Biology subjects

Sanchez, M. M.

Publications and source records attributed to Sanchez, M. M..

11 recordsLinked to original sources

bioRxiv2026

Increased CSF volume, altered brain development and emotional reactivity after postnatal Zika virus infection in infant rhesus macaques

Although congenital Zika virus (ZIKV) syndrome is well-characterized, the neurodevelopmental consequences of postnatal infection are less understood. Here we used a rhesus macaque model to investigate the developmental consequences of ZIKV infection during infancy on the brain and behavior, building on our prior research. Male and female infant rhesus macaques infected with ZIKV at 1 month of age were compared to sex-, age-, and rearing-matched uninfected controls and infants treated with the TLR3 agonist PolyIC as a control for activation of the innate immune system. Longitudinal behavioral assessments revealed alterations in emotional regulation following ZIKV exposure, including poor state control scores obtained from the Infant Neurobehavioral Assessment Scale early after ZIKV infection and longer-term displays of increased hostility during an acute stressor. While attachment bonds to caregivers were preserved, ZIKV-infected infants showed sex-specific alterations in behavioral regulation during caregiver separation compared to controls. At 3 months of age, MRI scans revealed larger total cerebrospinal fluid (CSF) volume and reduced volumes in visual processing regions in ZIKV-infected infants compared to controls. Postnatal ZIKV exposure also resulted in sex-specific brain structural alterations with males exhibiting amygdala hypertrophy, whereas ZIKV-infected females had volumetric reductions in temporal-limbic and temporal-auditory cortices. These findings demonstrate that postnatal ZIKV infection disrupts the development of sensory, social and emotion-regulatory systems and CSF function, highlighting the critical need for long-term monitoring of exposed children. One-Sentence SummaryPostnatal Zika virus infection disrupts emotional regulation and alters brain development in infant rhesus macaques, revealing a critical window of neurodevelopmental vulnerability that extends beyond the fetal period.

neuroscience↗

bioRxiv2026

Early life stress of maternal deprivation and peer-rearing jeopardize mesoprefrontal and mesolimbic dopamine receptors in the rhesus monkey

Early life stress (ELS) in primates alters dopamine function, contributing to addiction, hyperactivity, cognitive deficits, aggression, and social subordinance. To assess whether dopamine receptor densities are affected by ELS, male juvenile rhesus monkeys (Macaca mulatta) were either mother-reared (MR, N=6) in a semi-natural environment or nursery-reared (NR, N=6) with peers in a laboratory. At 1 [1/2] years of age, subjects were sacrificed and the left prefrontal cortex (PFC), striatum (caudate and putamen), nucleus accumbens (NAcc), and claustrum (CLA) were explored through quantitative autoradiographic studies of dopamine receptor-1 (DRD1) and -2 (DRD2) conducted using [125I]-(+)-SCH 23982 and 125I-Epidepride, which have high affinity and selectivity for DRD1 and DRD2, respectively. No group differences emerged in striatal or NAcc receptor binding. However, MR monkeys exhibited significantly greater DRD1 binding in the left orbital PFC and significantly greater DRD2 binding in both the left medial PFC and right CLA compared to NR. These findings implicate the medial PFC (stress vulnerability, cognition), orbital PFC (reward valuation), and CLA (anxiety modulation) as critical sites disrupted by maternal deprivation. Therefore, we propose that nursery-rearing induces a hypodopaminergic prefrontal-claustral ecophenotype, underlying the cognitive, affective, and social impairments observed in NR monkeys.

