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Individuals of the same species display remarkable variation in behavior, even in identical contexts. Increasing complexity in behavioral phenotypes brings with it an increase in individual variation in the manifestation of those phenotypes, and human behavior undoubtedly stands at the pinnacle of complexity. In this article, we discuss current knowledge of gene–environment interplay and how the complex interactions of genes, experiences, epigenetics, and developmental timing give rise to individual differences in behavior.

Variation in early life history traits often leads to differentially expressed morphological and behavioral phenotypes. We investigated whether variation in egg size and emergence timing influence subsequent morphology associated with migration timing in juvenile spring Chinook Salmon, Oncorhynchus tshawytscha. Based on evidence for a positive relationship between growth rate and migration timing, we predicted that fish from small eggs and fish that emerged earlier would have similar morphology to fall migrants, while fish from large eggs and individuals that emerged later would be more similar to older spring yearling migrants. We sorted eyed embryos within females into two size categories: small and large. We collected early and late‐emerging juveniles from each egg size category. We used landmark‐based geometric morphometrics and found that egg size appears to drive morphological differences. Egg size shows evidence for an absolute rather than relative effect on body morphology. Fish from small eggs were morphologically more similar to fall migrants, while fish from large eggs were morphologically more similar to older spring yearling migrants. Previous research has shown that the body morphology of fish that prefer the surface or bottom location in a tank soon after emergence also correlates with the morphological variations between wild fall and spring migrants, respectively. We found that late‐emerging fish spent more time near the surface. Our study shows that subtle differences in early life history characteristics may correlate with a diversity of future phenotypes.

The study of insect social behavior has offered tremendous insight into the molecular mechanisms mediating behavioral and phenotypic plasticity. Genomic applications to the study of eusocial insect species, in particular, have led to several hypotheses for the processes underlying the molecular evolution of behavior. Advances in understanding the genetic control of social organization have also been made, suggesting an important role for supergenes in the evolution of divergent behavioral phenotypes. Intensive study of social phenotypes across species has revealed that behavior and caste are controlled by an interaction between genetic and environmentally mediated effects and, further, that gene expression and regulation mediate plastic responses to environmental signals. However, several key methodological flaws that are hindering progress in the study of insect social behavior remain. After reviewing the current state of knowledge, we outline ongoing challenges in experimental design that remain to be overcome in order to advance the field.

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders with multiple biological etiologies and highly variable symptoms. Using a novel analytical framework that integrates cortex-wide MRI markers of vertical (i.e., thickness, tissue contrast) and horizontal (i.e., surface area, geodesic distance) cortical organization, we could show that a large multi-centric cohort of individuals with ASD falls into 3 distinctive anatomical subtypes (ASD-I: cortical thickening, increased surface area, tissue blurring; ASD-II: cortical thinning, decreased distance; ASD-III: increased distance). Bootstrap analysis indicated a high consistency of these biotypes across thousands of simulations, while analysis of behavioral phenotypes and resting-state fMRI showed differential symptom load (i.e., Autism Diagnostic Observation Schedule; ADOS) and instrinsic connectivity anomalies in communication and social-cognition networks. Notably, subtyping improved supervised learning approaches predicting ADOS score in single subjects, with significantly increased performance compared to a subtype-blind approach. The existence of different subtypes may reconcile previous results so far not converging on a consistent pattern of anatomical anomalies in autism, and possibly relate the presence of diverging corticogenic and maturational anomalies. The high accuracy for symptom severity prediction indicates benefits of MRI biotyping for personalized diagnostics and may guide the development of targeted therapeutic strategies.

Some individuals recover quickly from stressful events, while others do not; this suggests that there are individual differences in stress resilience. Previous studies in rats have shown that an animal’s ability to extinguish conditioned fear can predict their stress resilience. In the present study, we investigated whether rats who are resilient or vulnerable to fear conditioning would consistently show resilient or vulnerable behaviors in other behavioral tests. Male Wistar-Imamichi rats were subjected to a series of behavioral tests, including open field, conditioned place-preference (CPP), forced swim and auditory fear conditioning. The subjects were assigned to one of two different groups: resilient or vulnerable, based on their level of freezing during fear extinction, and their other behavioral phenotypes were then compared. Rats in the resilient group showed faster extinction in the methamphetamine-induced CPP test than rats in the vulnerable group. The results suggest that resilience to stressful events is associated with drug-dependence and that individuals’ abilities to recover from stressful situations and drug-dependence may share a common mechanism.

