The brain can develop conflicting multisensory principles to guide behavior.

Midbrain multisensory neurons undergo a significant postnatal transition in how they process cross-modal (e.g. visual-auditory) signals. In early stages, signals derived from common events are processed competitively; however, at later stages they are processed cooperatively such that their salience is enhanced. This transition reflects adaptation to cross-modal configurations that are consistently experienced and become informative about which correspond to common events. Tested here was the assumption that overt behaviors follow a similar maturation. Cats were reared in omnidirectional sound thereby compromising the experience needed for this developmental process. Animals were then repeatedly exposed to different configurations of visual and auditory stimuli (e.g. spatiotemporally congruent or spatially disparate) that varied on each side of space and their behavior was assessed using a detection/localization task. Animals showed enhanced performance to stimuli consistent with the experience provided: congruent stimuli elicited enhanced behaviors where spatially congruent cross-modal experience was provided, and spatially disparate stimuli elicited enhanced behaviors where spatially disparate cross-modal experience was provided. Cross-modal configurations not consistent with experience did not enhance responses. The presumptive benefit of such flexibility in the multisensory developmental process is to sensitize neural circuits (and the behaviors they control) to the features of the environment in which they will function. These experiments reveal that these processes have a high degree of flexibility, such that two (conflicting) multisensory principles can be implemented by cross-modal experience on opposite sides of space even within the same animal.

Plot twists and cutting corners with atypical SMCs.

In this issue of Molecular Cell, two papers provide insight into atypical structural maintenance of chromosomes protein complexes (SMCs). Jeppsson et al.1 link Smc5/6 to supercoiled DNA, and Roisné-Hamelin et al.2 show how Wadjet SMC bends and cleaves invading DNAs.

How do molecular motors fold the genome?

A potential mechanism of DNA loop extrusion by molecular motors is discussed.

Cross-modal exposure restores multisensory enhancement after hemianopia.

Hemianopia is a common consequence of unilateral damage to visual cortex that manifests as a profound blindness in contralesional space. A noninvasive cross-modal (visual-auditory) exposure paradigm has been developed in an animal model to ameliorate this disorder. Repeated stimulation of a visual-auditory stimulus restores overt responses to visual stimuli in the blinded hemifield. It is believed to accomplish this by enhancing the visual sensitivity of circuits remaining after a lesion of visual cortex; in particular, circuits involving the multisensory neurons of the superior colliculus. Neurons in this midbrain structure are known to integrate spatiotemporally congruent visual and auditory signals to amplify their responses, which, in turn, enhances behavioral performance. Here we evaluated the relationship between the rehabilitation of hemianopia and this process of multisensory integration. Induction of hemianopia also eliminated multisensory enhancement in the blinded hemifield. Both vision and multisensory enhancement rapidly recovered with the rehabilitative cross-modal exposures. However, although both reached pre-lesion levels at similar rates, they did so with different spatial patterns. The results suggest that the capability for multisensory integration and enhancement is not a pre-requisite for visual recovery in hemianopia, and that the underlying mechanisms for recovery may be more complex than currently appreciated.

Genome control by SMC complexes.

Many cellular processes require large-scale rearrangements of chromatin structure. Structural maintenance of chromosomes (SMC) protein complexes are molecular machines that can provide structure to chromatin. These complexes can connect DNA elements in cis, walk along DNA, build and processively enlarge DNA loops and connect DNA molecules in trans to hold together the sister chromatids. These DNA-shaping abilities place SMC complexes at the heart of many DNA-based processes, including chromosome segregation in mitosis, transcription control and DNA replication, repair and recombination. In this Review, we discuss the latest insights into how SMC complexes such as cohesin, condensin and the SMC5-SMC6 complex shape DNA to direct these fundamental chromosomal processes. We also consider how SMC complexes, by building chromatin loops, can counteract the natural tendency of alike chromatin regions to cluster. SMC complexes thus control nuclear organization by participating in a molecular tug of war that determines the architecture of our genome.

Predictability alters multisensory responses by modulating unisensory inputs.

The multisensory (deep) layers of the superior colliculus (SC) play an important role in detecting, localizing, and guiding orientation responses to salient events in the environment. Essential to this role is the ability of SC neurons to enhance their responses to events detected by more than one sensory modality and to become desensitized ('attenuated' or 'habituated') or sensitized ('potentiated') to events that are predictable via modulatory dynamics. To identify the nature of these modulatory dynamics, we examined how the repetition of different sensory stimuli affected the unisensory and multisensory responses of neurons in the cat SC. Neurons were presented with 2HZ stimulus trains of three identical visual, auditory, or combined visual-auditory stimuli, followed by a fourth stimulus that was either the same or different ('switch'). Modulatory dynamics proved to be sensory-specific: they did not transfer when the stimulus switched to another modality. However, they did transfer when switching from the visual-auditory stimulus train to either of its modality-specific component stimuli and vice versa. These observations suggest that predictions, in the form of modulatory dynamics induced by stimulus repetition, are independently sourced from and applied to the modality-specific inputs to the multisensory neuron. This falsifies several plausible mechanisms for these modulatory dynamics: they neither produce general changes in the neuron's transform, nor are they dependent on the neuron's output.

