Conserved structures of neural activity in sensorimotor cortex of freely moving rats allow cross-subject decoding.

Our knowledge about neuronal activity in the sensorimotor cortex relies primarily on stereotyped movements that are strictly controlled in experimental settings. It remains unclear how results can be carried over to less constrained behavior like that of freely moving subjects. Toward this goal, we developed a self-paced behavioral paradigm that encouraged rats to engage in different movement types. We employed bilateral electrophysiological recordings across the entire sensorimotor cortex and simultaneous paw tracking. These techniques revealed behavioral coupling of neurons with lateralization and an anterior-posterior gradient from the premotor to the primary sensory cortex. The structure of population activity patterns was conserved across animals despite the severe under-sampling of the total number of neurons and variations in electrode positions across individuals. We demonstrated cross-subject and cross-session generalization in a decoding task through alignments of low-dimensional neural manifolds, providing evidence of a conserved neuronal code.

Multichannel optogenetics combined with laminar recordings for ultra-controlled neuronal interrogation.

Simultaneous large-scale recordings and optogenetic interventions may hold the key to deciphering the fast-paced and multifaceted dialogue between neurons that sustains brain function. Here we have taken advantage of thin, cell-sized, optical fibers for minimally invasive optogenetics and flexible implantations. We describe a simple procedure for making those fibers side-emitting with a Lambertian emission distribution. Here we combined those fibers with silicon probes to achieve high-quality recordings and ultrafast multichannel optogenetic inhibition. Furthermore, we developed a multi-channel optical commutator and general-purpose patch-cord for flexible experiments. We demonstrate that our framework allows to conduct simultaneous laminar recordings and multifiber stimulations, 3D optogenetic stimulation, connectivity inference, and behavioral quantification in freely moving animals. Our framework paves the way for large-scale photo tagging and controlled interrogation of rapid neuronal communication in any combination of brain areas.

Distinct dynamics of neuronal activity during concurrent motor planning and execution.

The smooth conduct of movements requires simultaneous motor planning and execution according to internal goals. So far it remains unknown how such movement plans are modified without interfering with ongoing movements. Previous studies have isolated planning and execution-related neuronal activity by separating behavioral planning and movement periods in time by sensory cues. Here, we separate continuous self-paced motor planning from motor execution statistically, by experimentally minimizing the repetitiveness of the movements. This approach shows that, in the rat sensorimotor cortex, neuronal motor planning processes evolve with slower dynamics than movement-related responses. Fast-evolving neuronal activity precees skilled forelimb movements and is nested within slower dynamics. We capture this effect via high-pass filtering and confirm the results with optogenetic stimulations. The various dynamics combined with adaptation-based high-pass filtering provide a simple principle for separating concurrent motor planning and execution.

A starting kit for training and establishing in vivo electrophysiology, intracranial pharmacology, and optogenetics.

BACKGROUND: In accordance with the three R principles of research, animal usage should be limited as much as possible. Especially for the training of entry-level scientists in surgical techniques underlying opto- and electrophysiology, alternative training tools are required before moving on to live animals. We have developed a cost-effective rat brain model for training a wide range of surgical techniques, including, but not limited to optogenetics, electrophysiology, and intracranial pharmacological treatments. RESULTS: Our brain model creates a realistic training experience in animal surgery. The success of the surgeries (e.g. implantation accuracy) is readily assessable in cross sections of the model brain. Moreover, the model allows practicing electrophysiological recordings as well as testing for movement or light related artefacts. COMPARISON WITH EXISTING METHOD(S): The surgery and recording experience in our model closely resembles that in an actual rat in terms of the necessary techniques, considerations and time span. A few differences to an actual rat brain slightly reduce the difficulty in our model compared to a live animal. Thus, entry level scientists can first learn basic techniques in our model before moving on to the slightly more complex procedures in live animals. CONCLUSIONS: Our brain model is a useful training tool to equip scientist who are new in the field of electrophysiology and optogenetic manipulations with a basic skill set before applying it in live animals. It can be adapted to fit the desired training content or even to serve in testing and optimizing new lab equipment for more senior scientists.

Predictive factors for time to full enteral feeding after pyloromyotomy for infantile hypertrophic pyloric stenosis.

