The role of early visual experience in the development of spatial-frequency preference in the primary visual cortex.

KEY POINTS: The mature functioning of the primary visual cortex depends on postnatal visual experience, while the orientation/direction preference is established just after eye-opening, independently of visual experience. In this study, we find that visual experience is required for the normal development of spatial-frequency (SF) preference in mouse primary visual cortex. We show that age- and experience-dependent shifts in optimal SFs towards higher frequencies occurred similarly in excitatory neurons and parvalbumin-positive interneurons. We also show that some excitatory and parvalbumin-positive neurons preferentially responded to visual stimuli consisting of very high SFs and posterior directions, and that the preference was established at earlier developmental stages than the SF preference in the standard frequency range. These results suggest that early visual experience is required for the development of SF representation and shed light on the experience-dependent developmental mechanisms underlying visual cortical functions. ABSTRACT: Early visual experience is crucial for the maturation of visual cortical functions. It has been demonstrated that the orientation and direction preferences in individual neurons of the primary visual cortex are well established immediately after eye-opening. The postnatal development of spatial frequency (SF) tuning and its dependence on visual experience, however, has not been thoroughly quantified. In this study, macroscopic imaging with flavoprotein autofluorescence revealed that the optimal SFs shift towards higher frequency values during normal development in mouse primary visual cortex. This developmental shift was impaired by binocular deprivation during the sensitive period, postnatal 3 weeks (PW3) to PW6. Furthermore, two-photon Ca2+ imaging revealed that the developmental shift of the optimal SFs, depending on visual experience, concurrently occurs in excitatory neurons and parvalbumin-positive inhibitory interneurons (PV neurons). In addition, some excitatory and PV neurons exhibited a preference for visual stimuli consisting of particularly high SFs and posterior directions at relatively early developmental stages; this preference was not affected by binocular deprivation. Thus, there may be two distinct developmental mechanisms for the establishment of SF preference depending on the frequency values. After PW3, SF tuning for neurons tuned to standard frequency ranges was sharper in excitatory neurons and slightly broader in PV neurons, leading to considerably attenuated SF tuning in PV neurons compared to excitatory neurons by PW5. Our findings suggest that early visual experience is far more important than orientation/direction selectivity for the development of the neural representation of the diverse SFs.

Long-Range Interhemispheric Projection Neurons Show Biased Response Properties and Fine-Scale Local Subnetworks in Mouse Visual Cortex.

Integration of information processed separately in distributed brain regions is essential for brain functions. This integration is enabled by long-range projection neurons, and further, concerted interactions between long-range projections and local microcircuits are crucial. It is not well known, however, how this interaction is implemented in cortical circuits. Here, to decipher this logic, using callosal projection neurons (CPNs) in layer 2/3 of the mouse visual cortex as a model of long-range projections, we found that CPNs exhibited distinct response properties and fine-scale local connectivity patterns. In vivo 2-photon calcium imaging revealed that CPNs showed a higher ipsilateral (to their somata) eye preference, and that CPN pairs showed stronger signal/noise correlation than random pairs. Slice recordings showed CPNs were preferentially connected to CPNs, demonstrating the existence of projection target-dependent fine-scale subnetworks. Collectively, our results suggest that long-range projection target predicts response properties and local connectivity of cortical projection neurons.

Predictive impact of early mobilization on rehospitalization for elderly Japanese heart failure patients.