Structural basis of centromeric cohesion protection.

In the early stages of mitosis, cohesin is released from chromosome arms but not from centromeres. The protection of centromeric cohesin by SGO1 maintains the sister chromatid cohesion that resists the pulling forces of microtubules until all chromosomes are attached in a bipolar manner to the mitotic spindle. Here we present the X-ray crystal structure of a segment of human SGO1 bound to a conserved surface of the cohesin complex. SGO1 binds to a composite interface formed by the SA2 and SCC1RAD21 subunits of cohesin. SGO1 shares this binding interface with CTCF, indicating that these distinct chromosomal regulators control cohesin through a universal principle. This interaction is essential for the localization of SGO1 to centromeres and protects centromeric cohesin against WAPL-mediated cohesin release. SGO1-cohesin binding is maintained until the formation of microtubule-kinetochore attachments and is required for faithful chromosome segregation and the maintenance of a stable karyotype.

Proposing a Clinical Model for RBE Based on Proton Track-End Counts.

PURPOSE: In proton therapy, the clinical application of linear energy transfer (LET) optimization remains contentious, in part because of challenges associated with the definition and calculation of LET and its exact relationship with relative biological effectiveness (RBE) because of large variation in experimental in vitro data. This has raised interest in other metrics with favorable properties for biological optimization, such as the number of proton track ends in a voxel. In this work, we propose a novel model for clinical calculations of RBE, based on proton track end counts. METHODS AND MATERIALS: We developed an effective dose concept to translate between the total proton track-end count per unit mass in a voxel and a proton RBE value. Dose, track end, and dose-averaged LET (LETd) distributions were simulated using Monte Carlo models for a series of water phantoms, in vitro radiobiological studies, and patient treatment plans. We evaluated the correlation between track ends and regions of elevated biological effectiveness in comparison to LETd-based models of RBE. RESULTS: Track ends were found to correlate with biological effects in in vitro experiments with an accuracy comparable to LETd. In patient simulations, our track end model identified the same biological hotspots as predicted by LETd-based radiobiological models of proton RBE. CONCLUSIONS: These results suggest that, for clinical optimization and evaluation, an RBE model based on proton track end counts may match LETd-based models in terms of information provided while also offering superior statistical properties.

Ameliorating Hemianopia with Multisensory Training.

Hemianopia (unilateral blindness), a common consequence of stroke and trauma to visual cortex, is a debilitating disorder for which there are few treatments. Research in an animal model has suggested that visual-auditory stimulation therapy, which exploits the multisensory architecture of the brain, may be effective in restoring visual sensitivity in hemianopia. It was tested in two male human patients who were hemianopic for at least 8 months following a stroke. The patients were repeatedly exposed to congruent visual-auditory stimuli within their blinded hemifield during 2 h sessions over several weeks. The results were dramatic. Both recovered the ability to detect and describe visual stimuli throughout their formerly blind field within a few weeks. They could also localize these stimuli, identify some of their features, and perceive multiple visual stimuli simultaneously in both fields. These results indicate that the multisensory therapy is a rapid and effective method for restoring visual function in hemianopia.SIGNIFICANCE STATEMENT Hemianopia (blindness on one side of space) is widely considered to be a permanent disorder. Here, we show that a simple multisensory training paradigm can ameliorate this disorder in human patients.

Noise-rearing precludes the behavioral benefits of multisensory integration.

Concordant visual-auditory stimuli enhance the responses of individual superior colliculus (SC) neurons. This neuronal capacity for "multisensory integration" is not innate: it is acquired only after substantial cross-modal (e.g. auditory-visual) experience. Masking transient auditory cues by raising animals in omnidirectional sound ("noise-rearing") precludes their ability to obtain this experience and the ability of the SC to construct a normal multisensory (auditory-visual) transform. SC responses to combinations of concordant visual-auditory stimuli are depressed, rather than enhanced. The present experiments examined the behavioral consequence of this rearing condition in a simple detection/localization task. In the first experiment, the auditory component of the concordant cross-modal pair was novel, and only the visual stimulus was a target. In the second experiment, both component stimuli were targets. Noise-reared animals failed to show multisensory performance benefits in either experiment. These results reveal a close parallel between behavior and single neuron physiology in the multisensory deficits that are induced when noise disrupts early visual-auditory experience.

