Increased mutation and gene conversion within human segmental duplications.

Single-nucleotide variants (SNVs) in segmental duplications (SDs) have not been systematically assessed because of the limitations of mapping short-read sequencing data1,2. Here we constructed 1:1 unambiguous alignments spanning high-identity SDs across 102 human haplotypes and compared the pattern of SNVs between unique and duplicated regions3,4. We find that human SNVs are elevated 60% in SDs compared to unique regions and estimate that at least 23% of this increase is due to interlocus gene conversion (IGC) with up to 4.3 megabase pairs of SD sequence converted on average per human haplotype. We develop a genome-wide map of IGC donors and acceptors, including 498 acceptor and 454 donor hotspots affecting the exons of about 800 protein-coding genes. These include 171 genes that have 'relocated' on average 1.61 megabase pairs in a subset of human haplotypes. Using a coalescent framework, we show that SD regions are slightly evolutionarily older when compared to unique sequences, probably owing to IGC. SNVs in SDs, however, show a distinct mutational spectrum: a 27.1% increase in transversions that convert cytosine to guanine or the reverse across all triplet contexts and a 7.6% reduction in the frequency of CpG-associated mutations when compared to unique DNA. We reason that these distinct mutational properties help to maintain an overall higher GC content of SD DNA compared to that of unique DNA, probably driven by GC-biased conversion between paralogous sequences5,6.

Neural correlates of goal-directed and non-goal-directed movements.

What are the cortical neural correlates that distinguish goal-directed and non-goal-directed movements? We investigated this question in the monkey frontal eye field (FEF), which is implicated in voluntary control of saccades. Here, we compared FEF activity associated with goal-directed (G) saccades and non-goal-directed (nG) saccades made by the monkey. Although the FEF neurons discharged before these nG saccades, there were three major differences in the neural activity: First, the variability in spike rate across trials decreased only for G saccades. Second, the local field potential beta-band power decreased during G saccades but did not change during nG saccades. Third, the time from saccade direction selection to the saccade onset was significantly longer for G saccades compared with nG saccades. Overall, our results reveal unexpected differences in neural signatures for G versus nG saccades in a brain area that has been implicated selectively in voluntary control. Taken together, these data add critical constraints to the way we think about saccade generation in the brain.

Mixed Selectivity in the Cerebellar Purkinje-Cell Response during Visuomotor Association Learning.

Although the cerebellum has been traditionally considered to be exclusively involved in motor control, recent anatomic and clinical studies show that it also has a role in reward-processing. However, the way in which the movement-related and the reward-related neural activity interact at the level of the cerebellar cortex and contribute toward learning is still unclear. Here, we studied the simple spike activity of Purkinje cells in the mid-lateral cerebellum when 2 male monkeys learned to associate a right or left-hand movement with one of two visual symbolic cues. These cells had distinctly different discharge patterns between an overtrained symbol-hand association and a novel symbol-hand association, responding in association with the movement of both hands, although the kinematics of the movement did not change between the two conditions. The activity change was not related to the pattern of the visual symbols, the movement kinematics, the monkeys' reaction times, or the novelty of the visual symbols. The simple spike activity changed throughout the learning process, but the concurrent complex spikes did not instruct that change. Although these neurons also have reward-related activity, the reward-related and movement-related signals were independent. We suggest that this mixed selectivity may facilitate the flexible learning of difficult reinforcement learning problems.SIGNIFICANCE STATEMENT The cerebellum receives both motor-related and reward-related information. However, it is unclear how these two signals interact at the level of cerebellar cortex and contribute to learning nonmotor skills. Here we show that in the mid-lateral cerebellum, the reward information is encoded independently from the motor information such that during reward-based learning, only the reward information carried by the Purkinje cells inform learning while the motor information remains unchanged with learning.

The neurology clinic needs monkey research.

This report discusses how a number of currently incurable diseases might be treated by advances developed as the result of current ongoing research on monkeys. The diseases discussed include Parkinson's disease, amyotrophic lateral sclerosis, spinal cord injury, peripheral neuropathy, and stroke. Finally, the report discusses the devastating effect the animal rights movement and adverse publicity can have on basic neurobiological research on monkeys.

Attention, intention, and priority in the parietal lobe.

For many years there has been a debate about the role of the parietal lobe in the generation of behavior. Does it generate movement plans (intention) or choose objects in the environment for further processing? To answer this, we focus on the lateral intraparietal area (LIP), an area that has been shown to play independent roles in target selection for saccades and the generation of visual attention. Based on results from a variety of tasks, we propose that LIP acts as a priority map in which objects are represented by activity proportional to their behavioral priority. We present evidence to show that the priority map combines bottom-up inputs like a rapid visual response with an array of top-down signals like a saccade plan. The spatial location representing the peak of the map is used by the oculomotor system to target saccades and by the visual system to guide visual attention.

