a parallel reduction of excitation and inhibition driven by the deprived eye, while reducing the inhibition but preserving the excitation driven by the nondeprived eye. MD of longer periods causes larger changes in synaptic amplitude than MD of shorter periods. Furthermore, MD resulted in a shortening of onset latencies of synaptic inputs activated by both contralateral and ipsilateral eye stimulation, while the relative temporal relationship between excitation and inhibition driven by the same eye was not significantly affected. Our results suggest that OD plasticity is largely attributed to a reduction of feedforward input representing the deprived eye, and that an unexpected weakening of cortical inhibitory connections accounts for the increased responsiveness to the nondeprived eye.

Comparison of genome-wide DNA methylation in urothelial carcinomas of patients with and without arsenic exposure.

BACKGROUND: Arsenic is a well-documented carcinogen of human urothelial carcinoma (UC) with incompletely understood mechanisms. OBJECTIVES: This study aimed to compare the genome-wide DNA methylation profiles of arsenic-induced UC (AsUC) and non-arsenic-induced UC (Non-AsUC), and to assess associations between site-specific methylation levels and cumulative arsenic exposure. METHODS: Genome-wide DNA methylation profiles in 14 AsUC and 14 non-AsUC were analyzed by Illumina Infinium methylation27 BeadChip and validated by bisulfite pyrosequencing. Mean methylation levels (߯) in AsUC and non-AsUC were compared by their ratio (߯ ratio) and difference (Δ߯). Associations between site-specific methylation levels in UC and cumulative arsenic exposure were examined. RESULTS: Among 27,578 methylation sites analyzed, 231 sites had ߯ ratio >2 or <0.5 and 45 sites had Δ߯ >0.2 or <-0.2. There were 13 sites showing statistically significant (q<0.05) differences in ߯ between AsUC and non-AsUC including 12 hypermethylation sites in AsUC and only one hypermethylation site in non-AsUC. Significant associations between cumulative arsenic exposure and DNA methylation levels of 28 patients were observed in nine CpG sites of nine gens including PDGFD (Spearman rank correlation, 0.54), CTNNA2 (0.48), KCNK17 (0.52), PCDHB2 (0.57), ZNF132 (0.48), DCDC2 (0.48), KLK7 (0.48), FBXO39 (0.49), and NPY2R (0.45). These associations remained statistically significant for CpG sites in CTNNA2, KLK7, NPY2R, ZNF132 and KCNK17 in 20 non-smoking women after adjustment for tumor stage and age. CONCLUSIONS: Significant associations between cumulative arsenic exposure and methylation level of CTNNA2, KLK7, NPY2R, ZNF132 and KCNK17 were found in smoking-unrelated urothelial carcinoma. Arsenic exposure may cause urothelial carcinomas through the hypermethylation of genes involved in cell adhesion, proteolysis, transcriptional regulation, neuronal pathway, and ion transport. The findings of this study, which are limited by its small sample size and moderate dose-response relation, remain to be validated by further studies with large sample sizes.

Transport and trapping in two-dimensional nanoscale plasmonic optical lattice.

We report the transport and trapping behavior of 100 and 500 nm diameter nanospheres in a plasmon-enhanced two-dimensional optical lattice. An optical potential is created by a two-dimensional square lattice of gold nanostructures, illuminated by a Gaussian beam to excite plasmon resonance. The nanoparticles can be guided, trapped, and arranged using this optical potential. Stacking of 500 nm nanospheres into a predominantly hexagonal closed pack crystalline structure under such a potential is also reported.

Healthcare Utilization, Physical and Psychiatric Comorbidities Before Self-Injurious Behavior in Patients with Asthma: A Nested Case-Control Study.