Background: The aim of the study was to evaluate how different parameters in the preoperative, perioperative, and postoperative period affect time to full enteral feeding (TFEF) in children undergoing pyloromyotomy. Methods: A retrospective study of all children operated for infantile hypertrophic pyloric stenosis between 2001 and 2017 was conducted. Parameters in demographics and in the preoperative and postoperative period were evaluated against TFEF (hours) using linear regression models. Results: In the whole cohort of 175 children, mean TFEF was 47 hours with Standard Deviation (SD) of ±35. In the multivariate model, TFEF decreased with age [beta (B): -0.62; 95% confidence interval (95% CI) -1.05 to -0.19; p=0.005) and increased with the presence of severe underlying disease (congenital heart defect or syndrome) (B: 26.5; 95% CI 3.3 to 49.7; p=0.026). Hence, for every day of age, the time to fully fed decreased by 0.6 hour, and the presence of an underlying disease increased the time to fully fed with over one day. TFEF did not seem to be affected by prematurity, weight loss, symptom duration, preoperative acid/base balance or electrolyte values, surgical method, or method of postoperative feeding. Conclusions: TFEF decreased with higher age and increased in children with a severe underlying disease. These results may be useful in providing adequate parental information regarding what affects TFEF and the length of hospital stay.

Diagnostic Accuracy of History and Physical Examination for Predicting Major Adverse Cardiac Events Within 30 Days in Patients With Acute Chest Pain.

BACKGROUND: The cornerstones in the assessment of emergency department (ED) patients with suspected acute coronary syndrome (ACS) are patient history and physical examination, electrocardiogram, and cardiac troponins. Although there are several prior studies on this subject, they have in some cases produced inconsistent results. OBJECTIVE: The aim of this study was to evaluate the diagnostic and prognostic accuracy of elements of patient history and the physical examination in ED chest pain patients for predicting major adverse cardiac events (MACE) within 30 days. METHODS: This was a prospective observational study that included 1167 ED patients with nontraumatic chest pain. We collected clinical data during the initial ED assessment of the patients. Our primary outcome was 30-day MACE. RESULTS: Pain radiating to both arms increased the probability of 30-day MACE (positive likelihood ratio [LR+] 2.7), whereas episodic chest pain lasting seconds (LR+ 0.0) and >24 h (LR+ 0.1) markedly decreased the risk. In the physical examination, pulmonary rales (LR+ 3.0) increased the risk of 30-day MACE, while pain reproduced by palpation (LR+ 0.3) decreased the risk. Among cardiac risk factors, a history of diabetes (LR+ 3.0) and peripheral arterial disease (LR+ 2.7) were the most predictive factors. CONCLUSIONS: No clinical findings reliably ruled in 30-day MACE, whereas episodic chest pain lasting seconds and pain lasting more than 24 h markedly decreased the risk of 30-day MACE. Consequently, these two findings can be adjuncts in ruling out 30-day MACE.

Callosal Influence on Visual Receptive Fields Has an Ocular, an Orientation-and Direction Bias.

One leading hypothesis on the nature of visual callosal connections (CC) is that they replicate features of intrahemispheric lateral connections. However, CC act also in the central part of the binocular visual field. In agreement, early experiments in cats indicated that they provide the ipsilateral eye part of binocular receptive fields (RFs) at the vertical midline (Berlucchi and Rizzolatti, 1968), and play a key role in stereoscopic function. But until today callosal inputs to receptive fields activated by one or both eyes were never compared simultaneously, because callosal function has been often studied by cutting or lesioning either corpus callosum or optic chiasm not allowing such a comparison. To investigate the functional contribution of CC in the intact cat visual system we recorded both monocular and binocular neuronal spiking responses and receptive fields in the 17/18 transition zone during reversible deactivation of the contralateral hemisphere. Unexpectedly from many of the previous reports, we observe no change in ocular dominance during CC deactivation. Throughout the transition zone, a majority of RFs shrink, but several also increase in size. RFs are significantly more affected for ipsi- as opposed to contralateral stimulation, but changes are also observed with binocular stimulation. Noteworthy, RF shrinkages are tiny and not correlated to the profound decreases of monocular and binocular firing rates. They depend more on orientation and direction preference than on eccentricity or ocular dominance of the receiving neuron's RF. Our findings confirm that in binocularly viewing mammals, binocular RFs near the midline are constructed via the direct geniculo-cortical pathway. They also support the idea that input from the two eyes complement each other through CC: Rather than linking parts of RFs separated by the vertical meridian, CC convey a modulatory influence, reflecting the feature selectivity of lateral circuits, with a strong cardinal bias.

