Enhanced harm detection following maternal separation: Transgenerational transmission and reversibility by inhaled amiloride.

Early-life adversities are associated with altered defensive responses. Here, we demonstrate that the repeated cross-fostering (RCF) paradigm of early maternal separation is associated with enhancements of distinct homeostatic reactions: hyperventilation in response to hypercapnia and nociceptive sensitivity, among the first generation of RCF-exposed animals, as well as among two successive generations of their normally reared offspring, through matrilineal transmission. Parallel enhancements of acid-sensing ion channel 1 (ASIC1), ASIC2, and ASIC3 messenger RNA transcripts were detected transgenerationally in central neurons, in the medulla oblongata, and in periaqueductal gray matter of RCF-lineage animals.

Early Social Enrichment Modulates Tumor Progression and p53 Expression in Adult Mice.

Epidemiological evidence indicates that stress and aversive psychological conditions can affect cancer progression, while well-being protects against it. Although a large set of studies have addressed the impact of stress on cancer, not much is known about the mechanisms that protect from cancer in healthy psychological conditions. C57BL/6J mouse pups were exposed to an environmental enrichment condition consisting of being raised until weaning by the biological lactating mother plus a non-lactating virgin female (LnL = Lactating and non-Lactating mothers).

Animal models of developmental dyslexia: Where we are and what we are missing.

Developmental dyslexia (DD) is a complex neurodevelopmental disorder and the most common learning disability among both school-aged children and across languages. Recently, sensory and cognitive mechanisms have been reported to be potential endophenotypes (EPs) for DD, and nine DD-candidate genes have been identified. Animal models have been used to investigate the etiopathological pathways that underlie the development of complex traits, as they enable the effects of genetic and/or environmental manipulations to be evaluated.

Early life adversity affecting the attachment bond alters ventral tegmental area transcriptomic patterning and behavior almost exclusively in female mice.

Early life experiences that affect the attachment bond formation can alter developmental trajectories and result in pathological outcomes in a sex-related manner. However, the molecular basis of sex differences is quite unknown. The dopaminergic system originating from the ventral tegmental area has been proposed to be a key mediator of this process.

Mouse model of panic disorder: Vulnerability to early environmental instability is strain-dependent.

Early life experiences and genetic background shape phenotypic variation. Several mouse models based on early treatments have evaluated short- and long-term phenotypic alterations and explored their molecular mechanisms. The instability of maternal cues was used to model human separation anxiety in outbred mice, one of the etiopathogenetic factors that predict panic disorder (PD).

Resilience to anhedonia-passive coping induced by early life experience is linked to a long-lasting reduction of I current in VTA dopaminergic neurons.

Exposure to aversive events during sensitive developmental periods can affect the preferential coping strategy adopted by individuals later in life, leading to either stress-related psychiatric disorders, including depression, or to well-adaptation to future adversity and sources of stress, a behavior phenotype termed "resilience". We have previously shown that interfering with the development of mother-pups bond with the Repeated Cross Fostering (RCF) stress protocol can induce resilience to depression-like phenotype in adult C57BL/6J female mice. Here, we used patch-clamp recording in midbrain slice combined with both and pharmacology to test our hypothesis of a link between electrophysiological modifications of dopaminergic neurons in the intermediate Ventral Tegmental Area (VTA) of RCF animals and behavioral resilience.

Behavioral, neuromorphological, and neurobiochemical effects induced by omega-3 fatty acids following basal forebrain cholinergic depletion in aged mice.

Background: In recent years, mechanistic, epidemiologic, and interventional studies have indicated beneficial effects of omega-3 polyunsaturated fatty acids (n-3 PUFA) against brain aging and age-related cognitive decline, with the most consistent effects against Alzheimer's disease (AD) confined especially in the early or prodromal stages of the pathology. In the present study, we investigated the action of n-3 PUFA supplementation on behavioral performances and hippocampal neurogenesis, volume, and astrogliosis in aged mice subjected to a selective depletion of basal forebrain cholinergic neurons. Such a lesion represents a valuable model to mimic one of the most reliable hallmarks of early AD neuropathology.

Evaluation of μ-Opioid System Functionality in Mouse Pups: Ultrasonic Vocalizations as an Index of Infant Attachment.

The evaluation of ultrasonic vocalizations (USVs) during isolation in 6-8-day-old mouse pups can give an indication of the perception of pups' discomfort and need for caretaker presence to overcome the unpleasant condition. Time spent vocalizing changed according to opioid activation, stress exposure, and genetic profile of pups. Deficits in attachment suggest altered opioid functioning and predisposal for long-term defective social behaviors and reward processes.

Xlr4 as a new candidate gene underlying vulnerability to cocaine effects.