Auditory to Visual Cross-Modal Adaptation for Emotion: Psychophysical and Neural Correlates.

Adaptation is fundamental in sensory processing and has been studied extensively within the same sensory modality. However, little is known about adaptation across sensory modalities, especially in the context of high-level processing, such as the perception of emotion. Previous studies have shown that prolonged exposure to a face exhibiting one emotion, such as happiness, leads to contrastive biases in the perception of subsequently presented faces toward the opposite emotion, such as sadness. Such work has shown the importance of adaptation in calibrating face perception based on prior visual exposure. In the present study, we showed for the first time that emotion-laden sounds, like laughter, adapt the visual perception of emotional faces, that is, subjects more frequently perceived faces as sad after listening to a happy sound. Furthermore, via electroencephalography recordings and event-related potential analysis, we showed that there was a neural correlate underlying the perceptual bias: There was an attenuated response occurring at ∼ 400 ms to happy test faces and a quickened response to sad test faces, after exposure to a happy sound. Our results provide the first direct evidence for a behavioral cross-modal adaptation effect on the perception of facial emotion, and its neural correlate.

A spatially nonselective baseline signal in parietal cortex reflects the probability of a monkey's success on the current trial.

We recorded the activity of neurons in the lateral intraparietal area of two monkeys while they performed two similar visual search tasks, one difficult, one easy. Each task began with a period of fixation followed by an array consisting of a single capital T and a number of lowercase t's. The monkey had to find the capital T and report its orientation, upright or inverted, with a hand movement. In the easy task the monkey could explore the array with saccades. In the difficult task the monkey had to continue fixating and find the capital T in the visual periphery. The baseline activity measured during the fixation period, at a time in which the monkey could not know if the impending task would be difficult or easy or where the target would appear, predicted the monkey's probability of success or failure on the task. The baseline activity correlated inversely with the monkey's recent history of success and directly with the intensity of the response to the search array on the current trial. The baseline activity was unrelated to the monkey's spatial locus of attention as determined by the location of the cue in a cued visual reaction time task. We suggest that rather than merely reflecting the noise in the system, the baseline signal reflects the cortical manifestation of modulatory state, motivational, or arousal pathways, which determine the efficiency of cortical sensorimotor processing and the quality of the monkey's performance.

Feature attention evokes task-specific pattern selectivity in V4 neurons.

A hallmark of visual cortical neurons is their selectivity for stimulus pattern features, such as color, orientation, or shape. In most cases this feature selectivity is hard-wired, with selectivity manifest from the beginning of the response. Here we show that when a task requires that a monkey distinguish between patterns, V4 develops a selectivity for the sought-after pattern, which it does not manifest in a task that does not require the monkey to distinguish between patterns. When a monkey looks for a target object among an array of distractors, V4 neurons become selective for the target ∼50 ms after the visual latency independent of the impending saccade direction. However, when the monkey has to only make a saccade to the spatial location of the same objects without discriminating their pattern, V4 neurons do not distinguish the search target from the distractors. This selectivity for stimulus pattern develops roughly 40 ms after the same neurons' selectivity for basic pattern features like orientation or color. We suggest that this late-developing selectivity is related to the phenomenon of feature attention and may contribute to the mechanisms by which the brain finds the target in visual search.

Spatial representation and cognitive modulation of response variability in the lateral intraparietal area priority map.

The lateral intraparietal area (LIP) in the macaque contains a priority-based representation of the visual scene. We previously showed that the mean spike rate of LIP neurons is strongly influenced by spatially wide-ranging surround suppression in a manner that effectively sharpens the priority map. Reducing response variability can also improve the precision of LIP's priority map. We show that when a monkey plans a visually guided delayed saccade with an intervening distractor, variability (measured by the Fano factor) decreases both for neurons representing the saccade goal and for neurons representing the broad spatial surround. The reduction in Fano factor is maximal for neurons representing the saccade goal and steadily decreases for neurons representing more distant locations. LIP Fano factor changes are behaviorally significant: increasing expected reward leads to lower variability for the LIP representation of both the target and distractor locations, and trials with shorter latency saccades are associated with lower Fano factors in neurons representing the surround. Thus, the LIP Fano factor reflects both stimulus and behavioral engagement. Quantitative modeling shows that the interaction between mean spike count and target-receptive field (RF) distance in the surround during the predistractor epoch is multiplicative: the Fano factor increases more steeply with mean spike count further away from the RF. A negative-binomial model for LIP spike counts captures these findings quantitatively, suggests underlying mechanisms based on trial-by-trial variations in mean spike rate or burst-firing patterns, and potentially provides a principled framework to account simultaneously for the previously observed unsystematic relationships between spike rate and variability in different brain areas.

