Neonatal CSF vasopressin concentration predicts later medical record diagnoses of autism spectrum disorder.
Proceedings of the National Academy of Sciences of the United States of America
Blood oxytocin concentration positively predicts contagious yawning behavior in children with autism spectrum disorder.
Autism research : official journal of the International Society for Autism Research
Autism spectrum disorder (ASD) is a brain disorder characterized by social impairments. ASD is currently diagnosed on the basis of behavioral criteria because no robust biomarkers have been identified. However, we recently found that cerebrospinal fluid (CSF) concentration of the "social" neuropeptide arginine vasopressin (AVP) is significantly lower in pediatric ASD cases vs. controls. As an initial step in establishing the direction of causation for this association, we capitalized upon a rare biomaterials collection of newborn CSF samples to conduct a quasi-prospective test of whether this association held before the developmental period when ASD first manifests. CSF samples had been collected in the course of medical care of 0- to 3-mo-old febrile infants (n = 913) and subsequently archived at -70 °C. We identified a subset of CSF samples from individuals later diagnosed with ASD, matched them 1:2 with appropriate controls (n = 33 total), and quantified their AVP and oxytocin (OXT) concentrations. Neonatal CSF AVP concentrations were significantly lower among ASD cases than controls and individually predicted case status, with highest precision when cases with comorbid attention-deficit/hyperactivity disorder were removed from the analysis. The associations were specific to AVP, as ASD cases and controls did not differ in neonatal CSF concentrations of the structurally related neuropeptide, OXT. These preliminary findings suggest that a neurochemical marker of ASD may be present very early in life, and if replicated in a larger, prospective study, this approach could transform how ASD is detected, both in behaviorally symptomatic children, and in infants at risk for developing it.
View details for DOI 10.1073/pnas.1919050117
View details for PubMedID 32341146
A randomized placebo-controlled pilot trial shows that intranasal vasopressin improves social deficits in children with autism
SCIENCE TRANSLATIONAL MEDICINE
2019; 11 (491)
Cerebrospinal fluid vasopressin and symptom severity in children with autism.
Annals of neurology
Research suggests that children with autism spectrum disorder (ASD) may have reduced empathy, as measured by an impaired contagious yawn response, compared to typically developing (TD) children. Other research has failed to replicate this finding, instead attributing this phenomenon to group differences in attention paid to yawn stimuli. A third possibility is that only a subgroup of children with ASD exhibits the impaired contagious yawn response, and that it can be identified biologically. Here we quantified blood concentrations of the "social" neuropeptide oxytocin (OXT) and evaluated yawning behavior and attention rates during a laboratory task in children with ASD (N=34) and TD children (N=30) aged 6-12years. No group difference in contagious yawning behavior was found. However, a blood OXT concentration*group (ASD vs. TD) interaction positively predicted contagious yawning behavior (F1,50 =7.4987; P=0.0085). Specifically, blood OXT concentration was positively related to contagious yawning behavior in children with ASD, but not in TD children. This finding was not due to delayed perception of yawn stimuli and was observed whether attention paid to test stimuli and clinical symptom severity were included in the analysis or not. These findings suggest that only a biologically defined subset of children with ASD exhibits reduced empathy, as measured by the impaired contagious yawn response, and that prior conflicting reports of this behavioral phenomenon may be attributable, at least in part, to variable mean OXT concentrations across different ASD study cohorts. Autism Res 2019. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: People with autism may contagiously yawn (i.e., yawn in response to another's yawn) less often than people without autism. We find that people with autism who have lower levels of blood oxytocin (OXT), a hormone involved in social behavior and empathy, show decreased contagious yawning, but those who have higher blood OXT levels do not differ in contagious yawning from controls. This suggests that decreased contagious yawning may only occur in a biologically defined subset of people with autism.
View details for DOI 10.1002/aur.2135
View details for PubMedID 31132232
Arginine vasopressin in cerebrospinal fluid is a marker of sociality in nonhuman primates
SCIENCE TRANSLATIONAL MEDICINE
2018; 10 (439)
Autism is a brain disorder characterized by social impairments. Progress in understanding autism has been hindered by difficulty in obtaining brain-relevant tissues [e.g., cerebrospinal fluid (CSF)] by which to identify markers of disease and targets for treatment. Here we overcome this barrier by providing evidence that mean CSF concentration of the "social" neuropeptide arginine vasopressin (AVP) is lower in children with autism versus controls. CSF AVP concentration also significantly differentiates individual cases from controls and is associated with greater social symptom severity in children with autism. These findings indicate that AVP may be a promising CSF marker of autism's social deficits. This article is protected by copyright. All rights reserved.
