Perceptography unveils the causal contribution of inferior temporal cortex to visual perception.

Neurons in the inferotemporal (IT) cortex respond selectively to complex visual features, implying their role in object perception. However, perception is subjective and cannot be read out from neural responses; thus, bridging the causal gap between neural activity and perception demands independent characterization of perception. Historically, though, the complexity of the perceptual alterations induced by artificial stimulation of IT cortex has rendered them impossible to quantify. To address this old problem, we tasked male macaque monkeys to detect and report optical impulses delivered to their IT cortex. Combining machine learning with high-throughput behavioral optogenetics, we generated complex and highly specific images that were hard for the animal to distinguish from the state of being cortically stimulated. These images, named "perceptograms" for the first time, reveal and depict the contents of the complex hallucinatory percepts induced by local neural perturbation in IT cortex. Furthermore, we found that the nature and magnitude of these hallucinations highly depend on concurrent visual input, stimulation location, and intensity. Objective characterization of stimulation-induced perceptual events opens the door to developing a mechanistic theory of visual perception. Further, it enables us to make better visual prosthetic devices and gain a greater understanding of visual hallucinations in mental disorders.

Neural signatures of natural behaviour in socializing macaques.

Our understanding of the neurobiology of primate behaviour largely derives from artificial tasks in highly controlled laboratory settings, overlooking most natural behaviours that primate brains evolved to produce1-3. How primates navigate the multidimensional social relationships that structure daily life4 and shape survival and reproductive success5 remains largely unclear at the single-neuron level. Here we combine ethological analysis, computer vision and wireless recording technologies to identify neural signatures of natural behaviour in unrestrained, socially interacting pairs of rhesus macaques. Single-neuron and population activity in the prefrontal and temporal cortex robustly encoded 24 species-typical behaviours, as well as social context. Male-female partners demonstrated near-perfect reciprocity in grooming, a key behavioural mechanism supporting friendships and alliances6, and neural activity maintained a running account of these social investments. Confronted with an aggressive intruder, behavioural and neural population responses reflected empathy and were buffered by the presence of a partner. Our findings reveal a highly distributed neurophysiological ledger of social dynamics, a potential computational foundation supporting communal life in primate societies, including our own.

An analysis of risk factors for spontaneously occurring type 2 diabetes mellitus in rhesus macaques (Macaca mulatta).

BACKGROUND: Type 2 Diabetes Mellitus (T2D) is a chronic disease with a high prevalence worldwide. Human literature suggests factors beyond well-known risk factors (e.g., age, body mass index) for T2D: cytomegalovirus serostatus, season of birth, maternal age, birth weight, and depression. Nothing is known, however, about whether these variables are influential in primate models of T2D. METHODS: Using a retrospective methodology, we identified 22 cases of spontaneously occurring T2D among rhesus monkeys at our facility. A control sample of n = 1199 was identified. RESULTS: Animals born to mothers that were ≤5.5 years of age, and animals that showed heightened Activity and Emotionality in response to brief separation in infancy, had a greater risk for development of T2D in adulthood. CONCLUSIONS: Knowledge of additional risk factors for T2D could help colony managers better identify at-risk animals and enable diabetes researchers to select animals that might be more responsive to their manipulations.

Repeatability of measures of behavioral organization over two years in captive infant rhesus macaques, Macaca mulatta.

Individual differences of infant temperament have been associated with future health outcomes that provide explanatory power beyond adult personality. Despite the importance of such a metric, our developmental understanding of personality-like traits is poor. Therefore, we examined whether young primates show consistency in personality traits throughout development. We replicated a Biobehavioral Assessment (BBA) at three time periods: 3-4 months, 1 year, and 2 years of age in 47 rhesus macaque (Macaca mulatta) subjects from large mixed-sex outdoor social housing units at the California National Primate Research Center. We report results for tests focused on responses and adaptation to the temporary separation and relocation, responses to a threatening stimulus, and ratings of overall temperament. We found consistently repeatable associations in measures of Emotionality; these associations were stronger in males, but also present in females, and broadly consistent between Years 1 and 2. We also explored whether behavioral responses to this experimental relocation might be influenced by their experience being relocated for other reasons (i.e., hospitalizations) as individuals' responses might be influenced by similar experiences to the BBA procedure. Only locomotion, during one of the assessments, was associated with past hospitalization events. Overall, repeatability in Emotionality-associated behaviors was evident across the 2 years, in both sexes. We did, however, find evidence of the emergence of sex differences via differentiated expression of behavioral responses during the BBA. We emphasize that there is likely contextual nuance in the use of these BBA factor-associated behaviors. Further research is required to determine whether and how shifts occur in underlying factor structure and the expression of associated behaviors.