developmental biology↗

bioRxiv2026

Mechanisms of disrupted neurodevelopment after Zika virus infection in infancy

Congenital and early-life Zika virus (ZIKV) infection can result in neurologic deficits. Precise mechanisms of injury, especially in the more subtle presentation of postnatal infection, are not fully elucidated. Here, we defined the effects of ZIKV on the developing brain using single cell transcriptomics, histopathology and design-based stereology, diffusion MRI, and neurobehavioral assessments in infant rhesus macaques. ZIKV upregulated interferon-stimulated genes in activated microglia and cell death pathways in neurons and downregulated metabolism and differentiation genes in mature oligodendrocytes. Abnormal micro-organization of the corpus collosum and limbic white matter tracts was seen on diffusion weighted imaging. A curated gene set associated with autism spectrum disorder risk was negatively enriched in inhibitory and excitatory neurons from ZIKV-infected infants, with increased emotional reactivity already evident two weeks following infection. From single cells to organism-level behaviors, these results define the pathways and processes disrupted by early-life ZIKV infection.

neuroscience↗

bioRxiv2025

Cortical potentials evoked by stimulation of cervical vagus vs. auricular nerve: a comparative, parametric study in nonhuman primates

Stimulation of sensory vagal pathways is typically delivered via invasive, cervical vagus nerve stimulation (cVNS) or noninvasive, trans-auricular nerve stimulation (taNS). While both methods are investigated therapeutically, their effects on brain physiology remain poorly understood, hindering mechanistic understanding and stimulus optimization. In 6 awake nonhuman primates, we recorded cortical vagal-evoked potentials (VEPs) from subdural electrodes placed in prefrontal, sensorimotor and parietal cortical areas, in response to cVNS or taNS. Across 478 different taNS and cVNS protocols, we varied stimulation side, intensity, frequency, pulse count, and pulse width (PW) and assessed independent effects on amplitude and latency of early (EC; 30-100 ms), intermediate (IC; 101-200 ms) and late components (LC; 201-500 ms) of VEPs. Fixed and random effects of stimulation parameters and subjects, respectively, on VEP measurements, were assessed using a linear mixed-effects model. Overall, cVNS elicits more robust VEPs than taNS, with larger EC, IC and LC amplitudes in both hemispheres. cVNS-elicited ECs and LCs are largest in PFC and PC areas, whereas ICs are largest in SM areas. On the other hand, taNS generally does not elicit area-specific responses. cVNS-elicited ECs have slower latency than ta-NS elicited ECs. Higher stimulation frequencies and intensities and a longer pulse width elicit larger ECs and ICs for cVNS, and to some extent for taNS. Both short and long cVNS trains elicit stronger ECs, and long trains elicit slower ICs. Earlobe stimulation elicits VEPs that partially overlap with those from taNS. In conclusion, cVNS and taNS elicit cortical VEPs in a manner consistent with distinct engagement of ascending vagal pathways, and with similarities and differences in the effects of stimulation parameters on evoked responses.

neuroscience↗

bioRxiv2025

Effects of Social Status on Reproductive Success, Physiology and Maternal Care in Socially housed Female Rhesus Macaques