Extrafoveal preview benefit during free-viewing visual search in the monkey.

Previous studies have shown that subjects require less time to process a stimulus at the fovea after a saccade if they have viewed the same stimulus in the periphery immediately prior to the saccade. This extrafoveal preview benefit indicates that information about the visual form of an extrafoveally viewed stimulus can be transferred across a saccade. Here, we extend these findings by demonstrating and characterizing a similar extrafoveal preview benefit in monkeys during a free-viewing visual search task. We trained two monkeys to report the orientation of a target among distractors by releasing one of two bars with their hand; monkeys were free to move their eyes during the task. Both monkeys took less time to indicate the orientation of the target after foveating it, when the target lay closer to the fovea during the previous fixation. An extrafoveal preview benefit emerged even if there was more than one intervening saccade between the preview and the target fixation, indicating that information about target identity could be transferred across more than one saccade and could be obtained even if the search target was not the goal of the next saccade. An extrafoveal preview benefit was also found for distractor stimuli. These results aid future physiological investigations of the extrafoveal preview benefit.

A cerebro-cerebellar network for learning visuomotor associations.

Consensus is rapidly building to support a role for the cerebellum beyond motor function, but its contributions to non-motor learning remain poorly understood. Here, we provide behavioral, anatomical and computational evidence to demonstrate a causal role for the primate posterior lateral cerebellum in learning new visuomotor associations. Reversible inactivation of the posterior lateral cerebellum of male monkeys impeded the learning of new visuomotor associations, but had no effect on movement parameters, or on well-practiced performance of the same task. Using retrograde transneuronal transport of rabies virus, we identified a distinct cerebro-cerebellar network linking Purkinje cells in the posterior lateral cerebellum with a region of the prefrontal cortex that is critical in learning visuomotor associations. Together, these results demonstrate a causal role for the primate posterior lateral cerebellum in non-motor, reinforcement learning.

Perisaccadic and attentional remapping of receptive fields in lateral intraparietal area and frontal eye fields.

The nature and function of perisaccadic receptive field (RF) remapping have been controversial. We use a delayed saccade task to reduce previous confounds and examine the remapping time course in the lateral intraparietal area and frontal eye fields. In the delay period, the RF shift direction turns from the initial fixation to the saccade target. In the perisaccadic period, RFs first shift toward the target (convergent remapping), but around the time of saccade onset/offset, the shifts become predominantly toward the post-saccadic RF locations (forward remapping). Thus, unlike forward remapping that depends on the corollary discharge (CD) of the saccade command, convergent remapping appears to follow attention from the initial fixation to the target. We model the data with attention-modulated and CD-gated connections and show that both sets of connections emerge automatically in neural networks trained to update stimulus retinal locations across saccades. Our work thus unifies previous findings into a mechanism for transsaccadic visual stability.

Effects of parental age and polymer composition on short tandem repeat de novo mutation rates.

Short tandem repeats (STRs) are hotspots of genomic variability in the human germline because of their high mutation rates, which have long been attributed largely to polymerase slippage during DNA replication. This model suggests that STR mutation rates should scale linearly with a father's age, as progenitor cells continually divide after puberty. In contrast, it suggests that STR mutation rates should not scale with a mother's age at her child's conception, since oocytes spend a mother's reproductive years arrested in meiosis II and undergo a fixed number of cell divisions that are independent of the age at ovulation. Yet, mirroring recent findings, we find that STR mutation rates covary with paternal and maternal age, implying that some STR mutations are caused by DNA damage in quiescent cells rather than polymerase slippage in replicating progenitor cells. These results echo the recent finding that DNA damage in oocytes is a significant source of de novo single nucleotide variants and corroborate evidence of STR expansion in postmitotic cells. However, we find that the maternal age effect is not confined to known hotspots of oocyte mutagenesis, nor are postzygotic mutations likely to contribute significantly. STR nucleotide composition demonstrates divergent effects on de novo mutation (DNM) rates between sexes. Unlike the paternal lineage, maternally derived DNMs at A/T STRs display a significantly greater association with maternal age than DNMs at G/C-containing STRs. These observations may suggest the mechanism and developmental timing of certain STR mutations and contradict prior attribution of replication slippage as the primary mechanism of STR mutagenesis.