Hair and plasma cortisol throughout the first 3 years of development in infant rhesus macaques, Macaca mulatta.

Cortisol expression has been demonstrated to have variation across development in rhesus macaques (Macaca mulatta). There exists contradictory evidence for the nature of this change, and age at which it occurs, across biological sample types. Consequently, we lack a cohesive understanding for cortisol concentrations across the development of a major human health translational model. We examined hair cortisol concentrations over the first 3 years of life for 49 mother-reared infant macaques from mixed-sex outdoor units at the California National Primate Research Center. For 48 of these subjects at infancy, 1 year, and 2 years, we obtained plasma cortisol samples for response to a stressor, adjustment to prolonged stress, and response to dexamethasone injection. Hair cortisol concentrations decreased dramatically between 3 and 10 months, followed by relative stability up to the final sampling event at around 34 months of age. Plasma cortisol showed within-year consistency, and consistency between infancy and year 1. We document variability in the infant plasma cortisol samples, especially in percent change between samples 1 and 2. Our plasma cortisol results indicate that infants possess the physiological capacity to effectively inhibit the release of cortisol when stimulated, as effectively as later responses in juveniles. Age-related changes in hair cortisol parallel findings indicating a large decline in the weeks following postparturation.

Sex influences the effects of social status on socioemotional behavior and serotonin neurochemistry in rhesus monkeys.

BACKGROUND: Despite observed sex differences in the prevalence of stress-related psychiatric conditions, most preclinical and translational studies have only included male subjects. Therefore, it has not been possible to effectively assess how sex interacts with other psychosocial risk factors to impact the etiology and maintenance of stress-related psychopathology. One psychosocial factor that interacts with sex to impact risk for stress-related behavioral and physiological deficits is social dominance. The current study was designed to assess sex differences in the effects of social status on socioemotional behavior and serotonin neurochemistry in socially housed rhesus monkeys. We hypothesized that sex and social status interact to influence socioemotional behaviors as well as serotonin 1A receptor binding potential (5HT1AR-BP) in regions of interest (ROIs) implicated in socioemotional behavior. METHODS: Behavioral observations were conducted in gonadally intact adult female (n = 14) and male (n = 13) rhesus monkeys. 5HT1AR-BP was assessed via positron emission tomography using 4-(2'-Methoxyphenyl)-1-[2'-(N-2"-pyridinyl)-p[18F]fluorobenzamido]ethylpiperazine ([18F]MPPF). RESULTS: Aggression emitted was greater in dominant compared to subordinate animals, regardless of sex. Submission emitted was significantly greater in subordinate versus dominant animals and greater in females than males. Affiliative behaviors emitted were not impacted by sex, status, or their interaction. Anxiety-like behavior emitted was significantly greater in females than in males regardless of social status. Hypothalamic 5HT1AR-BP was significantly greater in females than in males, regardless of social status. 5HT1AR-BP in the dentate gyrus of the hippocampus was significantly impacted by a sex by status interaction whereby 5HT1AR-BP in the dentate gyrus was greater in dominant compared to subordinate females but was not different between dominant and subordinate males. There were no effects of sex, status, or their interaction on 5HT1AR-BP in the DRN and in the regions of the PFC studied. CONCLUSIONS: These data have important implications for the treatment of stress-related behavioral health outcomes, as they suggest that sex and social status are important factors to consider in the context of serotonergic drug efficacy.