Background: Patients with asthma experience more physical, psychological, and financial burdens; a link between asthma and suicidality has been reported in research. Purpose: This study analyzed the medical utilization and comorbidity before their self-injurious behavior in patients with asthma. Methods: We enrolled 186,862 patients newly diagnosed with asthma between 1999 and 2013 from the National Health Insurance Research Database in Taiwan. A total of 500 case subjects had ever conducted self-injurious behaviors during the study period. Based on a nested case-control study, each case was matched with 10 controls derived from the asthma cohort to analyze differences between them and their medical use models. Results: The results indicated that, compared to the control group, the cases presented higher frequencies of outpatient visits and hospitalizations. Regarding comorbidity, the cases had more cardiovascular diseases (adjusted odds ratio [aOR]=1.58; p<0.001), bipolar disorder (aOR=2.97; p<0.001), depression (aOR=4.44; p<0.001), and sleep disorder (aOR=1.83; p<0.001) than the controls. Conclusion: The evidence-based information serves as a reference for medical staff to reduce the occurrence of self-injurious behavior in patients with asthma.

Broadening of cortical inhibition mediates developmental sharpening of orientation selectivity.

Orientation selectivity (OS) of visual cortical neurons is progressively sharpened during development. However, synaptic circuit mechanisms underlying the OS sharpening remain unclear. In the current study, in vivo whole-cell voltage-clamp recordings from layer 4 excitatory neurons in the developing mouse primary visual cortex revealed changes of orientation tuning profiles of their excitatory and inhibitory inputs during a post-eye-opening period when OS of their spiking responses becomes sharpened. In addition to a parallel strengthening of excitation and inhibition during this developmental period, the orientation tuning of excitatory inputs keeps relatively constant, whereas the tuning of inhibitory inputs is broadened, and becomes significantly broader than that of excitatory inputs. Neuron modeling and dynamic-clamp recording demonstrated that this developmental broadening of the inhibitory tuning is sufficient for sharpening OS. Depriving visual experience by dark rearing impedes the normal developmental strengthening of excitation, but a similar broadening of inhibitory tuning, likely caused by a nonselective strengthening of inhibitory connections, results in the apparently normal OS sharpening in excitatory neurons. Our results thus provide the first demonstration that an inhibitory synaptic mechanism can primarily mediate the functional refinement of cortical neurons.

Broadening of inhibitory tuning underlies contrast-dependent sharpening of orientation selectivity in mouse visual cortex.

Orientation selectivity (OS) in the visual cortex has been found to be invariant to increases in stimulus contrast, a finding that cannot be accounted for by the original, purely excitatory Hubel and Wiesel model. This property of OS may be important for preserving the quality of perceived stimulus across a range of stimulus intensity. The synaptic mechanisms that can prevent a broadening of OS caused by contrast-dependent strengthening of excitatory inputs to cortical neurons remain unknown. Using in vivo loose-patch recordings, we found in excitatory neurons in layer 4 of mouse primary visual cortex (V1) that the spike response to the preferred orientation was elevated as contrast increased while that to the orthogonal orientation remained unchanged, resulting in an overall sharpening rather than a weakening of OS. Whole-cell voltage-clamp recordings further revealed that contrast increases resulted in a scaling up of excitatory conductance at all stimulus orientations. Inhibitory conductance was enhanced at a similar level as excitation for the preferred orientation, but at a significantly higher level for the orthogonal orientation. Modeling revealed that the resulting broadening of inhibitory tuning is critical for maintaining and sharpening OS at high contrast. Finally, two-photon imaging guided recordings from parvalbumin-positive (PV) inhibitory neurons revealed that the broadening of inhibition can be attributed to a contrast-dependent broadening of spike-response tuning of PV neurons. Together our results suggest that modulation of synaptic inhibition in the mouse V1 cortical circuit preserves the sharpness of response selectivity during changes of stimulus strength.

Functional cell types in the mouse superior colliculus.

The superior colliculus (SC) represents a major visual processing station in the mammalian brain that receives input from many types of retinal ganglion cells (RGCs). How many parallel channels exist in the SC, and what information does each encode? Here, we recorded from mouse superficial SC neurons under a battery of visual stimuli including those used for classification of RGCs. An unsupervised clustering algorithm identified 24 functional types based on their visual responses. They fall into two groups: one that responds similarly to RGCs and another with more diverse and specialized stimulus selectivity. The second group is dominant at greater depths, consistent with a vertical progression of signal processing in the SC. Cells of the same functional type tend to cluster near each other in anatomical space. Compared to the retina, the visual representation in the SC has lower dimensionality, consistent with a sifting process along the visual pathway.