Female Macaque Monkeys Research Articles

A Comparison of Rapid Rule-Learning Strategies in Humans and Monkeys.

Interspecies comparisons are key to deriving an understanding of the behavioral and neural correlates of human cognition from animal models. We perform a detailed comparison of the strategies of female macaque monkeys to male and female humans on a variant of the Wisconsin Card Sorting Test (WCST), a widely studied and applied task that provides a multiattribute measure of cognitive function and depends on the frontal lobe. WCST performance requires the inference of a rule change given ambiguous feedback. We found that well-trained monkeys infer new rules three times more slowly than minimally instructed humans. Input-dependent hidden Markov model-generalized linear models were fit to their choices, revealing hidden states akin to feature-based attention in both species. Decision processes resembled a win-stay, lose-shift strategy with interspecies similarities as well as key differences. Monkeys and humans both test multiple rule hypotheses over a series of rule-search trials and perform inference-like computations to exclude candidate choice options. We quantitatively show that perseveration, random exploration, and poor sensitivity to negative feedback account for the slower task-switching performance in monkeys.

Nociceptors are functionally male or female: from mouse to monkey to man.

The prevalence of many pain conditions often differs between sexes. In addition to such quantitative distinctions, sexual dimorphism may also be qualitative reflecting differences in mechanisms that promote pain in men and women. A major factor that influences the likelihood of pain perception is the threshold for activation of nociceptors. Peripheral nociceptor sensitization has been demonstrated to be clinically relevant in many pain conditions. Whether peripheral nociceptor sensitization can occur in a sexually dimorphic fashion, however, has not been extensively studied. To address this fundamental knowledge gap, we used patch clamp electrophysiology to evaluate the excitability of dorsal root ganglion neurones from male or female rodents, non-human primates, and humans following exposure to putative sensitizing agents. Previous studies from our laboratory, and others, have shown that prolactin promotes female-selective pain responses in rodents. Consistent with these observations, dorsal root ganglion neurones from female, but not male, mice were selectively sensitized by exposure to prolactin. The sensitizing action of prolactin was also confirmed in dorsal root ganglion neurones from a female macaque monkey. Critically, neurones recovered from female, but not male, human donors were also selectively sensitized by prolactin. In the course of studies of sleep and pain, we unexpectedly observed that an orexin antagonist could normalize pain responses in male animals. We found that orexin B produced sensitization of male, but not female, mouse, macaque, and human dorsal root ganglion neurones. Consistent with functional responses, increased prolactin receptor and orexin receptor 2 expression was observed in female and male mouse dorsal root ganglia, respectively. Immunohistochemical interrogation of cultured human sensory neurones and whole dorsal root ganglia also suggested increased prolactin receptor expression in females and orexin receptor 2 expression in males. These data reveal a functional double dissociation of nociceptor sensitization by sex, which is conserved across species and is likely directly relevant to human pain conditions. To our knowledge, this is the first demonstration of functional sexual dimorphism in human sensory neurones. Patient sex is currently not a common consideration for the choice of pain therapy. Precision medicine, based on patient sex could improve therapeutic outcomes by selectively targeting mechanisms promoting pain in women or men. Additional implications of these findings are that the design of clinical trials for pain therapies should consider the proportions of male or female patients enrolled. Lastly, re-examination of selected past failed clinical trials with subgroup analysis by sex may be warranted.

Variable cardiac responses in rhesus macaque monkeys after discrete mediodorsal thalamus manipulations

The control of some physiological parameters, such as the heart rate, is known to have a role in cognitive and emotional processes. Cardiac changes are also linked to mental health issues and neurodegeneration. Thus, it is not surprising that many of the brain structures typically associated with cognition and emotion also comprise a circuit—the central automatic network—responsible for the modulation of cardiovascular output. The mediodorsal thalamus (MD) is involved in higher cognitive processes and is also known to be connected to some of the key neural structures that regulate cardiovascular function. However, it is unclear whether the MD has any role in this circuitry. Here, we show that discrete manipulations (microstimulation during anaesthetized functional neuroimaging or localized cytotoxin infusions) to either the magnocellular or the parvocellular MD subdivisions led to observable and variable changes in the heart rate of female and male rhesus macaque monkeys. Considering the central positions that these two MD subdivisions have in frontal cortico-thalamocortical circuits, our findings suggest that MD contributions to autonomic regulation may interact with its identified role in higher cognitive processes, representing an important physiological link between cognition and emotion.