Females are more likely to suffer from stress-related conditions that impact socioemotional behavior compared to males. One thing that influences how sex impacts stress-related health problems is social dominance. We examined whether there are sex differences in the effects of social dominance on socioemotional behavior in socially housed rhesus monkeys. Because the neurotransmitter serotonin is important for socioemotional behavior, we also looked at the levels of the 5HT1AR receptor using neuroimaging. Aggression was greater in dominant compared to subordinate animals, and submission was significantly greater in subordinate versus dominant animals and greater in females than males. Anxiety and levels of 5HT1AR in the hypothalamus were significantly greater in females than in males. 5HT1AR in the hippocampus was greater in dominant compared to subordinate females but was not different between dominant and subordinate males. Overall, these data are important for the treatment of stress-related behavioral health outcomes because suggest that sex and social dominance are important factors to consider in the context of how effective drugs targeting the serotonin system are for treating stress-related behavioral health conditions.

Effect of short-term androgen supplementation on cognitive performance in older male rhesus macaques.

Old male rhesus macaques often show cognitive impairment, and also have attenuated circulating levels of testosterone and dehydroepiandrosterone sulfate (DHEAS). However, it is unclear if these age-associated decreases in circulating androgen levels are casually related to mechanisms that support cognition. To test this possibility, old male rhesus macaques were given daily supplements of testosterone and DHEA for ∼7 months, using a paradigm designed to mimic the 24-hour circulating hormone patterns of young adults. Animals completed the Delayed Match-to-Sample (DMS) task to assess recognition, and the Delayed Response (DR) task to assess working memory. The animals all showed significant delay-dependent performance, with longer delays resulting in lower accuracy; and timepoint-dependent performance, showing improvement with the repeated opportunities for practice. However, there were no differences between the androgen supplemented animals and age-matched controls. These data indicate that the specific short-term supplementation paradigm employed here offers no obvious benefits for DMS or DR task performance.

Optimising a computational model of human auditory cortex with an evolutionary algorithm.

We demonstrate how the structure of auditory cortex can be investigated by combining computational modelling with advanced optimisation methods. We optimise a well-established auditory cortex model by means of an evolutionary algorithm. The model describes auditory cortex in terms of multiple core, belt, and parabelt fields. The optimisation process finds the optimum connections between individual fields of auditory cortex so that the model is able to reproduce experimental magnetoencephalographic (MEG) data. In the current study, this data comprised the auditory event-related fields (ERFs) recorded from a human subject in an MEG experiment where the stimulus-onset interval between consecutive tones was varied. The quality of the match between synthesised and experimental waveforms was 98%. The results suggest that neural activity caused by feedback connections plays a particularly important role in shaping ERF morphology. Further, ERFs reflect activity of the entire auditory cortex, and response adaptation due to stimulus repetition emerges from a complete reorganisation of AC dynamics rather than a reduction of activity in discrete sources. Our findings constitute the first stage in establishing a new non-invasive method for uncovering the organisation of the human auditory cortex.

The biology of aging in a social world: Insights from free-ranging rhesus macaques.

Social adversity can increase the age-associated risk of disease and death, yet the biological mechanisms that link social adversities to aging remain poorly understood. Long-term naturalistic studies of nonhuman animals are crucial for integrating observations of social behavior throughout an individual's life with detailed anatomical, physiological, and molecular measurements. Here, we synthesize the body of research from one such naturalistic study system, Cayo Santiago, which is home to the world's longest continuously monitored free-ranging population of rhesus macaques (Macaca mulatta). We review recent studies of age-related variation in morphology, gene regulation, microbiome composition, and immune function. We also discuss ecological and social modifiers of age-markers in this population. In particular, we summarize how a major natural disaster, Hurricane Maria, affected rhesus macaque physiology and social structure and highlight the context-dependent and domain-specific nature of aging modifiers. Finally, we conclude by providing directions for future study, on Cayo Santiago and elsewhere, that will further our understanding of aging across different domains and how social adversity modifies aging processes.

Dynamic finite element modelling of the macaque mandible during a complete mastication gape cycle.

