Showing papers in "Frontiers in Behavioral Neuroscience in 2019"
TL;DR: The results suggest that the laterality of visuospatial attention affects the sensorimotor gating system depending on the attentional condition, and the process of visual information processing may differ between the left and right brain.
Abstract: The integration of multiple sensory modalities allows us to adapt to the environment of the outside world. It is widely known that visual stimuli interfere with the processing of auditory information, which is involved in the ability to pay attention. Additionally, visuospatial attention has the characteristic of laterality. It is unclear whether this laterality of visuospatial attention affects the processing of auditory stimuli. The sensorimotor gating system is a neurological process, which filters out unnecessary stimuli from environmental stimuli in the brain. Prepulse inhibition (PPI) is an operational measure of the sensorimotor gating system, which a weaker prestimulus (prepulse), such as a visual stimulus, inhibits the startle reflex elicited by a subsequent robust startling stimulus (pulse) such as a tone. Therefore, we investigated whether the visual stimulus from the left or right visual space affects the sensorimotor gating system in a "rest" task (low attentional condition) and a "selective attention" task (high attentional condition). In the selective attention task, we found that the target prepulse presented in the left and bilateral visual fields suppressed the startle reflex more than that presented in the right visual field. By contrast, there was no laterality of PPI in the no-target prepulse condition, and there was no laterality of PPI in the rest task. These results suggest that the laterality of visuospatial attention affects the sensorimotor gating system depending on the attentional condition. Moreover, the process of visual information processing may differ between the left and right brain.
117 citations
TL;DR: To improve the dialog between human and animal studies as well as to accelerate the development of effective therapeutics, the need to examine both sex differences and remote timescales in rodent models is emphasized.
Abstract: The generalization of fear memories is an adaptive neurobiological process that promotes survival in complex and dynamic environments. When confronted with a potential threat, an animal must select an appropriate defensive response based on previous experiences that are not identical, weighing cues and contextual information that may predict safety or danger. Like other aspects of fear memory, generalization is mediated by the coordinated actions of prefrontal, hippocampal, amygdalar, and thalamic brain areas. In this review article, we describe the current understanding of the behavioral, neural, genetic, and biochemical mechanisms involved in the generalization of fear. Fear generalization is a hallmark of many anxiety and stress-related disorders, and its emergence, severity, and manifestation are sex-dependent. Therefore, to improve the dialog between human and animal studies as well as to accelerate the development of effective therapeutics, we emphasize the need to examine both sex differences and remote timescales in rodent models.
103 citations
TL;DR: Differential influences of deprivation and threat on cognitive and emotional outcomes even in early childhood are suggested, suggesting increased risk for negative outcomes associated with adversity exposure, such as psychopathology.
Abstract: Early-life adversity (ELA) is strongly associated with risk for psychopathology. Within adversity, deprivation, and threat may lead to psychopathology through different intermediary pathways. Specifically, deprivation, defined as the absence of expected cognitive and social inputs, is associated with lower performance on complex cognitive tasks whereas threatening experiences, defined as the presence of experiences that reflect harm to the child, are associated with atypical fear learning and emotional processes. However, distinct associations of deprivation and threat on behavioral outcomes have not been examined in early childhood. The present study examines how deprivation and threat are associated with cognitive and emotional outcomes in early childhood. Children 4-7 years old completed behavioral tasks assessing cognitive control (N = 58) and fear conditioning (N = 45); deprivation and threat were assessed using child interview and parent questionnaires. Regression analyses were performed including deprivation and threat scores and controls for age, gender, and IQ. Because this is the first time these variables have been examined in early childhood, interactions with age were also examined. Deprivation, but not threat was associated with worse performance on the cognitive control task. Threat, but not deprivation interacted with age to predict fear learning. Young children who experienced high levels of threat showed evidence of fear learning measured by differential skin conductance response even at the earliest age measured. In contrast, for children not exposed to threat, fear learning emerged only in older ages. Children who experienced higher levels of threat also showed blunted reactivity measured by amplitude of skin conductance response to the reinforced stimuli regardless of age. Results suggest differential influences of deprivation and threat on cognitive and emotional outcomes even in early childhood. Future work should examine the neural mechanisms underlying these behavioral changes and link changes with increased risk for negative outcomes associated with adversity exposure, such as psychopathology.
99 citations
TL;DR: This review highlights the long-term behavioral consequences of adolescent social isolation rearing in rodents with a specific focus on anxiety- and addiction-related behaviors and considers changes in monoaminergic neurotransmission as one possible mechanism for the behavioral effects described.
Abstract: Adolescence is a developmental period associated with vast neural and behavioral changes which are accompanied by altered sensitivity to stimuli, both stressful and rewarding. Perturbations, especially stressful stimuli, during this period have been shown to alter behavior in adulthood. Social isolation rearing is one such perturbation. This review highlights the long-term behavioral consequences of adolescent social isolation rearing in rodents with a specific focus on anxiety- and addiction-related behaviors. Sex-specific effects are discussed where data are available. We then consider changes in monoaminergic neurotransmission as one possible mechanism for the behavioral effects described. This research on both normative and perturbed adolescent development is crucial to understanding and treating the increased vulnerability to psychiatric disorders seen in humans during this life stage.
92 citations
TL;DR: The most common preclinical models of addictive behavior, including non-contingent models in which animals are passively exposed to rewarding substances, as well as widely used contingent models such as drug self-administration and relapse are reviewed.