The aim of this study was to determine whether early mobilization was associated with rehospitalization among elderly heart failure patients. We measured the time from admission to mobilization and other clinical characteristics for 190 heart failure patients (mean age, 80.7 years). The primary outcome was heart failure rehospitalization. Kaplan-Meier survival curves were plotted and the hazard ratios for rehospitalization were determined using Cox proportional hazards regression models. During a median follow-up period of 750 days, 58 patients underwent rehospitalization. The time from admission to mobilization was significantly longer for these patients than for those who were not rehospitalized. Univariate and multivariate Cox proportional hazards analyses showed that the time from admission to mobilization was an independent predictor of rehospitalization, and receiver-operating characteristic analysis determined an optimal cutoff value of 3 days for differentiating the patients more likely to experience a subsequent cardiac event (sensitivity, 76%; specificity, 69%; area under the curve, 0.667). Kaplan-Meier survival curve analysis showed a significantly lower event rate in the ≤ 3-day group (p = 0.001, log-rank test). In conclusion, the time from admission to mobilization may be one of the strongest predictors of rehospitalization in elderly heart failure patients. Early mobilization within 3 days may be an initial target for the acute phase treatment of heart failure.

The difference in determinant factor of six-minute walking distance between sarcopenic and non-sarcopenic elderly patients with heart failure.

BACKGROUND: The purpose of this study was to identify the factors determining exercise capacity in elderly patients with heart failure (HF) with and without sarcopenia. METHODS: We studied 186 consecutive patients with HF who met the criteria of being >60 years, with no physical disability. During hospitalization, we measured the 6-min walking distance (6MWD) and other physical functional parameters and evaluated echocardiographic and laboratory measurements indicating the severity of HF. First, we divided patients into two groups (the sarcopenia group and the nonsarcopenia group) according to the presence of sarcopenia defined as fulfilling more than or equal to two criteria-body mass index <18.5, walking speed <0.8m/s, and grip strength <26kg in males, or <18kg in females. Then the association between the 6MWD and the clinical variables mentioned above was analyzed by univariate and multiple logistic regression analyses. RESULTS: The sarcopenia group comprised 77 patients (41.2%). In univariate analysis, age, grip strength, walking speed, and knee extensor muscle strength were significantly correlated with the 6MWD (p<0.05), whereas other clinical parameters were not. In multivariate analysis, walking speed was selected as an independent factor determining the 6MWD in both groups; however, knee extensor muscle strength was selected as an independent factor determining the 6MWD only in the sarcopenia group. CONCLUSION: We demonstrated that knee extensor muscle strength was an independent factor determining exercise capacity-especially in elderly patients with HF with sarcopenia, and provided useful information in terms of exercise prescription.

Hypothalamic neuronal circuits regulating hunger-induced taste modification.

The gustatory system plays a critical role in sensing appetitive and aversive taste stimuli for evaluating food quality. Although taste preference is known to change depending on internal states such as hunger, a mechanistic insight remains unclear. Here, we examine the neuronal mechanisms regulating hunger-induced taste modification. Starved mice exhibit an increased preference for sweetness and tolerance for aversive taste. This hunger-induced taste modification is recapitulated by selective activation of orexigenic Agouti-related peptide (AgRP)-expressing neurons in the hypothalamus projecting to the lateral hypothalamus, but not to other regions. Glutamatergic, but not GABAergic, neurons in the lateral hypothalamus function as downstream neurons of AgRP neurons. Importantly, these neurons play a key role in modulating preferences for both appetitive and aversive tastes by using distinct pathways projecting to the lateral septum or the lateral habenula, respectively. Our results suggest that these hypothalamic circuits would be important for optimizing feeding behavior under fasting.

Fabry Disease with Pacemaker Implantation as the Initial Event.

Fabry disease (FD) is a rare X-linked hereditary disorder (Xq22) caused by a deficiency in alpha-galactosidase activity. A 34-year-old man was referred to our hospital because of renal dysfunction. He had previously undergone pacemaker implantation at 24 years of age. Investigations revealed undetectable alpha-galactosidase A activity levels. Renal biopsy results indicated vacuolization of podocytes. A genetic analysis revealed that the patient carried the W340X mutation. Enzyme replacement therapy with agalsidase beta was started. This case is novel because most cases of FD nephropathy precede cardiac disease. In our patient, the cardiac event was the initial event, and renal impairment followed.

A Catastrophic Case of Idiopathic Cholesterol Crystal Embolism with Multiple Lethal Complications: A Labyrinth Underneath the Diagnosis of Skin Ulcers in Chronic Kidney Disease Patients.