Predator-prey interactions often vary on the basis of the traits of the individual predators and prey involved. Here we examine whether the multidimensional behavioral diversity of predator groups shapes prey mortality rates and selection on prey behavior. We ran individual sea stars (Pisaster ochraceus) through three behavioral assays to characterize individuals’ behavioral phenotype along three axes. We then created groups that varied in the volume of behavioral space that they occupied. We further manipulated the ability of predators to interact with one another physically via the addition of barriers. Prey snails (Chlorostome funebralis) were also run through an assay to evaluate their predator avoidance behavior before their use in mesocosm experiments. We then subjected pools of prey to predator groups and recorded the number of prey consumed and their behavioral phenotypes. We found that predator-predator interactions changed survival selection on prey traits: when predators were prevented from interacting, more fearful snails had higher survival rates, whereas prey fearfulness had no effect on survival when predators were free to interact. We also found that groups of predators that occupied a larger volume in behavioral trait space consumed 35% more prey snails than homogeneous predator groups. Finally, we found that behavioral hypervolumes were better predictors of prey survival rates than single behavioral traits or other multivariate statistics (i.e., principal component analysis). Taken together, predator-predator interactions and multidimensional behavioral diversity determine prey survival rates and selection on prey traits in this system.

Vestibular hair cells of the inner ear are specialized receptors that detect mechanical stimuli from gravity and motion via the deflection of a polarized bundle of stereocilia located on their apical cell surfaces. The orientation of stereociliary bundles is coordinated between neighboring cells by core PCP proteins including the large adhesive G-protein coupled receptor Celsr1. We show that mice lacking Celsr1 have vestibular behavioral phenotypes including circling. In addition, we show that Celsr1 is asymmetrically distributed at cell boundaries between hair cells and neighboring supporting cells in the developing vestibular and auditory sensory epithelia. In the absence of Celsr1 the stereociliary bundles of vestibular hair cells are misoriented relative to their neighbors, a phenotype that is greatest in the cristae of the semicircular canals. Since horizontal semi-circular canal defects lead to circling in other mutant mouse lines, we propose that this PCP phenotype is the cellular basis of the circling behavior in Celsr1 mutants.

Individuals respond differently to traumatic experiences, including their propensity to develop posttraumatic stress disorder (PTSD). Understanding individual differences in PTSD vulnerability will allow the development of improved prevention and treatment options. Here we characterized fear conditioning and extinction in rats selectively bred for differences in their locomotor response to a novel environment. Selectively bred high-responder (bHR) and low-responder (bLR) male rats are known to differ in their emotional reactivity on a range of measures of spontaneous anxiety- and depressive-like behaviors. We demonstrate that bHRs have facilitated extinction learning and retention compared with outbred Sprague Dawley rats, whereas bLRs show reduced extinction learning and retention. This indicates that bLRs are more vulnerable to PTSD-like behavior. Fibroblast growth factor 2 (FGF2) has previously been implicated in the development of these behavioral phenotypes and facilitates extinction learning in outbred animals, therefore we examined the effects of early-life FGF2 on bHR and bLR behavior. FGF2 administered on the day after birth facilitated extinction learning and retention in bHRs, but not in bLRs or control rats, during adulthood. This indicates that, under the current fear conditioning paradigm, early-life FGF2 has protective effects only in resilient animals. This stands in contrast to FGF2’s ability to protect vulnerable animals in milder tests of anxiety. These results provide a unique animal model of individual differences in PTSD-like behavior, allowing the study of genetic, developmental, and environmental factors in its expression.

Border and Keller argue that candidate gene approaches are outdated and out-of-touch with the current understanding of the genetic architecture of complex behavioral traits and should be abandoned in favor of unbiased, genome-wide approaches. Border and Keller further suggest that a candidate gene should not be selected for in-depth investigation unless identified by a well-powered genome-wide association study (GWAS). An alternative perspective is offered that candidate approaches can be sensible for developmental and deep-phenotyping studies aimed at elucidating particular biological pathways responsible for the emergence of psychological phenotypes, and that candidates should not necessarily be expected to be confirmed by, or solely selected based on, GWAS. Both candidate and whole genome strategies have limitations, and each approach is useful and valid in the quest to identify the elusive genetic architecture of complex behavioral phenotypes.

