High-dimensional topographic organization of visual features in the primate temporal lobe.

The inferotemporal cortex supports our supreme object recognition ability. Numerous studies have been conducted to elucidate the functional organization of this brain area, but there are still important questions that remain unanswered, including how this organization differs between humans and non-human primates. Here, we use deep neural networks trained on object categorization to construct a 25-dimensional space of visual features, and systematically measure the spatial organization of feature preference in both male monkey brains and human brains using fMRI. These feature maps allow us to predict the selectivity of a previously unknown region in monkey brains, which is corroborated by additional fMRI and electrophysiology experiments. These maps also enable quantitative analyses of the topographic organization of the temporal lobe, demonstrating the existence of a pair of orthogonal gradients that differ in spatial scale and revealing significant differences in the functional organization of high-level visual areas between monkey and human brains.

Spike desensitisation as a mechanism for high-contrast selectivity in retinal ganglion cells.

In the vertebrate retina, several dozens of parallel channels relay information about the visual world to the brain. These channels are represented by the different types of retinal ganglion cells (RGCs), whose responses are rendered selective for distinct sets of visual features by various mechanisms. These mechanisms can be roughly grouped into synaptic interactions and cell-intrinsic mechanisms, with the latter including dendritic morphology as well as ion channel complement and distribution. Here, we investigate how strongly ion channel complement can shape RGC output by comparing two mouse RGC types, the well-described ON alpha cell and a little-studied ON cell that is EGFP-labelled in the Igfbp5 mouse line and displays an unusual selectivity for stimuli with high contrast. Using patch-clamp recordings and computational modelling, we show that a higher activation threshold and a pronounced slow inactivation of the voltage-gated Na+ channels contribute to the distinct contrast tuning and transient responses in ON Igfbp5 RGCs, respectively. In contrast, such a mechanism could not be observed in ON alpha cells. This study provides an example for the powerful role that the last stage of retinal processing can play in shaping RGC responses.

The Impact of Glycolipid Metabolic Disorders on Severity Stage-Specific Variation of Cardiac Autonomic Function in Obstructive Sleep Apnea: A Data-Driven Clinical Study.

BACKGROUND: Cardiac autonomic dysfunction (CAD) is a common pathology in cardiovascular diseases; however, the role of glycolipid metabolic disorders in CAD development in obstructive sleep apnea (OSA) remains poorly understood. METHODS: In total, 4152 patients with suspected OSA were recruited in our sleep center. Metabolic characteristics including anthropometric and glycolipid data were collected. Heart rate variability (HRV) was measured to assess the risk of CAD; its dose-response relationship with OSA severity was evaluated via restricted cubic spline (RCS) analysis. A segmented multivariate linear regression (SMLR) model was used to evaluate the roles of metabolic variables in different stages of OSA. RESULTS: The RCS showed that CAD risk increased in a nonlinear relationship pattern with OSA severity, from slow fluctuation at earlier stages to rapid change in later stages. After integrating the clinical definition and RCS selected knots, we obtained the new four OSA severity stages. SMLR model showed that the overall value of glycolipid variables for prediction of HRV abnormalities was greater than the value of OSA variables at earlier stages, while OSA variables were more effective predictors in more severe stages. The discordance in respective relationship of HRV with metabolic and OSA variables sheds the light how metabolic disorders promoted the development of CAD in OSA, the later further in turn deteriorates cardiac function. CONCLUSION: These results are indicative of stage-specific involvement of glycolipid metabolic factors underlying CAD nonlinear changes in patients with OSA. Early control glycolipid disorders may help the control of CAD development in patients with OSA.

Transforming absolute value to categorical choice in primate superior colliculus during value-based decision making.

Value-based decision making involves choosing from multiple options with different values. Despite extensive studies on value representation in various brain regions, the neural mechanism for how multiple value options are converted to motor actions remains unclear. To study this, we developed a multi-value foraging task with varying menu of items in non-human primates using eye movements that dissociates value and choice, and conducted electrophysiological recording in the midbrain superior colliculus (SC). SC neurons encoded "absolute" value, independent of available options, during late fixation. In addition, SC neurons also represent value threshold, modulated by available options, different from conventional motor threshold. Electrical stimulation of SC neurons biased choices in a manner predicted by the difference between the value representation and the value threshold. These results reveal a neural mechanism directly transforming absolute values to categorical choices within SC, supporting highly efficient value-based decision making critical for real-world economic behaviors.