A 66-year-old man was admitted to our hospital because of multiple refractory skin ulcers. Based on his severe systemic arterial calcification and severe calcium-phosphate imbalance due to severe kidney dysfunction, we initially considered calciphylaxis. However, a skin biopsy provided a diagnosis of cholesterol crystal embolization. Although we initiated hemodialysis, steroid treatment, and low-density lipoprotein-cholesterol apheresis, he died of multiple intestinal perforation. An autopsy showed cholesterol crystals occluding multiple organ arterioles. This case suggests that skin ulcers in patients with chronic kidney disease may be an important diagnostic hallmark and may be associated with several serious diseases.

Experience-Dependent Development of Feature-Selective Synchronization in the Primary Visual Cortex.

Early visual experience is essential for the maturation of visual functions in which the primary visual cortex plays crucial roles. The extraction of visual features based on response selectivity of individual neurons, a fundamental process in the cortex, is basically established by eye opening in rodents, suggesting that visual experience is required for the development of neural functions other than feature extraction. Here, we show that synchronized firing, which is important for visual information processing, occurs selectively in adjacent neurons sharing similar orientation or spatial frequency preferences in layers 2-4 (upper layer) of rat visual cortex. This feature-selective spike synchrony was rudimentary when the eyes opened and became prominent during the first few weeks after eye opening only in the presence of pattern vision. In contrast, synchronization in layers 5-6 (lower layer) was almost independent of orientation similarity and more weakly dependent on spatial frequency similarity compared with upper layer synchrony. Lower layer synchronization was strengthened during development after eye opening independently of visual experience as a whole. However, the feature selectivity of synchronization was regulated by visual inputs, whereas the inputs without contours were sufficient for this regulation. Therefore, we speculate that feature-selective synchronization in the upper layer may convey detailed information on visual objects to the higher-order cortex, whereas weakly feature-selective synchronization in the lower layer may covey rather rough visual information to the subcortical areas or higher-order cortex. A major role of visual experience may be to establish the specific neural circuits underlying highly feature-selective synchronization.SIGNIFICANCE STATEMENT The neuronal mechanisms underlying experience-dependent improvement of visual functions still remain unresolved. In this study, we investigated whether early visual experience contributes to the development of synchronized neural firing in the primary visual cortex, which plays important roles in visual information processing. We found that synchronized firing depends more remarkably on the similarity of preferred visual stimuli in the upper than lower layer neurons. Pattern vision during development was required for the establishment of spike synchrony in the upper but not the lower layer. These findings provide a new view regarding the role of sensory experience in the functional development of the cortex and the differences in the modes of information processing in the upper and lower cortical layers.

Activation of SF1 Neurons in the Ventromedial Hypothalamus by DREADD Technology Increases Insulin Sensitivity in Peripheral Tissues.

The ventromedial hypothalamus (VMH) regulates glucose and energy metabolism in mammals. Optogenetic stimulation of VMH neurons that express steroidogenic factor 1 (SF1) induces hyperglycemia. However, leptin acting via the VMH stimulates whole-body glucose utilization and insulin sensitivity in some peripheral tissues, and this effect of leptin appears to be mediated by SF1 neurons. We examined the effects of activation of SF1 neurons with DREADD (designer receptors exclusively activated by designer drugs) technology. Activation of SF1 neurons by an intraperitoneal injection of clozapine-N-oxide (CNO), a specific hM3Dq ligand, reduced food intake and increased energy expenditure in mice expressing hM3Dq in SF1 neurons. It also increased whole-body glucose utilization and glucose uptake in red-type skeletal muscle, heart, and interscapular brown adipose tissue, as well as glucose production and glycogen phosphorylase a activity in the liver, thereby maintaining blood glucose levels. During hyperinsulinemic-euglycemic clamp, such activation of SF1 neurons increased insulin-induced glucose uptake in the same peripheral tissues and tended to enhance insulin-induced suppression of glucose production by suppressing gluconeogenic gene expression and glycogen phosphorylase a activity in the liver. DREADD technology is thus an important tool for studies of the role of the brain in the regulation of insulin sensitivity in peripheral tissues.