Environmental stimuli present during incubation can impact the behavior of birds post-hatch. To determine the effect of exposing broiler chicken embryos to light on fear-related behavior post-hatch, we conducted two experiments in which we incubated eggs under various light schedules, and then measured fear responses when the chickens (N = 720) were 3–6 wk of age. In Expt. 1, the incubation photoperiods were 0L:24D, 12L:12D, and 24L:0D, and tonic immobility (TI) and inversion (INV) tests were administered. In Expt. 2, the incubation photoperiods were 0L:24D, 1L:23D, 6L:18D, and 12L:12D; and an approach test (APPR) and an emergence (EMRG) test were administered in addition to TI and INV. In Expt. 1, both 12L:12D and 24L:0D had shorter latencies to right during TI (213.5 ± 23.7 and 231.8 ± 24.2 s, respectively) than 0L:24D (305.5 ± 26.1 s) and also wing flapped less intensely during INV (12L:12D 5.0 ± 0.1 wing flaps; 24L:0D 5.4 ± 0.2) than 0L:24D (5.7 ± 0.1). In Expt. 2, the 12L:12D birds once again had shorter latencies to right during TI (120.0 ± 16.5 s) and wing flapped less intensely during INV (4.7 ± 0.1 wing flaps) than 0L:24D (201.4 ± 24.9 and 5.5 ± 0.1, respectively). They also had shorter latencies to exit the dark box in EMRG (28.9 ± 3.3 s), and were less active (28 ± 2%), vocalized less (178.8 ± 9.3 times/3 min) and spent more time closer to the observer during APPR (63 ± 3%) than 0L:12D (42.9 ± 5.0 s, 35 ± 3%, 211.2 ± 10.4 times/3 min, 51 ± 3). The 1L:23D and 6L:18D showed some reductions in fearfulness compared to 0L:24D, but these were not consistent across tests. The 6L:18D and 12L:12D birds demonstrated lateralization in the direction to leave the box in EMRG, whereas 1L:23D and 0L:12D exited left or right at chance levels. The results of these experiments indicate that providing at 12 h of light stimulation daily during embryogenesis results in long-term reductions in fearfulness as measured by multiple tests, and that this may be related to cerebral lateralization. In conjunction with other research, these findings show that light exposure during embryogenesis has important implications for behavioral phenotypes and welfare in chickens.

The study of verbal behavior focuses on communicative functions of the speakers/producers as they affect the behavior of listeners/observers. Effects on the listener reinforce the speaker and the listener/observer benefits (i.e., is reinforced) from the behavior of the speaker/producer. The interlocking of, and exchange of, the speaker and listener behavior between individuals and within one’s own skin constitute bidirectional operants. These bidirectional operants are instances of social interactions and measures of social behavior. Evidence suggests that the act of listening, among other observing responses, is initially developmentally independent from speaker behavior. How they become joined parallels the biological phenomenon of metamorphosis. The succession of changes has been empirically identified as a succession of verbal behavior development cusps, which are described in their sequence biologically as a manifestation of functional metamorphosis. The onset of a cusp constitutes first instances of behavior and accompanying stimulus control that allows infants and children to contact parts of the environment for the first time resulting in their learning things impossible to learn before or learning faster. Cusps for the intercept of the speaker and listener lead to bidirectional operants and provide explanations for how children incidentally learn the names of things, become increasingly social, and make subsequent complex behavior possible. Many of the cusps identified in our research resulted from the missing behavior and stimulus control of children with autism. Once cusps were established, these children learned things they could not learn before, learned faster, and learned by contacting parts of the social environment they could not contact before. These findings led to a theory of verbal behavior development that point to the selection of bidirectional operants as behavioral phenotypes during functional metamorphosis, which has enhanced the survival of Homo sapiens through emergent symbolic skills for more effective collaboration between two or more individuals.

Summary Multiple mazes are routinely used to test the performance of animals because each has disadvantages inherent to its shape. However, the maze shape cannot be flexibly and rapidly reproduced in a repeatable and scalable way in a single environment. Here, to overcome the lack of flexibility, scalability, reproducibility, and repeatability, we develop a reconfigurable maze system that consists of interlocking runways and an array of accompanying parts. It allows experimenters to rapidly and flexibly configure a variety of maze structures along the grid pattern in a repeatable and scalable manner. Spatial navigational behavior and hippocampal place coding were not impaired by the interlocking mechanism. As a proof-of-principle demonstration, we demonstrate that the maze morphing induces location remapping of the spatial receptive field. The reconfigurable maze thus provides flexibility, scalability, repeatability, and reproducibility, therefore facilitating consistent investigation into the neuronal substrates for learning and memory and allowing screening for behavioral phenotypes., Graphical Abstract, Highlights • The reconfigurable maze enables flexibly in building a variety of maze paths • The maze ensures reproducibility, repeatability, and scalability • The maze does not impair spatial navigational behavior or neuronal activity • Various tests of learning and memory can be conducted in a single environment, Neuroscience; Behavioral Neuroscience; Techniques in Neuroscience

Volatile anesthetics are compounds which are commonly used to induce a reversable loss of consciousness (LOC) in animals. The molecular mechanism of how anesthetics induce LOC is largely unknown. However, observations have been made which show that there are genetically-encoded traits which influence the effective concentration of anesthetics in the inducement of LOC. Despite this long-term observation, little progress has been made in identifying genes involved in anesthetic sensitivity. One reason for this is that many techniques to test anesthetic sensitivity are technically challenging and are inhibitory for high-throughput studies. Here we introduce a technique for testing volatiles and aerosols with positional recording (VAAPR), a method which allows for high-throughput testing of the effect of anesthetics and other aerosolized drugs using Drosophila. Using VAAPR we show that the enzyme phospholipase D (PLD) significantly shifts the concentration of diethyl ether, chloroform, and isoflurane needed to induce LOC in Drosophila. We also show that PLD is required for a paradoxical hyperactivity phenotype. We expect that this technique will allow for additional genes to be found which control anesthetic sensitivity as well as other behavioral phenotypes.