The cohesin acetylation cycle controls chromatin loop length through a PDS5A brake mechanism.

Cohesin structures the genome through the formation of chromatin loops and by holding together the sister chromatids. The acetylation of cohesin's SMC3 subunit is a dynamic process that involves the acetyltransferase ESCO1 and deacetylase HDAC8. Here we show that this cohesin acetylation cycle controls the three-dimensional genome in human cells. ESCO1 restricts the length of chromatin loops, and of architectural stripes emanating from CTCF sites. HDAC8 conversely promotes the extension of such loops and stripes. This role in controlling loop length turns out to be distinct from the canonical role of cohesin acetylation that protects against WAPL-mediated DNA release. We reveal that acetylation controls the interaction of cohesin with PDS5A to restrict chromatin loop length. Our data support a model in which this PDS5A-bound state acts as a brake that enables the pausing and restart of loop enlargement. The cohesin acetylation cycle hereby provides punctuation in the process of genome folding.

A walk through the SMC cycle: From catching DNAs to shaping the genome.

SMC protein complexes are molecular machines that provide structure to chromosomes. These complexes bridge DNA elements and by doing so build DNA loops in cis and hold together the sister chromatids in trans. We discuss how drastic conformational changes allow SMC complexes to build such intricate DNA structures. The tight regulation of these complexes controls fundamental chromosomal processes such as transcription, recombination, repair, and mitosis.

A Mediator-cohesin axis controls heterochromatin domain formation.

The genome consists of regions of transcriptionally active euchromatin and more silent heterochromatin. We reveal that the formation of heterochromatin domains requires cohesin turnover on DNA. Stabilization of cohesin on DNA through depletion of its release factor WAPL leads to a near-complete loss of heterochromatin domains. We observe the opposite phenotype in cells deficient for subunits of the Mediator-CDK module, with an almost binary partition of the genome into dense H3K9me3 domains, and regions devoid of H3K9me3 spanning the rest of the genome. We suggest that the Mediator-CDK module might contribute to gene expression by limiting the formation of dense heterochromatin domains. WAPL deficiency prevents the formation of heterochromatin domains, and allows for gene expression even in the absence of the Mediator-CDK subunit MED12. We propose that cohesin and Mediator affect heterochromatin in different ways to enable the correct distribution of epigenetic marks, and thus to ensure proper gene expression.

Technical Note: Four-dimensional deformable digital phantom for MRI sequence development.

PURPOSE: MR-guided radiotherapy has different requirements for the images than diagnostic radiology, thus requiring development of novel imaging sequences. MRI simulation is an excellent tool for optimizing these new sequences; however, currently available software does not provide all the necessary features. In this paper, we present a digital framework for testing MRI sequences that incorporates anatomical structure, respiratory motion, and realistic presentation of MR physics. METHODS: The extended Cardiac-Torso (XCAT) software was used to create T1 , T2 , and proton density maps that formed the anatomical structure of the phantom. Respiratory motion model was based on the XCAT deformation vector fields, modified to create a motion model driven by a respiration signal. MRI simulation was carried out with JEMRIS, an open source Bloch simulator. We developed an extension for JEMRIS, which calculates the motion of each spin independently, allowing for deformable motion. RESULTS: The performance of the framework was demonstrated through simulating the acquisition of a two-dimensional (2D) cine and demonstrating expected motion ghosts from T2 weighted spin echo acquisitions with different respiratory patterns. All simulations were consistent with behavior previously described in literature. Simulations with deformable motion were not more time consuming than with rigid motion. CONCLUSIONS: We present a deformable four-dimensional (4D) digital phantom framework for MR sequence development. The framework incorporates anatomical structure, realistic breathing patterns, deformable motion, and Bloch simulation to achieve accurate simulation of MRI. This method is particularly relevant for testing novel imaging sequences for the purpose of MR-guided radiotherapy in lungs and abdomen.

Association Cortex Is Essential to Reverse Hemianopia by Multisensory Training.

Hemianopia induced by unilateral visual cortex lesions can be resolved by repeatedly exposing the blinded hemifield to auditory-visual stimuli. This rehabilitative "training" paradigm depends on mechanisms of multisensory plasticity that restore the lost visual responsiveness of multisensory neurons in the ipsilesional superior colliculus (SC) so that they can once again support vision in the blinded hemifield. These changes are thought to operate via the convergent visual and auditory signals relayed to the SC from association cortex (the anterior ectosylvian sulcus [AES], in cat). The present study tested this assumption by cryogenically deactivating ipsilesional AES in hemianopic, anesthetized cats during weekly multisensory training sessions. No signs of visual recovery were evident in this condition, even after providing animals with up to twice the number of training sessions required for effective rehabilitation. Subsequent training under the same conditions, but with AES active, reversed the hemianopia within the normal timeframe. These results indicate that the corticotectal circuit that is normally engaged in SC multisensory plasticity has to be operational for the brain to use visual-auditory experience to resolve hemianopia.