Abstract: Drug addiction is a neuropsychiatric disorder with grave personal consequences that has an extraordinary global economic impact. Despite decades of research, the options available to treat addiction are often ineffective because our rudimentary understanding of drug-induced pathology in brain circuits and synaptic physiology inhibits the rational design of successful therapies. This understanding will arise first from animal models of addiction where experimentation at the level of circuits and molecular biology is possible. We will review the most common preclinical models of addictive behavior and discuss the advantages and disadvantages of each. This includes non-contingent models in which animals are passively exposed to rewarding substances, as well as widely used contingent models such as drug self-administration and relapse. For the latter, we elaborate on the different ways of mimicking craving and relapse, which include using acute stress, drug administration or exposure to cues and contexts previously paired with drug self-administration. We further describe paradigms where drug-taking is challenged by alternative rewards, such as appetitive foods or social interaction. In an attempt to better model the individual vulnerability to drug abuse that characterizes human addiction, the field has also established preclinical paradigms in which drug-induced behaviors are ranked by various criteria of drug use in the presence of negative consequences. Separation of more vulnerable animals according to these criteria, along with other innate predispositions including goal- or sign-tracking, sensation-seeking behavior or impulsivity, has established individual genetic susceptibilities to developing drug addiction and relapse vulnerability. We further examine current models of behavioral addictions such as gambling, a disorder included in the DSM-5, and exercise, mentioned in the DSM-5 but not included yet due to insufficient peer-reviewed evidence. Finally, after reviewing the face validity of the aforementioned models, we consider the most common standardized tests used by pharmaceutical companies to assess the addictive potential of a drug during clinical trials.
88 citations
TL;DR: This study included 57 children born very preterm followed longitudinally from birth who underwent 3-D T1 MRI neuroimaging at ∼8 years and found that neonatal clinical factors and genotypes accounted for 46% of the overall variance in volumes of hippocampal subregions, tracts, basal ganglia, thalamus and amygdala.
Abstract: Altered hippocampal morphology and reduced volumes have been found in children born preterm compared to full-term. Stress inhibits neurogenesis in the hippocampus, and neonatal stress/noxious stimulation in rodent pups are associated with long-term alterations in hippocampal volumes. We have previously shown reduced cortical thickness and cerebellar volumes in relation to more exposure to pain-related stress of neonatal invasive procedures in children born very preterm. We have reported targeted gene-by-pain environment interactions that contribute to long-term brain development and outcomes in this population. We now aim to determine whether exposure to pain-related stress (adjusted for clinical factors and genotype) differentially impacts regional structures within the limbic system and thalamus, and investigate relationships with outcomes in very preterm children. Our study included 57 children born very preterm (<32 weeks GA) followed longitudinally from birth who underwent 3-D T1 MRI neuroimaging at ∼8 years. Hippocampal subfields and white matter tracts, thalamus and amygdala were automatically segmented using the MAGeT Brain algorithm. The relationship between those subcortical brain volumes (adjusted for total brain volume) and neonatal invasive procedures, gestational age (GA), illness severity, postnatal infection, days of mechanical ventilation, number of surgeries, morphine exposure, and genotype (COMT, SLC6A4, and BDNF) was examined using constrained principal component analysis. We found that neonatal clinical factors and genotypes accounted for 46% of the overall variance in volumes of hippocampal subregions, tracts, basal ganglia, thalamus and amygdala. After controlling for clinical risk factors and total brain volume, greater neonatal invasive procedures was associated with lower volumes in the amygdala and thalamus (p = 0.0001) and an interaction with COMT genotype predicted smaller hippocampal subregional volume (p = 0.0001). More surgeries, days of ventilation, and lower GA were also related to smaller volumes in various subcortical regions (p < 0.002). These reduced volumes were in turn differentially related to poorer cognitive, visual-motor and behavioral outcomes. Our findings highlight the complexity that interplays when examining how exposure to early-life stress may impact brain development both at the structural and functional level, and provide new insight on possible novel avenues of research to discover brain-protective treatments to improve the care of children born preterm.
72 citations
TL;DR: The known effects of witnessing violence during the perinatal period on socio-emotional development and the possible pathways by which IPV affects brain and stress-regulating systems are described and embedded in the context of the resource depletion hypothesis are described.
Abstract: Exposure to intimate partner violence (IPV) can have long-lasting effects on a child's socio-emotional and neurological development. Research has focused on the effects of IPV on women or older children, while the developmental consequences of exposure to domestic violence during early childhood are less well documented. However, one would expect significant developmental effects since the infant's brain and stress-related systems are especially susceptible to environmental stimuli. The goal of this mini-review is to examine how findings on infant exposure to IPV can be related to risk and resilience of development in infancy. We describe the known effects of witnessing violence during the perinatal period on socio-emotional development and the possible pathways by which IPV affects brain and stress-regulating systems. Exposure to IPV during infancy disrupts the infant's emotional and cognitive development, the development of the Hypothalamus-Pituitary-Adrenal (HPA) axis and brain structures related to witnessing itself (auditory and visual cortex). The findings are embedded in the context of the resource depletion hypothesis. A central problem is the dearth of research on exposure to IPV during infancy, its effect on caregiving, and infant development. Nonetheless, the available evidence makes it clear that policies for prevention of IPV are critically needed.
66 citations
TL;DR: The findings point to the importance of timing of early life stress and provide the foundation for future studies to probe the neurobiological mechanisms of risk and resilience conferred by variation in the early life environment.
Abstract: Epidemiological evidence identifies early life adversity as a significant risk factor for the development of mood disorders. Much evidence points to the role of early life experience in susceptibility and, to a lesser extent, resilience, to stress in adulthood. While many models of these phenomena exist in the literature, results are often conflicting and a systematic comparison of multiple models is lacking. Here, we compare effects of nine manipulations spanning the early postnatal through peri-adolescent periods, both at baseline and following exposure to chronic social defeat stress in adulthood, in male mice. By applying rigorous criteria across three commonly used measures of depression- and anxiety-like behavior, we identify manipulations that increase susceptibility to subsequent stress in adulthood and other pro-resilient manipulations that mitigate the deleterious consequences of adult stress. Our findings point to the importance of timing of early life stress and provide the foundation for future studies to probe the neurobiological mechanisms of risk and resilience conferred by variation in the early life environment.
64 citations
TL;DR: It is concluded that the anxiolytic and antidepressant effects of B. adolescentis are related to reducing inflammatory cytokines and rebalancing the gut microbiota.