Three-dimensional finite element models (FEMs) are powerful tools for studying the mechanical behaviour of the feeding system. Using validated, static FEMs we have previously shown that in rhesus macaques the largest food-related differences in strain magnitudes during unilateral postcanine chewing extend from the lingual symphysis to the endocondylar ridge of the balancing-side ramus. However, static FEMs only model a single time point during the gape cycle and probably do not fully capture the mechanical behaviour of the jaw during mastication. Bone strain patterns and moments applied to the mandible are known to vary during the gape cycle owing to variation in the activation peaks of the jaw-elevator muscles, suggesting that dynamic models are superior to static ones in studying feeding biomechanics. To test this hypothesis, we built dynamic FEMs of a complete gape cycle using muscle force data from in vivo experiments to elucidate the impact of relative timing of muscle force on mandible biomechanics. Results show that loading and strain regimes vary across the chewing cycle in subtly different ways for different foods, something which was not apparent in static FEMs. These results indicate that dynamic three-dimensional FEMs are more informative than static three-dimensional FEMs in capturing the mechanical behaviour of the jaw during feeding by reflecting the asymmetry in jaw-adductor muscle activations during a gape cycle. This article is part of the theme issue 'Food processing and nutritional assimilation in animals'.

A view-based decision mechanism for rewards in the primate amygdala.

Primates make decisions visually by shifting their view from one object to the next, comparing values between objects, and choosing the best reward, even before acting. Here, we show that when monkeys make value-guided choices, amygdala neurons encode their decisions in an abstract, purely internal representation defined by the monkey's current view but not by specific object or reward properties. Across amygdala subdivisions, recorded activity patterns evolved gradually from an object-specific value code to a transient, object-independent code in which currently viewed and last-viewed objects competed to reflect the emerging view-based choice. Using neural-network modeling, we identified a sequence of computations by which amygdala neurons implemented view-based decision making and eventually recovered the chosen object's identity when the monkeys acted on their choice. These findings reveal a neural mechanism in the amygdala that derives object choices from abstract, view-based computations, suggesting an efficient solution for decision problems with many objects.

Ventrolateral prefrontal neurons of the monkey encode instructions in the 'pragmatic' format of the associated behavioral outcomes.

The prefrontal cortex plays an important role in coding rules and producing context-appropriate behaviors. These processes necessarily require the generation of goals based on current context. Indeed, instructing stimuli are prospectively encoded in prefrontal cortex in relation to behavioral demands, but the coding format of this neural representation is, to date, largely unknown. In order to study how instructions and behaviors are encoded in prefrontal cortex, we recorded the activity of monkeys (Macaca mulatta) ventrolateral prefrontal neurons in a task requiring to perform (Action condition) or withhold (Inaction condition) grasping actions on real objects. Our data show that there are neurons responding in different task phases, and that the neuronal population discharge is stronger in the Inaction condition when the instructing cue is presented, and in the Action condition in the subsequent phases, from object presentation to action execution. Decoding analyses performed on neuronal populations showed that the neural activity recorded during the initial phases of the task shares the same type of format with that recorded during the final phases. We propose that this format has a pragmatic nature, that is instructions and goals are encoded by prefrontal neurons as predictions of the behavioral outcome.

Assessment of Blood Pressure in Irradiated Rhesus Macaques (Macaca mulatta).

There is increasing evidence that circulatory disease incidence and mortality is associated with radiation exposure. Wake Forest School of Medicine is home to a unique cohort of total-body irradiated macaques, some with evidence of vascular end-organ disease in the brain, kidney and heart. Because there is a link between high blood pressure and vascular disease in all these sites, we undertook a retrospective study to evaluate blood pressure and radiation in this cohort of animals. In this work, we utilized a cohort of nonhuman primates (rhesus macaques, Macaca mulatta) long-term survivors of high-dose total-body irradiation (1.1-8.5 Gy, N = 129) and controls (N = 37) to evaluate the effects of radiation on blood pressure and obesity. Subjects were between 3 and 22 years of age (median 9 years). Blood pressure (BP) was measured 1-14 years postirradiation (median 4 years). Subjects were sedated with a combination of ketamine HCl (15 mg/kg body weight, IM) and midazolam (0.1 mg/kg body weight, IM) and systolic, diastolic, and mean arterial pressures were measured using a high definition oscillometer. Obesity was defined by dual energy X-ray absorptiometry as a body fat percentage >35%. Statistical analysis of the collected data indicated significant increases in blood pressure with increasing age and obesity. However, radiation did not significantly alter blood pressure in irradiated animals relative to controls, radiation dose, or age of irradiation.

Weak evidence for neural correlates of task-switching in macaque V1.

