Differences In Behavioral Phenotypes Research Articles

A dog's life: Early life histories influence methylation of glucocorticoid (NR3C1) and oxytocin (OXTR) receptor genes, cortisol levels, and attachment styles.

Early life deprivation and stress can contribute to life-long, problematic consequences, including epigenetic variations related to behavior and health. Domestic dogs share human environments and social-cognitive traits, making them a promising comparative model to examine developmental plasticity. We examined 47 owner-dog dyads, including dogs rescued from abusive or neglectful environments, and matched control dogs for changes in DNA methylation of glucocorticoid (NR3C1) and oxytocin (OXTR) receptor genes previously shown to be affected by early life stress in other species including humans. We used an attachment paradigm, which included a separation event to examine cortisol levels and owner-dog attachment styles. Overall, dogs with adverse histories had different NR3C1 methylation patterns as a function of age and less OXTR methylation than comparison dogs. Dogs with adverse histories did not differ in their cortisol change from baseline to poststressor from comparison dogs, but the change in cortisol was associated with NR3C1 methylation. In addition, dogs with a history of early life stress had more insecure attachment styles; for every unit increase of OXTR methylation, the odds increased for insecure attachment style. This study demonstrates that adverse life histories lead to methylation differences, resulting in the hypothalamic-pituitary-adrenal (HPA) axis's dysregulation and differences in behavioral phenotypes.

Abstract WMP75: Neurobehavioral Outcomes Following Left- and Right-Sided Intracerebral Hemorrhage in Mice

Background: Injury location is an established outcome predictor in intracerebral hemorrhage (ICH), with most studies focusing on outcomes relating to motor deficits. However, location may also affect other neurobehavioral deficits following ICH, such as mood and cognitive decline. To address this gap, we studied neurobehavioral outcomes following left and right-sided ICH in mice. Methods: Three-month-old male mice (C57BL/6) were given a left (n=5) or right-sided (n=5) ICH. In short, type VII collagenase was injected into the left or right striatum (0.0 mm anterior, +/- 2.3 mm lateral, and 3.6 mm deep from bregma). Naïve mice (n=5) were used as controls. Behavior was assessed at day 28 post-ICH using a video-recorded three-chamber sociability task in which one chamber had an enclosed male stranger mouse. Distance traveled, time in each chamber, and time exploring the stranger mouse were quantified using automated software (AnyMaze). Data were analyzed by one-way ANOVA and Tukey post-hoc tests. Results: ICH location had differential effects on behavioral outcomes. Compared to naïve and right-sided ICH mice, left-sided ICH mice traveled a greater overall distance exploring the chambers (both p<0.05), spent a greater overall time immobile in the stranger mouse zone (both p<0.001) and less time oriented towards the stranger mouse (both p<0.05). Furthermore, when comparing naive and left-sided ICH mice, left-sided mice had a higher frequency of investigations of the empty cage (p<0.05). No significant differences were found between the naïve and right-sided ICH mice. Conclusions: These results reveal differences in behavioral phenotypes associated with left- and right-sided ICH.

Poorer White Matter Microstructure Predicts Slower and More Variable Reaction Time Performance: Evidence for a Neural Noise Hypothesis in a Large Lifespan Cohort.

Most prior research has focused on characterizing averages in cognition, brain characteristics, or behavior, and attempting to predict differences in these averages among individuals. However, this overwhelming focus on mean levels may leave us with an incomplete picture of what drives individual differences in behavioral phenotypes by ignoring the variability of behavior around an individual's mean. In particular, enhanced white matter (WM) structural microstructure has been hypothesized to support consistent behavioral performance by decreasing Gaussian noise in signal transfer. Conversely, lower indices of WM microstructure are associated with greater within-subject variance in the ability to deploy performance-related resources, especially in clinical populations. We tested a mechanistic account of the "neural noise" hypothesis in a large adult lifespan cohort (Cambridge Centre for Ageing and Neuroscience) with over 2500 adults (ages 18-102; 1508 female; 1173 male; 2681 behavioral sessions; 708 MRI scans) using WM fractional anisotropy to predict mean levels and variability in reaction time performance on a simple behavioral task using a dynamic structural equation model. By modeling robust and reliable individual differences in within-person variability, we found support for a neural noise hypothesis (Kail, 1997), with lower fractional anisotropy predicted individual differences in separable components of behavioral performance estimated using dynamic structural equation model, including slower mean responses and increased variability. These effects remained when including age, suggesting consistent effects of WM microstructure across the adult lifespan unique from concurrent effects of aging. Crucially, we show that variability can be reliably separated from mean performance using advanced modeling tools, enabling tests of distinct hypotheses for each component of performance.SIGNIFICANCE STATEMENT Human cognitive performance is defined not just by the long-run average, but trial-to-trial variability around that average. However, investigations of cognitive abilities and changes during aging have largely ignored this variability component of behavior. We provide evidence that white matter (WM) microstructure predicts individual differences in mean performance and variability in a sample spanning the adult lifespan (18-102). Unlike prior studies of cognitive performance and variability, we modeled variability directly and distinct from mean performance using a dynamic structural equation model, which allows us to decouple variability from mean performance and other complex features of performance (e.g., autoregression). The effects of WM were robust above the effect of age, highlighting the role of WM in promoting fast and consistent performance.