Interventions for treating genital Chlamydia trachomatis infection in pregnancy.

BACKGROUND: Genital Chlamydia trachomatis (C.trachomatis) infection may lead to pregnancy complications such as miscarriage, preterm labour, low birthweight, preterm rupture of membranes, increased perinatal mortality, postpartum endometritis, chlamydial conjunctivitis and C.trachomatis pneumonia.This review supersedes a previous review on this topic. OBJECTIVES: To establish the most efficacious and best-tolerated therapy for treatment of genital chlamydial infection in preventing maternal infection and adverse neonatal outcomes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (26 June 2017) and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) as well as studies published in abstract form assessing interventions for treating genital C.trachomatis infection in pregnancy. Cluster-RCTs were also eligible for inclusion but none were identified. Quasi-randomised trials and trials using cross-over design are not eligible for inclusion in this review. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion, assessed trial quality and extracted the data using the agreed form. Data were checked for accuracy. Evidence was assessed using the GRADE approach. MAIN RESULTS: We included 15 trials (involving 1754 women) although our meta-analyses were based on fewer numbers of studies/women. All of the included studies were undertaken in North America from 1982 to 2001. Two studies were low risk of bias in all domains, all other studies had varying risk of bias. Four other studies were excluded and one study is ongoing.Eight comparisons were included in this review; three compared antibiotic (erythromycin, clindamycin, amoxicillin) versus placebo; five compared an antibiotic versus another antibiotic (erythromycin, clindamycin, amoxicillin, azithromycin). No study reported different antibiotic regimens. Microbiological cure (primary outcome) Antibiotics versus placebo: Erythromycin (average risk ratio (RR) 2.64, 95% confidence interval (CI) 1.60 to 4.38; two trials, 495 women; I2 = 68%; moderate-certainty evidence), and clindamycin (RR 4.08, 95% CI 2.35 to 7.08; one trial, 85 women;low-certainty evidence) were associated with improved microbiological cure compared to a placebo control. In one very small trial comparing amoxicillin and placebo, the results were unclear, but the evidence was graded very low (RR 2.00, 95% CI 0.59 to 6.79; 15 women). One antibiotic versus another antibiotic: Amoxicillin made little or no difference in microbiological cure in comparison to erythromycin (RR 0.97, 95% CI 0.93 to 1.01; four trials, 466 women; high-certainty evidence), probably no difference compared to clindamycin (RR 0.96, 95% CI 0.89 to 1.04; one trial, 101 women; moderate-quality evidence), and evidence is very low certainty when compared to azithromycin so the effect is not certain (RR 0.89, 95% CI 0.71 to 1.12; two trials, 144 women; very low-certainty evidence). Azithromycin versus erythromycin (average RR 1.11, 95% CI 1.00 to 1.23; six trials, 374 women; I2 = 53%; moderate-certainty evidence) probably have similar efficacy though results appear to favour azithromycin. Clindamycin versus erythromycin (RR 1.06, 95% CI 0.97 to 1.15; two trials, 173 women; low-certainty evidence) may have similar numbers of women with a microbiological cure between groups.Evidence was downgraded for design limitations, inconsistency, and imprecision in effect estimates. Side effects of the treatment (maternal) (secondary outcome) Antibiotics versus placebo: side effects including nausea, vomiting, and abdominal pain, were reported in two studies (495 women) but there was no clear evidence whether erythromycin was associated with more side effects than placebo and a high level of heterogeneity (I2 = 78%) was observed (average RR 2.93, 95% CI 0.36 to 23.76). There was no clear difference in the number of women experiencing side effects when clindamycin was compared to placebo in one small study (5/41 versus 1/44) (RR 6.35, 95% CI 0.38 to 107.45, 62 women). The side effects reported were mostly gastrointestinal and also included resolving skin rashes. One antibiotic versus another antibiotic: There was no clear difference in incidence of side effects (including nausea, vomiting, diarrhoea and abdominal pain) when amoxicillin was compared to azithromycin based on data from one small study (36 women) (RR 0.56, 95% CI 0.24 to 1.31).However, amoxicillin was associated with fewer side effects compared to erythromycin with data from four trials (513 women) (RR 0.31, 95% CI 0.21 to 0.46; I2 = 27%). Side effects included nausea, vomiting, diarrhoea, abdominal cramping, rash, and allergic reaction.Both azithromycin (RR 0.24, 95% CI 0.17 to 0.34; six trials, 374 women) and clindamycin (RR 0.44, 95% CI 0.22 to 0.87; two trials, 183 women) were associated with a lower incidence of side effects compared to erythromycin. These side effects included nausea, vomiting, diarrhoea and abdominal cramping.One small study (101 women) reported there was no clear difference in the number of women with side effects when amoxicillin was compared with clindamycin (RR 0.57, 95% CI 0.14 to 2.26; 107 women). The side effects reported included rash and gastrointestinal complaints. Other secondary outcomes Single trials reported data on repeated infections, preterm birth, preterm rupture of membranes, perinatal mortality and low birthweight and found no clear differences between treatments.Many of this review's secondary outcomes were not reported in the included studies. AUTHORS' CONCLUSIONS: Treatment with antibacterial agents achieves microbiological cure from C.trachomatis infection during pregnancy. There was no apparent difference between assessed agents (amoxicillin, erythromycin, clindamycin, azithromycin) in terms of efficacy (microbiological cure and repeat infection) and pregnancy complications (preterm birth, preterm rupture of membranes, low birthweight). Azithromycin and clindamycin appear to result in fewer side effects than erythromycin.All of the studies in this review were conducted in North America, which may limit the generalisability of the results. In addition, study populations may differ in low-resource settings and these results are therefore only applicable to well-resourced settings. Furthermore, the trials in this review mainly took place in the nineties and early 2000's and antibiotic resistance may have changed since then.Further well-designed studies, with appropriate sample sizes and set in a variety of settings, are required to further evaluate interventions for treating C.trachomatis infection in pregnancy and determine which agents achieve the best microbiological cure with the least side effects. Such studies could report on the outcomes listed in this review.