The Italian Twin Registry (ITR), established in 2001, is a population-based registry of voluntary twins. To date, it consists of approximately 29,000 twins who gave their consent to participate in the studies proposed by the ITR research group. The database comprises 11,500 monozygotic and 16,700 dizygotic twins resident throughout the country and belonging to a wide age range (from 0 to 95 years, mean 36.8 years). This article provides an overview of the recruitment strategies along with the major phenotypes investigated during an 18 years’ research period. Over the years, several self-reported questionnaire data were collected, together with saliva/blood samples and measurements taken during in-person interviews or outpatient clinical examinations. Mental and behavioral phenotypes as well as atherosclerotic traits were studied in depth across different age groups. A birth cohort of twins was established and followed up. Novel research hypotheses are also being tested in ongoing projects. The ITR is involved in international studies in collaboration with other twin registries and represents a valuable resource for national and international research initiatives regarding a broad spectrum of health-related characteristics.

This review describes several transgenic mouse models of Alzheimer's disease (AD), a devastating neurodegenerative disorder that causes progressive cognitive decline and is diagnosed postmortem by the presence of extracellular amyloid-β (Aβ) plaques and intraneuronal tau neurofibrillary tangles in the cerebral cortex. Currently there is no intervention that cures, prevents, or even slows disease progression. Its complex etiology and pathology pose significant challenges for animal model development, and there is no single model that faithfully recapitulates both the pathological aspects and behavioral phenotypes of AD. Nearly 200 transgenic rodent models of AD have been generated primarily based on mutations linked to Aβ protein misprocessing in the familial form of the disease. More recent models incorporate mutations in tau protein, as well as mutations associated with the sporadic form of the disease. The salient features, strengths, limitations, and key differentiators for the most commonly used and best characterized of these models are considered here. While the translational utility of many of these models to assess the potential of novel therapeutics is in dispute, knowledge of the different models available and a detailed understanding of their features can aid in the selection of the optimal model to explore disease mechanisms or evaluate candidate medications. We comment on the predictive utility of these models considering recent clinical trial failures and discuss trends and future directions in the development of models for AD based on the plethora of clinical data that have been generated over the last decade. © 2019 by John Wiley & Sons, Inc.

Background and Objectives The relative reinforcing value (RRV) of food is associated with increased energy intake and obesity and increases in RRV of food after repeated intake (sensitization) are related cross-sectionally and prospectively to higher BMI in adults. We examined the factors, such as delay discounting (DD), associated with sensitization of RRV of high energy density (HED) and low energy density (LED) food and how sensitization relates to zBMI in adolescents. We hypothesized that sensitization to HED food would be positively associated with zBMI, that sensitization to LED food would be negatively associated with zBMI, that DD would be associated with HED sensitization, and that LED sensitization and DD would moderate the relationships between HED sensitization and zBMI. Subjects and Methods A population-based sample of 207 adolescents without obesity, aged 12 – 14 years was studied from June 2016 – March 2019. The RRV of LED and HED foods were measured before and after two weeks of daily consumption along with zBMI and other potential factors related to eating and weight, including dietary restraint, hunger, food liking, and delay discounting (DD). Hierarchical regression models were used to determine the associations between these factors and sensitization and zBMI. We also examined LED sensitization and DD as potential moderators of the relationship between sensitization and zBMI. Results As hypothesized, dietary restraint and sensitization to HED food were associated with greater zBMI. Contrary to our original hypotheses, DD was not associated with sensitization, there was no relationship between sensitization to LED food and zBMI and neither LED sensitization or DD moderated the relationship between HED sensitization and zBMI. Conclusions Sensitization to repeated intake of HED food was associated with higher zBMI in adolescents without obesity. Sensitization may be a novel behavioral phenotype that may relate to overweight in youth.

Individually ventilated caging (IVC) systems for rodents are increasingly common in laboratory animal facilities. However, the impact of such substantial change in housing conditions on animal physiology and behavior is still debated. Most importantly, there arise the questions regarding reproducibility and comparison of previous or new phenotypes between the IVC and open cages. The present study was set up for detailed and systematic comparison of behavioral phenotypes in male and female mice of three widely used inbred strains (C57BL/6JRccHsd, DBA/2JRccHsd, 129S2/SvHSd) after being kept in two housing environments (IVC and open cages) for 6 weeks (since 4 weeks of age) before behavioral testing. The tests addressed exploratory, anxiety‐like and stress‐related behavior (light‐dark box, open field, forced swim test, stress‐induced hyperthermia), social approach and species‐specific behavior (nest building, marble burying). In all tests, large and expected strain differences were found. Somewhat surprisingly, the most striking effect of environment was found for basal body temperature and weight loss after one night of single housing in respective cages. In addition, the performance in light‐dark box and open field was affected by environment. Several parameters in different tests showed significant interaction between housing and genetic background. In summary, the IVC housing did not invalidate the well‐known differences between the mouse strains which have been established by previous studies. However, within the strains the results can be influenced by sex and housing system depending on the behavioral tasks applied. The bottom‐line is that the environmental conditions should be described explicitly in all publications., The individually ventilated caging housing did not invalidate the well‐known differences between the mouse strains established by previous studies. However, within the strains the results can be influenced by sex and housing system depending on the behavioral tasks applied.