Abstract: Stress disturbs the balance of the gut microbiota and stimulates inflammation-to-brain mechanisms. Moreover, stress leads to anxiety and depressive disorders. Bifidobacterium adolescentis displays distinct anti-inflammatory effects. However, no report has focused on the anxiolytic and antidepressant effects of B. adolescentis related to the gut microbiome and the inflammation on chronic restraint stress (CRS) in mice. We found that pretreatment with B. adolescentis increased the time spent in the center of the open field apparatus, increased the percentage of entries into the open arms of the elevated plus-maze (EPM) and the percentage of time spent in the open arms of the EPM, and decreased the immobility duration in the tail suspension test as well as the forced swimming test (FST). Moreover, B. adolescentis increased the sequence proportion of Lactobacillus and reduced the sequence proportion of Bacteroides in feces. Furthermore, B. adolescentis markedly reduced the protein expression of interleukin-1β (IL-1β), tumor necrosis factor α (TNF-α), p-nuclear factor-kappa B (NF-κB) p65 and Iba1 and elevated brain derived neurotrophic factor (BDNF) expression in the hippocampus. We conclude that the anxiolytic and antidepressant effects of B. adolescentis are related to reducing inflammatory cytokines and rebalancing the gut microbiota.
63 citations
TL;DR: Findings are reviewed that define the CA2 as a region distinct from both CA1 and CA3, with a unique set of cortical inputs and outputs and contributions to cognitive processes, and discuss the parallels between CA2 dysfunction and social impairments.
Abstract: The CA2 region of the hippocampus is a somewhat obscure area lacking in an understanding of its form and function. Until recently, the CA2 has been thought of as merely an extension of the CA3, with some referring to it as the CA3a region. Recent investigations into this area have not only delineated the CA2, but also defined it as a region distinct from both CA1 and CA3, with a unique set of cortical inputs and outputs and contributions to cognitive processes. One such process that has been shown to depend on the CA2 is the ability to recognize a novel or familiar conspecific, known as social recognition memory. Here, we review these findings and discuss the parallels between CA2 dysfunction and social impairments.
58 citations
TL;DR: Functional evidence is provided that microbiota affects depression-like behavior through influencing brain tryptophan accessibility and the serotonergic system, and GF mice after tryPTophan reduction behave more similarly to SPF mice.
Abstract: During the past decade, there has been a substantial rise in the knowledge about the effects of gut microbiota on host physiology and behavior, including depressive behavior. Initial studies determined that gut microbiota can regulate host tryptophan levels, which is a main serotonin precursor. A dysfunctional serotonergic system is considered to be one of the main factors contributing to the development of depression. Therefore, we hypothesized that regulation of brain tryptophan and serotonin can explain, at least partly, the effects of microbiota on depressive behavior. To test this hypothesis, we examined depressive-like behavior and brain levels of serotonin and tryptophan, of germ free (GF) and specific-pathogen free (SPF) mice under basal conditions, or after acute tryptophan depletion (ATD) procedure, which is a method to decrease tryptophan and serotonin levels in the brain. In basal conditions, GF mice exhibited less depressive-like behavior in sucrose preference, tail-suspension and forced swim tests, compared to SPF mice. In addition, in mice that were not subjected to ATD, GF mice displayed higher levels of tryptophan, serotonin and 5-hydroxyindoleacetic acid (the main degradation product of serotonin) in medial prefrontal cortex (mPFC) and hippocampus (HIPPO), compared to SPF mice. Interestingly, ATD increased depressive-like behavior of GF, but not of SPF mice. These behavioral changes were accompanied by a stronger reduction of tryptophan, serotonin and 5-hydroxyindoleacetic acid in mPFC and HIPPO in GF mice after ATD, when compared to SPF mice. Therefore, the serotonergic system of GF mice is more vulnerable to the acute challenge of tryptophan reduction, and GF mice after tryptophan reduction behave more similarly to SPF mice. These data provide functional evidence that microbiota affects depression-like behavior through influencing brain tryptophan accessibility and the serotonergic system.
TL;DR: Findings point to a modulatory function of the cerebellum in terminating or initiating actions through regulation of the prefrontal cortices, which may be crucial for restraining ongoing actions when environmental conditions change by adjusting prefrontal activity in response to the new external and internal stimuli, thereby promoting flexible behavioral control.
Abstract: Growing evidence associates cerebellar abnormalities with several neuropsychiatric disorders in which compulsive symptomatology and impulsivity are part of the disease pattern. Symptomatology of autism, addiction, obsessive-compulsive (OCD), and attention deficit/hyperactivity (ADHD) disorders transcends the sphere of motor dysfunction and essentially entails integrative processes under control of prefrontal-thalamic-cerebellar loops. Patients with brain lesions affecting the cortico-striatum thalamic circuitry and the cerebellum indeed exhibit compulsive symptoms. Specifically, lesions of the posterior cerebellar vermis cause affective dysregulation and deficits in executive function. These deficits may be due to impairment of one of the main functions of the cerebellum, implementation of forward internal models of the environment. Actions that are independent of internal models may not be guided by predictive relationships or a mental representation of the goal. In this review article, we explain how this deficit might affect executive functions. Additionally, regionalized cerebellar lesions have been demonstrated to impair other brain functions such as the emergence of habits and behavioral inhibition, which are also altered in compulsive disorders. Similar to the infralimbic cortex, clinical studies and research in animal models suggest that the cerebellum is not required for learning goal-directed behaviors, but it is critical for habit formation. Despite this accumulating data, the role of the cerebellum in compulsive symptomatology and impulsivity is still a matter of discussion. Overall, findings point to a modulatory function of the cerebellum in terminating or initiating actions through regulation of the prefrontal cortices. Specifically, the cerebellum may be crucial for restraining ongoing actions when environmental conditions change by adjusting prefrontal activity in response to the new external and internal stimuli, thereby promoting flexible behavioral control. We elaborate on this explanatory framework and propose a working hypothesis for the involvement of the cerebellum in compulsive and impulsive endophenotypes.