Mucinous cholangiocarcinoma: Clinicopathological features of the rarest type of cholangiocarcinoma.

Mucinous cholangiocarcinoma is extremely rare and its clinicopathological features remain unclear. The present study aimed to analyze published data on mucinous cholangiocarcinoma. Medical databases were searched from 1980 to 2016, and clinicopathological data for 16 mucinous cholangiocarcinoma patients were obtained. Characteristic imaging findings, including hypovascular tumor with peripheral enhancement on computed tomography and angiography, extremely high intensity on T2-weighted magnetic resonance images, intratumoral calcification and luminal communication between the tumor and bile duct on cholangiography, were noted. Mucinous cholangiocarcinoma was correctly diagnosed in one patient only, with some patients diagnosed as low-malignant biliary cystic tumors preoperatively. Five cases were followed up after the first medical examination, and three of these were initially diagnosed as biliary cystadenoma or intraductal papillary neoplasm of the bile duct. All five tumors showed marked enlargement within 4 months of follow up. Macroscopically, the resected tumors were non-cystic/solid in seven cases, and cystic in seven. Tumor diameter ranged from 5 cm to 22 cm, and mucoid cut surface, lobulation, lack of capsule and papillary growth were observed. Microscopically, co-existing intraductal papillary neoplasm of the bile duct was noted in three of five patients with available data. Nine of 10 cases in whom the pathological stage was reported had advanced disease with lymph node and/or distant metastasis, and 5-year survival was achieved in one microinvasive case only. Overall 1- and 3-year survival rates were 60.1% and 40.1%, respectively. The possibility of mucinous cholangiocarcinoma should be considered when biliary cystic tumors are detected on imaging modalities, despite the rarity of this tumor.

Microglia contact induces synapse formation in developing somatosensory cortex.

Microglia are the immune cells of the central nervous system that play important roles in brain pathologies. Microglia also help shape neuronal circuits during development, via phagocytosing weak synapses and regulating neurogenesis. Using in vivo multiphoton imaging of layer 2/3 pyramidal neurons in the developing somatosensory cortex, we demonstrate here that microglial contact with dendrites directly induces filopodia formation. This filopodia formation occurs only around postnatal day 8-10, a period of intense synaptogenesis and when microglia have an activated phenotype. Filopodia formation is preceded by contact-induced Ca(2+) transients and actin accumulation. Inhibition of microglia by genetic ablation decreases subsequent spine density, functional excitatory synapses and reduces the relative connectivity from layer 4 neurons. Our data provide the direct demonstration of microglial-induced spine formation and provide further insights into immune system regulation of neuronal circuit development, with potential implications for developmental disorders of immune and brain dysfunction.

Spatiotemporal characteristics of surround suppression in primary visual cortex and lateral geniculate nucleus of the cat.

In the primary visual cortex (V1), a neuronal response to stimulation of the classical receptive field (CRF) is predominantly suppressed by a stimulus presented outside the CRF (extraclassical receptive field, ECRF), a phenomenon referred to as ECRF suppression. To elucidate the neuronal mechanisms and origin of ECRF suppression in V1 of anesthetized cats, we examined the temporal properties of the spatial extent and orientation specificity of ECRF suppression in V1 and the lateral geniculate nucleus (LGN), using stationary-flashed sinusoidal grating. In V1, we found three components of ECRF suppression: (1) local and fast, (2) global and fast, and (3) global and late. The local and fast component, which resulted from within 2° of the boundary of the CRF, started no more than 10 ms after the onset of the CRF response and exhibited low specificity for the orientation of the ECRF stimulus. These spatiotemporal properties corresponded to those of geniculate ECRF suppression, suggesting that the local and fast component of V1 is inherited from the LGN. In contrast, the two global components showed rather large spatial extents ∼5° from the CRF boundary and high specificity for orientation, suggesting that their possible origin is the cortex, not the LGN. Correspondingly, the local component was observed in all neurons of the thalamocortical recipient layer, while the global component was biased toward other layers. Therefore, we conclude that both subcortical and cortical mechanisms with different spatiotemporal properties are involved in ECRF suppression.