Hi-C analyses with GENOVA: a case study with cohesin variants.

Conformation capture-approaches like Hi-C can elucidate chromosome structure at a genome-wide scale. Hi-C datasets are large and require specialised software. Here, we present GENOVA: a user-friendly software package to analyse and visualise chromosome conformation capture (3C) data. GENOVA is an R-package that includes the most common Hi-C analyses, such as compartment and insulation score analysis. It can create annotated heatmaps to visualise the contact frequency at a specific locus and aggregate Hi-C signal over user-specified genomic regions such as ChIP-seq data. Finally, our package supports output from the major mapping-pipelines. We demonstrate the capabilities of GENOVA by analysing Hi-C data from HAP1 cell lines in which the cohesin-subunits SA1 and SA2 were knocked out. We find that ΔSA1 cells gain intra-TAD interactions and increase compartmentalisation. ΔSA2 cells have longer loops and a less compartmentalised genome. These results suggest that cohesinSA1 forms longer loops, while cohesinSA2 plays a role in forming and maintaining intra-TAD interactions. Our data supports the model that the genome is provided structure in 3D by the counter-balancing of loop formation on one hand, and compartmentalization on the other hand. By differentially controlling loops, cohesinSA1 and cohesinSA2 therefore also affect nuclear compartmentalization. We show that GENOVA is an easy to use R-package, that allows researchers to explore Hi-C data in great detail.

Multisensory enhancement of overt behavior requires multisensory experience.

The superior colliculus (SC) is richly endowed with neurons that integrate cues from different senses to enhance their physiological responses and the overt behaviors they mediate. However, in the absence of experience with cross-modal combinations (e.g., visual-auditory), they fail to develop this characteristic multisensory capability: Their multisensory responses are no greater than their most effective unisensory responses. Presumably, this impairment in neural development would be reflected as corresponding impairments in SC-mediated behavioral capabilities such as detection and localization performance. Here, we tested that assumption directly in cats raised to adulthood in darkness. They, along with a normally reared cohort, were trained to approach brief visual or auditory stimuli. The animals were then tested with these stimuli individually and in combination under ambient light conditions consistent with their rearing conditions and home environment as well as under the opposite lighting condition. As expected, normally reared animals detected and localized the cross-modal combinations significantly better than their individual component stimuli. However, dark-reared animals showed significant defects in multisensory detection and localization performance. The results indicate that a physiological impairment in single multisensory SC neurons is predictive of an impairment in overt multisensory behaviors.

Stimulus value gates multisensory integration.

The brain enhances its perceptual and behavioral decisions by integrating information from its multiple senses in what are believed to be optimal ways. This phenomenon of "multisensory integration" appears to be pre-conscious, effortless, and highly efficient. The present experiments examined whether experience could modify this seemingly automatic process. Cats were trained in a localization task in which congruent pairs of auditory-visual stimuli are normally integrated to enhance detection and orientation/approach performance. Consistent with the results of previous studies, animals more reliably detected and approached cross-modal pairs than their modality-specific component stimuli, regardless of whether the pairings were novel or familiar. However, when provided evidence that one of the modality-specific component stimuli had no value (it was not rewarded) animals ceased integrating it with other cues, and it lost its previous ability to enhance approach behaviors. Cross-modal pairings involving that stimulus failed to elicit enhanced responses even when the paired stimuli were congruent and mutually informative. However, the stimulus regained its ability to enhance responses when it was associated with reward. This suggests that experience can selectively block access of stimuli (i.e., filter inputs) to the multisensory computation. Because this filtering process results in the loss of useful information, its operation and behavioral consequences are not optimal. Nevertheless, the process can be of substantial value in natural environments, rich in dynamic stimuli, by using experience to minimize the impact of stimuli unlikely to be of biological significance, and reducing the complexity of the problem of matching signals across the senses.

On the choreography of genome folding: A grand pas de deux of cohesin and CTCF.

Cohesin and CTCF are key to the 3D folding of interphase chromosomes. Cohesin forms chromatin loops via loop extrusion, a process that involves the formation and enlargement of DNA loops. The architectural protein CTCF controls this process by acting as an anchor for chromatin looping. How CTCF controls cohesin has long been a mystery. Recent work shows that CTCF dictates chromatin looping via a direct interaction of its N-terminus with cohesin. CTCF's ability to regulate chromatin looping turns out to also be partially dependent on several RNA-binding domains. In this review, we discuss recent insights and consider how cohesin and CTCF together may orchestrate the folding of the genome into chromosomal loops.