View details for PubMedID 30152888
Biomarker discovery for disease status and symptom severity in children with autism.
2017; 89: 39–45
Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by core social impairments. ASD remains poorly understood because of the difficulty in studying disease biology directly in patients and the reliance on mouse models that lack clinically relevant, complex social cognition abilities. We use ethological observations in rhesus macaques to identify male monkeys with naturally occurring low sociality. These monkeys showed differences in specific neuropeptide and kinase signaling pathways compared to socially competent male monkeys. Using a discovery and replication design, we identified arginine vasopressin (AVP) in cerebrospinal fluid (CSF) as a key marker of group differences in monkey sociality; we replicated these findings in an independent monkey cohort. We also confirmed in an additional monkey cohort that AVP concentration in CSF is a stable trait-like measure. Next, we showed in a small pediatric cohort that CSF AVP concentrations were lower in male children with ASD compared to age-matched male children without ASD (but with other medical conditions). We demonstrated that CSF AVP concentration was sufficient to accurately distinguish ASD cases from medical controls. These data suggest that AVP and its signaling pathway warrant consideration in future research studies investigating new targets for diagnostics and drug development in ASD.
View details for PubMedID 29720452
Preference for novel faces in male infant monkeys predicts cerebrospinal fluid oxytocin concentrations later in life.
Autism spectrum disorder (ASD) is characterized by social impairments and repetitive behaviors, and affects 1 in 68 US children. Despite ASD's societal impact, its disease mechanisms remain poorly understood. Recent preclinical ASD biomarker discovery research has implicated the neuropeptides oxytocin (OXT) and arginine vasopressin (AVP), and their receptors, OXTR and AVPR1A, in animal models. Efforts to translate these findings to individuals with ASD have typically involved evaluating single neuropeptide measures as biomarkers of ASD and/or behavioral functioning. Given that ASD is a heterogeneous disorder, and unidimensional ASD biomarker studies have been challenging to reproduce, here we employed a multidimensional neuropeptide biomarker analysis to more powerfully interrogate disease status and symptom severity in a well characterized child cohort comprised of ASD patients and neurotypical controls. These blood-based neuropeptide measures, considered as a whole, correctly predicted disease status for 57 out of 68 (i.e., 84%) participants. Further analysis revealed that a composite measure of OXTR and AVPR1A gene expression was the key driver of group classification, and that children with ASD had lower neuropeptide receptor mRNA levels compared to controls. Lower neuropeptide receptor mRNA levels also predicted greater symptom severity for core ASD features (i.e., social impairments and stereotyped behaviors), but were unrelated to intellectual impairment, an associated feature of ASD. Findings from this research highlight the value of assessing multiple related biological measures, and their relative contributions, in the same study, and suggest that low blood neuropeptide receptor availability may be a promising biomarker of disease presence and symptom severity in ASD.
View details for PubMedID 29309996
Intranasal oxytocin treatment for social deficits and biomarkers of response in children with autism.
Proceedings of the National Academy of Sciences
2017; 114 (30): 8119-8124
The ability to recognize individuals is a critical skill acquired early in life for group living species. In primates, individual recognition occurs predominantly through face discrimination. Despite the essential adaptive value of this ability, robust individual differences in conspecific face recognition exist, yet its associated biology remains unknown. Although pharmacological administration of oxytocin has implicated this neuropeptide in face perception and social memory, no prior research has tested the relationship between individual differences in face recognition and endogenous oxytocin concentrations. Here we show in a male rhesus monkey cohort (N = 60) that infant performance in a task used to determine face recognition ability (specifically, the ability of animals to show a preference for a novel face) robustly predicts cerebrospinal fluid, but not blood, oxytocin concentrations up to five years after behavioural assessment. These results argue that central oxytocin biology may be related to individual face perceptual abilities necessary for group living, and that these differences are stable traits.