A Toolbox for Optophysiological Experiments in Freely Moving Rats.

Simultaneous recordings and manipulations of neural circuits that control the behavior of animals is one of the key techniques in modern neuroscience. Rapid advances in optogenetics have led to a variety of probes combining multichannel readout and optogenetic write in. Given the complexity of the brain, it comes as no surprise that the choice of the device is constrained by several factors such as the animal model, the structure and location of the brain area of interest, as well as the behavioral read out. Here we provide an overview of available devices for chronic simultaneous neural recordings and optogenetic manipulation in awake behaving rats. We focus on two fixed arrays and two moveable drives. For both options, we present data from one custom-made (in house) and one commercially available device. Here we provide evidence that simultaneous neural recordings and optogenetic manipulations are feasible with all four tested devices. Further we give detailed information about the recording quality, and also contrast the different features of the probes. As we provide detailed information about equipment and building procedures for combined chronic multichannel readout and optogenetic control with maximum performance at minimized costs, this overview might help especially researchers who want to enter the field of in vivo optophysiology.

A Principle for Describing and Verifying Brain Mechanisms Using Ongoing Activity.

Not even the most informed scientist can setup a theory that takes all brain signals into account. A neuron not only receives neuronal short range and long range input from all over the brain but a neuron also receives input from the extracellular space, astrocytes and vasculature. Given this complexity, how does one describe and verify a typical brain mechanism in vivo? Common to most described mechanisms is that one focuses on how one specific input signal gives rise to the activity in a population of neurons. This can be an input from a brain area, a population of neurons or a specific cell type. All remaining inputs originating from all over the brain are lumped together into one background input. The division into two inputs is attractive since it can be used to quantify the relative importance of either input. Here we have chosen to extract the specific and the background input by means of recording and inhibiting the specific input. We summarize what it takes to estimate the two inputs on a single trial level. The inhibition should not only be strong but also fast and the specific input measurement has to be tailor-made to the inhibition. In essence, we suggest ways to control electrophysiological experiments in vivo. By applying those controls it may become possible to describe and verify many brain mechanisms, and it may also allow the study of the integration of spontaneous and ongoing activity, which in turn governs cognition and behavior.