Interrelationships among common predictors of cardiovascular diseases in patients of OSA: A large-scale observational study.

BACKGROUND AND AIMS: The apolipoprotein B/apolipoprotein A-I (ApoB/ApoA-I) and insulin resistance has been recognized as common cardiovascular diseases (CVD) risk factors. However, whether they were biomarkers for 10-year CVD risk in obstructive sleep apnea (OSA) had been rarely studied. Besides, interrelationships between the ApoB/ApoA-I, insulin resistance and OSA remain unclear. METHODS AND RESULTS: A total of 4010 subjects were finally included. Anthropometric, fasting biochemical, and polysomnographic parameters were collected. 10-year Framingham CVD risk score (FRS) was calculated for each subjects. The relationships between insulin resistance, OSA risk and the ApoB/ApoA-I was evaluated through logistic regressions analysis, restricted cubic spline (RCS) analysis and mediation analysis. ApoB/ApoA-I, HOMA-IR and AHI were all risk factors for high10-year CVD risk as assessed by FRS (odds ratios (OR) = 5.365, 1.094, 1.010, respectively, all P < 0.001)). The fully adjusted OR (95% confidence intervals) for both OSA [1 (reference), 1.308 (1.027-1.665), 1.517 (1.178-1.953), and 1.803 (1.371-2.372)] and insulin resistance [1 (reference), 1.457 (1.173-1.711), 1.701 (1.369-2.113), 2.051(1.645-2.558)] increased from the first to the fourth quartiles of the ApoB/ApoA-I. The RCS mapped a nonlinear dose-effect relationship between the ApoB/ApoA-I and risk of insulin resistance and OSA. Mediation analyses showed HOMA-IR explain 9.7%, 4.7% and 10.8% of the association between apnea-hypopnea index, oxygen desaturation index, micro-arousal index and ApoB/ApoA-I, respectively. CONCLUSIONS: Our study revealed that ApoB/ApoA-I, insulin resistance and OSA were risk factors for CVD. Insulin resistance may serve as a potential mediator in OSA-related lipoprotein disorders and further increase CVD risk.

Differential roles of NaV1.2 and NaV1.6 in regulating neuronal excitability at febrile temperature and distinct contributions to febrile seizures.

Dysregulation of voltage-gated sodium channels (VGSCs) is associated with multiple clinical disorders, including febrile seizures (FS). The contribution of different sodium channel subtypes to environmentally triggered seizures is not well understood. Here we demonstrate that somatic and axonal sodium channels primarily mediated through NaV1.2 and NaV1.6 subtypes, respectively, behave differentially at FT, and might play distinct roles in FS generation. In contrast to sodium channels on the main axonal trunk, somatic ones are more resistant to inactivation and display significantly augmented currents, faster gating rates and kinetics of recovery from inactivation at FT, features that promote neuronal excitabilities. Pharmacological inhibition of NaV1.2 by Phrixotoxin-3 (PTx3) suppressed FT-induced neuronal hyperexcitability in brain slice, while up-regulation of NaV1.2 as in NaV1.6 knockout mice showed an opposite effect. Consistently, NaV1.6 knockout mice were more susceptible to FS, exhibiting much lower temperature threshold and shorter onset latency than wildtype mice. Neuron modeling further suggests that NaV1.2 is the major subtype mediating FT-induced neuronal hyperexcitability, and predicts potential outcomes of alterations in sodium channel subtype composition. Together, these data reveal a role of native NaV1.2 on neuronal excitability at FT and its important contribution to FS pathogenesis.

Time compression of visual perception around microsaccades.

