Neural Oscillations and Multisensory Processing.

Neural oscillations play a role in sensory processing by coordinating synchronized neuronal activity. Synchronization of gamma oscillations is engaged in local computation of feedforward signals and synchronization of alpha-beta oscillations is engaged in feedback processing over long-range areas. These spatially and spectrally segregated bi-directional signals may be integrated by a mechanism of cross-frequency coupling. Synchronization of neural oscillations has also been proposed as a mechanism for information integration across multiple sensory modalities. A transient stimulus or rhythmic stimulus from one modality may lead to phase alignment of ongoing neural oscillations in multiple sensory cortices, through a mechanism of cross-modal phase reset or cross-modal neural entrainment. Synchronized activities in multiple sensory cortices are more likely to boost stronger activities in downstream areas. Compared to synchronized oscillations, asynchronized oscillations may impede signal processing, and may contribute to sensory selection by setting the oscillations in the target-related cortex and the oscillations in the distractor-related cortex to opposite phases.

Dorsal BNST DRD2+ neurons mediate sex-specific anxiety-like behavior induced by chronic social isolation.

The dorsal bed nucleus of stria terminalis (dBNST) is a pivotal hub for stress response modulation. Dysfunction of dopamine (DA) network is associated with chronic stress, but the roles of DA network of dBNST in chronic stress-induced emotional disorders remain unclear. We examine the role of dBNST Drd1+ and Drd2+ neurons in post-weaning social isolation (PWSI)-induced behavior deficits. We find that male, but not female, PWSI rats exhibit negative emotional phenotypes and the increase of excitability and E-I balance of dBNST Drd2+ neurons. More importantly, hypofunction of dBNST Drd2 receptor underlies PWSI-stress-induced male-specific neuronal plasticity change of dBNST Drd2+ neurons. Furthermore, chemogenetic activation of dBNST Drd2+ neurons is sufficient to induce anxiogenic effects, while Kir4.1-mediated chronic inhibition of dBNST Drd2+ neurons ameliorate PWSI-induced anxiety-like behaviors. Our findings reveal an important neural mechanism underlying PWSI-induced sex-specific behavioral abnormalities and potentially provide a target for the treatment of social stress-related emotional disorder.

Evolution and neural representation of mammalian cooperative behavior.

Cooperation is common in nature and is pivotal to the development of human society. However, the details of how and why cooperation evolved remain poorly understood. Cross-species investigation of cooperation may help to elucidate the evolution of cooperative strategies. Thus, we design an automated cooperative behavioral paradigm and quantitatively examine the cooperative abilities and strategies of mice, rats, and tree shrews. We find that social communication plays a key role in the establishment of cooperation and that increased cooperative ability and a more efficient cooperative strategy emerge as a function of the evolutionary hierarchy of the tested species. Moreover, we demonstrate that single-unit activities in the orbitofrontal and prelimbic cortex in rats represent neural signals that may be used to distinguish between the cooperative and non-cooperative tasks, and such signals are distinct from the reward signals. Both signals may represent distinct components of the internal drive for cooperation.

Correction to: Projection from the Anterior Cingulate Cortex to the Lateral Part of Mediodorsal Thalamus Modulates Vicarious Freezing Behavior.

The authors found that in this article.

Spike Phase Shift Relative to Beta Oscillations Mediates Modality Selection.

How does the brain selectively process signals from stimuli of different modalities? Coherent oscillations may function in coordinating communication between neuronal populations simultaneously involved in such cognitive behavior. Beta power (12-30 Hz) is implicated in top-down cognitive processes. Here we test the hypothesis that the brain increases encoding and behavioral influence of a target modality by shifting the relationship of neuronal spike phases relative to beta oscillations between primary sensory cortices and higher cortices. We simultaneously recorded neuronal spike and local field potentials in the posterior parietal cortex (PPC) and the primary auditory cortex (A1) when male rats made choices to either auditory or visual stimuli. Neuronal spikes exhibited modality-related phase locking to beta oscillations during stimulus sampling, and the phase shift between neuronal subpopulations demonstrated faster top-down signaling from PPC to A1 neurons when animals attended to auditory rather than visual stimuli. Importantly, complementary to spike timing, spike phase predicted rats' attended-to target in single trials, which was related to the animals' performance. Our findings support a candidate mechanism that cortices encode targets from different modalities by shifting neuronal spike phase. This work may extend our understanding of the importance of spike phase as a coding and readout mechanism.