A Functional Gradient in the Rodent Prefrontal Cortex Supports Behavioral Inhibition.

The ability to plan and execute appropriately timed responses to external stimuli is based on a well-orchestrated balance between movement initiation and inhibition. In impulse control disorders involving the prefrontal cortex (PFC) [1], this balance is disturbed, emphasizing the critical role that PFC plays in appropriately timing actions [2-4]. Here, we employed optogenetic and electrophysiological techniques to systematically analyze the functional role of five key subareas of the rat medial PFC (mPFC) and orbitofrontal cortex (OFC) in action control [5-9]. Inactivation of mPFC subareas induced drastic changes in performance, namely an increase (prelimbic cortex, PL) or decrease (infralimbic cortex, IL) of premature responses. Additionally, electrophysiology revealed a significant decrease in neuronal activity of a PL subpopulation prior to premature responses. In contrast, inhibition of OFC subareas (mainly the ventral OFC, i.e., VO) significantly impaired the ability to respond rapidly after external cues. Consistent with these findings, mPFC activity during response preparation predicted trial outcomes and reaction times significantly better than OFC activity. These data support the concept of opposing roles of IL and PL in directing proactive behavior and argue for an involvement of OFC in predominantly reactive movement control. By attributing defined roles to rodent PFC sections, this study contributes to a deeper understanding of the functional heterogeneity of this brain area and thus may guide medically relevant studies of PFC-associated impulse control disorders in this animal model for neural disorders [10-12].

Selective interhemispheric circuits account for a cardinal bias in spontaneous activity within early visual areas.

Ongoing brain activity exhibits patterns resembling neural ensembles co-activated by stimulation or task performance. Such patterns have been attributed to the brain's functional architecture, e.g. selective long-range connections. Here, we directly investigate the contribution of selective connections between hemispheres to spontaneous and evoked maps in cat area 18 close to the 17/18 border. We recorded voltage-sensitive dye imaging maps and spiking activity while manipulating interhemispheric input by reversibly deactivating corresponding contralateral areas. During deactivation, spontaneous maps continued to be generated with similar frequency and quality as in the intact network but a baseline cardinal bias disappeared. Consistently, neurons preferring either horizontal (HN) or vertical (VN), as opposed to oblique contours, decreased their resting state activity. HN decreased their rates also when stimulated visually. We conclude that structured spontaneous maps are primarily generated by thalamo- and/or intracortical connectivity. However, selective long-range connections through the corpus callosum - in perpetuation of the long-range intracortical network - contribute to a cardinal bias, possibly, because they are stronger or more frequent between neurons preferring horizontal and/or cardinal contours. As those contours are easier perceived and appear more frequently in natural environment, long-range connections might provide visual cortex with a grid for probabilistic grouping operations in a larger visual scene.

Estimating Neural Background Input with Controlled and Fast Perturbations: A Bandwidth Comparison between Inhibitory Opsins and Neural Circuits.

To test the importance of a certain cell type or brain area it is common to make a "lack of function" experiment in which the neuronal population of interest is inhibited. Here we review physiological and methodological constraints for making controlled perturbations using the corticothalamic circuit as an example. The brain with its many types of cells and rich interconnectivity offers many paths through which a perturbation can spread within a short time. To understand the side effects of the perturbation one should record from those paths. We find that ephaptic effects, gap-junctions, and fast chemical synapses are so fast that they can react to the perturbation during the few milliseconds it takes for an opsin to change the membrane potential. The slow chemical synapses, astrocytes, extracellular ions and vascular signals, will continue to give their physiological input for around 20 ms before they also react to the perturbation. Although we show that some pathways can react within milliseconds the strength/speed reported in this review should be seen as an upper bound since we have omitted how polysynaptic signals are attenuated. Thus the number of additional recordings that has to be made to control for the perturbation side effects is expected to be fewer than proposed here. To summarize, the reviewed literature not only suggests that it is possible to make controlled "lack of function" experiments, but, it also suggests that such a "lack of function" experiment can be used to measure the context of local neural computations.

Estimating Fast Neural Input Using Anatomical and Functional Connectivity.