Sleep disturbances are common in people with monogenic neurological disorders and they dramatically affect the life of individuals with the disorders and their families. The associated sleep problems are probably caused by multiple factors that have not been elucidated. Study of the underlying molecular cause, behavioral phenotypes, and reciprocal interactions in several single-gene disorders (Angelman Syndrome, Fragile X Syndrome, Rett Syndrome, and Huntington's Disease) leads to the suggestion that sleep disruption and other symptoms may directly result from abnormal operation of circadian systems due to genetic alteration and/or conflicting environmental cues for clock entrainment. Therefore, because circadian patterns modify the symptoms of neurological disorders, treatments that modulate our daily rhythms may identify heretofore unappreciated therapies for the underlying disorders.

AIM To determine the nature and frequency of behavioral phenotypes and sleep disturbances in individuals with SATB2-associated syndrome (SAS). METHOD The Strengths and Difficulties Questionnaire (SDQ) and an age-appropriate sleep questionnaire were distributed to the parents of individuals with SAS. All scores were compared to available normative data. RESULTS Thirty-one individuals completed the assessment (18 females, 13 males; mean age 7y 4mo [SD 4y 1mo], range 2-16y). Individuals with SAS had significantly higher Total Difficulty scores than the normative sample (14.9 [SD 5.8] vs 7.1 [SD 5.7], p

Background: One of the key behavioral phenotypes in infancy are different temperament traits, and certain early life temperament traits have been shown to precede later mental health problems. Differences in the gut microbiota composition (GMC) have been suggested to link with neurodevelopment. For example, toddler temperament traits have been found to associate with differences in GMC; however, studies in infants are lacking although infancy is a rapid period of neurodevelopment as well as GM development. Thus, we aimed to investigate association between infant GMC and temperament. Methods: The study population (n = 301, 53% boys) was drawn from the FinnBrain Birth Cohort Study. Stool samples were collected from the 2.5-month-old infants and sequenced with 16S Illumina MiSeq platform. GMC taxonomic composition (at Genus and OTU level), observed sample clusters, diversity and richness were investigated in relation to the maternal reports of Infant Behavior Questionnaire -Revised (IBQ-R) at the age of 6 months. Results: Three sample clusters (Bifidobacterium/Enterobacteriaceae, Bacteroides, V. Dispar) based on GMC were identified, of which Bifidobacterium/Enterobacteriaceae–cluster presented with higher scores on the IBQ-R main dimension regulation and its subscale duration of orienting compared to Bacteroides-cluster. The clusters associated with temperament in a sex-dependent manner. The IBQ-R main dimension surgency (positive emotionality) was associated positively both with genus Bifidobacterium and Streptococcus. Alpha diversity had a negative association with negative emotionality and fear reactivity. Conclusion This is the first study demonstrating associations, but not causal connections, between GMC and temperament in young infants in a prospective design.

Background Alcohol use has been reliably associated with smaller subcortical and cortical regional gray matter volumes (GMVs). Whether these associations reflect shared predisposing risk factors or causal consequences of alcohol use remains poorly understood. Methods Data came from 3 neuroimaging samples (N = 2423), spanning childhood or adolescence to middle age, with prospective or family-based data. First, we identified replicable GMV correlates of alcohol use. Next, we used family-based and longitudinal data to test whether these associations may plausibly reflect a predispositional liability for alcohol use or a causal consequence of alcohol use. Finally, we used heritability, gene-set enrichment, and transcriptome-wide association study approaches to evaluate whether genome-wide association study–defined genomic risk for alcohol consumption is enriched for genes that are preferentially expressed in regions that were identified in our neuroimaging analyses. Results Smaller right dorsolateral prefrontal cortex (DLPFC) (i.e., middle and superior frontal gyri) and insula GMVs were associated with increased alcohol use across samples. Family-based and prospective longitudinal data suggest that these associations are genetically conferred and that DLPFC GMV prospectively predicts future use and initiation. Genomic risk for alcohol use was enriched in gene sets that were preferentially expressed in the DLPFC and was associated with replicable differential gene expression in the DLPFC. Conclusions These data suggest that smaller DLPFC and insula GMV plausibly represent genetically conferred predispositional risk factors for, as opposed to consequences of, alcohol use. DLPFC and insula GMV represent promising biomarkers for alcohol-consumption liability and related psychiatric and behavioral phenotypes.