Even during fixation, our eyes are in constant motion. For example, microsaccades are small (typically <1°) eye movements that occur 1~3 times/second. Despite their tiny and transient nature, our percept of visual space is compressed before microsaccades (Hafed ZM, Lovejoy LP, Krauzlis RJ. Eur J Neurosci 37: 1169-1181, 2013). As visual space and time are interconnected at both the physical and physiological levels, we asked whether microsaccades also affect the temporal aspects of visual perception. Here we demonstrate that the perceived interval between transient visual stimuli was compressed if accompanied by microsaccades. This temporal compression extended approximately ±200 ms from microsaccade occurrence, and depending on their particular pattern, multiple microsaccades further enhanced or counteracted this temporal compression. The compression of time surrounding microsaccades resembles that associated with more voluntary macrosaccades (Morrone MC, Ross J, Burr D. Nat Neurosci 8: 950-954, 2005). Our results suggest common neural processes underlying both saccade and microsaccade misperceptions, mediated, likely, through extraretinal mechanisms.NEW & NOTEWORTHY Here we show that humans perceive the duration of visual events as compressed if they are accompanied by microsaccades. Despite the tiny and transient nature of microsaccades, time compression extended more than ±200 ms from their occurrence. Moreover, the number, pattern, and temporal coincidence of microsaccades relative to visual events all contribute to this time misperception. Our results reveal a detailed picture of how our visual time percepts are altered by microsaccades.

Distinct severity stages of obstructive sleep apnoea are correlated with unique dyslipidaemia: large-scale observational study.

BACKGROUND: Dyslipidaemia is an intermediary exacerbation factor for various diseases but the impact of obstructive sleep apnoea (OSA) on dyslipidaemia remains unclear. METHODS: A total of 3582 subjects with suspected OSA consecutively admitted to our hospital sleep centre were screened and 2983 (2422 with OSA) were included in the Shanghai Sleep Health Study. OSA severity was quantified using the apnoea-hypopnea index (AHI), the oxygen desaturation index and the arousal index. Biochemical indicators and anthropometric data were also collected. The relationship between OSA severity and the risk of dyslipidaemia was evaluated via ordinal logistic regression, restricted cubic spline (RCS) analysis and multivariate linear regressions. RESULTS: The RCS mapped a nonlinear dose-effect relationship between the risk of dyslipidaemia and OSA severity, and yielded knots of the AHI (9.4, 28.2, 54.4 and 80.2). After integrating the clinical definition and RCS-selected knots, all subjects were regrouped into four AHI severity stages. Following segmented multivariate linear modelling of each stage, distinguishable sets of OSA risk factors were quantified: low-density lipoprotein cholesterol (LDL-C), apolipoprotein E and high-density lipoprotein cholesterol (HDL-C); body mass index and/or waist to hip ratio; and HDL-C, LDL-C and triglycerides were specifically associated with stage I, stages II and III, and stages II-IV with different OSA indices. CONCLUSIONS: Our study revealed the multistage and non-monotonic relationships between OSA and dyslipidaemia and quantified the relationships between OSA severity indexes and distinct risk factors for specific OSA severity stages. Our study suggests that a new interpretive and predictive strategy for dynamic assessment of the risk progression over the clinical course of OSA should be adopted.

Microsaccade direction reflects the economic value of potential saccade goals and predicts saccade choice.

Microsaccades are small-amplitude (typically <1°), ballistic eye movements that occur when attempting to fixate gaze. Initially thought to be generated randomly, it has recently been established that microsaccades are influenced by sensory stimuli, attentional processes, and certain cognitive states. Whether decision processes influence microsaccades, however, is unknown. Here, we adapted two classic economic tasks to examine whether microsaccades reflect evolving saccade decisions. Volitional saccade choices of monkey and human subjects provided a measure of the subjective value of targets. Importantly, analyses occurred during a period of complete darkness to minimize the known influence of sensory and attentional processes on microsaccades. As the time of saccadic choice approached, microsaccade direction became the following: 1) biased toward targets as a function of their subjective value and 2) predictive of upcoming, voluntary choice. Our results indicate that microsaccade direction is influenced by and is a reliable tell of evolving saccade decisions. Our results are consistent with dynamic decision processes within the midbrain superior colliculus; that is, microsaccade direction is influenced by the transition of activity toward caudal saccade regions associated with high saccade value and/or future saccade choice.

A Subtype of Inhibitory Interneuron with Intrinsic Persistent Activity in Human and Monkey Neocortex.

A critical step in understanding the neural basis of human cognitive functions is to identify neuronal types in the neocortex. In this study, we performed whole-cell recording from human cortical slices and found a distinct subpopulation of neurons with intrinsic persistent activity that could be triggered by single action potentials (APs) but terminated by bursts of APs. This persistent activity was associated with a depolarizing plateau potential induced by the activation of a persistent Na+ current. Single-cell RT-PCR revealed that these neurons were inhibitory interneurons. This type of neuron was found in different cortical regions, including temporal, frontal, occipital, and parietal cortices in human and also in frontal and temporal lobes of nonhuman primate but not in rat cortical tissues, suggesting that it could be unique to primates. The characteristic persistent activity in these inhibitory interneurons may contribute to the regulation of pyramidal cell activity and participate in cortical processing.