The lateral intraparietal area codes the location of saccade targets and not the dimension of the saccades that will be made to acquire them.

Activity in the lateral intraparietal area (LIP) represents a priority map that can be used to direct attention and guide eye movements. However, it is not known whether this activity represents the location of saccade targets or the actual eye movement made to acquire them. We recorded single neurons from rhesus macaques (Macaca mulatta) while they performed memory-guided delayed saccades to characterize the response profiles of LIP cells. We then separated the saccade target from the saccade end point by saccadic adaptation, a method that induces a change in the gain of the oculomotor system. We plotted LIP activity for all three epochs of the memory-guided delayed-response task (visual, delay period, and presaccadic responses) as a function of target location and saccade end point. We found that under saccadic adaptation the response profile for all three epochs was unchanged as a function of target location. We conclude that neurons in LIP reliably represent the locations of saccade targets, not the amplitude of the saccade required to acquire those targets. Although LIP transmits target information to the motor system, that information represents the location of the target and not the amplitude of the saccade that the monkey will make.

Perisaccadic and Attentional Remapping of Receptive Fields in Lateral Intraparietal Area and Frontal Eye Fields.

The nature and function of perisaccadic receptive-field (RF) remapping have been controversial. We used a delayed saccade task to reduce previous confounds and examined the remapping time course in areas LIP and FEF. In the delay period, the RF shift direction turned from the initial fixation to the saccade target. In the perisaccadic period, RFs first shifted toward the target (convergent remapping) but around the time of saccade onset/offset, the shifts became predominantly toward the post-saccadic RF locations (forward remapping). Thus, unlike forward remapping that depends on the corollary discharge (CD) of the saccade command, convergent remapping appeared to follow attention from the initial fixation to the target. We modelled the data with attention-modulated and CD-gated connections, and showed that both sets of connections emerged automatically in neural networks trained to update stimulus retinal locations across saccades. Our work thus unifies previous findings into a mechanism for transsaccadic visual stability.

Effects of parental age and polymer composition on short tandem repeat de novo mutation rates.

Short tandem repeats (STRs) are hotspots of genomic variability in the human germline because of their high mutation rates, which have long been attributed largely to polymerase slippage during DNA replication. This model suggests that STR mutation rates should scale linearly with a father's age, as progenitor cells continually divide after puberty. In contrast, it suggests that STR mutation rates should not scale with a mother's age at her child's conception, since oocytes spend a mother's reproductive years arrested in meiosis II and undergo a fixed number of cell divisions that are independent of the age at ovulation. Yet, mirroring recent findings, we find that STR mutation rates covary with paternal and maternal age, implying that some STR mutations are caused by DNA damage in quiescent cells rather than the classical mechanism of polymerase slippage in replicating progenitor cells. These results also echo the recent finding that DNA damage in quiescent oocytes is a significant source of de novo SNVs and corroborate evidence of STR expansion in postmitotic cells. However, we find that the maternal age effect is not confined to previously discovered hotspots of oocyte mutagenesis, nor are post-zygotic mutations likely to contribute significantly. STR nucleotide composition demonstrates divergent effects on DNM rates between sexes. Unlike the paternal lineage, maternally derived DNMs at A/T STRs display a significantly greater association with maternal age than DNMs at GC-containing STRs. These observations may suggest the mechanism and developmental timing of certain STR mutations and are especially surprising considering the prior belief in replication slippage as the dominant mechanism of STR mutagenesis.

Mice require proprioception to establish long-term visuospatial memory.

Because the retina moves constantly, the retinotopic representation of the visual world is spatially inaccurate and the brain must transform this spatially inaccurate retinal signal to a spatially accurate signal usable for perception and action. One of the salient discoveries of modern neuroscience is the role of the hippocampus in establishing gaze-independent, long-term visuospatial memories. The rat hippocampus has neurons which report the animal's position in space regardless of its angle of gaze. Rats with hippocampal lesions are unable to find the location of an escape platform hidden in a pool of opaque fluid, the Morris Water Maze (MWM) based on the visual aspects of their surrounding environment. Here we show that the representation of proprioception in the dysgranular zone of primary somatosensory cortex is equivalently necessary for mice to learn the location of the hidden platform, presumably because without it they cannot create a long-term gaze-independent visuospatial representation of their environment from the retinal signal. They have no trouble finding the platform when it is marked by a flag, and they have no motor or vestibular deficits.

Stereoselective and regiospecific hydroxylation of ketamine and norketamine.