A central goal of systems neuroscience is to understand how populations of sensory neurons encode and relay information to the rest of the brain. Three key quantities of interest are 1) how mean neural activity depends on the stimulus (sensitivity), 2) how neural activity (co)varies around the mean (noise correlations), and 3) how predictive these variations are of the subject's behavior (choice probability). Previous empirical work suggests that both choice probability and noise correlations are affected by task training, with decision-related information fed back to sensory areas and aligned to neural sensitivity on a task-by-task basis. We used Utah arrays to record activity from populations of primary visual cortex (V1) neurons from two macaque monkeys that were trained to switch between two coarse orientation-discrimination tasks. Surprisingly, we find no evidence for significant trial-by-trial changes in noise covariance between tasks, nor do we find a consistent relationship between neural sensitivity and choice probability, despite recording from well-tuned task-sensitive neurons, many of which were histologically confirmed to be in supragranular V1, and despite behavioral evidence that the monkeys switched their strategy between tasks. Thus our data at best provide weak support for the hypothesis that trial-by-trial task-switching induces changes to noise correlations and choice probabilities in V1. However, our data agree with a recent finding of a single "choice axis" across tasks. They also raise the intriguing possibility that choice-related signals in early sensory areas are less indicative of task learning per se and instead reflect perceptual learning that occurs in highly overtrained subjects.NEW & NOTEWORTHY Converging evidence suggests that decision processes affect sensory neural activity, and this has informed numerous theories of neural processing. We set out to replicate and extend previous results on decision-related information and noise correlations in V1 of macaque monkeys. However, in our data, we find little evidence for a number of expected effects. Our null results therefore call attention to differences in task training, stimulus design, recording, and analysis techniques between our and prior studies.

Progressive neuronal plasticity in primate visual cortex during stimulus familiarization.

The primate brain is equipped to learn and remember newly encountered visual stimuli such as faces and objects. In the macaque inferior temporal (IT) cortex, neurons mark the familiarity of a visual stimulus through response modification, often involving a decrease in spiking rate. Here, we investigate the emergence of this neural plasticity by longitudinally tracking IT neurons during several weeks of familiarization with face images. We found that most neurons in the anterior medial (AM) face patch exhibited a gradual decline in their late-phase visual responses to multiple stimuli. Individual neurons varied from days to weeks in their rates of plasticity, with time constants determined by the number of days of exposure rather than the cumulative number of presentations. We postulate that the sequential recruitment of neurons with experience-modified responses may provide an internal and graded measure of familiarity strength, which is a key mnemonic component of visual recognition.

Multifocal electroretinography increases following experimental glaucoma in nonhuman primates with retinal ganglion cell axotomy.

PURPOSE: To determine whether short-latency changes in multifocal electroretinography (mfERG) observed in experimental glaucoma (EG) are secondary solely to retinal ganglion cell (RGC) loss or whether there is a separate contribution from elevated intraocular pressure (IOP). METHODS: Prior to operative procedures, a series of baseline mfERGs were recorded from six rhesus macaques using a 241-element unstretched stimulus. Animals then underwent hemiretinal endodiathermy axotomy (HEA) by placing burns along the inferior 180° of the optic nerve margin in the right eye (OD). mfERG recordings were obtained in each animal at regular intervals following for 3-4 months to allow stabilization of the HEA effects. Laser trabecular meshwork destruction (LTD) to elevate IOP was then performed; first-order kernel (K1) waveform root-mean-square (RMS) amplitudes for the short-latency segment of the mfERG wave (9-35 ms) were computed for two 7-hexagon groupings-the first located within the superior (non-axotomized) macula and the second within the inferior (axotomized) macula. Immunohistochemistry for glial fibrillary acidic protein (GFAP) was done. RESULTS: By 3 months post HEA, there was marked thinning of the inferior nerve fiber layer as measured by optical coherence tomography. Compared with baseline, no statistically significant changes in 9-35 ms K1 RMS amplitudes were evident in either the axotomized or non-axotomized portions of the macula. Following LTD, mean IOP in HEA eyes rose to 46 ± 9 compared with 20 ± 2 mmHg (SD) in the fellow control eyes. In the HEA + EG eyes, statistically significant increases in K1 RMS amplitude were present in both the axotomized inferior and non-axotomized superior portions of the OD retinas. No changes in K1 RMS amplitude were found in the fellow control eyes from baseline to HEA epoch, but there was a smaller increase from baseline to HEA + EG. Upregulation of GFAP in the Müller cells was evident in both non-axotomized and axotomized retina in eyes with elevated IOP. CONCLUSIONS: The RMS amplitudes of the short-latency mfERG K1 waveforms are not altered following axotomy but undergo marked increases following elevated IOP. This suggests that the increase in mfERG amplitude was not solely a result of RGC loss and may reflect photoreceptor and bipolar cell dysfunction and/or changes in Müller cells.