Comparative characterization of 5XFAD and hAbetaSAA mouse models of familial AD

AbstractBackgroundThe failure of most clinical Alzheimer’s disease (AD) trials has been partially attributed to the lack of translatability of current AD mouse models to human patients. A recently developed model of familial AD (fAD), expressing Swedish, Arctic and Austrian mutations in App (hAbetaSAA), has been shown to be a useful amyloidogenic model which recapitulates many aspects of human AD, including plaque distribution and microglial transcriptional changes. Our aim is to further characterize the hAbetaSAA model and compare it to the widely used 5xFAD transgenic model.MethodMotion Sequencing (MoSeq) software was used to model the underlying structure of spontaneous behaviors recorded in an open field in hAbetaSAA and 5xFAD mice longitudinally from 10 to 18 months of age. Aged hAbetaSAA and 5xFAD brain tissue was used for spatial transcriptomic/proteomic profiling, performed by Nanostring’s GeoMx®, which allowed for quantification of gene and protein expression in plaque‐associated and non‐plaque‐associated regions of interest. A fluorophore‐conjugated amyloid antibody (Methoxy‐X04) was administered to cohorts of hAbetaSAA and 5xFAD prior to harvest at various ages. An additional fluorophore‐conjugated antibody (lectin Dylight®594) was administered to 19‐month‐old cohorts permitting visualization of cerebral amyloid angiopathy (CAA). Whole brains were sectioned/imaged using Serial Two‐Photon Tomography on the TissueCyte (TissueVision), creating indexed tissue sections and high‐resolution 3D models of each brain. Subsequent rounds of staining permitted characterization of disease‐associated microglia (DAM) and dystrophic neurites. An independent cohort was evaluated for EEG telemetry.ResultMoSeq revealed divergent behaviors of 5xFAD and hAbetaSAA mice suggesting differences in behavioral phenotypes of these two models. Preliminary GeoMx data shows upregulation of DAM genes localized to plaques in hAbetaSAA homozygotes as identified by RNA‐seq; correlating 5xFAD data is in progress. Further assessments of bulk RNA‐Seq, amyloid distribution, CAA burden and cortical EEG spectral analysis are underway.ConclusionComparison of hAbetaSAA and 5xFAD using innovative modes of assessment showcase hAbetaSAA as an amyloidogenic mouse model of fAD that aligns more closely with human than 5xFAD. This model is available for preclinical research with no licensing restrictions and is devoid of artifacts related to transgenic overexpression, positioning it as an improved mouse model for studying fAD mutations.

Gene-environment interaction counterbalances social impairment in mouse models of autism

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social communication deficits and repetitive/restricted behaviors. Although gene-environment interactions may explain the heterogeneous etiology of ASD, it is still largely unknown how the gene-environment interaction affects behavioral symptoms and pathophysiology in ASD. To address these questions, we used Cntnap2 knockout mice (genetic factor, G) exposed to valproic acid during embryonic development (environmental factor, E) as a gene-environment interaction (G × E) model. Paradoxically, the social deficits observed in the respective G and E models were improved in the G × E model; however, the high seizure susceptibility was more severe in the G × E -model than in the G and E models. Repetitive self-grooming and hyperactivity did not differ among the three models. The amplitudes of miniature excitatory postsynaptic currents in layer 2/3 pyramidal neurons of the medial prefrontal cortex were aberrant and similar in the G × E model when compared to the control group. Our findings suggest that the interaction of two risk factors does not always aggravate ASD symptoms but can also alleviate them, which may be key to understanding individual differences in behavioral phenotypes and symptom intensity.

Brief Report: Sex/Gender Differences in Symptomology and Camouflaging in Adults with Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is more prevalent in males than females. Previous research indicates females camouflage ASD symptoms more than males, potentially contributing to the difference in prevalence. This study investigated sex/gender differences in behavioral phenotypes in 17 males and 11 females with ASD, as well camouflaging in ASD, in an attempt to partially replicate findings from Lai et al. (Autism 21(6):690-702, 2017). Overall ASD symptoms were measured by the autism spectrum quotient (AQ). Mean AQ in females with ASD was higher than males with ASD, with the difference approaching statistical significance. Camouflaging was found to be more common in females with ASD, and not associated to social phobia. Furthermore, camouflaging correlated negatively with emotional expressivity in females, but not males, with ASD. These findings strengthen previous findings regarding camouflaging being more common in females and add to the literature on how camouflaging may be different in females versus males.