In the last 20 years there has been an increased interest in estimating signals that are sent between neurons and brain areas. During this time many new methods have appeared for measuring those signals. Here we review a wide range of methods for which connected neurons can be identified anatomically, by tracing axons that run between the cells, or functionally, by detecting if the activity of two neurons are correlated with a short lag. The signals that are sent between the neurons are represented by the activity in the neurons that are connected to the target population or by the activity at the corresponding synapses. The different methods not only differ in the accuracy of the signal measurement but they also differ in the type of signal being measured. For example, unselective recording of all neurons in the source population encompasses more indirect pathways to the target population than if one selectively record from the neurons that project to the target population. Infact, this degree of selectivity is similar to that of optogenetic perturbations; one can perturb selectively or unselectively. Thus it becomes possible to match a given signal measurement method with a signal perturbation method, something that allows for an exact input control to any neuronal population.

Input and output gain modulation by the lateral interhemispheric network in early visual cortex.

Neurons in the cerebral cortex are constantly integrating different types of inputs. Dependent on their origin, these inputs can be modulatory in many ways and, for example, change the neuron's responsiveness, sensitivity, or selectivity. To investigate the modulatory role of lateral input from the same level of cortical hierarchy, we recorded in the primary visual cortex of cats while controlling synaptic input from the corresponding contralateral hemisphere by reversible deactivation. Most neurons showed a pronounced decrease in their response to a visual stimulus of different contrasts and orientations. This indicates that the lateral network acts via an unspecific gain-setting mechanism, scaling the output of a neuron. However, the interhemispheric input also changed the contrast sensitivity of many neurons, thereby acting on the input. Such a contrast gain mechanism has important implications because it extends the role of the lateral network from pure response amplification to the modulation of a specific feature. Interestingly, for many neurons, we found a mixture of input and output gain modulation. Based on these findings and the known physiology of callosal connections in the visual system, we developed a simple model of lateral interhemispheric interactions. We conclude that the lateral network can act directly on its target, leading to a sensitivity change of a specific feature, while at the same time it also can act indirectly, leading to an unspecific gain setting. The relative contribution of these direct and indirect network effects determines the outcome for a particular neuron.

Genome wide expression analysis of radiation-induced DNA damage responses in isogenic HCT116 p53+/+ and HCT116 p53-/- colorectal carcinoma cell lines.

PURPOSE: To study the kinetics of gene expression alterations following radiation exposure of isogenic HCT116 p53 +/+ and HCT116 p53-/- cell lines. MATERIALS AND METHODS: Cells were exposed to 5 Gy of irradiation (Cs-137) and genome-wide temporal expression analysis using Illumina bead chip arrays was performed. Signalling pathways were explored using Metacore (Genego). Biological responses including cell cycle checkpoint activation, centrosome amplification and senescence induction were analyzed. RESULTS: Significant differences in the radiation response were observed between the p53+/+ and the p53-/- cell lines. In p53+/+ cells concurrent G1- and G2-arrests were activated followed by senescence induction. Increased expression of genes associated with senescence, senescence associated secretory phenotype (SASP) and repression of genes essential for G2-M transition were detected. P53-/- cells arrested mainly in G2 followed by centrosome amplification, mitotic slippage and a subsequent increase of polyploid cells. Furthermore, changes in expression correlated well with these signs of mitotic catastrophe. CONCLUSIONS: The presence or absence of p53 triggers different signalling cascades with different endpoints. Elucidating these differences is important as it enables improvement of radiation treatment and could be used to develop new combination treatments with specific inhibitors of key regulators of these cell death modalities.

Alterations in gene expression during radiation-induced mitotic catastrophe in HeLa Hep2 cells.

AIM: To explore kinetic changes in the gene expression profile during radiation-induced mitotic catastrophes. MATERIALS AND METHODS: Gene expression changes were measured in HPV-infected HeLa Hep2 tumor cells following exposure to 5 Gy of ionizing radiation ((60)Co). Signaling pathways were explored and correlated to the biological responses linked to mitotic catastrophe. RESULTS: Following irradiation a transient G2-arrest was induced. Anaphase bridge formation and centrosome hyperamplification was observed. These phenotypical changes correlated well with the observed gene expression changes. Genes with altered expression were found to be involved in mitotic processes as well as G2- and spindle assembly checkpoints. Also centrosome-associated genes displayed an increased expression. CONCLUSION: This study elucidates specific characteristics in the altered gene expression pattern induced by irradiation, which can be correlated to the events of mitotic catastrophe in HeLa Hep2 cells. Therapeutic strategies modulating these alterations might potentiate future therapy and enhance tumor cell killing.