Experience-dependent emergence of fine-scale networks in visual cortex.

Visual cortical neurons selectively respond to particular features of visual stimuli and this selective responsiveness emerges from specific connectivity in the cortex. Most visual response properties are basically established by eye opening and are thereafter modified or refined by visual experience based on activity-dependent synaptic modifications during an early postnatal period. Visual deprivation during this period impairs development of visual functions, such as visual acuity. We previously demonstrated that fine-scale networks composed of a population of interconnected layer 2/3 (L2/3) pyramidal neurons receiving common inputs from adjacent neurons are embedded in a small area in rat visual cortex. We suggested that this network could be a functional unit for visual information processing. In this study, we investigated the effects of early visual experience on the development of fine-scale networks and individual synaptic connections in rat visual cortical slices. We used two kinds of deprivation, binocular deprivation and dark rearing, which allowed visual inputs with only diffuse light and no visual input, respectively. The probability and strength of excitatory connections to L2/3 pyramidal cells increased during the 2 weeks after eye opening, and these changes were prevented by dark rearing, but not binocular deprivation. Fine-scale networks were absent just after eye opening and established during the following 2 weeks in rats reared with normal visual experience, but not with either type of deprivation. These results indicate that patterned vision is required for the emergence of the fine-scale network, whereas diffuse light stimulation is sufficient for the maturation of individual synapses.

Effects of stimulus spatial frequency, size, and luminance contrast on orientation tuning of neurons in the dorsal lateral geniculate nucleus of cat.

It is generally thought that orientation selectivity first appears in the primary visual cortex (V1), whereas neurons in the lateral geniculate nucleus (LGN), an input source for V1, are thought to be insensitive to stimulus orientation. Here we show that increasing both the spatial frequency and size of the grating stimuli beyond their respective optimal values strongly enhance the orientation tuning of LGN neurons. The resulting orientation tuning was clearly contrast-invariant. Furthermore, blocking intrathalamic inhibition by iontophoretically administering γ-aminobutyric acid (GABA)A receptor antagonists, such as bicuculline and GABAzine, slightly but significantly weakened the contrast invariance. Our results suggest that orientation tuning in the LGN is caused by an elliptical classical receptive field and orientation-tuned surround suppression, and that its contrast invariance is ensured by local GABAA inhibition. This contrast-invariant orientation tuning in LGN neurons may contribute to the contrast-invariant orientation tuning seen in V1 neurons.

Inspiration from chemical photography: accelerated photoconversion of AgCl to functional silver nanoparticles mediated by DNA.

We demonstrate a facile approach for converting AgCl to functional silver nanoparticles (AgNPs) via photoreduction in the presence of DNA. The resulting AgNPs are biofunctionalized, and exhibit photostable luminescence and DNA-specific Raman signatures, showing high potential for use in DNA-directed recognition and advanced bioimaging.

Expression of 5'-AMP-activated protein kinase with starvation in murine thymocytes.

The 5'-AMP-activated protein kinase (AMPK) is a key enzyme in the protection of cells during energy crisis. AMPK is a heterotrimer consisting of a catalytic α (α1, 2) subunit and two regulatory subunits, ß (ß1, 2) and γ (γ1-3). To elucidate the role of AMPK in thymocytes with starvation, we investigated the expression of AMPK in murine thymocytes. The main isoforms expressed were α2, ß1, and γ1, of which expression increased time-dependently with starvation, together with an increase in the amount of the active form of AMPK, phospho-AMPKα. In cultured thymocytes, expression of AMPK was induced by dexamethasone, but not by a low glucose concentration in medium. Increased expression was inhibited by glucocorticoid receptor antagonist RU486. Phosphorylation of AMPKα showed an increase with low glucose concentration, but not with dexamethasone. These results suggest that increased expression of AMPK in starved mouse thymocytes is induced by an increase in glucocorticoids and that activation is induced by hypoglycemia.