TL;DR: The authors' data demonstrate that different stress models can promote specific maternal patterns of behavior, and observe an overall increase in nursing and licking/grooming behaviors, which are essential for pup development.
Abstract: Background: Maternal care refers to the behavior performed by the dam to nourish and protect her litter during its early development. Frequent and high-quality performance of such maternal behaviors is critical for the neurodevelopment of the pups. Maternal exposure to stress during early development can impair maternal care and amplify the deleterious effects of poor maternal caregiving and neglect. As such, a thorough understanding of the effects caused by several models of early life stress on maternal care may yield more insights into the relationship between stress and maternal behavior. Methods: A systematic review was performed to identify and address the effects of early life stress on maternal behavior. The search was conducted using three online databases: PUBMED, Embase, and Web of Science. To provide clear evidence of the impact of stress on maternal care, in every study, the stress group was always compared to a control group. Outcomes were categorized into eight different behaviors: (1) licking/grooming; (2) arched-back nursing; (3) blanket-nursing/passive nursing; (4) nest building; (5) contact with pups; (6) harmful/adverse caregiving; (7) no contact; (8) nest exits. Additionally, the methodological quality of the studies was evaluated. Results: A total of 12 different early life stress protocols were identified from the 56 studies included in this systematic review. Our data demonstrate that different stress models can promote specific maternal patterns of behavior. Regarding the maternal separation protocol, we observed an overall increase in nursing and licking/grooming behaviors, which are essential for pup development. An increase in the number of nest exits, which represents a fragmentation of maternal care, was observed in the limited bedding protocol, but the total amount of maternal care appears to remain similar between groups. Conclusions: Each stress protocol has unique characteristics that increase the difficulty of rendering comparisons of maternal behavior. The increase in maternal care observed in the maternal separation protocol may be an attempt to overcompensate for the time off-nest. Fragmented maternal care is a key component of the limited bedding protocol. Moreover, the methodological approaches to evaluate maternal behavior, such as time, duration, and behavior type should be more homogeneous across studies.
TL;DR: The present review article summarizes empirical and conceptual advances in the field to understand the role of the “dark side” in driving the risky and detrimental substance use that is associated with negative urgency in addiction.
Abstract: Negative urgency is a unique dimension of impulsivity that involves acting rashly when in extreme distress and impairments in inhibitory control. It has been hypothesized to derive from stress that is related to negative emotional states that are experienced during the withdrawal/negative affect stage of the addiction cycle. Classically, a transition to compulsive drug use prevents or relieves negative emotional states that result from abstinence or stressful environmental circumstances. Recent work suggests that this shift to the "dark side" is also implicated in impulsive use that derives from negative urgency. Stress and anxious, depressed, and irritable mood have high comorbidity with addiction. They may trigger bouts of drug seeking in humans via both negative reinforcement and negative urgency. The neurocircuitry that has been identified in the "dark side" of addiction involves key neuropeptides in the central extended amygdala, including corticotropin-releasing factor. The present review article summarizes empirical and conceptual advances in the field to understand the role of the "dark side" in driving the risky and detrimental substance use that is associated with negative urgency in addiction.
TL;DR: Results suggest that the propensity to dart does not reflect a simple hyperactivity, and that despite conceptual overlap across the two tests, the behavioral strategies engaged by an individual animal in each are likely driven by discrete mechanisms.
Abstract: Symptoms of trauma and stressor related disorders such as post-traumatic stress disorder (PTSD) often develop well after the traumatic experience has occurred, and so identifying early predictors of risk or resilience is important for the implementation of interventional therapies. For example, passive coping strategies such as tonic immobility and peritraumatic dissociation during the trauma itself are risk factors for the developments of PTSD, especially in women. However, discrete, sex-specific coping responses that predict later outcomes in animal models have not been rigorously defined. Recently, we identified an active, escape-like response exhibited primarily by a subset of female rats in a classic auditory fear conditioning task ("darting"). Here, we asked whether darting during conditioning predicted active responding in a single forced swim (SFS) session to study the potential for darting to reflect a trait-like behavioral strategy that translated across stress models. Male and female Sprague-Dawley (SD) rats were tested in auditory fear conditioning acquisition and memory tests to identify Darters, and then a 15-min SFS 2 weeks later. We observed a significant effect of sex in conditioned freezing behavior, with males exhibiting greater freezing than females across conditioning and testing trials in comparison to females. However, females demonstrated higher velocities in response to shock presentations, and were more likely to exhibit darting behavior in response to the conditioned stimulus (CS). In SFS measures, females engaged in active behaviors such as climbing, head shaking, and diving in greater proportions than males, while males spent more time immobile throughout testing. Despite females exhibiting a more diverse behavioral repertoire in both tests, Darters did not differ from Non-darters in any SFS measure. These results suggest that the propensity to dart does not reflect a simple hyperactivity, and that despite conceptual overlap across the two tests (inescapable stress exposure and the ability to measure active vs. passive coping), the behavioral strategies engaged by an individual animal in each are likely driven by discrete mechanisms. We discuss potential challenges in interpretation of standard behavioral outcomes in classic models across the sexes, and consider the potential need for novel models that better tap into motivational states in females.
TL;DR: The “Delayed Neural Commitment (DNC)” framework proposes that, in addition to slower skill acquisition, dyslexic children take longer to build the neural networks that underpin the acquisition of reading.
Abstract: It is now evident that explanations of many developmental disorders need to include a network perspective. In earlier work, we proposed that developmental dyslexia (DD) is well-characterized in terms of impaired procedural learning within the language networks, with the cerebellum being the key structure involved. Here, we deepen the analysis to include the child's developmental process of constructing these networks. The "Delayed Neural Commitment (DNC)" framework proposes that, in addition to slower skill acquisition, dyslexic children take longer to build (and to rebuild) the neural networks that underpin the acquisition of reading. The framework provides an important link backwards in time to the development of executive function networks and the earlier development of networks for language and speech. It is consistent with many theories of dyslexia while providing fruitful suggestions for further research at the genetic, brain, cognitive and behavioral levels of explanation. It also has significant implications for assessment and teaching.