Projection from the Anterior Cingulate Cortex to the Lateral Part of Mediodorsal Thalamus Modulates Vicarious Freezing Behavior.

Emotional contagion, a primary form of empathy, is present in rodents. Among emotional contagion behaviors, social transmission of fear is the most studied. Here, we modified a paradigm used in previous studies to more robustly assess the social transmission of fear in rats that experienced foot-shock. We used resting-state functional magnetic resonance imaging to show that foot-shock experience enhances the regional connectivity of the anterior cingulate cortex (ACC). We found that lesioning the ACC specifically attenuated the vicarious freezing behavior of foot-shock-experienced observer rats. Furthermore, ablation of projections from the ACC to the mediodorsal thalamus (MDL) bilaterally delayed the vicarious freezing responses, and activation of these projections decreased the vicarious freezing responses. Overall, our results demonstrate that, in rats, the ACC modulates vicarious freezing behavior via a projection to the MDL and provide clues to understanding the mechanisms underlying empathic behavior in humans.

Persistent Neuronal Activity in Anterior Cingulate Cortex Correlates with Sustained Attention in Rats Regardless of Sensory Modality.

The anterior cingulate cortex (ACC) has long been thought to regulate conflict between an object of attention and distractors during goal-directed sustained attention. However, it is unclear whether ACC serves to sustained attention itself. Here, we developed a task in which the time course of sustained attention could be controlled in rats. Then, using pharmacological lesion experiments, we employed it to assess function of ACC in sustained attention. We then recorded neuronal activity in ACC using multichannel extracellular recording techniques and identified specific ACC neurons persistently activated during the period of attention. Further experiments showed that target modality had minimal influence on the neuronal activity, and distracting external sensory input during the attention period did not perturb persistent neuronal activity. Additionally, minimal trial-to-trial variability in neuronal activity observed during sustained attention supports a role for ACC neurons in that behavior. Therefore, we conclude that the ACC neuronal activity correlates with sustained attention.

The Fast Spiking Subpopulation of Striatal Neurons Coding for Temporal Cognition of Movements.

Background: Timing dysfunctions occur in a number of neurological and psychiatric disorders such as Parkinson's disease, obsessive-compulsive disorder, autism and attention-deficit-hyperactivity disorder. Several lines of evidence show that disrupted timing processing is involved in specific fronto-striatal abnormalities. The striatum encodes reinforcement learning and procedural motion, and consequently is required to represent temporal information precisely, which then guides actions in proper sequence. Previous studies highlighted the temporal scaling property of timing-relevant striatal neurons; however, it is still unknown how this is accomplished over short temporal latencies, such as the sub-seconds to seconds range. Methods: We designed a task with a series of timing behaviors that required rats to reproduce a fixed duration with robust action. Using chronic multichannel electrode arrays, we recorded neural activity from dorso-medial striatum in 4 rats performing the task and identified modulation response of each neuron to different events. Cell type classification was performed according to a multi-criteria clustering analysis. Results: Dorso-medial striatal neurons (n = 557) were recorded, of which 113 single units were considered as timing-relevant neurons, especially the fast-spiking subpopulation that had trial-to-trial ramping up or ramping down firing modulation during the time estimation period. Furthermore, these timing-relevant striatal neurons had to calibrate the spread of their firing pattern by rewarded experience to express the timing behavior accurately. Conclusion: Our data suggests that the dynamic activities of timing-relevant units encode information about the current duration and recent outcomes, which is needed to predict and drive the following action. These results reveal the potential mechanism of time calibration in a short temporal resolution, which may help to explain the neural basis of motor coordination affected by certain physiological or pathological conditions.

Periaqueductal Gray Neuronal Activities Underlie Different Aspects of Defensive Behaviors.