Inference of Electrical Stimulation Sensitivity from Recorded Activity of Primate Retinal Ganglion Cells.

High-fidelity electronic implants can in principle restore the function of neural circuits by precisely activating neurons via extracellular stimulation. However, direct characterization of the individual electrical sensitivity of a large population of target neurons, to precisely control their activity, can be difficult or impossible. A potential solution is to leverage biophysical principles to infer sensitivity to electrical stimulation from features of spontaneous electrical activity, which can be recorded relatively easily. Here, this approach is developed and its potential value for vision restoration is tested quantitatively using large-scale multielectrode stimulation and recording from retinal ganglion cells (RGCs) of male and female macaque monkeys ex vivo Electrodes recording larger spikes from a given cell exhibited lower stimulation thresholds across cell types, retinas, and eccentricities, with systematic and distinct trends for somas and axons. Thresholds for somatic stimulation increased with distance from the axon initial segment. The dependence of spike probability on injected current was inversely related to threshold, and was substantially steeper for axonal than somatic compartments, which could be identified by their recorded electrical signatures. Dendritic stimulation was largely ineffective for eliciting spikes. These trends were quantitatively reproduced with biophysical simulations. Results from human RGCs were broadly similar. The inference of stimulation sensitivity from recorded electrical features was tested in a data-driven simulation of visual reconstruction, revealing that the approach could significantly improve the function of future high-fidelity retinal implants.SIGNIFICANCE STATEMENT This study demonstrates that individual in situ primate retinal ganglion cells of different types respond to artificially generated, external electrical fields in a systematic manner, in accordance with theoretical predictions, that allows for prediction of electrical stimulus sensitivity from recorded spontaneous activity. It also provides evidence that such an approach could be immensely helpful in the calibration of clinical retinal implants.

The Existence of the StartReact Effect Implies Reticulospinal, Not Corticospinal, Inputs Dominate Drive to Motoneurons during Voluntary Movement.

Reaction time is accelerated if a loud (startling) sound accompanies the cue—the “StartReact” effect. Animal studies revealed a reticulospinal substrate for the startle reflex; StartReact may similarly involve the reticulospinal tract, but this is currently uncertain. Here we trained two female macaque monkeys to perform elbow flexion/extension movements following a visual cue. The cue was sometimes accompanied by a loud sound, generating a StartReact effect in electromyogram response latency, as seen in humans. Extracellular recordings were made from antidromically identified corticospinal neurons in primary motor cortex (M1), from the reticular formation (RF), and from the spinal cord (SC; C5–C8 segments). After loud sound, task-related activity was suppressed in M1 (latency, 70–200 ms after cue), but was initially enhanced (70–80 ms) and then suppressed (140–210 ms) in RF. SC activity was unchanged. In a computational model, we simulated a motoneuron pool receiving input from different proportions of the average M1 and RF activity recorded experimentally. Motoneuron firing generated simulated electromyogram, allowing reaction time measurements. Only if ≥60% of motoneuron drive came from RF (≤40% from M1) did loud sound shorten reaction time. The extent of shortening increased as more drive came from RF. If RF provided <60% of drive, loud sound lengthened the reaction time—the opposite of experimental findings. The majority of the drive for voluntary movements is thus likely to originate from the brainstem, not the cortex; changes in the magnitude of the StartReact effect can measure a shift in the relative importance of descending systems.SIGNIFICANCE STATEMENT Our results reveal that a loud sound has opposite effects on neural spiking in corticospinal cells from primary motor cortex, and in the reticular formation. We show that this fortuitously allows changes in reaction time produced by a loud sound to be used to assess the relative importance of reticulospinal versus corticospinal control of movement, validating previous noninvasive measurements in humans. Our findings suggest that the majority of the descending drive to motoneurons producing voluntary movement in primates comes from the reticulospinal tract, not the corticospinal tract.

Both Corticospinal and Reticulospinal Tracts Control Force of Contraction.