View details for DOI 10.1038/s41598-017-13109-5
View details for PubMedCentralID PMC5636831
Hippocampal Y2 receptor-mediated mossy fiber plasticity is implicated in nicotine abstinence-related social anxiety-like behavior in an outbred rat model of the novelty-seeking phenotype.
Pharmacology, biochemistry, and behavior
2014; 125: 48–54
Autism spectrum disorder (ASD) is characterized by core social deficits. Prognosis is poor, in part, because existing medications target only associated ASD features. Emerging evidence suggests that the neuropeptide oxytocin (OXT) may be a blood-based biomarker of social functioning and a possible treatment for ASD. However, prior OXT treatment trials have produced equivocal results, perhaps because of variability in patients' underlying neuropeptide biology, but this hypothesis has not been tested. Using a double-blind, randomized, placebo-controlled, parallel design, we tested the efficacy and tolerability of 4-wk intranasal OXT treatment (24 International Units, twice daily) in 32 children with ASD, aged 6-12 y. When pretreatment neuropeptide measures were included in the statistical model, OXT compared with placebo treatment significantly enhanced social abilities in children with ASD [as measured by the trial's primary outcome measure, the Social Responsiveness Scale (SRS)]. Importantly, pretreatment blood OXT concentrations also predicted treatment response, such that individuals with the lowest pretreatment OXT concentrations showed the greatest social improvement. OXT was well tolerated, and its effects were specific to social functioning, with no observed decrease in repetitive behaviors or anxiety. Finally, as with many trials, some placebo-treated participants showed improvement on the SRS. This enhanced social functioning was mirrored by a posttreatment increase in their blood OXT concentrations, suggesting that increased endogenous OXT secretion may underlie this improvement. These findings indicate that OXT treatment enhances social abilities in children with ASD and that individuals with pretreatment OXT signaling deficits may stand to benefit the most from OXT treatment.
View details for DOI 10.1073/pnas.1705521114
View details for PubMedCentralID PMC5544319
Nicotine-induced anxiety-like behavior in a rat model of the novelty-seeking phenotype is associated with long-lasting neuropeptidergic and neuroplastic adaptations in the amygdala: Effects of the cannabinoid receptor 1 antagonist AM251
2012; 63 (8): 1335-1345
Experimentally naïve outbred rats display varying rates of locomotor reactivity in response to the mild stress of a novel environment. Namely, some display high rates (HR) whereas some display low rates (LR) of locomotor reactivity. Previous reports from our laboratory show that HRs, but not LRs, develop locomotor sensitization to a low dose nicotine challenge and exhibit increased social anxiety-like behavior following chronic intermittent nicotine training. Moreover, the hippocampus, specifically hippocampal Y2 receptor (Y2R)-mediated neuropeptide Y signaling is implicated in these nicotine-induced behavioral effects observed in HRs. The present study examines the structural substrates of the expression of locomotor sensitization to a low dose nicotine challenge and associated social anxiety-like behavior following chronic intermittent nicotine exposure during adolescence in the LRHR hippocampi. Our data showed that the expression of locomotor sensitization to the low dose nicotine challenge and the increase in social anxiety-like behavior were accompanied by an increase in mossy fiber terminal field size, as well as an increase in spinophilin mRNA levels in the hippocampus in nicotine pre-trained HRs compared to saline pre-trained controls. Furthermore, a novel, selective Y2R antagonist administered systemically during 1wk of abstinence reversed the behavioral, molecular and neuromorphological effects observed in nicotine-exposed HRs. These results suggest that nicotine-induced neuroplasticity within the hippocampus may regulate abstinence-related negative affect in HRs, and implicate hippocampal Y2R in vulnerability to the behavioral and neuroplastic effects of nicotine in the novelty-seeking phenotype.