The objective was to determine the cytochrome P450s (CYPs) responsible for the stereoselective and regiospecific hydroxylation of ketamine [(R,S)-Ket] to diastereomeric hydroxyketamines, (2S,6S;2R,6R)-HK (5a) and (2S,6R;2R,6S)-HK (5b) and norketamine [(R,S)-norKet] to hydroxynorketamines, (2S,6S;2R,6R)-HNK (4a), (2S,6R;2R,6S)-HNK (4b), (2S,5S;2R,5R)-HNK (4c), (2S,4S;2R,4R)-HNK (4d), (2S,4R;2R,4S)-HNK (4e), (2S,5R;2R,5S)-HNK (4f). The enantiomers of Ket and norKet were incubated with characterized human liver microsomes (HLMs) and expressed CYPs. Metabolites were identified and quantified using LC/MS/MS and apparent kinetic constants estimated using single-site Michaelis-Menten, Hill or substrate inhibition equation. 5a was predominantly formed from (S)-Ket by CYP2A6 and N-demethylated to 4a by CYP2B6. 5b was formed from (R)- and (S)-Ket by CYP3A4/3A5 and N-demethylated to 4b by multiple enzymes. norKet incubation produced 4a, 4c and 4f and minor amounts of 4d and 4e. CYP2A6 and CYP2B6 were the major enzymes responsible for the formation of 4a, 4d and 4f, and CYP3A4/3A5 for the formation of 4e. The 4b metabolite was not detected in the norKet incubates. 5a and 4b were detected in plasma samples from patients receiving (R,S)-Ket, indicating that 5a and 5b are significant Ket metabolites. Large variations in HNK concentrations were observed suggesting that pharmacogenetics and/or metabolic drug interactions may play a role in therapeutic response.

Mutational Signatures of Replication Timing and Epigenetic Modification Persist through the Global Divergence of Mutation Spectra across the Great Ape Phylogeny.

Great ape clades exhibit variation in the relative mutation rates of different three-base-pair genomic motifs, with closely related species having more similar mutation spectra than distantly related species. This pattern cannot be explained by classical demographic or selective forces, but imply that DNA replication fidelity has been perturbed in different ways on each branch of the great ape phylogeny. Here, we use whole-genome variation from 88 great apes to investigate whether these species' mutation spectra are broadly differentiated across the entire genome, or whether mutation spectrum differences are driven by DNA compartments that have particular functional features or chromatin states. We perform principal component analysis (PCA) and mutational signature deconvolution on mutation spectra ascertained from compartments defined by features including replication timing and ancient repeat content, finding evidence for consistent species-specific mutational signatures that do not depend on which functional compartments the spectra are ascertained from. At the same time, we find that many compartments have their own characteristic mutational signatures that appear stable across the great ape phylogeny. For example, in a mutation spectrum PCA compartmentalized by replication timing, the second principal component explaining 21.2% of variation separates all species' late-replicating regions from their early-replicating regions. Our results suggest that great ape mutation spectrum evolution is not driven by epigenetic changes that modify mutation rates in specific genomic regions, but instead by trans-acting mutational modifiers that affect mutagenesis across the whole genome fairly uniformly.

Tuning curves vs. population responses, and perceptual consequences of receptive-field remapping.

Sensory processing is often studied by examining how a given neuron responds to a parameterized set of stimuli (tuning curve) or how a given stimulus evokes responses from a parameterized set of neurons (population response). Although tuning curves and the corresponding population responses contain the same information, they can have different properties. These differences are known to be important because the perception of a stimulus should be decoded from its population response, not from any single tuning curve. The differences are less studied in the spatial domain where a cell's spatial tuning curve is simply its receptive field (RF) profile. Here, we focus on evaluating the common belief that perrisaccadic forward and convergent RF shifts lead to forward (translational) and convergent (compressive) perceptual mislocalization, respectively, and investigate the effects of three related factors: decoders' awareness of RF shifts, changes of cells' covering density near attentional locus (the saccade target), and attentional response modulation. We find that RF shifts alone produce either no shift or an opposite shift of the population responses depending on whether or not decoders are aware of the RF shifts. Thus, forward RF shifts do not predict forward mislocalization. However, convergent RF shifts change cells' covering density for aware decoders (but not for unaware decoders) which may predict convergent mislocalization. Finally, attentional modulation adds a convergent component to population responses for stimuli near the target. We simulate the combined effects of these factors and discuss the results with extant mislocalization data. We speculate that perisaccadic mislocalization might be the flash-lag effect unrelated to perisaccadic RF remapping but to resolve the issue, one has to address the question of whether or not perceptual decoders are aware of RF shifts.