UNLABELLED: Defense is a basic survival mechanism when animals face danger. Previous studies have suggested that the midbrain periaqueductal gray (PAG) is essential for the generation of defensive reactions. Here we showed that optogenetic activation of neurons in the PAG in mice was sufficient to induce a series of defensive responses (including running, freezing, and avoidance). However, the endogenous neural dynamics of the PAG underlying defensive behaviors still remain elusive. Using chronic extracellular recording, we recorded the spiking activities of PAG neurons in freely behaving mice exposed to natural threats (rats). We observed that there exist distinct neuronal subsets within the PAG participating in respective detection (risk assessment) and response (flight) aspects of defensive behaviors. Our results demonstrate the important role of PAG neuronal activities in the control of different aspects of defensive behaviors, and provide novel insights for investigating defense from an electrophysiological perspective. SIGNIFICANCE STATEMENT: Defense is crucial for animals' survival in nature. Here, using optogenetic stimulation and in vivo recording in behaving mice reacting to threats, we explored the role of the midbrain periaqueductal gray (PAG) in defense. We show that optogenetic activation of PAG neurons is sufficient to elicit different aspects of defensive responses. Consistently, the present study provides in vivo evidence demonstrating that activity of the population of dorsal PAG neurons is activated during defense. Also, different subpopulations of units recorded in the dorsal PAG participate in distinct aspects of defensive behaviors. These findings help us understand the role of the PAG in animal behavior at the single neuron level.

Transmembrane channel-like (tmc) gene regulates Drosophila larval locomotion.

Drosophila larval locomotion, which entails rhythmic body contractions, is controlled by sensory feedback from proprioceptors. The molecular mechanisms mediating this feedback are little understood. By using genetic knock-in and immunostaining, we found that the Drosophila melanogaster transmembrane channel-like (tmc) gene is expressed in the larval class I and class II dendritic arborization (da) neurons and bipolar dendrite (bd) neurons, both of which are known to provide sensory feedback for larval locomotion. Larvae with knockdown or loss of tmc function displayed reduced crawling speeds, increased head cast frequencies, and enhanced backward locomotion. Expressing Drosophila TMC or mammalian TMC1 and/or TMC2 in the tmc-positive neurons rescued these mutant phenotypes. Bending of the larval body activated the tmc-positive neurons, and in tmc mutants this bending response was impaired. This implicates TMC's roles in Drosophila proprioception and the sensory control of larval locomotion. It also provides evidence for a functional conservation between Drosophila and mammalian TMCs.

Neural activity of orbitofrontal cortex contributes to control of waiting.

The willingness to wait for delayed reward and information is of fundamental importance for deliberative behaviors. The orbitofrontal cortex (OFC) is thought to be a core component of the neural circuitry underlying the capacity to control waiting. However, the neural correlates of active waiting and the causal role of the OFC in the control of waiting still remain largely unknown. Here, we trained rats to perform a waiting task (waiting for a pseudorandom time to obtain the water reward), and recorded neuronal ensembles in the OFC throughout the task. We observed that subset OFC neurons exhibited ramping activities throughout the waiting process. Receiver operating characteristic analysis showed that neural activities during the waiting period even predicted the trial outcomes (patient vs. impatient) on a trial-by-trial basis. Furthermore, optogenetic activation of the OFC during the waiting period improved the waiting performance, but did not influence rats' movement to obtain the reward. Taken together, these findings reveal that the neural activity in the OFC contributes to the control of waiting.

Suppression of human hepatocellular cancer cell proliferation by Brucea javanica oil-loaded liposomes via induction of apoptosis.

INTRODUCTION: Hepatocellular carcinoma (HCC) is a type of malignancy with high incidence and poor prognosis. Brucea javanica is extracted from Simaroubaceae plants. It is found to have low toxicity but high anti-cancer efficiency. The aim of this study is to determine the effects of Brucea javanica oil-loaded liposomes (BJOL) on human hepatocellular cancer cell line HepG2. The related molecular mechanisms were determined. MATERIAL AND METHODS: Morphologic changes of HepG2 cells were observed by transmission electron microscope after treatment with BJOL in vitro. Cell proliferation was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay after cell treatment with different doses of BJOL. Flow cytometry was performed. Nude mice were divided into 4 groups randomly and treated with different doses of BJOL. The apoptosis hepatocellular carcinoma was detected by TUNEL. RESULTS: Proliferation of HepG2 was inhibited significantly by BJOL in a dose-dependent manner (2.5 mg/l or 5 mg/l). Compared with the animal models treated with the negative control, the animal models in the BJOL group had higher weight and lower metastasis rates (p < 0.01). The rate of apoptosis in hepatocellular carcinoma tissue of the BJOL groups was increased when compared with the control group (p < 0.05). CONCLUSIONS: Brucea javanica oil-loaded liposomes inhibits proliferation of HepG2. The effect appears to be dose-dependent, possibly by inducing apoptosis of cancer cells.

MicroRNA-21 Down-regulates Rb1 Expression by Targeting PDCD4 in Retinoblastoma.