TL;DR: The results indicated that the reason why females performed not so well in large-scale spatial ability was that they were more susceptible to emotions and their parahippocampal gyrus worked less efficiently than males; Females performed notSo well in small- scale spatial ability because they mostly adopted the egocentric strategy and their sub-gyral also worked less efficient than males.
Abstract: Background: As we human beings are living in a multidimensional space all the time. Therefore, spatial ability is vital for the survival and development of individuals. However, males and females show gender differences in this ability. So, are these gender differences influenced by the scale type of spatial ability? It's not well specified. Therefore, to tackle this issue, we conducted the current research from the behavioral and neural level. Methods: Study 1 used the general meta-analysis method to explore whether individuals display the same gender differences in large- and small-scale spatial ability. Study 2 used the method of Activation Likelihood Estimation to identify the commonalities and distinctions of the brain activity between males and females on large- and small-scale spatial ability. Results: Study 1 showed that in behavior performance, males outperformed females in both large-scale and small-scale spatial ability, but the effect size of the gender difference in large-scale spatial ability is significantly greater than that in small-scale spatial ability. In addition, Study 2 showed that in terms of neural activity, males and females exhibited both similarities and differences no matter in large-scale or small-scale spatial ability. Especially, the contrast analysis between females and males demonstrated a stronger activation in the brain regions of bilateral lentiform nucleus and bilateral parahippocampal gyrus in large-scale spatial ability, and correspondence in right sub-gyral, right precuneus, and left middle frontal gyrus in small-scale spatial ability. Conclusions: The results indicated that the reason why females performed not so well in large-scale spatial ability was that they were more susceptible to emotions and their parahippocampal gyrus worked less efficiently than males; females performed not so well in small-scale spatial ability because they mostly adopted the egocentric strategy and their sub-gyral also worked less efficiently than males. The two different reasons have made for gender differences in favor of males in terms of spatial ability and such gender differences have different manifestations in large-scale and small-scale spatial ability. Possible implications of the results for understanding the issue of gender differences in spatial ability are discussed.
TL;DR: Interdisciplinary clinicians using the Neurosequential Model of Therapeutics reported on the timing and type of treatment-seeking children’s stressful experiences during four developmental periods, and a severe lack of positive relational experiences was associated with the Sensory Integration and Self-Regulation factors.
Abstract: Early-life stress (ELS) poses risks for developmental and mental health problems throughout the lifespan. More research is needed regarding how specific ELS experiences influence specific aspects of neurodevelopment. We examined the association between ELS, defined as severe adversity (e.g., domestic violence, caregiver drug use) and severe relational poverty (e.g., caregiver neglect, lack of caregiver attunement), occurring during the first 2 months of life and a variety of brain-related, clinician-rated functions, including self-regulation and relational capacities. Interdisciplinary clinicians using the Neurosequential Model of Therapeutics (NMT), an approach to clinical problem solving, reported on the timing and type of treatment-seeking children's (N = 2,155; 8-10 years) stressful experiences during four developmental periods: Perinatal (0-2 months), Infancy (2-12 months), Early Childhood (13 months to 4 years), and Childhood (4-11 years). They also reported on children's current functioning in 32 brain-related domains (e.g., sleep, arousal, impulsivity, empathy, concrete cognition). Non-negative matrix factorization (NMF) was conducted on the 32 brain-related domains to identify latent factors, yielding four factors comprising Sensory Integration, Self-Regulation, Relational, and Cognitive functioning. Regularized hierarchical models were then used to identify associations between ELS and each latent factor while controlling for stress occurring during subsequent developmental periods, and children's current degree of relational health. ELS (stress occurring during the first 2 months of life), specifically a severe lack of positive relational experiences (e.g., caregiver neglect, lack of caregiver attunement), was associated with the Sensory Integration and Self-Regulation factors. The Relational factor was better explained by stress occurring during childhood, and the Cognitive factor by stress occurring during infancy and childhood. Implications for how the timing and type of stress experiences may influence brain-related outcomes that are observed in clinical settings are discussed. Future directions include longitudinal follow-ups and greater specification of environmental variables, such as types of interventions received and when they were received, that may interact with ELS experiences to influence brain-related outcomes.
TL;DR: Examination of age and gender effects in self-reported sensitivity to different types of social rewards implies that the social reward of social interactions is a nuanced and complex construct, which encompasses multiple components that show unique effects with age andGender.
Abstract: Adolescence is a sensitive period for socio-cultural processing and a vast literature has established that adolescents are exceptionally attuned to the social context. Theoretical accounts posit that the social reward of social interactions plays a large role in adolescent sensitivity to the social context. Yet, to date it is unclear how sensitivity to social reward develops across adolescence and young adulthood and whether there are gender differences. The present cross-sectional study (N = 271 participants, age 11-28 years) examined age and gender effects in self-reported sensitivity to different types of social rewards. In order to achieve this aim, the Dutch Social Reward Questionnaire for Adolescents was validated. Findings revealed that each type of social reward was characterized by distinct age and gender effects. Feeling rewarded by gaining positive attention from others showed a peak in late adolescence, while enjoying positive reciprocal relationships with others showed a linear increase with age. Enjoying cruel behavior toward others decreased with age for girls, while boys showed no changes with age and reported higher levels across ages. Reward from giving others control showed a mid-adolescent dip, while enjoying group interactions did not show any changes with age. Taken together, the results imply that the social reward of social interactions is a nuanced and complex construct, which encompasses multiple components that show unique effects with age and gender. These findings enable us to gain further traction on the ubiquitous effects of the social context on decision-making in adolescent's lives.