This study examined the long-term effects of low social status on reproductive success and seasonal changes in reproductive and stress hormones of adult female rhesus macaques. Rhesus are a matriarchal, matrilineal species that form hierarchical social hierarchies maintained by aggression. Thus, animals in the bottom of the hierarchy (low social status: subordinate) experience high levels of aggression from those in higher social ranks and therefore must remain vigilant. Social subordination generates chronic psychosocial stress and could negatively impact reproductive function. Twenty-seven adult female rhesus monkeys (13 dominant -DOM-, 14 subordinate -SUB-; 8-11 years old) were studied for stress neuroendocrine function -measuring basal plasma levels of cortisol-, as well as for reproductive endocrine function -measuring basal levels of estradiol (E2). In addition, we examined the reproductive success rates of these females (defined as number of live births/years with male access), their success rates raising infants that survived to 1 year, and the characteristics and effectiveness of their maternal care. Our findings show significantly lower reproductive success rates in SUB than DOM females, blunted E2 seasonal changes, driven by higher E2 levels in the anovulatory season and more attentive maternal care of offspring early in life than dominant females. Age at first birth was negatively associated with infant survival rate across ranks. Interestingly, higher levels of reproductive hormones (E2) during the anovulatory season predicted lower reproductive success, although the effect was driven by animals lactating at that point. Overall, these findings suggest that subordinate female macaques show a phenotype consistent with impaired reproductive function. Simple SummaryThis study examined the long-term effects of low social status on reproductive success and seasonality of reproductive and stress physiology of female rhesus monkeys. The despotic rhesus social hierarchy is matrilineal and maintained by aggression. Males leave their natal group in bachelor groups around puberty, but females remain, so social status of group members is passed down the female line. Rhesus with low social status (subordinate) experience significantly more aggression and harassment than their higher-ranking counter parts (dominant). This makes rhesus macaques an ideal model for studying chronic psychosocial stress and its long-term effects. Our findings show significantly lower reproductive success rates (number of live births based on access to males; lower infant survival rates) in subordinate than dominant females. Subordinate females also show blunted seasonal changes of the gonadal hormone estradiol (E2), driven by higher E2 levels in the anovulatory season than dominant animals, as well as more attentive maternal care of offspring early in life than dominant animals. Age at first birth was negatively associated with infant survival rate across ranks. Interestingly, higher levels of reproductive hormones (E2) during the anovulatory season were associated with lower reproductive success, although the effect was driven by animals lactating at that point. Overall, these findings suggest that female macaques with lower social status show a phenotype consistent with impaired reproductive function, though the biological mechanisms involved need to be further explored.

developmental biology↗

bioRxiv2025

The effects of chronic social stress on cognitive flexibility in adult female macaques

Chronic social subordination stress in macaques, particularly beginning early in life, is associated with negative health and cognitive aging outcomes. Utilizing a longitudinal, translational monkey model of early life stress in Rhesus macaques (Macaca mulatta), we assessed adult female cognitive performance that had received social subordination stress associated with Low Social Status (LSS) since birth. This chronic social stress in lower ranked monkeys produces physiological stress responses that over time can accelerate biological and cognitive aging. We compared 14 adult females of Low Birth Rank that had received higher levels of social subordination stress since infancy with 11 adult females of High Birth Rank that had received lower levels of chronic social stress. We followed these two groups longitudinally from birth to adolescence to assess long-term behavioral, physiological, and neural consequences of social stress. As they reached adulthood (ages 7-8 years), we measured executive function/cognitive flexibility using the Intra-/Extra-dimensional shift task (ID/ED), relevant for age-related cognitive decline. Only mild differences between High and Low ranking subjects were observed on the simple discrimination, and the reversal learning stages of the task. We did find an interaction between High Birth Rank and performance across the three dimensional-shift stages that was not present in the low-ranking subjects. Thus, although at this first age, we did not yet detect the presence of accelerated cognitive decline following chronic social stress, the low-ranking females showed mild deficits in cognitive flexibility compared to high-ranking subjects. We discuss additional factors impacting performance, and comparisons with neuroimaging data.

neuroscience↗

bioRxiv2025

Structural Effects of Low Social Status and Obesogenic Diet on Social and Emotional Neurocircuits in Female Macaques: A Longitudinal Study from Infancy to Adulthood