Low-dimensional encoding of decisions in parietal cortex reflects long-term training history.

Neurons in parietal cortex exhibit task-related activity during decision-making tasks. However, it remains unclear how long-term training to perform different tasks over months or even years shapes neural computations and representations. We examine lateral intraparietal area (LIP) responses during a visual motion delayed-match-to-category task. We consider two pairs of male macaque monkeys with different training histories: one trained only on the categorization task, and another first trained to perform fine motion-direction discrimination (i.e., pretrained). We introduce a novel analytical approach-generalized multilinear models-to quantify low-dimensional, task-relevant components in population activity. During the categorization task, we found stronger cosine-like motion-direction tuning in the pretrained monkeys than in the category-only monkeys, and that the pretrained monkeys' performance depended more heavily on fine discrimination between sample and test stimuli. These results suggest that sensory representations in LIP depend on the sequence of tasks that the animals have learned, underscoring the importance of considering training history in studies with complex behavioral tasks.

Variation in infant rhesus monkeys' (Macaca mulatta) neutrophil-to-lymphocyte ratio is associated with environmental conditions, emotionality, and cortisol concentrations, and predicts disease-related outcomes.

The neutrophil-to-lymphocyte ratio (NLR) is a predictor of morbidity for a variety of medical conditions, but little is known about how variation in NLR arises. We examined variation in this measure in a sample of 4577 infant rhesus monkeys (54.8 % female), who participated in the BioBehavioral Assessment program at the California National Primate Research Center at 3-4 months of age. Lower values for NLR were seen for animals reared indoors, for animals that were raised to be free of specific pathogens, and for males. In addition lower NLR was associated with higher stress values of cortisol and with greater emotionality in response to an acute stressor. Finally, lower NLR in infancy was associated with greater risk for developing airways hyperresponsiveness (a hallmark of asthma); with display of diarrhea up to 3.97 years later; and with greater viral load when infected with the simian immunodeficiency virus at a mean of 6.1 years of age. Infant NLR was a better predictor of viral load than was a contemporaneously obtained measure of NLR. Infant and adult values of NLR were only modestly correlated; one reason may be that the infant measure was obtained during stressful conditions and the adult measure was obtained under baseline conditions. We propose that NLR is an integrated outcome measure reflecting organization and interaction of stress-response and immune systems. As such, assessment of NLR under conditions of stress may be a particularly useful marker of individual differences in morbidity, especially for conditions in which stress plays an important role, as in asthma, diarrhea/colitis, and AIDS.

Image-dependence of the detectability of optogenetic stimulation in macaque inferotemporal cortex.

Artificial activation of neurons in early visual areas induces perception of simple visual flashes.1,2 Accordingly, stimulation in high-level visual cortices is expected to induce perception of complex features.3,4 However, results from studies in human patients challenge this expectation. Stimulation rarely induces any detectable visual event, and never a complex one, in human subjects with closed eyes.2 Stimulation of the face-selective cortex in a human patient led to remarkable hallucinations only while the subject was looking at faces.5 In contrast, stimulations of color- and face-selective sites evoke notable hallucinations independent of the object being viewed.6 These anecdotal observations suggest that stimulation of high-level visual cortex can evoke perception of complex visual features, but these effects depend on the availability and content of visual input. In this study, we introduce a novel psychophysical task to systematically investigate characteristics of the perceptual events evoked by optogenetic stimulation of macaque inferior temporal (IT) cortex. We trained macaque monkeys to detect and report optogenetic impulses delivered to their IT cortices7,8,9 while holding fixation on object images. In a series of experiments, we show that detection of cortical stimulation is highly dependent on the choice of images presented to the eyes and it is most difficult when fixating on a blank screen. These findings suggest that optogenetic stimulation of high-level visual cortex results in easily detectable distortions of the concurrent contents of vision.