Emotion plays a crucial role, both in general human experience and in psychiatric illnesses. Despite the importance of emotion, the relative lack of objective methodologies to scientifically studying emotional phenomena limits our current understanding and thereby calls for the development of novel methodologies, such us the study of illustrative animal models. Analysis of Drosophila and other insects has unlocked new opportunities to elucidate the behavioral phenotypes of fundamentally emotional phenomena. Here we propose an integrative model of basic emotions based on observations of this animal model. The basic emotions are internal states that are modulated by neuromodulators, and these internal states are externally expressed as certain stereotypical behaviors, such as instinct, which is proposed as ancient mechanisms of survival. There are four kinds of basic emotions: happiness, sadness, fear, and anger, which are differentially associated with three core affects: reward (happiness), punishment (sadness), and stress (fear and anger). These core affects are analogous to the three primary colors (red, yellow, and blue) in that they are combined in various proportions to result in more complex "higher order" emotions, such as love and aesthetic emotion. We refer to our proposed model of emotions as called the "Three Primary Color Model of Basic Emotions."

Fragile X syndrome (FXS) is caused by silencing of the FMR1 gene leading to loss of the protein product fragile X mental retardation protein (FMRP). FXS is the most common monogenic cause of intellectual disability. There are two known mammalian paralogs of FMRP, FXR1P, and FXR2P. The functions of FXR1P and FXR2P and their possible roles in producing or modulating the phenotype observed in FXS are yet to be identified. Previous studies have revealed that mice lacking Fxr2 display similar behavioral abnormalities as Fmr1 knockout (KO) mice. In this study, we expand upon the behavioral phenotypes of Fmr1 KO and Fxr2+/&minus, (Het) mice and compare them with Fmr1 KO/Fxr2 Het mice. We find that Fmr1 KO and Fmr1 KO/Fxr2 Het mice are similarly hyperactive compared to WT and Fxr2 Het mice. Fmr1 KO/Fxr2 Het mice have more severe learning and memory impairments than Fmr1 KO mice. Fmr1 KO mice display significantly impaired social behaviors compared to WT mice, which are paradoxically reversed in Fmr1 KO/Fxr2 Het mice. These results highlight the important functional consequences of loss or reduction of FMRP and FXR2P.

Transgenerational epigenetic inheritance is a burgeoning field that has recently garnered much attention. A growing body of evidence identifies behavioral phenotypes associated with inter-, multi-, and transgenerational studies following a wide variety of parental exposures. This chapter in current topics in behavioral neurogenomics examines the evidence for the presence of behavioral phenotypes and, in particular, the varied and often opposite behavioral responses observed with protocol shifts. Effects following parental exposure to drugs of abuse are used as an example of the wide range of behavioral outcomes and the variability associated with these multiple generation studies. The behavioral phenotypes associated with drug exposure are reviewed in depth.

In this chapter, we briefly review the use of rats as a genetic model for the study of behavior. Rats were the first mammalian species used for genetic and biological research. Since the development of the first inbred rat strain in 1909, more than 700 unique inbred and outbred rat lines have been generated. Although rats have been somewhat eclipsed by mice in the last few decades, a renewed appreciation of the advantages of rats for behavioral and other types of research is upon us. We briefly review the pertinent characteristics of the rat and highlight the key advantages of using the rat to examine behavioral phenotypes.

Optogenetics is a cutting-edge tool in neuroscience that employs light-sensitive proteins and controlled illumination for neuromodulation. Its main advantage is the ability to demonstrate causal relationships by manipulating the activity of specific neuronal populations and observing behavioral phenotypes. However, the tethering system used to deliver light to optogenetic tools can constrain both natural animal behaviors and experimental design. Here, we present an optically powered and controlled wireless optogenetic system using near-infrared (NIR) light for high transmittance through live tissues. In vivo optogenetic stimulations using this system induced whisker movement in channelrhodopsin-expressing mice, confirming the photovoltaics-generated electrical power was sufficient, and the remote controlling system operated successfully. The proposed optogenetic system provides improved optogenetic applications in freely moving animals.

BodyNonhuman primates (NHPs) are critical for translational research due to their close genetic, physiological, and behavioral similarity to humans. In particular, higher brain functions depend on brain regions and neural circuits that evolved differently between primates and rodents. Thus, NHPs are a strong translational model system to investigate the pathophysiology and relevant biological correlates of mental disorders. This talk will focus on translational approaches leveraging NHP models to advance our understanding of environmentally induced epigenetic changes in post-traumatic stress disorder (PTSD). Environmental factors including early life stress significantly contribute to risk and resilience for psychiatric disorders including PTSD. However, human studies are often confounded, and it remains challenging to identify robust epigenetic signals in clinical populations even in large studies. We investigate the natural spectrum of behavioral phenotypes in rhesus macaques to complement human studies with a focus on stress and fear. This talk will present data on epigenetic signatures of fear and the effects of early life stress in rhesus monkeys and their relationship to human studies.DisclosureNo significant relationships.