TL;DR: In this paper, the acute and long-term effects of Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) on object memory, anxiety-like behavior, and activity levels in adolescent and adult mice of both sexes were examined.
Abstract: The rise in cannabinoid legalization and decriminalization in the US has been paired with an increase in adolescents that perceive marijuana as a “no risk” drug. However, a comprehensive review of human literature indicates that cannabinoid usage may have both beneficial and detrimental effects, with adolescent exposure being a critical window for harming cognitive development. Although the cannabinoids Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are often used together for recreational and medical purposes, no study has previously observed the acute and long-lasting effects of THC+CBD in a battery of behavioral assays analogous to subjective human reports. The current study observed the acute and long-term effects of THC, CBD, and THC+CBD on object memory, anxiety-like behavior, and activity levels in adolescent and adult mice of both sexes. Acute THC alone and in combination with CBD resulted in robust effects on anxiety-like and locomotor behavior. A history of repeated cannabinoid treatment followed by a period without drug administration resulted in minimal effects in these behavioral assays. Most notably, the strongest effects of repeated cannabinoid treatment were seen in adult females administered THC+CBD, which significantly impaired their object recognition. No effects of repeated cannabinoid history were present on hippocampal protein expression. These studies represent a detailed examination of age- and sex-effects of acute and repeated cannabinoid administration. However, the acute and long-term effects of THC with and without CBD on additional behaviors in adolescents and adults will need to be examined for a more complete picture of these drug effects.
TL;DR: It is demonstrated that RT fluctuates even when the stimulus ambiguity remains unchanged, and hypothesize that RT is affected by the processes preceding the decision-making stage, e.g., encoding visual sensory information and extracting decision-relevant features from raw sensory information.
Abstract: Behavioral experiments evidence that attention is not maintained at a constant level, but fluctuates in time. Recent studies associate such fluctuations with dynamics of attention-related cortical networks, however the exact mechanism remains unclear. To address this issue, we consider functional neuronal interactions during the accomplishment of a reaction time (RT) task which requires sustained attention. The participants are subjected to a binary classification of a large number of presented ambiguous visual stimuli with different degree of ambiguity. Generally, high ambiguity causes high RT and vice versa. However, we demonstrate that RT fluctuates even when the stimulus ambiguity remains unchanged. The analysis of neuronal activity reveals that the subject's behavioral response is preceded by the formation of a distributed functional network in the $\beta$-frequency band. This network is characterized by high connectivity in frontal cortex and supposed to subserve a decision-making process. We show that neither the network structure nor the duration of its formation depend on RT and stimulus ambiguity. In turn, RT is related to the moment of time when the $\beta$-band functional network emerges. We hypothesize that RT is affected by the processes preceding the decision-making stage, e.g. encoding visual sensory information and extracting decision-relevant features from raw sensory information.
TL;DR: This review will describe the progress that has been made in understanding the high degree of plasticity observed in the model crustacean Daphnia, and provide a comprehensive overview on the molecular mechanisms of ad hoc environmental phenotypic adaptation.
Abstract: Ecological communities are organized in trophic levels that share manifold interactions forming complex food webs. Infochemicals can further modify these interactions, e.g., by inducing defenses in prey. The micro-crustacean Daphnia is able to respond to predator-specific chemical cues indicating an increased predation risk. Daphnia shows plastic responses by adapting its morphology, behavior, and physiology, increasing organism, and population fitness. This stabilizes community structures. This review will describe the progress that has been made in understanding the high degree of plasticity observed in the model crustacean Daphnia. I summarize current knowledge on the processes of predator detection, ranging from the nature of biologically active chemical cues to the underlying neurophysiological mechanisms. With this, I aim to provide a comprehensive overview on the molecular mechanisms of ad hoc environmental phenotypic adaptation. In times of climate change and pollution understanding information transfer in aquatic systems is valuable as it will allow us to predict whether and how community structures are being affected.
TL;DR: Whether ES alters the characteristics of the AVP- and OXT- systems in rodents, and whether these changes are associated with later alterations in aggression, social recognition, and social motivation, is discussed.
Abstract: Exposure to stress during the early postnatal period (i.e., early life stress, ES) can impact brain physiology and modify individual variability in adult social behavior. Arginine vasopressin (AVP) and oxytocin (OXT) are two centrally released neuropeptides that are involved in shaping essential social behaviors, like aggression, social recognition, and social motivation. AVP and OXT modulate activity in brain regions important for the establishment of social behavior, and may be particularly sensitive to ES. In this review, we discuss whether ES alters the characteristics of the AVP- and OXT- systems in rodents, and whether these changes are associated with later alterations in aggression, social recognition, and social motivation. We have integrated causal studies indicating that (1) ES affects AVP/OXT, and (2) that changing AVP/OXT in affected regions alters social behavior. Although there is encouraging evidence that ES causes AVP- and OXT-system changes, and that these may mediate social behavior, a comprehensive understanding of the exact nature of AVP- and OXT changes and whether they are causal in establishing these behavioral disturbances needs further investigation. As there are indications that ES alters AVP- and OXT characteristics in humans as well, and that these may interact with adult predisposition to psychopathology with social dysfunction, future rodent studies may lay ground for a better understanding of such changes in humans. Ultimately, this may assist in developing therapeutic strategies to target ES effects on social behavior.
TL;DR: M measuring lifetime stress exposure and event-related potentials to social reward support the utility of ERP measures in measuring individual differences in social reward processing that can be applied to better understand neural processes involved in the development of depression, and highlight the importance of considering specific dimensions of stressful life experiences.