A DNA Methylation Signature of Addiction in T Cells and Its Reversal With DHEA Intervention.

Previous studies in animal models of cocaine craving have delineated broad changes in DNA methylation profiles in the nucleus accumbens. A crucial factor for progress in behavioral and mental health epigenetics is the discovery of epigenetic markers in peripheral tissues. Several studies in primates and humans have associated differences in behavioral phenotypes with changes in DNA methylation in T cells and brain. Herein, we present a pilot study (n = 27) showing that the T cell DNA methylation profile differentiates persons with a substance use disorder from controls. Intervention with dehydroepiandrosterone (DHEA), previously shown to have a long-term therapeutic effect on human addicts herein resulted in reversal of DNA methylation changes in genes related to pathways associated with the addictive state.

Bidirectionality of hormone-behavior relationships and satellite-caller dynamics in green treefrogs

Interpretation of hormonal disparities among alternative mating phenotypes is confounded by the bidirectionality of hormone–behavior relationships. We show that size, condition, and vocal attractiveness predicted mating tactic switches during vocal playback experiments in green treefrogs, but hormone level did not, even though hormone administration has been shown to cause changes in tactic expression. Results suggest no clear “cause versus consequence” dichotomy associated with hormonal differences in behavioral phenotypes because multiple factors contribute to tactic expression.

Associations between oxytocin receptor gene (OXTR) methylation, plasma oxytocin, and attachment across adulthood.

The neuropeptide oxytocin (OT) has been implicated in a wide range of affiliative processes. OT exerts its functions via OT receptors, which are encoded by the oxytocin receptor gene (OXTR). Epigenetic modification of OXTR through the process of DNA methylation has been associated with individual differences in behavioral phenotypes. Specifically, lower levels of OXTR methylation have been linked to better social and affective functioning. However, research on epigenetic mechanisms of OXTR is scarce in non-clinical populations, and even less is known about epigenetic variability across adulthood. The present study assessed methylation levels at OXTR CpG site -934 and plasma OT levels in 22 young (20-31 years, M = 23.6) and 34 older (63-80 years, M = 71.4) participants. Lower levels of OXTR methylation and higher plasma OT levels were associated with less self-reported attachment anxiety in young but not older participants, with largely independent contributions of OXTR methylation and plasma OT levels. In contrast, in the overall sample, lower levels of OXTR methylation were associated with higher self-reported attachment avoidance. Age analysis suggested that these results were largely driven by young adults. Plasma OT levels were unrelated to attachment avoidance. Taken together, these findings support the emerging notion in the literature that epigenetic properties of OXTR, in addition to endogenous OT levels, are related to adult attachment. Further, the age effects observed in the associations between OXTR methylation, plasma OT, and adult attachment emphasize the importance of adopting a developmental perspective when studying properties of the OT system and their relation to affiliative processes. Findings contribute to growing evidence suggesting that epigenetic modification of genes regulating OT pathways and endogenous OT levels are associated with the way people form and maintain intimate social relationships.

Sex differences in avoidance behavior after perceiving potential risk in mice

BackgroundSex has been considered as a potential factor regulating individual behaviors in different contexts. Recently, findings on sex differences in the neuroendocrine circuit have expanded due to exact measurements and control of neuronal activity, while findings on sex differences in behavioral phenotypes are limited. One efficient way to determine the miscellaneous aspects of a sexually different behavior is to segment it into a set of simpler responses induced by discrete scenes.MethodsIn the present study, we conducted a battery of behavioral tests within a variety of unique risky scenes, to determine where and how sex differences arise in responses under those scenes.ResultsA significant sex difference was observed in the avoidance responses measured in the two-way active and the passive avoidance tests. The phenotype observed was higher mobility in male mice and reduced mobility in female mice, and required associative learning between an escapable risk and its predictive cue. This was limited in other scenes where escapable risk or predictive cue or both were missing.ConclusionsTaken together, the present study found that the primary sex difference occurs in mobility in the avoidance response after perceiving escapable risks.