Objective Individuals with anorexia nervosa (AN) and body dysmorphic disorder (BDD) exhibit distorted perception and negative evaluations of their own appearance; however, little is known about how they perceive others' appearance, and whether or not the conditions share perceptual distortions. Method Thirty participants with BDD, 22 with AN, now weight-restored, and 39 healthy comparison participants (HC) rated photographs of others' faces and bodies on attractiveness, how overweight or underweight they were, and how much photographs triggered thoughts of their own appearance. We compared responses among groups by stimulus type and by level-of-detail (spatial frequency). Results Compared to HCs, AN and BDD had lower attractiveness ratings for others' bodies and faces for high-detail and low-detail images, rated bodies as more overweight, and were more triggered to think of their own appearance for faces and bodies. In AN, symptom severity was associated with greater triggering of thoughts of own appearance and higher endorsement of overweight ratings for bodies. In BDD, symptom severity was associated with greater triggering of thoughts of own appearance for bodies and higher overweight ratings for low-detail images. BDD was more triggered to think of own facial appearance than AN. Discussion AN and BDD show similar behavioral phenotypes of negative appearance evaluations for others' faces and bodies, and have thoughts of their own appearance triggered even for images outside of their primary appearance concerns, suggesting a more complex cross-disorder body-image phenotype than previously assumed. Future treatment strategies may benefit from addressing how these individuals evaluate others in addition to themselves. © 2016 Wiley Periodicals, Inc. (Int J Eat Disord 2016)

Objective Genetically tractable fruit flies have been used for decades to study seizure disorders. However, there is a paucity of data specifically correlating fly and human seizure phenotypes. We have previously shown that mutation of orthologous PRICKLE genes from flies to humans produce seizures. This study aimed to determine whether the prickle-mediated seizure phenotypes in flies closely parallel the epilepsy syndrome found in PRICKLE patients. Methods Virtually all fly seizure studies have relied upon characterizing seizures that are evoked. We have developed two novel approaches to more precisely characterize seizure-related phenotypes in their native state in prickle mutant flies. First, we used high-resolution videography to document spontaneous, unprovoked seizure events. Second, we developed a locomotion coordination assay to assess whether the prickle mutant flies were ataxic. Third, we treated the mutant flies with levetiracetam to determine whether the behavioral phenotypes could be suppressed by a common antiepileptic drug. Results We find that the prickle mutant flies exhibit myoclonic-like spontaneous seizure events and are severely ataxic. Both these phenotypes are found in human patients with PRICKLE mutations, and can be suppressed by levetiracetam, providing evidence that the phenotypes are due to neurological dysfunction. These results document for the first time spontaneous, unprovoked seizure events at high resolution in a fly human seizure disorder model, capturing seizures in their native state. Interpretation Collectively, these data underscore the striking similarities between the fly and human PRICKLE-mediated epilepsy syndromes, and provide a genetically tractable model for dissecting the underlying causes of the human syndromic phenotypes.

The fearful withdrawal response to humans was studied with regard to the effect of hereditary and environmental factors in four consecutive generations of minipigs bred at the Institute of Cytology and Genetics (ICG). Variation in the withdrawal response was tested in four heterotypic settings. The standard aversive stimulus was the presence of a human as the animals were being given food either as a group or one-by-one after 14–16 or 2 h of food deprivation. All the studied factors are ranged with regard to their contributions to the overall phenotypic variation of the response as follows: sex (0.0–0.4%), age (0.1–4.7%), social isolation (0.1–2.1%), coloring types (2.9–7.8%), boar genotype (10.8%), food motivation (6.1–12.8%), and the genotype–food motivation interaction (2.7–56.4%). This was the first demonstration of a hereditary polymorphism of this behavioral reaction in minipigs, which includes three classes of behavioral phenotypes. Sex and age do not affect the withdrawal response in piglets aged from 1.5 months to 4.1 months. It was found that the age-related changes in the behavior of sows depend on the indirect selection of individuals with a quiet phenotype, where the frequency of this phenotype increases from 29% (the reared stock) to 63%. Social isolation and food motivation significantly influence the response in piglets aged 1.5 and 4.1 months, but not in sows aged 10.4 and 22.5 months. An adverse consequence of the environmental influence of food motivation and its interaction is a broad variability (CV within 95–120%) of the withdrawal response. The obtained results will contribute to the study of the genetics of the fearful-defensive response to humans and to the correction of the method for evaluating this behavior, valuable for breeding, in ICG minipigs.