Retinoblastoma (RB) is a children's ocular cancer caused by mutated retinoblastoma 1 (Rb1) gene on both alleles. Rb1 and other related genes could be regulated by microRNAs (miRNA) via complementarily pairing with their target sites. MicroRNA-21 (miR-21) possesses the oncogenic potential to target several tumor suppressor genes, including PDCD4, and regulates tumor progression and metastasis. However, the mechanism of how miR-21 regulates PDCD4 is poorly understood in RB. We investigated the expression of miRNAs in RB cell lines and identified that miR-21 is one of the most deregulated miRNAs in RB. Using qRT-PCR, we verified the expression level of several miRNAs identified by independent microarray assays, and analyzed miRNA expression patterns in three RB cell lines, including Weri-Rb1, Y79 and RB355. We found that miR-19b, -21, -26a, -195 and -222 were highly expressed in all three cell lines, suggesting their potential role in RB tumorigenesis. Using the TargetScan program, we identified a list of potential target genes of these miRNAs, of which PDCD4 is one the targets of miR-21. In this study, we focused on the regulatory mechanism of miR-21 on PDCD4 in RB. We demonstrated an inverse correlation between miR-21 and PDCD4 expression in Weri-Rb1 and Y79 cells. These data suggest that miR-21 down-regulates Rb1 by targeting PDCD4 tumor suppressor. Therefore, miR-21 could serve as a therapeutic target for retinoblastoma.

The role of PPK26 in Drosophila larval mechanical nociception.

In Drosophila larvae, the class IV dendritic arborization (da) neurons are polymodal nociceptors. Here, we show that ppk26 (CG8546) plays an important role in mechanical nociception in class IV da neurons. Our immunohistochemical and functional results demonstrate that ppk26 is specifically expressed in class IV da neurons. Larvae with mutant ppk26 showed severe behavioral defects in a mechanical nociception behavioral test but responded to noxious heat stimuli comparably to wild-type larvae. In addition, functional studies suggest that ppk26 and ppk (also called ppk1) function in the same pathway, whereas piezo functions in a parallel pathway. Consistent with these functional results, we found that PPK and PPK26 are interdependent on each other for their cell surface localization. Our work indicates that PPK26 and PPK might form heteromeric DEG/ENaC channels that are essential for mechanotransduction in class IV da neurons.

Parallel pathways convey olfactory information with opposite polarities in Drosophila.

In insects, olfactory information received by peripheral olfactory receptor neurons (ORNs) is conveyed from the antennal lobes (ALs) to higher brain regions by olfactory projection neurons (PNs). Despite the knowledge that multiple types of PNs exist, little is known about how these different neuronal pathways work cooperatively. Here we studied the Drosophila GABAergic mediolateral antennocerebral tract PNs (mlPNs), which link ipsilateral AL and lateral horn (LH), in comparison with the cholinergic medial tract PNs (mPNs). We examined the connectivity of mlPNs in ALs and found that most mlPNs received inputs from both ORNs and mPNs and participated in AL network function by forming gap junctions with other AL neurons. Meanwhile, mlPNs might innervate LH neurons downstream of mPNs, exerting a feedforward inhibition. Using dual-color calcium imaging, which enables a simultaneous monitoring of neural activities in two groups of PNs, we found that mlPNs exhibited robust odor responses overlapping with, but broader than, those of mPNs. Moreover, preferentially down-regulation of GABA in most mlPNs caused abnormal courtship and aggressive behaviors in male flies. These findings demonstrate that in Drosophila, olfactory information in opposite polarities are carried coordinately by two parallel and interacted pathways, which could be essential for appropriate behaviors.

Upregulated expression levels of ADAM10 and EGFR and downregulated expression levels of E-cadherin in hepatocellular carcinomas.

The aim of this study was to investigate the expression and significance of a disintegrin and metalloproteinase 10 (ADAM10), epidermal growth factor receptor (EGFR) and E-cadherin protein in hepatocellular carcinomas. The expression levels of ADAM10, EGFR and E-cadherin were analyzed in 40 cases of hepatocellular carcinoma using immunohistochemistry and quantitative polymerase chain reaction (qPCR). The expression levels of ADAM10, EGFR and E-cadherin were significantly correlated with portal vein thrombosis, intrahepatic metastasis, differentiation degree and tumor size (P<0.05). In hepatocellular carcinoma, the expression levels of ADAM10 and EGFR were increased and the levels of E-cadherin were decreased compared with those in the adjacent tissues. The elevated expression levels of ADAM10 and EGFR may be associated with the malignancy of the tumors. E-cadherin expression is negatively correlated with the degree of malignancy. The detection of ADAM10, EGFR and E-cadherin expression levels may contribute to an understanding of the oncogenesis and development of hepatocellular carcinomas.