A substantial body of literature has demonstrated a consistent link between psychosocial stress and obesity in children, particularly in those from low socioeconomic backgrounds. Despite evidence indicating a complex interplay between stress, diet and obesity, there is a limited understanding of the specific versus potentially synergistic effects of obesity and stress on brain structural and functional development. This study investigates the developmental and long-term brain structural alterations resulting from exposure to chronic social stress due to low (subordinate -SUB-) social status and postnatal obesogenic diets. Forty-one female rhesus macaques (Dominants -DOM-, n=21; Subordinates -SUB-, n=20) were assigned to either only low-calorie diet (LCD) or to both high-calorie diet (HCD) and LCD (Choice diet) from birth through the juvenile period. After menarche, all subjects were maintained on a LCD-only diet through adulthood. Twenty-seven animals (DOM: n=13, SUB: n=14) were studied again in adulthood to investigate the long-term effects of early diet and social rank on brain structure. Cumulative Kcal consumption was measured from birth through 16 months and body weights were measured at all time points. Overall, the findings show specific effects of obesogenic diet and psychosocial stress on cortical and corticolimbic brain regions. Animals with access to the obesogenic diet had larger overall brain size (measured as intracranial volume -ICV-) and larger overall volumes of prefrontal cortex, insula, superior temporal sulcus (defined as temporo-parieto-occipital area rostral and caudal regions (TPOr and TPOc)) than those in the low-calorie diet. Most of these regional diet effects, except for the insula, were driven by general effects of the diet on brain size. The diet effects were lost when adding the adult data to the longitudinal analysis, suggesting transient effects of obesogenic diets while the animals were consuming it, but not long-term, persistent effects. These findings highlight the potential of brain rescue mechanisms that could offset lasting developmental effects of early-life obesogenic diet consumption. With respect to social rank, SUB exhibited larger volumes in brain regions related to social cognition and emotional processing than DOM animals. When the adult data was added to the longitudinal analysis, the effects of social rank were prominent in the hippocampus, superior temporal sulcus, temporo-parieto-occipital rostral region, and the temporal auditory cortices after ICV data correction, suggesting long-term, persistent and cumulative effects of these social experiences, in contrast to the transient diet effects.

neuroscience↗

bioRxiv2023

RNA in extracellular vesicles during adolescence reveal immune, energetic and microbial imprints of early life adversity.

Exposure to early life adversity (ELA), including childhood maltreatment, is one of the most significant risk factors for the emergence of neuropsychiatric disorders in adolescence and adulthood. Despite this relationship being well established, the underlying mechanisms remain unclear. One way to achieve this understanding is to identify molecular pathways and processes that are perturbed as a consequence of childhood maltreatment. Ideally, these perturbations would be evident as changes in DNA, RNA or protein profiles in easily accessible biological samples collected in the shadow of childhood maltreatment. In this study, we isolated circulating extracellular vesicles (EVs) from plasma collected from adolescent rhesus macaques that had either experienced nurturing maternal care (CONT) or maternal maltreatment (MALT) in infancy. RNA sequencing of RNA in plasma EVs and gene enrichment analysis revealed that genes related to translation, ATP synthesis, mitochondrial function and immune response were downregulated in MALT samples, while genes involved in ion transport, metabolism and cell differentiation were upregulated. Interestingly, we found that a significant proportion of EV RNA aligned to the microbiome and that MALT altered the diversity of microbiome-associated RNA signatures found in EVs. Part of this altered diversity suggested differences in prevalence of bacterial species in CONT and MALT animals noted in the RNA signatures of the circulating EVs. Our findings provide evidence that immune function, cellular energetics and the microbiome may be important conduits via which infant maltreatment exerts effects on physiology and behavior in adolescence and adulthood. As a corollary, perturbations of RNA profiles related to immune function, cellular energetics and the microbiome may serve as biomarkers of responsiveness to ELA. Our results demonstrate that RNA profiles in EVs can serve as a powerful proxy to identify biological processes that might be perturbed by ELA and that may contribute to the etiology of neuropsychiatric disorders in the aftermath of ELA.

zoology↗

bioRxiv2020

Chronic Psychosocial Stress and Experimental Pubertal Delay Affect Socioemotional Behavior and Amygdala Functional Connectivity in Adolescent Female Rhesus Macaques