Developmental reduction of asynchronous GABA release from neocortical fast-spiking neurons.

Delayed asynchronous release (AR) evoked by bursts of presynaptic action potentials (APs) occurs in certain types of hippocampal and neocortical inhibitory interneurons. Previous studies showed that AR provides long-lasting inhibition and desynchronizes the activity in postsynaptic cells. However, whether AR undergoes developmental change remains unknown. In this study, we performed whole-cell recording from fast-spiking (FS) interneurons and pyramidal cells (PCs) in prefrontal cortical slices obtained from juvenile and adult rats. In response to AP trains in FS neurons, AR occurred at their output synapses during both age periods, including FS autapses and FS-PC synapses; however, the AR strength was significantly weaker in adults than that in juveniles. Further experiments suggested that the reduction of AR in adult animals could be attributable to the rapid clearance of residual Ca(2+) from presynaptic terminals. Together, our results revealed that the AR strength was stronger at juvenile but weaker in adult, possibly resulting from changes in presynaptic Ca(2+) dynamics. AR changes may meet the needs of the neural network to generate different types of oscillations for cortical processing at distinct behavioral states.

Action potential initiation in neocortical inhibitory interneurons.

Action potential (AP) generation in inhibitory interneurons is critical for cortical excitation-inhibition balance and information processing. However, it remains unclear what determines AP initiation in different interneurons. We focused on two predominant interneuron types in neocortex: parvalbumin (PV)- and somatostatin (SST)-expressing neurons. Patch-clamp recording from mouse prefrontal cortical slices showed that axonal but not somatic Na+ channels exhibit different voltage-dependent properties. The minimal activation voltage of axonal channels in SST was substantially higher (∼7 mV) than in PV cells, consistent with differences in AP thresholds. A more mixed distribution of high- and low-threshold channel subtypes at the axon initial segment (AIS) of SST cells may lead to these differences. Surprisingly, NaV1.2 was found accumulated at AIS of SST but not PV cells; reducing NaV1.2-mediated currents in interneurons promoted recurrent network activity. Together, our results reveal the molecular identity of axonal Na+ channels in interneurons and their contribution to AP generation and regulation of network activity.

Regulation of action potential waveforms by axonal GABAA receptors in cortical pyramidal neurons.

GABAA receptors distributed in somatodendritic compartments play critical roles in regulating neuronal activities, including spike timing and firing pattern; however, the properties and functions of GABAA receptors at the axon are still poorly understood. By recording from the cut end (bleb) of the main axon trunk of layer -5 pyramidal neurons in prefrontal cortical slices, we found that currents evoked by GABA iontophoresis could be blocked by picrotoxin, indicating the expression of GABAA receptors in axons. Stationary noise analysis revealed that single-channel properties of axonal GABAA receptors were similar to those of somatic receptors. Perforated patch recording with gramicidin revealed that the reversal potential of the GABA response was more negative than the resting membrane potential at the axon trunk, suggesting that GABA may hyperpolarize the axonal membrane potential. Further experiments demonstrated that the activation of axonal GABAA receptors regulated the amplitude and duration of action potentials (APs) and decreased the AP-induced Ca2+ transients at the axon. Together, our results indicate that the waveform of axonal APs and the downstream Ca2+ signals are modulated by axonal GABAA receptors.

Dopaminergic modulation of axonal potassium channels and action potential waveform in pyramidal neurons of prefrontal cortex.