Black-tea polyphenols decrease micellar solubility of cholesterol in vitro and intestinal absorption of cholesterol in rats.

Administration of black-tea polyphenols (BTP) simultaneously reduced lymphatic recovery of both (3)H-cholesterol and (14)C-trioleoylglycerol in rats that were cannulated in the thoracic duct. BTP decreased the in vitro micellar solubility of cholesterol in a dose-dependent manner. When purified theaflavins, which are components of BTP, were used, theaflavin-monogallates (TFMGs), theaflavin-3-gallate (TF3G), and theaflavin-3'-gallate (TF3'G) were effective in eliminating cholesterol from bile salt micelles in vitro. Theaflavin (TF) and theaflavin-3,3'-digallate (TFDG) had no effect on the micellar solubility of cholesterol. The concentration of bile acid in the micelles was not influenced by the addition of any BTPs or theaflavins. These results suggest that the reduction of micellar cholesterol by BTP could be important to reducing cholesterol absorption.

Temporal properties of spatial frequency tuning of surround suppression in the primary visual cortex and the lateral geniculate nucleus of the cat.

In primary visual cortex (V1) neurons, a stimulus placed in the extraclassical receptive field suppresses the response to a stimulus within the classical receptive field (CRF), a phenomenon referred to as surround suppression. The aim of the present study was to elucidate the mechanisms of surround suppression in V1. Using stationary-flashed sinusoidal grating as stimuli, we observed temporal changes of surround suppression in V1 and the lateral geniculate nucleus (LGN) and of the response to CRF stimulation in V1. The spatial frequency (SF) tuning of surround suppression in V1 neurons changed over time after the stimulus onset. In the early phase (< 50 ms), the SF tuning was low-pass, but later became band-pass that tuned to the optimal SF in response to CRF stimulation. On the other hand, the SF tuning of CRF responses in V1 was band-pass throughout the response time whereas the SF peak shifted slightly toward high SF. Thus, SF tuning properties of the CRF response dissociated from that of surround suppression in V1 only in the early phase. We also confirmed that the temporal changes of the SF tuning of surround suppression in the LGN occurred in the same direction as surround suppression in V1, but the shift from low-pass to band-pass SF tuning started later than that in V1. From these results, we suggest that subcortical mechanisms contribute to early surround suppression in V1, whereas cortical mechanisms contribute to late surround suppression.

Enriched expression of serotonin 1B and 2A receptor genes in macaque visual cortex and their bidirectional modulatory effects on neuronal responses.

To study the molecular mechanism how cortical areas are specialized in adult primates, we searched for area-specific genes in macaque monkeys and found striking enrichment of serotonin (5-hydroxytryptamine, 5-HT) 1B receptor mRNA, and to a lesser extent, of 5-HT2A receptor mRNA, in the primary visual area (V1). In situ hybridization analyses revealed that both mRNA species were highly concentrated in the geniculorecipient layers IVA and IVC, where they were coexpressed in the same neurons. Monocular inactivation by tetrodotoxin injection resulted in a strong and rapid (<3 h) downregulation of these mRNAs, suggesting the retinal activity dependency of their expression. Consistent with the high expression level in V1, clear modulatory effects of 5-HT1B and 5-HT2A receptor agonists on the responses of V1 neurons were observed in in vivo electrophysiological experiments. The modulatory effect of the 5-HT1B agonist was dependent on the firing rate of the recorded neurons: The effect tended to be facilitative for neurons with a high firing rate, and suppressive for those with a low firing rate. The 5-HT2A agonist showed opposite effects. These results suggest that this serotonergic system controls the visual response in V1 for optimization of information processing toward the incoming visual inputs.