The control of contraction strength is a key part of movement control. In primates, both corticospinal and reticulospinal cells provide input to motoneurons. Corticospinal discharge is known to correlate with force, but there are no previous reports of how reticular formation (RF) activity modulates with different contractions. Here we trained two female macaque monkeys (body weight, 5.9-6.9 kg) to pull a handle that could be loaded with 0.5-6 kg weights and recorded from identified pyramidal tract neurons (PTNs) in primary motor cortex and RF cells during task performance. Population-averaged firing rate increased monotonically with higher force for the RF, but showed a complex profile with little net modulation for PTNs. This reflected a more heterogeneous profile of rate modulation across the PTN population, leading to cancellation in the average. Linear discriminant analysis classified the force based on the time course of rate modulation equally well for PTNs and RF cells. Peak firing rate had significant linear correlation with force for 43 of 92 PTNs (46.7%) and 21 of 46 RF cells (43.5%). For almost all RF cells (20 of 21), the correlation coefficient was positive; similar numbers of PTNs (22 vs 21) had positive versus negative coefficients. Considering the timing of force representation, similar fractions (PTNs: 61.2%; RF cells: 55.5%) commenced coding before the onset of muscle activity. We conclude that both corticospinal and reticulospinal tracts contribute to the control of contraction force; the reticulospinal tract seems to specify an overall signal simply related to force, whereas corticospinal cell activity would be better suited for fine-scale adjustments.SIGNIFICANCE STATEMENT For the first time, we compare the coding of force for corticospinal and reticular formation cells in awake behaving monkeys, over a wide range of contraction strengths likely to come close to maximum voluntary contraction. Both cortical and brainstem systems coded similarly well for force, but whereas reticular formation cells carried a simple uniform signal, corticospinal neurons were more heterogeneous. This may reflect a role in the gross specification of a coordinated movement, versus more fine-grained adjustments around individual joints.

Chronic Behavioral Manipulation via Orally Delivered Chemogenetic Actuator in Macaques.

The chemogenetic technology referred to as designer receptors exclusively activated by designer drugs (DREADDs) offers reversible means to control neuronal activity for investigating its functional correlation with behavioral action. Deschloroclozapine (DCZ), a recently developed highly potent and selective DREADD actuator, displays a capacity to expand the utility of DREADDs for chronic manipulation without side effects in nonhuman primates, which has not yet been validated. Here we investigated the pharmacokinetics and behavioral effects of orally administered DCZ in female and male macaque monkeys. Pharmacokinetic analysis and PET occupancy examination demonstrated that oral administration of DCZ yielded slower and prolonged kinetics, and that its bioavailability was 10%-20% of that in the case of systemic injection. Oral DCZ (300-1000 μg/kg) induced significant working memory impairments for at least 4 h in monkeys with hM4Di expressed in the dorsolateral prefrontal cortex (Brodmann's area 46). Repeated daily oral doses of DCZ consistently caused similar impairments over two weeks without discernible desensitization. Our results indicate that orally delivered DCZ affords a less invasive strategy for chronic but reversible chemogenetic manipulation of neuronal activity in nonhuman primates, and this has potential for clinical application.SIGNIFICANCE STATEMENT The use of designer receptors exclusively activated by designer drugs (DREADDs) for chronic manipulation of neuronal activity for days to weeks may be feasible for investigating brain functions and behavior on a long time-scale, and thereby for developing therapeutics for brain disorders, such as epilepsy. Here we performed pharmacokinetics and in vivo occupancy study of orally administered deschloroclozapine to determine a dose range suitable for DREADDs studies. In monkeys expressing hM4Di in the prefrontal cortex, single and repeated daily doses significantly induced working-memory impairments for hours and over two weeks, respectively, without discernible desensitization. These results indicate that orally delivered deschloroclozapine produces long-term stable chemogenetic effects, and holds great promise for the translational use of DREADDs technology.

Intramuscular Administration of Placenta-Derived Stromal Cells Enhances Survival of Rhesus Macaque Monkeys Exposed to Total Body Irradiation