An updated midline rule: visual callosal connections anticipate shape and motion in ongoing activity across the hemispheres.

It is generally thought that callosal connections (CCs) in primary visual cortices serve to unify the visual scenery parted in two at the vertical midline (VM). Here, we present evidence that this applies also to visual features that do not cross yet but might cross the VM in the future. During reversible deactivation of the contralateral visual cortex in cats, we observed that ipsilaterally recorded neurons close to the border between areas 17 and 18 receive selective excitatory callosal input on both ongoing and evoked activity. In detail, neurons responding well to a vertical Gabor patch moving away from the deactivated hemifield decreased prestimulus and stimulus-driven activity much more than those preferring motion toward the cooled hemifield. Further, activity of neurons responding to horizontal lines decreased more than the response to vertical lines. Embedding a single Gabor into a collinear line context selectively stabilized responses, especially when the context was limited to the intact hemifield. These findings indicate that CCs interconnect not only neurons coding for similar orientations but also for similar directions of motion. We conclude that CCs anticipate stimulus features that are potentially relevant for both hemifields (i.e., coherent motion but also collinear shape) because already prestimulus activity and activity to stimuli not crossing the VM revealed feature specificity. Finally, we hypothesize that intrinsic and callosal networks processing different orientations and directions are anisotropic close to the VM facilitating perceptual grouping along likely future motion or (shape) trajectories before the visual stimulus arrives.

Multiplicative mechanism of lateral interactions revealed by controlling interhemispheric input.

Long-range horizontal connections are thought to modulate the responsiveness of neurons by supplying contextual information. A special type of long-range connections are interhemispheric projections, linking the 2 cerebral hemispheres. To investigate the action of those projections in a causal approach, we recorded in cat primary visual cortex while deactivating corresponding regions on the contralateral hemisphere. Interestingly, the action of callosal projections turned out to depend on the local and global composition of the stimulus: Full-field stimulation with gratings revealed moderate rate decreases (modulation index -0.24) and some significant increases (+0.21), whereas with lesser salient random dot textures, much more neurons were affected and reacted with pronounced rate decreases (-0.4). However, orientation and direction selectivity of those neurons were only slightly influenced by callosal input. This invariance could be achieved by scaling responses multiplicatively. Indeed, we could quantify the action of callosal input as a multiplicative scaling of responses, but additive scaling also occurred, especially for grating stimulation. We conclude that the quantitative action of long-range horizontal connections is by no means fixed but depends on how the network is driven by an external stimulus. Qualitatively, those connections seem to adjust the response gain of neurons, thereby preserving their selectivity.

Visual cortex combines a stimulus and an error-like signal with a proportion that is dependent on time, space, and stimulus contrast.

Even though the visual cortex is one of the most studied brain areas, the neuronal code in this area is still not fully understood. In the literature, two codes are commonly hypothesized, namely stimulus and predictive (error) codes. Here, we examined whether and how these two codes can coexist in a neuron. To this end, we assumed that neurons could predict a constant stimulus across time or space, since this is the most fundamental type of prediction. Prediction was examined in time using electrophysiology and voltage-sensitive dye imaging in the supragranular layers in area 18 of the anesthetized cat, and in space using a computer model. The distinction into stimulus and error code was made by means of the orientation tuning of the recorded unit. The stimulus was constructed as such that a maximum response to the non-preferred orientation indicated an error signal, and the maximum response to the preferred orientation indicated a stimulus signal. We demonstrate that a single neuron combines stimulus and error-like coding. In addition, we observed that the duration of the error coding varies as a function of stimulus contrast. For low contrast the error-like coding was prolonged by around 60-100%. Finally, the combination of stimulus and error leads to a suboptimal free energy in a recent predictive coding model. We therefore suggest a straightforward modification that can be applied to the free energy model and other predictive coding models. Combining stimulus and error might be advantageous because the stimulus code enables a direct stimulus recognition that is free of assumptions whereas the error code enables an experience dependent inference of ambiguous and non-salient stimuli.