View details for DOI 10.1016/j.pbb.2014.08.004
View details for PubMedID 25158103
Long-term effects of juvenile nicotine exposure on abstinence-related social anxiety-like behavior and amygdalar cannabinoid receptor 1 (CB1R) mRNA expression in the novelty-seeking phenotype
BEHAVIOURAL BRAIN RESEARCH
2012; 228 (1): 236-239
A rat model of the novelty-seeking phenotype predicts vulnerability to the expression of behavioral sensitization to nicotine, where locomotor reactivity to novelty is used to screen experimentally-naïve rats for high (HR) versus low (LR) responders. The present study examines the long-term neuropeptidergic and neuroplastic adaptations associated with the expression of locomotor sensitization to a low dose nicotine challenge and social anxiety-like behavior following chronic intermittent nicotine exposure during adolescence in the LRHR phenotype. Our data show that the expression of behavioral sensitization to nicotine and abstinence-related anxiety are detected in nicotine pre-exposed HRs even across a long (3 wks) abstinence. Moreover, these behavioral effects of nicotine are accompanied by a persistent imbalance between neuropeptide Y and corticotrophin releasing factor systems, and a persistent increase in brain-derived neurotrophic factor (BDNF) and spinophilin mRNA levels in the amygdala. Furthermore, treatment with the cannabinoid receptor 1 antagonist, AM251 (5 mg/kg) during a short (1 wk) abstinence is ineffective in reversing nicotine-induced anxiety, fluctuations in BDNF and spinophilin mRNAs, and the neuropeptidergic dysregulations in the amygdala; although this treatment is effective in reversing the expression of locomotor sensitization to challenge nicotine even after a long abstinence. Interestingly, the identical AM251 treatment administered during the late phase of a long abstinence further augments anxiety and associated changes in BDNF and spinophilin mRNA in the basolateral nucleus of the amygdala in nicotine pre-exposed HRs. These findings implicate long-lasting neuropeptidergic and neuroplastic changes in the amygdala in vulnerability to the behavioral effects of nicotine in the novelty-seeking phenotype.
View details for DOI 10.1016/j.neuropharm.2012.08.016
View details for Web of Science ID 000310947700007
View details for PubMedID 22959963
CHRONIC VARIABLE PHYSICAL STRESS DURING THE PERIPUBERTAL-JUVENILE PERIOD CAUSES DIFFERENTIAL DEPRESSIVE AND ANXIOGENIC EFFECTS IN THE NOVELTY-SEEKING PHENOTYPE: FUNCTIONAL IMPLICATIONS FOR HIPPOCAMPAL AND AMYGDALAR BRAIN-DERIVED NEUROTROPHIC FACTOR AND THE MOSSY FIBRE PLASTICITY
2011; 192: 334-344
A rat model of novelty-seeking phenotype predicts vulnerability to nicotine relapse where locomotor reactivity to novelty is used to rank high (HR) versus low (LR) responders. Present study investigates implication of cannabinoid receptor 1 (CB1R) in the basolateral (BLA) and the central (CeA) nuclei of amygdala in behaviorally sensitizing effects of nicotine and accompanying social anxiety following juvenile nicotine training and a 1- or 3-wk injection-free period in the novelty-seeking phenotype. Sprague-Dawley rats were phenotype screened, and received four, saline (1 ml/kg; s.c) or nicotine (0.35 mg/kg; s.c) injections, followed by a 1- or 3-wk injection-free period. Subsequently, animals were challenged with a low dose of nicotine (0.1 mg/kg; s.c.), subjected to the social interaction test and sacrificed. In situ hybridization histochemistry was used to assess CB1R messenger RNA (mRNA) levels in the amygdala. Nicotine pre-trained HRs displayed expression of locomotor sensitization to nicotine challenge along with enhanced social anxiety compared to saline pre-trained controls following a 1- or 3-wk injection-free period. HR-specific behavioral effects were accompanied by decreased CB1R mRNA levels in the CeA and the BLA following a 1-wk injection-free period. Decreased CB1R mRNA levels in both compartments of the amygdala were also observed following nicotine challenge in saline pre-trained HRs after a 3-wk injection-free period compared to HRs after a 1-wk injection-free period. These findings show robust, long-lasting expression of behavioral sensitization to nicotine in HRs associated with changes in amygdalar CB1R mRNA as a potential substrate for abstinence-related anxiety.