Abstract: Exposure to social stress is a well-established risk factor for the development and recurrence of depression. Reduced neural responsiveness to monetary reward has been associated with greater symptoms following stress exposure. However, it remains unclear whether reduced reward responsiveness serves as a mediator or moderator of the effects of stress on internalizing symptoms or whether similar patterns emerge with responses to social reward. We addressed this issue by measuring lifetime stress exposure and event-related potentials (ERPs) to social reward in 231 emerging adults (M = 18.16, SD = 0.41 years old). Participants completed the Stress and Adversity Inventory (STRAIN) to assess severity of lifetime stressors and self-report measures of current internalizing symptoms. In addition, participants completed the Island Getaway task in which the reward positivity (RewP) ERP was recorded in response to social acceptance, adjusting for responses to rejection (RewP residual). In this task, participants vote to accept or reject peers and receive reward/acceptance and rejection feedback. Stressors were divided into social and non-social stress severity scores. Analyses were conducted to test social reward responsiveness as a mediator or moderator of the effects of social and non-social stress on internalizing symptoms. Both social and non-social stress exposure over the life course predicted symptoms of depression (ps < 0.001) and social anxiety (ps < 0.002). The effect of social stress on depression was moderated by the residual RewP to social reward, adjusting for responses to social rejection (p =0.024), such that greater lifetime social stress exposure and a relatively blunted RewP to social reward were associated with greater depressive symptoms. Social reward responsiveness did not mediate effects of stress on internalizing symptoms. Reduced processing of social reward may be a vulnerability for depression that increases risk for symptoms following exposure to social stress. Blunted social reward responsiveness appears to be a relatively unique vulnerability for depression, rather than social anxiety. Results support the utility of ERP measures in measuring individual differences in social reward processing that can be applied to better understand neural processes involved in the development of depression, and highlight the importance of considering specific dimensions of stressful life experiences.
TL;DR: The LBN model of ELA may drive a more complex constellation of effects on maternal behavior driving a pattern of increased dam-pup interactions and increased abuse-like kicking behavior, with unique consequences for pup outcomes.
Abstract: Early life adversity (ELA) is associated with altered neural development and increased risk for the development of psychopathology across the lifespan. Rodent models of ELA are an important tool for investigating the possible mechanistic underpinnings of pathology development. We used a limited bedding and nesting model (LBN) to induce stress in the dam and alter dam-pup interactions during a sensitive period in early postnatal development. The primary characteristics previously identified in this model include fragmented and unpredictable maternal care and possibly neglect. However, previous studies have not considered the effects of this manipulation over the full circadian cycle and the evolution of changes of maternal behavior throughout the duration of the manipulation. In the current study, we leverage a novel continuous video monitoring setup to unobtrusively observe and subsequently analyze maternal behaviors. Through this more in-depth analysis, we discovered that LBN dams spent more time than control dams on their nest, returned to their nest more frequently than control dams, and showed intact maternal care. Importantly, a subset of LBN dams (~40%) engaged in abusive-like kicking, a behavioral pattern not previously identified in this paradigm. Exposure to ELA and abusive-like kicking were associated with differences in risk-taking behavior in adulthood. The LBN model of ELA may drive a more complex constellation of effects on maternal behavior driving a pattern of increased dam-pup interactions and increased abuse-like kicking behavior, with unique consequences for pup outcomes.
TL;DR: The data suggest that maternal prenatal distress leads to sexually dimorphic structural changes in the offspring’s limbic system and that these changes are also linked to behavioral difficulties, providing further support for the notion that prenatal stress impacts child development.
Abstract: Prenatal stress is associated with child behavioral outcomes increasing susceptibility for psychiatric disorders in later life. Altered fetal brain development might partly mediate this association, as some studies suggest. With this study, we investigated the relation between prenatal stress, child’s brain structure and behavioral problems. The association between self-reported maternal pregnancy-related anxiety (PRAQ-R2 questionnaire, second and third trimester) and brain gray matter volume was probed in 27 four-year-old children (13 female). Voxel based morphometry was applied with an age-matched template in SPM for the whole-brain analyses, and amygdala volume was assessed with manual segmentation. Possible pre- and postnatal confounders, such as maternal depression and anxiety among others, were controlled for. Child behavioral problems were assessed with the Strength and Difficulties Questionnaire by maternal report. We found a significant interaction effect of pregnancy-related anxiety and child’s sex on child’s amygdala volume, i.e., higher pregnancy-related anxiety in the second trimester was related to significantly greater left relative amygdala volume in girls compared to boys. Further exploratory analyses yielded that both maternal pregnancy-related anxiety and child’s amygdala volume are related to child emotional and behavioral difficulties: While higher pregnancy-related anxiety was associated with more emotional symptoms, peer relationship problems and overall child difficulties, greater left amygdala volume was related to less of these child difficulties and might partly mediate sex-specific associations between pregnancy-related anxiety and child behavioral difficulties. Our data suggest that maternal prenatal distress leads to sexually dimorphic structural changes in the offspring’s limbic system and that these changes are also linked to behavioral difficulties. Our results provide further support for the notion that prenatal stress impacts child development.
TL;DR: Results support the use of predator-threat stress exposure in combination with stress-susceptibility phenotype classification as a model for examining the unique drug response profiles and altered neuronal function that emerge as a consequence of the heterogeneity of psychophysiological response to stress.
Abstract: Post-traumatic stress disorder (PTSD) currently has no FDA-approved treatments that reduce symptoms in the majority of patients. The ability to extinguish fear memory associations is impaired in PTSD individuals. As such, the development of extinction-enhancing pharmacological agents to be used in combination with exposure therapies may benefit the treatment of PTSD. Both mGlu5 and CB1 receptors have been implicated in contextual fear extinction. Thus, here we tested the ability of the mGlu5 positive allosteric modulator 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) and cannabidiol (CBD) to reduce both conditioned and unconditioned fear. We used a predator-threat animal model of PTSD which we and others have previously shown to capture the heterogeneity of anxiety responses observed in humans exposed to trauma. Here, 1 week following a 10-min exposure to predator scent stress, rats were classified into stress-Susceptible and stress-Resilient phenotypes using behavioral criteria for elevated plus maze and acoustic startle response performance. Two weeks after classification, rats underwent 3 days of contextual fear extinction and were treated with vehicle, CDPPB or CBD prior to each session. Finally, the light-dark box test was employed to assess phenotypic differences and the effects of CDPPB and CBD on unconditioned anxiety. CDPBB but not CBD, reduced freezing in Susceptible rats relative to vehicle. In the light-dark box test for unconditioned anxiety, CBD, but not CDPPB, reduced anxiety in Susceptible rats. Resilient rats displayed reduced anxiety in the light-dark box relative to Susceptible rats. Taken together, the present data indicate that enhancement of mGlu5 receptor signaling in populations vulnerable to stress may serve to offset a resistance to fear memory extinction without producing anxiogenic effects. Furthermore, in a susceptible population, CBD attenuates unconditioned but not conditioned fear. Taken together, these findings support the use of predator-threat stress exposure in combination with stress-susceptibility phenotype classification as a model for examining the unique drug response profiles and altered neuronal function that emerge as a consequence of the heterogeneity of psychophysiological response to stress.