In females, pubertal onset appears to signal the opening of a window of increased vulnerability to the effects of stress on neurobehavioral development. What is the impact of pubertal timing on this process? We assessed the effects of pubertal timing and stress on behavior and amygdala functional connectivity (FC) in adolescent female macaques, whose social hierarchy provides an ethologically valid model of chronic psychosocial stress. Monkeys experienced puberty spontaneously (n=34) or pubertal delay via Lupron treatment from age 16-33 months (n=36). We examined the effects of stress (continuous dimension spanning dominant/low-stress to subordinate/high-stress) and experimental pubertal delay (Lupron-treated vs. Control) on socioemotional behavior and FC at 43-46 months, after all animals had begun puberty. Regardless of treatment, subordinate monkeys were more submissive and less affiliative, and exhibited weaker FC between amygdala and dorsolateral prefrontal cortex and stronger FC between amygdala and temporal pole. Regardless of social rank, Lupron-treated monkeys were also more submissive, less affiliative, and explored less in a "Human Intruder" task but were less anxious than untreated monkeys; they exhibited stronger FC between amygdala and orbitofrontal cortex. No interactions between rank and Lupron treatment were observed. These data suggest that some of the effects of chronic subordination stress and delayed puberty overlap behaviorally, such that late-onset puberty-linked exposure to female hormones mimics chronic stress. In the brain, however, delayed puberty and subordination stress had separable effects, suggesting that the overlapping socioemotional outcomes may be mediated by distinct neuroplastic mechanisms. To gain further insights, additional longitudinal studies are required.

neuroscience↗

bioRxiv2019

Heritability and relationship of oxytocin receptor gene variants with social behavior and central oxytocin in colony-reared adult female rhesus macaques

The genetic contributions to sociality are an important research focus for understanding individual variation in social function and risk of social deficits in neurodevelopmental disorders (e.g. autism). The neuropeptide oxytocin (OXT) and its receptor, OXTR, influence social behavior across species. In humans and animals, common variants within the OXTR gene (OXTR) have been associated with varying socio-behavioral traits. However, the reported magnitude of influence of individual variants on complex behavior has been inconsistent. Compared to human studies, non-human primate (NHP) studies in controlled environments have the potential to result in robust effects detectable in relatively small samples. Here we estimate heritability of social behavior and central OXT concentrations in 214 socially-housed adult female rhesus macaques, a species sharing high similarity with humans in genetics, physiology, brain and social complexity. We present a bioinformatically-informed approach for identifying single nucleotide polymorphisms (SNPs) with likely biological relevance. We tested 13 common SNPs in regulatory and coding regions of OXTR for associations with behavior (pro-social, anxiety-like, and aggressive) and OXT concentration in cerebrospinal fluid (CSF). We found moderate rates of heritability for both social behavior and CSF OXT concentrations. No tested SNPs showed significant associations with behaviors or CSF in this sample. Associations between OXT CSF and social behavior were not significant either. SNP effect sizes were generally comparable to those reported in human studies of complex traits. While environmental control and a socio-biological similarity with humans is an advantage of rhesus models for detecting smaller genetic effects, it is insufficient to obviate large sample sizes necessary for appropriate statistical power.

neuroscience↗

bioRxiv2019

Long-term alterations in brain and behavior after postnatal Zika virus infections in infant macaques

Considering the impact that Zika virus (ZIKV) infection has on the fetal nervous system and given that the postnatal period is also a time of rapid brain growth, it is important to understand the potential neurobehavioral consequences of ZIKV infection during infancy. Postnatal ZIKV infection in a rhesus macaque (RM) model resulted in long-term behavioral, motor, and cognitive changes, including increased emotional reactivity, decreased social contact, loss of balance, and deficits in visual recognition memory at one year of age. Structural and functional MRI showed that ZIKV-infected infant RMs had persistent enlargement of lateral ventricles, smaller volumes and altered functional connectivity between brain areas important for socioemotional behavior, cognitive, and motor function (e.g. amygdala, hippocampus, cerebellum). Neuropathological changes corresponded with neuroimaging results and were consistent with the behavioral and memory deficits. Overall, this study demonstrates that postnatal ZIKV infection of infants in this model has long lasting neurodevelopmental consequences.

neuroscience↗