View details for DOI 10.1016/j.bbr.2011.11.015
View details for Web of Science ID 000300472600029
View details for PubMedID 22119710
Effects of a selective Y2R antagonist, JNJ-31020028, on nicotine abstinence-related social anxiety-like behavior, neuropeptide Y and corticotropin releasing factor mRNA levels in the novelty-seeking phenotype
BEHAVIOURAL BRAIN RESEARCH
2011; 222 (2): 332-341
Experimentally naive rats show variance in their locomotor reactivity to novelty, some displaying higher (HR) while others displaying lower (LR) reactivity, associated with vulnerability to stress. We employed a chronic variable physical stress regimen incorporating intermittent and random exposures of physical stressors or control handling during the peripubertal-juvenile period to assess interactions between stress and the LRHR phenotype in depressive- and anxiety-like behaviors on the forced swim and social interaction tests, respectively. A decrease in immobility in the forced swim test along with a decrease in social contact in the social interaction test were observed in the juvenile HRs, coupled with increases in brain-derived neurotrophic factor (BDNF) mRNA in the hippocampus and in the basolateral amygdala with chronic variable physical stress. In contrast, an increase in immobility in the forced swim test and a decrease in social contact was observed in the LR counterparts coupled with an increase in the BDNF mRNA in the basolateral amygdala following chronic variable physical stress. Furthermore, chronic physical stress led to increased H3 and H4 acetylation at the P2 and P4 promoters of the hippocampal BDNF gene in the HR rats that is associated with increased suprapyramidal mossy fibre (SP-MF) terminal field volume. In contrast, chronic variable physical stress led to decreased H4 acetylation at the P4 promoter, associated with decreased SP-MF volume in the LR rats. These findings show dissociation in depressive- and anxiety-like behaviors following chronic variable physical stress in the juvenile HR animals that may be mediated by increased levels of BDNF in the hippocampus and in the amygdala, respectively. Moreover, chronic variable physical stress during the peripubertal-juvenile period results in opposite effects in depressive-like behavior in the LRHR rats by way of inducing differential epigenetic regulation of the hippocampal BDNF gene that, in turn, may mediate mossy fibre sprouting.
View details for DOI 10.1016/j.neuroscience.2011.06.077
View details for Web of Science ID 000295555100031
View details for PubMedID 21767611
Stressful environmental and social stimulation in adolescence causes antidepressant-like effects associated with epigenetic induction of the hippocampal BDNF and mossy fibre sprouting in the novelty-seeking phenotype
2011; 501 (2): 107-111
An outbred rat model of novelty-seeking phenotype has predictive value for the expression of locomotor sensitization to nicotine. When experimentally naïve rats are exposed to a novel environment, some display high rates of locomotor reactivity (HRs, scores ranking at top 1/3rd of the population), whereas some display low rates (LRs, scores ranking at bottom 1/3rd of the population). Basally, HRs display lower anxiety-like behavior compared to LRs along with higher neuropeptide Y (NPY) mRNA in the amygdala and the hippocampus. Following an intermittent behavioral sensitization to nicotine regimen and 1 wk of abstinence, HRs show increased social anxiety-like behavior in the social interaction test and robust expression of locomotor sensitization to a low dose nicotine challenge. These effects are accompanied by a deficit in NPY mRNA levels in the medial nucleus of the amygdala and the CA3 field of the hippocampus, and increases in Y2R mRNA levels in the CA3 field and corticotropin releasing factor (CRF) mRNA levels in the central nucleus of the amygdala. Systemic and daily injections of a Y2R antagonist, JNJ-31020028, during abstinence fully reverse nicotine-induced social anxiety-like behavior, the expression of locomotor sensitization to nicotine challenge, the deficit in the NPY mRNA levels in the amygdala and the hippocampus, as well as result an increase in Y2R mRNA levels in the hippocampus and the CRF mRNA levels in the amygdala in HRs. These findings implicate central Y2R in neuropeptidergic regulation of social anxiety in a behavioral sensitization to nicotine regimen in the LRHR rats.