Placenta-derived stromal cells named PLX-R18 have been shown in-vitro to secrete pro-hematopoiesis proteins, induce bone marrow migration, and promote colony formation. Murine in-vivo studies indicated that placental cells are capable of reducing lethality from the Hematopoietic Sub-syndrome of Acute Radiation Syndrome (HS-ARS).A NIAID-supported pilot study with non-human primate (NHP) rhesus macaque monkeys was conducted with the objective to characterize the effect of PLX-R18 on HS-ARS, including survival and hematological parameters in irradiated NHP. 62 male and female rhesus macaque monkeys were divided into irradiated and non-irradiated cohorts. Non-irradiated or irradiated NHPs were treated with three intramuscular doses of PLX-R18 at 1 and 5 days post irradiation, or with placebo control. All doses of PLX-R18 improved outcome of irradiated NHPs relative to placebo (dose of 4, 10 and 20M cells/kg increased survival by 33.3, 35.7 and 16.7% respectively).A tendency towards earlier recovery of blood lineages was evident in all doses tested, particularly, for the two lower doses. The 4 million cells/kg dose of PLX-R18 reduced the duration of critical neutropenia, thrombocytopenia, and anemia (NEUT< 0.1x10^9/L, PLT< 10x10^9/L, HGB< 65 g/L) by 1.5, 1.5, and 0.7 days respectively. Importantly, NHP results recapitulate findings from mouse studies with respect to non-irradiated animals in that hematological parameters are minimally affected.Taken together, all doses of PLX-R18 positively affected survival rates and multiple hematological parameters of HS-ARS in rhesus monkeys and had no negative effects in either irradiated or non-irradiated monkeys. This supports the intended development of PLX-R18 as a treatment for HS-ARS. DisclosuresSher:Pluristem LTD: Employment, Equity Ownership. Prezma:Pluristem LTD: Employment, Equity Ownership. Fuchs-Telem:Pluristem LTD: Employment, Equity Ownership. Shraga- Heled:Pluristem LTD: Employment, Equity Ownership. Authier:CiToxLAB: Employment. Chang:SRI International: Employment. Ascah:CiToxLAB: Employment. Bakke:SRI International: Employment. Gahagen:SRI International: Employment. Ofir:Pluristem LTD: Employment, Equity Ownership.

Rich Club Characteristics of Alcohol-Naïve Functional Brain Networks Predict Future Drinking Phenotypes in Rhesus Macaques.

Purpose: A fundamental question for Alcohol use disorder (AUD) is how and when naïve brain networks are reorganized in response to alcohol consumption. The current study aimed to determine the progression of alcohol’s effect on functional brain networks during transition from the naïve state to chronic consumption.Procedures: Resting-state brain networks of six female rhesus macaque (Macaca mulatta) monkeys were acquired using magnetoencephalography (MEG) prior to alcohol exposure and after free-access to alcohol using a well-established model of chronic heavy alcohol consumption. Functional brain network metrics were derived at each time point.Results: The average connection frequency (p < 0.024) and membership of the Rich Club (p < 0.022) changed significantly over time. Metrics describing network topology remained relatively stable from baseline to free-access drinking. The minimum degree of the Rich Club prior to alcohol exposure was significantly predictive of future free-access drinking (r = −0.88, p < 0.001).Conclusions: Results suggest naïve brain network characteristics may be used to predict future alcohol consumption, and that alcohol consumption alters functional brain networks, shifting hubs and Rich Club membership away from previous regions in a non-systematic manner. Further work to refine these relationships may lead to the identification of a high-risk drinking phenotype.

Pholcodine-induced Stevens-Johnson syndrome in a patient with COVID-19

Reaction time is accelerated if a loud (startling) sound accompanies the cue—the “StartReact” effect. Animal studies revealed a reticulospinal substrate for the startle reflex; StartReact may similarly involve the reticulospinal...

Spatial and Temporal Arrangement of Recurrent Inhibition in the Primate Upper Limb.

Renshaw cells mediate recurrent inhibition between motoneurons within the spinal cord. The function of this circuit is not clear; we previously suggested based on computational modeling that it may cancel oscillations in muscle activity around 10 Hz, thereby reducing physiological tremor. Such tremor is especially problematic for dexterous hand movements, yet knowledge of recurrent inhibitory function is sparse for the control of the primate upper limb, where no direct measurements have been made to date. In this study, we made intracellular penetrations into 89 motoneurons in the cervical enlargement of four terminally anesthetized female macaque monkeys, and recorded recurrent IPSPs in response to antidromic stimulation of motor axons. Recurrent inhibition was strongest to motoneurons innervating shoulder muscles and elbow extensors, weak to wrist and digit extensors, and almost absent to the intrinsic muscles of the hand. Recurrent inhibitory connections often spanned joints, for example from motoneurons innervating wrist and digit muscles to those controlling the shoulder and elbow. Wrist and digit flexor motoneurons sometimes inhibited the corresponding extensors, and vice versa. This complex connectivity presumably reflects the flexible usage of the primate upper limb. Using trains of stimuli to motor nerves timed as a Poisson process and coherence analysis, we also examined the temporal properties of recurrent inhibition. The recurrent feedback loop effectively carried frequencies up to 100 Hz, with a coherence peak around 20 Hz. The coherence phase validated predictions from our previous computational model, supporting the idea that recurrent inhibition may function to reduce tremor.SIGNIFICANCE STATEMENT We present the first direct measurements of recurrent inhibition in primate upper limb motoneurons, revealing that it is more flexibly organized than previous observations in cat. Recurrent inhibitory connections were relatively common between motoneurons controlling muscles that act at different joints, and between flexors and extensors. As in the cat, connections were minimal for motoneurons innervating the most distal intrinsic hand muscles. Empirical data are consistent with previous modeling: temporal properties of the recurrent inhibitory feedback loop are compatible with a role in reducing physiological tremor by suppressing oscillations around 10 Hz.