TL;DR: Data suggest that preferences for familiar peers in prairie voles are maintained in part by aggression toward unfamiliar individuals, as in mate partnerships, and social tolerance is an important feature of meadow vole peer affiliation, demonstrated by low aggression toward familiar conspecifics, and consistent with field data on winter tolerance.
Abstract: Relationships between adult peers are central to the structure of social groups. In some species, selective preferences for specific peers provide a foundation for consistent group composition. These preferences may be shaped by affiliation toward familiar individuals, and/or by aversion to unfamiliar individuals. We compared peer interactions in two vole species that form selective preferences for familiar same-sex individuals but differ in mating system. Prairie voles (Microtus ochrogaster) form pair bonds with mates and may reside in family groups. Meadow voles (Microtus pennsylvanicus) are promiscuous breeders that form communal winter groups in the wild, and exhibit greater social behavior in short day (SD) lengths in the laboratory. We characterized affiliative, anxiety-like, and aggressive interactions with familiar and novel same-sex conspecifics in meadow and prairie voles housed in summer- or winter-like photoperiods. Species differences in affective behaviors were pronounced, with prairie voles exhibiting more aggressive behavior and less anxiety-like behavior relative to meadow voles. Meadow voles housed in short (vs. long) day lengths were more affiliative and more interactive with strangers; prosocial behavior was also facilitated by a history of social housing. Prairie voles exhibited partner preferences regardless of sex or day length, indicating that selective peer preferences are the norm in prairie voles. Prairie vole females formed preferences for new same-sex social partners following re-pairing; males were often aggressive upon re-pairing. These data suggest that preferences for familiar peers in prairie voles are maintained in part by aggression toward unfamiliar individuals, as in mate partnerships. In contrast, social tolerance is an important feature of meadow vole peer affiliation, demonstrated by low aggression toward unfamiliar conspecifics, and consistent with field data on winter tolerance.
TL;DR: Potentials for assessing novel biomarkers to predict, diagnose, and treat PTSD more efficiently are discussed in view of developing a precision medicine for improved PTSD pharmacological treatments.
Abstract: Post-traumatic stress disorder (PTSD) is a debilitating undertreated condition that affects 8%-13% of the general population and 20%-30% of military personnel. Currently, there are no specific medications that reduce PTSD symptoms or biomarkers that facilitate diagnosis, inform treatment selection or allow monitoring drug efficacy. PTSD animal models rely on stress-induced behavioral deficits that only partially reproduce PTSD neurobiology. PTSD heterogeneity, including comorbidity and symptoms overlap with other mental disorders, makes this attempt even more complicated. Allopregnanolone, a neurosteroid that positively, potently and allosterically modulates GABAA receptors and, by this mechanism, regulates emotional behaviors, is mainly synthesized in brain corticolimbic glutamatergic neurons. In PTSD patients, allopregnanolone down-regulation correlates with increased PTSD re-experiencing and comorbid depressive symptoms, CAPS-IV scores and Simms dysphoria cluster scores. In PTSD rodent models, including the socially isolated mouse, decrease in corticolimbic allopregnanolone biosynthesis is associated with enhanced contextual fear memory and impaired fear extinction. Allopregnanolone, its analogs or agents that stimulate its synthesis offer treatment approaches for facilitating fear extinction and, in general, for neuropsychopathologies characterized by a neurosteroid biosynthesis downregulation. The socially isolated mouse model reproduces several other deficits previously observed in PTSD patients, including altered GABAA receptor subunit subtypes and lack of benzodiazepines pharmacological efficacy. Transdiagnostic behavioral features, including expression of anxiety-like behavior, increased aggression, a behavioral component to reproduce behavioral traits of suicidal behavior in humans, as well as alcohol consumption are heightened in socially isolated rodents. Potentials for assessing novel biomarkers to predict, diagnose, and treat PTSD more efficiently are discussed in view of developing a precision medicine for improved PTSD pharmacological treatments.
TL;DR: It is suggested that stimulating the prefrontal cortex promotes successful self-regulation by altering the balance in activity between the cortex and subcortical regions involved in emotion and reward processing.
Abstract: Self-regulation enables individuals to guide their thoughts, feelings, and behaviors in a purposeful manner. Self-regulation is thus crucial for goal-directed behavior and contributes to many consequential outcomes in life including physical health, psychological well-being, ethical decision making, and strong interpersonal relationships. Neuroscientific research has revealed that the prefrontal cortex plays a central role in self-regulation, specifically by exerting top-down control over subcortical regions involved in reward (e.g., striatum) and emotion (e.g., amygdala). To orient readers, we first offer a methodological overview of tDCS and then review experiments using non-invasive brain stimulation techniques (especially transcranial direct current stimulation) to target prefrontal brain regions implicated in self-regulation. We focus on brain stimulation studies of self-regulatory behavior across three broad domains of response: persistence, delay behavior, and impulse control. We suggest that stimulating the prefrontal cortex promotes successful self-regulation by altering the balance in activity between the prefrontal cortex and subcortical regions involved in emotion and reward processing.