Photoperiod influences the behavioral and physiological phenotype during ontogeny

Behavioral, physiological, and life-history traits can be modified through interactions with environmental conditions during ontogeny. Until recently, the ecological and social circumstances influencing the developing phenotype have not been investigated in much detail. Nevertheless, they represent an important step in niche construction by which the developing organism can in principle adjust to predictable aspects of its life history. By dynamically changing photoperiod during gestation, we tested how behavioral phenotypes (BPs) and physiology of juvenile cavies (Cavia aperea) adjust to seasonal differences in prenatal photoperiod. The prenatal photoperiod, simulating spring or autumn, led to faster or slower maturation in females but the relative size rank in litter also exerted a major influence on the onset of maturation. In addition, prenatal photoperiod strongly influenced BP and stress response in juvenile animals. Heavy females born into autumn developed a less explorative, more shy BP, whereas heavy females born into spring produced more explorative, bolder BP. Smaller sisters did not differ in the onset of maturation and, correspondingly, we found no differences in the BP. We did not find differences in the BP in males also. Early personality traits, though repeatable, changed over ontogeny to such an extent that early group differences in BP had completely disappeared in adults. Our results indicate high developmental plasticity with respect to predicted optimal life history and suggest long-term plasticity in response to photoperiod.

An Itch To Be Scratched

The description of itch (formally known as pruritus) as an "unpleasant sensation that elicits the desire or reflex to scratch" (Ikoma et al., 2006) is immediately familiar. Research in the field of pruritoception has added to our understanding of this area of sensory neurobiology as it pertains to both normal and pathological conditions. In particular, much progress has been made on the mechanisms and circuits of itch, which we review here.

Neurophysiology of CSWS‐associated cognitive dysfunction

The phenomenon of continuous spikes and waves during slow-wave sleep (CSWS) is associated with a number of epileptic syndromes, which share a behavioral phenotype characterized by deterioration of cognitive, behavioral, or sensorimotor functions. Available evidence seems to suggest that spike-wave activity is a result of a complex interaction between cortical and subcortical inhibitory networks and can "per se" produce a transient loss of underlying cortical functions. Syndromes like Landau-Kleffner syndrome, CSWS, and phenomena such as negative myoclonus could share in common--at least at the neurophysiological level--some similarities. Differences in behavioral phenotypes could be explained in term of maturational and genetic differences, as well as by the functional specificity of the involved areas.

Genetic subtype differences in neural circuitry of food motivation in Prader-Willi syndrome

BackgroundDifferences in behavioral phenotypes between the two most common subtypes of Prader-Willi syndrome (PWS) [chromosome 15q deletions and maternal uniparental disomy 15 (UPD)] indicate that distinct neural networks may be affected. Though both subtypes display hyperphagia, the deletion subgroup demonstrates reduced behavioral inhibition around food, whereas those with UPD are generally more able to maintain cognitive control over food intake impulses.ObjectiveTo examine the neural basis of phenotypic differences to better understand relationships between genetic subtypes and behavioral outcomes. We predicted greater food motivation circuitry activity in the deletion subtype and greater activity in higher order cognitive regions in the UPD group, especially after eating.Design and SubjectsNine individuals with PWS due to UPD and 9 individuals with PWS due to (type 2) deletion, matched for age, gender, and BMI, underwent fMRI scanning while viewing food images during two food motivation states: one before (pre-meal) and one after (post-meal) eating a standardized 500 kcal meal.ResultsBoth PWS subgroups demonstrated greater activity in response to food pre- and post-meal compared to the healthy-weight group. Compared to UPD, the deletion subtype showed increased food motivation network activation both pre- and post-meal, especially in the medial prefrontal cortex and amygdala. In contrast, the UPD group demonstrated greater activation than the deletion subtype post-meal in the dorsolateral prefrontal cortex and parahippocampal gyrus.ConclusionThese preliminary findings are the first functional neuroimaging findings to support divergent neural mechanisms associated with behavioral phenotypes in genetic subtypes of PWS. Results are discussed within the framework of genetic mechanisms such as haploinsufficiency and gene dosage effects and their differential influence on deletion and UPD subtypes, respectively.

Two naturally occurring amino acid substitutions of the 5-HT 2A receptor: Similar prevalence in patients with seasonal affective disorder and controls

We screened the 5-HT2A receptor gene coding region in 50 patients with seasonal affective disorder (SAD) using a single strand conformational polymorphism analysis and estimated the frequencies of two synonymous and two non-synonymous substitutions we detected in 70 Centre d'Etude du Polymorphism Humain (CEPH) population controls and 62 normal controls. Both of the amino acid substitutions: Ala447-Val447 and His452-Tyr452, were located within the cytoplasmic. C-terminal tail of the receptor. Rarer allele frequencies in CEPH were 0.7% and 9.3% for Val447 and Tyr452, respectively. Allele frequencies of all four polymorphisms, including the two amino acid substitutions, were not significantly different in SAD patients as compared to CEPH and normal controls. Lack of association of Val447 and Tyr452 to SAD is consistent with observations showing normal 5-HT2A receptor Ca2+ response in platelets with this disorder, however, the two 5-HT2A amino acid substitutions may lead to differences in behavioral phenotypes.