Cortical, Corticospinal, and Reticulospinal Contributions to Strength Training.

Following a program of resistance training, there are neural and muscular contributions to the gain in strength. Here, we measured changes in important central motor pathways during strength training in 2 female macaque monkeys. Animals were trained to pull a handle with one arm; weights could be added to increase load. On each day, motor-evoked potentials in upper limb muscles were first measured after stimulation of the primary motor cortex (M1), corticospinal tract (CST), and reticulospinal tract (RST). Monkeys then completed 50 trials with weights progressively increased over 8-9 weeks (final weight ∼6 kg, close to the animal's body weight). Muscle responses to M1 and RST stimulation increased during strength training; there were no increases in CST responses. Changes persisted during a 2 week washout period without weights. After a further 3 months of strength training, an experiment under anesthesia mapped potential responses to CST and RST stimulation in the cervical enlargement of the spinal cord. We distinguished the early axonal volley and later spinal synaptic field potentials, and used the slope of the relationship between these at different stimulus intensities as a measure of spinal input-output gain. Spinal gain was increased on the trained compared with the untrained side of the cord within the intermediate zone and motor nuclei for RST, but not CST, stimulation. We conclude that neural adaptations to strength training involve adaptations in the RST, as well as intracortical circuits within M1. By contrast, there appears to be little contribution from the CST.SIGNIFICANCE STATEMENT We provide the first report of a strength training intervention in nonhuman primates. Our results indicate that strength training is associated with neural adaptations in intracortical and reticulospinal circuits, whereas corticospinal and motoneuronal adaptations are not dominant factors.

Long-latency Responses to a Mechanical Perturbation of the Index Finger Have a Spinal Component.

In an uncertain external environment, the motor system may need to respond rapidly to an unexpected stimulus. Limb displacement causes muscle stretch; the corrective response has multiple activity bursts, which are suggested to originate from different parts of the neuraxis. The earliest response is so fast, it can only be produced by spinal circuits; this is followed by slower components thought to arise from primary motor cortex (M1) and other supraspinal areas. Spinal cord (SC) contributions to the slower components are rarely considered. To address this, we recorded neural activity in M1 and the cervical SC during a visuomotor tracking task, in which 2 female macaque monkeys moved their index finger against a resisting motor to track an on-screen target. Following the behavioral trial, an increase in motor torque rapidly returned the finger to its starting position (lever velocity >200°/s). Many cells responded to this passive mechanical perturbation (M1: 148 of 211 cells, 70%; SC: 67 of 119 cells, 56%). The neural onset latency was faster for SC compared with M1 cells (21.7 ± 11.2 ms vs 25.5 ± 10.7 ms, respectively, mean ± SD). Using spike-triggered averaging, some cells in both regions were identified as likely premotor cells, with monosynaptic connections to motoneurons. Response latencies for these cells were compatible with a contribution to the muscle responses following the perturbation. Comparable fractions of responding neurons in both areas were active up to 100 ms after the perturbation, suggesting that both SC circuits and supraspinal centers could contribute to later response components.SIGNIFICANCE STATEMENT Following a limb perturbation, multiple reflexes help to restore limb position. Given conduction delays, the earliest part of these reflexes can only arise from spinal circuits. By contrast, long-latency reflex components are typically assumed to originate from supraspinal centers. We recorded from both spinal and motor cortical cells in monkeys responding to index finger perturbations. Many spinal interneurons, including those identified as projecting to motoneurons, responded to the perturbation; the timing of responses was compatible with a contribution to both short- and long-latency reflexes. We conclude that spinal circuits also contribute to long-latency reflexes in distal and forearm muscles, alongside supraspinal regions, such as the motor cortex and brainstem.

Electrocorticogram (ECoG) Is Highly Informative in Primate Visual Cortex.