A novel Bayesian seamless phase I/II design.

This paper proposes a novel bayesian phase I/II design featuring using a hybrid mTPI method in phase I for targeting the MTD level and a randomization allocation schema for adaptively assigning patients to desirable doses in phase II. The mechanism of simultaneously escalating dose in phase I and expanding promising doses to phase II is inherited from a design proposed in literature. Extensive simulation studies indicate that our proposed design can vastly save sample size and efficiently assign more patients to optimal dose when compared to two competing designs.

Downregulation of ADAM10 expression inhibits metastasis and invasiveness of human hepatocellular carcinoma HepG2 cells.

OBJECTIVE: This study aims to investigate the effects of ADAM10 expression on metastasis and invasiveness of human hepatocellular carcinoma HepG2 cells. METHODS: The HepG2 cells were transfected with medium only, the empty vector, the control siRNA, or siRNA against ADAM10, respectively. Cell migration assay and Transwell invasiveness assay were performed to detect the effects of ADAM10 knockdown on migration and invasiveness of HepG2 cells. Western blotting and real-time RT PCR were performed to investigate the effects of knock-down of ADAM10 on protein and mRNA levels of E-cadherin gene. RESULTS: Cell migration and invasiveness of HepG2 cells transfected with ADAM10 siRNA were significantly decreased, when compared with the cells transfected with the control siRNA, suggesting that the downregulation of ADAM10 expression inhibits cell migration and invasiveness. The Western blotting results suggest that the down-regulation of ADAM10 expression increases E-cadherin protein levels. The real-time RT-PCR results indicated that the mRNA level of E-cadherin is not detectably affected by the knock-down of ADAM10 gene. CONCLUSIONS: Expression of ADAM10 may be related to cell migration and invasiveness of human hepatocellular carcinoma HepG2 cells via a mechanism related to E-cadherin.

NOMPC is likely a key component of Drosophila mechanotransduction channels.

Mechanotransduction is the basis of several sensory modalities, including touch, hearing, proprioception and gravity sensation. Despite its importance to sensory processing and behavior, the molecular mechanisms underlying mechanotransduction remain to be fully understood. In particular, the identity of the ion channels serving mechanotransduction is still unknown in many species. Drosophila melanogaster nompC (no mechanoreceptor potential C) has been shown to be essential for mechanotransduction in flies, yet there is no direct evidence demonstrating that NOMPC is indeed a mechanotransducing ion channel in Drosophila. To dissect the functional roles of NOMPC in mechanotransduction, we found that NOMPC-dependent transient adapting mechanoreceptor current (MRC) in the external bristle sensory organ was also chloride dependent. However, this chloride-dependent current was not necessary for spike generation. Furthermore, ectopic expression of wild-type NOMPC conferred mechanosensitivity on the interneurons in the antennal lobe (AL) and cation-mediated inward mechanocurrent was recorded, while a point mutation in the putative selective filter region of NOMPC failed to produce the mechanocurrent in the AL interneurons. These functional studies imply that NOMPC is likely to be a crucial component of mechanotransducers that accounts for mechanotransductions in mechanosensory neurons of Drosophila.

Functional study of hyperpolarization activated channel (Ih) in Drosophila behavior.

Hyperpolarization-activated, cyclic nucleotide-gated and cation-nonselective ion channels (I ( h ) channels, or HCN channels) are known to play important roles in mammals. Their physiological functions in invertebrate remain largely unclear. Here, we report our studies with I ( h ) channel in Drosophila melanogaster. Drosophila Ih channel mutants are found with several defects by behavioral analyses. Their lifespan is reduced, and their chemical sensitivity is shifted. In addition, their length of sleep at light-dark condition is mildly reduced. We generated transgenic flies of I ( h ) promoter-driven Gal4 and examined its expression pattern in both larvae and adult flies. Our results suggest that I ( h ) channel may play diverse roles in Drosophila and provide a basis to further expand our understanding of Drosophila Ih channel function in vivo.