Voltage-gated K(+) (KV) channels play critical roles in shaping neuronal signals. KV channels distributed in the perisomatic regions and thick dendrites of cortical pyramidal neurons have been extensively studied. However, the properties and regulation of KV channels distributed in the thin axons remain unknown. In this study, by performing somatic and axonal patch-clamp recordings from layer 5 pyramidal neurons of prefrontal cortical slices, we showed that the rapidly inactivating A-currents mediated the transient K(+) currents evoked by action potential (AP) waveform command (KAP) at the soma, whereas the rapidly activating but slowly inactivating KV1-mediated D-currents dominated the KAP at the axon. In addition, activation of D1-like receptors for dopamine decreased the axonal K(+) currents, as a result of an increase in the activity of cAMP-PKA pathway. In contrast, activation of D2-like receptors showed an opposite effect on the axonal K(+) currents. Further experiments demonstrated that functional D1-like receptors were expressed at the main axon trunk and their activation could broaden the waveforms of axonal APs. Together, these results show that axonal KV channels were subjected to dopamine modulation, and this modulation could regulate the waveforms of propagating APs at the axon, suggesting an important role of dopaminergic modulation of axonal KV channels in regulating neuronal signalling.

Enhancement of asynchronous release from fast-spiking interneuron in human and rat epileptic neocortex.

Down-regulation of GABAergic inhibition may result in the generation of epileptiform activities. Besides spike-triggered synchronous GABA release, changes in asynchronous release (AR) following high-frequency discharges may further regulate epileptiform activities. In brain slices obtained from surgically removed human neocortical tissues of patients with intractable epilepsy and brain tumor, we found that AR occurred at GABAergic output synapses of fast-spiking (FS) neurons and its strength depended on the type of connections, with FS autapses showing the strongest AR. In addition, we found that AR depended on residual Ca²âº at presynaptic terminals but was independent of postsynaptic firing. Furthermore, AR at FS autapses was markedly elevated in human epileptic tissue as compared to non-epileptic tissue. In a rat model of epilepsy, we found similar elevation of AR at both FS autapses and synapses onto excitatory neurons. Further experiments and analysis showed that AR elevation in epileptic tissue may result from an increase in action potential amplitude in the FS neurons and elevation of residual Ca²âº concentration. Together, these results revealed that GABAergic AR occurred at both human and rat neocortex, and its elevation in epileptic tissue may contribute to the regulation of epileptiform activities.

Membrane potential-dependent modulation of recurrent inhibition in rat neocortex.

Dynamic balance of excitation and inhibition is crucial for network stability and cortical processing, but it is unclear how this balance is achieved at different membrane potentials (V(m)) of cortical neurons, as found during persistent activity or slow V(m) oscillation. Here we report that a V(m)-dependent modulation of recurrent inhibition between pyramidal cells (PCs) contributes to the excitation-inhibition balance. Whole-cell recording from paired layer-5 PCs in rat somatosensory cortical slices revealed that both the slow and the fast disynaptic IPSPs, presumably mediated by low-threshold spiking and fast spiking interneurons, respectively, were modulated by changes in presynaptic V(m). Somatic depolarization (>5 mV) of the presynaptic PC substantially increased the amplitude and shortened the onset latency of the slow disynaptic IPSPs in neighboring PCs, leading to a narrowed time window for EPSP integration. A similar increase in the amplitude of the fast disynaptic IPSPs in response to presynaptic depolarization was also observed. Further paired recording from PCs and interneurons revealed that PC depolarization increases EPSP amplitude and thus elevates interneuronal firing and inhibition of neighboring PCs, a reflection of the analog mode of excitatory synaptic transmission between PCs and interneurons. Together, these results revealed an immediate V(m)-dependent modulation of cortical inhibition, a key strategy through which the cortex dynamically maintains the balance of excitation and inhibition at different states of cortical activity.

Distinct contributions of Na(v)1.6 and Na(v)1.2 in action potential initiation and backpropagation.

The distal end of the axon initial segment (AIS) is the preferred site for action potential initiation in cortical pyramidal neurons because of its high Na(+) channel density. However, it is not clear why action potentials are not initiated at the proximal AIS, which has a similarly high Na(+) channel density. We found that low-threshold Na(v)1.6 and high-threshold Na(v)1.2 channels preferentially accumulate at the distal and proximal AIS, respectively, and have distinct functions in action potential initiation and backpropagation. Patch-clamp recording from the axon cut end of pyramidal neurons in the rat prefrontal cortex revealed a high density of Na(+) current and a progressive reduction in the half-activation voltage (up to 14 mV) with increasing distance from the soma at the AIS. Further modeling studies and simultaneous somatic and axonal recordings showed that distal Na(v)1.6 promotes action potential initiation, whereas proximal Na(v)1.2 promotes its backpropagation to the soma.