Neural signals recorded at different scales contain information about environment and behavior and have been used to control Brain Machine Interfaces with varying degrees of success. However, a direct comparison of their efficacy has not been possible due to different recording setups, tasks, species, etc. To address this, we implanted customized arrays having both microelectrodes and electrocorticogram (ECoG) electrodes in the primary visual cortex of 2 female macaque monkeys, and also recorded electroencephalogram (EEG), while they viewed a variety of naturalistic images and parametric gratings. Surprisingly, ECoG had higher information and decodability than all other signals. Combining a few ECoG electrodes allowed more accurate decoding than combining a much larger number of microelectrodes. Control analyses showed that higher decoding accuracy of ECoG compared with local field potential was not because of differences in low-level visual features captured by them but instead because of larger spatial summation of the ECoG. Information was high in the 30-80 Hz range and at lower frequencies. Information in different frequencies and scales was nonredundant. These results have strong implications for Brain Machine Interface applications and for study of population representation of visual stimuli.SIGNIFICANCE STATEMENT Electrophysiological signals captured across scales by different recording electrodes are regularly used for Brain Machine Interfaces, but the information content varies due to electrode size and location. A systematic comparison of their efficiency for Brain Machine Interfaces is important but technically challenging. Here, we recorded simultaneous signals across four scales: spikes, local field potential, electrocorticogram (ECoG), and EEG, and compared their information and decoding accuracy for a large variety of naturalistic stimuli. We found that ECoGs were highly informative and outperformed other signals in information content and decoding accuracy.

Spiking Noise and Information Density of Neurons in Visual Area V2 of Infant Monkeys.

Encoding of visual information requires precisely timed spiking activity in the network of cortical neurons; irregular spiking can interfere with information processing especially for low-contrast images. The vision of newborn infants is impoverished. An infant's contrast sensitivity is low and the ability to discriminate complex stimuli is poor. The neural mechanisms that limit the visual capacities of infants are a matter of debate. Here we asked whether noisy spiking and/or crude information processing in visual cortex limit infant vision. Since neurons beyond the primary visual cortex (V1) have rarely been studied in neonates or infants, we focused on the firing pattern of neurons in visual area V2, the earliest extrastriate visual area of both male and female macaque monkeys (Maccaca mulatta). For eight stimulus contrasts ranging from 0% to 80%, we analyzed spiking irregularity by calculating the square of the coefficient of variation (CV2) in interspike intervals, the trial-to-trial fluctuation in spiking (Fano factor), and the amount of information on contrast conveyed by each spiking (information density). While the contrast sensitivity of infant neurons was reduced as expected, spiking noise, both the magnitude of spiking irregularity and the trial-to-trial fluctuations, was much lower in the spike trains of infant V2 neurons compared with those of adults. However, information density for V2 neurons was significantly lower in infants. Our results suggest that poor contrast sensitivity combined with lower information density of extrastriate neurons, despite their lower spiking noise, may limit behaviorally determined contrast sensitivity soon after birth.SIGNIFICANCE STATEMENT Despite >50 years of investigations on the postnatal development of the primary visual cortex (V1), cortical mechanisms that may limit infant vision are still unclear. We investigated the quality and strength of neuronal firing in primate visual area V2 by analyzing contrast sensitivity, spiking variability, and the amount of information on contrast conveyed by each action potential (information density). Here we demonstrate that the firing rate, contrast sensitivity, and dynamic range of V2 neurons were depressed in infants compared with adults. Although spiking noise was less, information density was lower in infant V2. Impoverished neuronal drive and lower information density in extrastriate visual areas, despite lower spiking noise, largely explain the impoverished visual sensitivity of primates near birth.

Attention Enhances the Efficacy of Communication in V1 Local Circuits.