The size of neural stem cell (NSC) pool at birth determines the starting point of adult neurogenesis. Aberrant neurogenesis is associated with major mental illness, in which ULK4 is proposed as a rare risk factor. Little is known about factors regulating the NSC pool, or function of the ULK4. Here, we showed that Ulk4tm1a/tm1a mice displayed a dramatically reduced NSC pool at birth. Ulk4 was expressed in a cell cycle-dependent manner and peaked in G2/M phases. Targeted disruption of the Ulk4 perturbed mid-neurogenesis and significantly reduced cerebral cortex in postnatal mice. Pathway analyses of dysregulated genes in Ulk4tm1a/tm1a mice revealed Ulk4 as a key regulator of cell cycle and NSC proliferation, partially through regulation of the Wnt signaling. In addition, we identified hemizygous deletion of ULK4 gene in 1.2/1,000 patients with pleiotropic symptoms including severe language delay and learning difficulties. ULK4, therefore, may significantly contribute to neurodevelopmental, neuropsychiatric, and neurodegenerative disorders.

The nematode Caenorhabditis elegans utilizes gap junctions in different fashions in virtually all of its cells. This model animal has a surprisingly large number of innexin genes within its genome, and many nematode cell types can express multiple innexins at once, leading to the formation of diverse junction types and enough redundancy to limit the effect of single gene knockdowns on animal development or behavioral phenotypes. Here, we review the general properties of these junctions, their expression patterns, and their known roles in tissue development and in the animal's connectome. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 587-596, 2017.

With the development of bio-imaging techniques, an increasing number of studies apply these techniques to generate a myriad of image data. Its applications range from quantification of cellular, tissue, organismal and behavioral phenotypes of model organisms, to human facial phenotypes. The bio-imaging approaches to automatically detect, quantify, and profile phenotypic changes related to specific biological questions open new doors to studying phenotype-genotype associations and to precisely evaluating molecular changes associated with quantitative phenotypes. Here, we review major applications of bioimage-based quantitative phenotype analysis. Specifically, we describe the biological questions and experimental needs addressable by these analyses, computational techniques and tools that are available in these contexts, and the new perspectives on phenotype-genotype association uncovered by such analyses.

Laboratory reared fruit flies may have different behavioral phenotypes as compared to the wild in the field. The domesticated lab setting and the absence of factors from the natural environment on lab reared insects may result in different behavioral patterns, such as the length of life cycle. This study was performed to conduct a regression analysis of the ratio of odorant binding protein 99b (OBP99b) expression from 4 to 12-d-old oriental fruit fly males, relative to 1-d-old males to estimate the physical ages of wild male fruit flies. We established two polynomial linear regression equations based on 4–12 days old lab-reared flies using proteomics and qPCR. The equations are Y = − 0.7768 + 0.7205X, R 2 = 0.89 (for proteomics) and Y = − 0.6478 + 0.344X, R 2 = 0.64 (for qPCR). We used these equations to estimate the physical ages of wild-caught male fruit flies. These results indicate that despite multiple behavioral differences between laboratory reared and field-caught flies, the physical ages of both groups are identical. We suggest proteomics and qPCR analysis of selected genes and the proteins they encode may be developed into reliable tools for determining the ages of wild-caught animals, including oriental fruit flies.

Methyphenidate (MPH) is the primary drug treatment of choice for ADHD. It is also frequently used off-label as a cognitive enhancer by otherwise healthy individuals from all age groups and walks of life. Military personnel, students, and health professionals use MPH illicitly to increase attention and improve workplace performance over extended periods of work activity. Despite the frequency of its use, the efficacy of MPH to enhance cognitive function across individuals and in a variety of circumstances is not well characterized. We sought to better understand MPH׳s cognitive enhancing properties in two different rodent models of attention. We found that MPH could enhance performance in a sustained attention task, but that its effects in this test were subject dependent. More specifically, MPH increased attention in low baseline performing rats but had little to no effect on high performing rats. MPH exerted a similar subject specific effect in a test of flexible attention, i.e. the attention set shifting task. In this test MPH increased behavioral flexibility in animals with poor flexibility but impaired performance in more flexible animals. Overall, our results indicate that the effects of MPH are subject-specific and depend on the baseline level of performance. Furthermore, good performance in in the sustained attention task was correlated with good performance in the flexible attention task; i.e. animals with better vigilance exhibited greater behavioral flexibility. The findings are discussed in terms of potential neurobiological substrates, in particular noradrenergic mechanisms, that might underlie subject specific performance and subject specific responses to MPH. This article is part of a Special Issue entitled SI: Noradrenergic System.

Autism spectrum disorders (ASDs) present unique challenges in the fields of genetics and neurobiology because of the clinical and molecular heterogeneity underlying these disorders. Genetic mutations found in ASD patients provide opportunities to dissect the molecular and circuit mechanisms underlying autistic behaviors using animal models. Ongoing studies of genetically modified models have offered critical insight into possible common mechanisms arising from different mutations, but links between molecular abnormalities and behavioral phenotypes remain elusive. The challenges encountered in modeling autism in mice demand a new analytic paradigm that integrates behavioral assessment with circuit-level analysis in genetically modified models with strong construct validity.