View details for DOI 10.1016/j.bbr.2011.03.067
View details for Web of Science ID 000291836400009
View details for PubMedID 21497168
Vulnerability to nicotine abstinence-related social anxiety-like behavior: Molecular correlates in neuropeptide Y, Y2 receptor and corticotropin releasing factor
2011; 490 (3): 220-225
An outbred rat model of novelty-seeking phenotype can differentiate between rats that show high rates (high responders; HRs) versus low rates (low responders; LRs) of locomotor reactivity to a novel environment. In the present study, LR and HR rats were exposed to a regimen of environmental and social stimuli (ESS) consisting of 14 random exposures of isolation, crowding or novel environment, once per day during the peripubertal-juvenile period (postnatal days 28-41) or handled as controls. Twenty-four hours after the last ESS exposure or control handling, all animals were tested on the forced swim and social interaction tests for depressive-like and social anxiety-like behaviors respectively. The ESS exposure during the peripubertal-juvenile period led to antidepressive-like effects on the forced swim test associated with increase in acetylation of histones 3 and 4 at the promoter regions P2 and P4 of the brain-derived neurotrophic factor (BDNF) gene in the dorsal hippocampus of HRs. Moreover, epigenetic activation of the hippocampal BDNF in the HRs following ESS exposure was accompanied by increase in the supra-pyramidal mossy fibre (SP-MF) and total mossy fibre terminal field volumes compared to handled controls. These findings suggest that the ESS exposure in the peripubertal-juvenile period may constitute an example of environmental induction of the hippocampal BDNF, and may mimic behavioral effects of exogenous antidepressants in the HR phenotype.
View details for DOI 10.1016/j.neulet.2011.06.058
View details for Web of Science ID 000294317600010
View details for PubMedID 21767606
Effects of a cannabinoid receptor (CB) 1 antagonist AM251 on behavioral sensitization to nicotine in a rat model of novelty-seeking behavior: correlation with hippocampal 5HT
2009; 203 (1): 23-32
An outbred rat model of the novelty-seeking phenotype is used to study nicotine vulnerability, where experimentally naïve rats were phenotype screened as high or low responders (HRs or LRs, ranking in the upper or lower one-third of the population respectively) based on locomotor activity displayed in a novel environment. Following nicotine training and abstinence, HR animals pre-trained with nicotine showed expression of locomotor sensitization to nicotine challenge along with enhanced social anxiety-like behavior in the social interaction test compared to saline pre-trained controls. HR rats also showed a downregulation in neuropeptide Y (NPY) mRNA levels in the medial nucleus of amygdala and the CA1 field of the hippocampus, an upregulation in Y2 mRNA levels in the CA3 field of the hippocampus, and an upregulation in the corticotropin releasing factor (CRF) mRNA levels in the central nucleus of the amygdala. These findings implicate dysregulations in the NPY-CRF systems in the HR hippocampus and amygdala associated with the emergence of social anxiety-like behavior, and a novel Y2R-mediated pathway in nicotine relapse.
View details for DOI 10.1016/j.neulet.2010.12.056
View details for Web of Science ID 000287794700013
View details for PubMedID 21195134
There are marked individual differences in the efficacy of mainstream nicotine cessation agents in preventing relapse. A rat model of novelty-seeking phenotype was reported to have predictive value for psychostimulant taking behavior where locomotor reactivity to novelty is used to rank high (HR, highest 1/3) versus low (LR, lowest 1/3) responsiveness to novelty in outbred rats. We tested the hypothesis that a cannabinoid receptor (CB) 1 antagonist that is in clinical trials for smoking cessation may reverse behaviorally sensitizing effects of nicotine in HRs and repeated nicotine-induced elevations in hippocampal 5HT.Adolescent LRHR rats underwent intermittent behavioral sensitization to nicotine regimen with or without a CB1 receptor antagonist AM251 or bupropion treatment following nicotine training during 1 week of nicotine-free period. Expression of behavioral sensitization to nicotine was assessed in response to a low-dose nicotine challenge. Using the same sensitization regimen and therapeutic treatments, hippocampal 5HT levels were measured via in vivo microdialysis in response to the nicotine challenge.HR but not LR animals showed behavioral sensitization to a low-dose nicotine challenge following intermittent nicotine training and 1 week of injection-free period. AM251 (5 mg/kg, i.p.) but not bupropion administration during injection-free period successfully reversed locomotor sensitization to nicotine challenge in HRs. AM251 treatment also reversed nicotine-induced elevations in extracellular 5HT in the HR hippocampal hilus.These data suggest that CB1 antagonists may prevent locomotor sensitization to nicotine and reverse nicotine-induced elevations in hippocampal 5HT in high novelty seekers.
View details for DOI 10.1007/s00213-008-1366-6
View details for Web of Science ID 000263423100003
View details for PubMedID 18936914