Attention is a critical component of visual perception; however, the mechanisms of attention at the granular level are poorly understood. One possible mechanism by which attention modulates neuronal activity is to control the efficacy of communication between connected neurons; however, it is unclear whether attention alters communication efficacy across a variety of neuronal circuits. In parallel, attentional modulation of neuronal firing rate is not uniform but depends upon the match between neuronal feature selectivity and the feature required for successful task completion. Here we tested whether modulation of communication efficacy is a viable mechanism of attention by assessing whether it is consistent across a variety of neuronal circuits and dependent upon the type of information conveyed in each circuit. We identified monosynaptically connected pairs of V1 neurons through cross-correlation of neuronal spike trains recorded in adult female macaque monkeys performing attention-demanding contrast-change detection tasks. Attention toward the stimulus in the receptive field of recorded neurons significantly facilitated the efficacy of communication among connected pairs of V1 neurons. The amount of attentional enhancement depended upon neuronal physiology, with larger facilitation for circuits conveying information about task-relevant features. Furthermore, presynaptic activity was more determinant of attentional enhancement of communication efficacy than postsynaptic activity, and feedforward local circuits often displayed the largest facilitation with attention. Together, these findings highlight attentional modulation of communication efficacy as a generalized mechanism of attention and demonstrate that attentional modulation at the granular level depends on the relevance of feature-specific information conveyed by neuronal circuits.SIGNIFICANCE STATEMENT How we pay attention to objects and locations in the visual environment has a profound impact on visual perception. Individual neurons in the visual cortex are similarly regulated by shifts in visual attention; however, the rules that govern whether and how attention alters neuronal activity are not known. In this study, we explored whether attention regulates communication between connected pairs of neurons in the primary visual cortex. We observed robust attentional facilitation of communication among these circuits. Furthermore, the extent to which the circuits were facilitated by attention depended on whether the information they conveyed was relevant for the particular attention task.

Oxytocin and vasopressin increase male-directed threats and vocalizations in female macaques

In a previous study, we reported that intranasal delivery of both oxytocin (OT) and arginine vasopressin (AVP) to male macaques relaxes spontaneous social interactions, flattens the existing dominance hierarchy, and increases behavioral synchrony with other monkeys. Here we report that intranasal OT and AVP administration modulates the behaviors of female macaque monkeys, but in robustly different ways from males. Most notably, both neuropeptides increase threatening and vocalization behaviors of females when they encounter males, and these behaviors effectively increase the social status of females over males. While OT and AVP heighten the confrontational nature of intersexual encounters, both peptides relax interactions between females. Finally, as previously reported for males, treating an individual female monkey with OT or AVP significantly modulates the behavior of her non-treated partner. Together, these findings show that OT and AVP can either inhibit or promote aggression, depending on sex and behavioral context, and call for a more careful, systematic examination of the functions of these neuropeptides in both sexes, especially in the context of therapeutics for human social disorders.

Altered Balance of Receptive Field Excitation and Suppression in Visual Cortex of Amblyopic Macaque Monkeys.

In amblyopia, a visual disorder caused by abnormal visual experience during development, the amblyopic eye (AE) loses visual sensitivity whereas the fellow eye (FE) is largely unaffected. Binocular vision in amblyopes is often disrupted by interocular suppression. We used 96-electrode arrays to record neurons and neuronal groups in areas V1 and V2 of six female macaque monkeys (Macaca nemestrina) made amblyopic by artificial strabismus or anisometropia in early life, as well as two visually normal female controls. To measure suppressive binocular interactions directly, we recorded neuronal responses to dichoptic stimulation. We stimulated both eyes simultaneously with large sinusoidal gratings, controlling their contrast independently with raised-cosine modulators of different orientations and spatial frequencies. We modeled each eye's receptive field at each cortical site using a difference of Gaussian envelopes and derived estimates of the strength of central excitation and surround suppression. We used these estimates to calculate ocular dominance separately for excitation and suppression. Excitatory drive from the FE dominated amblyopic visual cortex, especially in more severe amblyopes, but suppression from both the FE and AEs was prevalent in all animals. This imbalance created strong interocular suppression in deep amblyopes: increasing contrast in the AE decreased responses at binocular cortical sites. These response patterns reveal mechanisms that likely contribute to the interocular suppression that disrupts vision in amblyopes.SIGNIFICANCE STATEMENT Amblyopia is a developmental visual disorder that alters both monocular vision and binocular interaction. Using microelectrode arrays, we examined binocular interaction in primary visual cortex and V2 of six amblyopic macaque monkeys (Macaca nemestrina) and two visually normal controls. By stimulating the eyes dichoptically, we showed that, in amblyopic cortex, the binocular combination of signals is altered. The excitatory influence of the two eyes is imbalanced to a degree that can be predicted from the severity of amblyopia, whereas suppression from both eyes is prevalent in all animals. This altered balance of excitation and suppression reflects mechanisms that may contribute to the interocular perceptual suppression that disrupts vision in amblyopes.

Experimental evidence that primate trichromacy is well suited for detecting primate social colour signals.

Primate trichromatic colour vision has been hypothesized to be well tuned for detecting variation in facial coloration, which could be due to selection on either signal wavelengths or the sensitivities of the photoreceptors themselves. We provide one of the first empirical tests of this idea by asking whether, when compared with other visual systems, the information obtained through primate trichromatic vision confers an improved ability to detect the changes in facial colour that female macaque monkeys exhibit when they are proceptive. We presented pairs of digital images of faces of the same monkey to human observers and asked them to select the proceptive face. We tested images that simulated what would be seen by common catarrhine trichromatic vision, two additional trichromatic conditions and three dichromatic conditions. Performance under conditions of common catarrhine trichromacy, and trichromacy with narrowly separated LM cone pigments (common in female platyrrhines), was better than for evenly spaced trichromacy or for any of the dichromatic conditions. These results suggest that primate trichromatic colour vision confers excellent ability to detect meaningful variation in primate face colour. This is consistent with the hypothesis that social information detection has acted on either primate signal spectral reflectance or photoreceptor spectral tuning, or both.

Clustering of PCOS-like traits in naturally hyperandrogenic female rhesus monkeys.

Do naturally occurring, hyperandrogenic (≥1 SD of population mean testosterone, T) female rhesus monkeys exhibit traits typical of women with polycystic ovary syndrome (PCOS)? Hyperandrogenic female monkeys exhibited significantly increased serum levels of androstenedione (A4), 17-hydroxyprogesterone (17-OHP), estradiol (E2), LH, antimullerian hormone (AMH), cortisol, 11-deoxycortisol and corticosterone, as well as increased uterine endometrial thickness and evidence of reduced fertility, all traits associated with PCOS. Progress in treating women with PCOS is limited by incomplete knowledge of its pathogenesis and the absence of naturally occurring PCOS in animal models. A female macaque monkey, however, with naturally occurring hyperandrogenism, anovulation and polyfollicular ovaries, accompanied by insulin resistance, increased adiposity and endometrial hyperplasia, suggests naturally occurring origins for PCOS in nonhuman primates. As part of a larger study, circulating serum concentrations of selected pituitary, ovarian and adrenal hormones, together with fasted insulin and glucose levels, were determined in a single, morning blood sample obtained from 120 apparently healthy, ovary-intact, adult female rhesus monkeys (Macaca mulatta) while not pregnant or nursing. The monkeys were then sedated for somatometric and ultrasonographic measurements. Female monkeys were of prime reproductive age (7.2 ± 0.1 years, mean ± SEM) and represented a typical spectrum of adult body weight (7.4 ± 0.2 kg; maximum 12.5, minimum 4.6 kg). Females were defined as having normal (n = 99) or high T levels (n = 21; ≥1 SD above the overall mean, 0.31 ng/ml). Electronic health records provided menstrual and fecundity histories. Steroid hormones were determined by tandem LC-MS-MS; AMH was measured by enzymeimmunoassay; LH, FSH and insulin were determined by radioimmunoassay; and glucose was read by glucose meter. Most analyses were limited to 80 females (60 normal T, 20 high T) in the follicular phase of a menstrual cycle or anovulatory period (serum progesterone <1 ng/ml). Of 80 monkeys, 15% (n = 12) exhibited classifiable PCOS-like phenotypes. High T females demonstrated elevations in serum levels of LH (P < 0.036), AMH (P < 0.021), A4 (P < 0.0001), 17-OHP (P < 0.008), E2 (P < 0.023), glucocorticoids (P < 0.02-0.0001), the serum T/E2 ratio (P < 0.03) and uterine endometrial thickness (P < 0.014) compared to normal T females. Within the high T group alone, anogenital distance, a biomarker for fetal T exposure, positively correlated (P < 0.015) with serum A4 levels, while clitoral volume, a biomarker for prior T exposure, positively correlated (P < 0.002) with postnatal age. Only high T females demonstrated positive correlations between serum LH, and both T and A4. Five of six (83%) high T females with serum T ≥2 SD above T mean (0.41 ng/ml) did not produce live offspring. N/A. This is an initial study of a single laboratory population in a single nonhuman primate species. While two biomarkers suggest lifelong hyperandrogenism, phenotypic expression during gestation, prepuberty, adolescence, mid-to-late reproductive years and postmenopause has yet to be determined. Characterizing adult female monkeys with naturally occurring hyperandrogenism has identified individuals with high LH and AMH combined with infertility, suggesting developmental linkage among traits with endemic origins beyond humans. PCOS may thus be an ancient phenotype, as previously proposed, with a definable pathogenic mechanism(s). Funded by competitive supplement to P51 OD011106 (PI: Mallick), by P50 HD028934 (PI: Marshall) and by P50 HD044405 (PI: Dunaif). The authors have no potential conflicts of interest.