Although several studies have been performed in rodents, non-human primates and humans, the biological basis of vulnerability to develop cocaine addiction remains largely unknown. Exposure to critical early events (as Repeated Cross Fostering (RCF)) has been reported to increase sensitivity to cocaine effects in adult C57BL/6J female mice. Using a microarray approach, here we report data showing a strong engagement of X-linked lymphocyte-regulated 4a and 4b (Xlr4) genes in cocaine effects.

Sex-dependent effects of early unstable post-natal environment on response to positive and negative stimuli in adult mice.

Alterations in early environmental conditions that interfere with the creation of a stable mother-pup bond have been suggested to be a risk factor for the development of stress-related psychopathologies later in life. The long-lasting effects of early experiences are mediated by changes in various cerebral circuits, such as the corticolimbic system, which processes aversive and rewarding stimuli. However, it is evident that the early environment is not sufficient per se to induce psychiatric disorders; interindividual (eg, sex-based) differences in the response to environmental challenges exist.

Amiloride modulation of carbon dioxide hypersensitivity and thermal nociceptive hypersensitivity induced by interference with early maternal environment.

Background: Early life adversities are risk factors for anxiety disorders and for pain syndromes, which are, in turn, highly comorbid with anxiety disorders. Repeated cross-fostering mouse pups to adoptive lactating females induces epigenetic modification and heightened mRNA-expression of the acid-sensing-ion-channel-1 gene, altered nociception, and hypersensitivity to 6% carbon dioxide air mixtures, a trait marker of specific human anxiety disorders such as, most clearly and prominently, panic disorder.

Aims: We hypothesized that the acid-sensing ion channel inhibitor amiloride can modulate repeated cross-fostering animals' exaggerated responses to carbon dioxide and nociceptive thermal stimulation.

Conserved DNA Methylation Signatures in Early Maternal Separation and in Twins Discordant for CO Sensitivity.

Respiratory and emotional responses to blood-acidifying inhalation of CO are markers of some human anxiety disorders, and can be enhanced by repeatedly cross-fostering (RCF) mouse pups from their biological mother to unrelated lactating females. Yet, these dynamics remain poorly understood. We show RCF-associated intergenerational transmission of CO sensitivity in normally-reared mice descending from RCF-exposed females, and describe the accompanying alterations in brain DNA methylation patterns.

Early-onset behavioral and neurochemical deficits in the genetic mouse model of phenylketonuria.

Phenylketonuria (PKU) is one of the most common human inborn errors of metabolism, caused by phenylalanine hydroxylase deficiency, leading to high phenylalanine and low tyrosine levels in blood and brain causing profound cognitive disability, if untreated. Since 1960, population is screened for hyperphenylalaninemia shortly after birth and submitted to early treatment in order to prevent the major manifestations of the disease. However, the dietetic regimen (phenylalanine free diet) is difficult to maintain, and despite the recommendation to a strict and lifelong compliance, up to 60% of adolescents partially or totally abandons the treatment.

Sensitivity to cocaine in adult mice is due to interplay between genetic makeup, early environment and later experience.

Although early aversive postnatal events are known to increase the risk to develop psychiatric disorders later in life, rarely they determine alone the nature and outcome of the psychopathology, indicating that interaction with genetic factors is crucial for expression of psychopathologies in adulthood. Moreover, it has been suggested that early life experiences could have negative consequences or confer adaptive value in different individuals. Here we suggest that resilience or vulnerability to adult cocaine sensitivity depends on a "triple interaction" between genetic makeup x early environment x later experience.

Age-specific autistic-like behaviors in heterozygous Fmr1-KO female mice.

Fragile X syndrome (FXS) is a major developmental disorder and the most frequent monogenic cause of autism. Surprisingly, most existing studies on the Fmr1-KO mouse model for FXS have focused on males, although FX women, who are mostly heterozygous for the Fmr1 mutation, are known to exhibit several behavioral deficits, including autistic-like features. Furthermore, most animal research has been carried out on adults only; so that little is known about the age progression of the behavioral phenotype of Fmr1 mutants, which is a crucial issue to optimize the impact of therapeutic interventions.

Early Social Enrichment Improves Social Motivation and Skills in a Monogenic Mouse Model of Autism, the Oprm1 (-/-) Mouse.

Environmental enrichment has been proven to have positive effects on both behavioral and physiological phenotypes in rodent models of mental and neurodevelopmental disorders. In this study, we used mice lacking the µ-opioid receptor gene (Oprm1 (-/-)), which has been shown to have deficits in social competence and communication, to assess the hypothesis that early enrichment can ameliorate sociability during development and adulthood. Due to the immaturity of sensory-motor capabilities of young pups, we chose as environmental stimulation a second lactating female, who provided extra maternal care and stimulation from birth.

Histone Modifications in a Mouse Model of Early Adversities and Panic Disorder: Role for Asic1 and Neurodevelopmental Genes.

Hyperventilation following transient, CO2-induced acidosis is ubiquitous in mammals and heritable. In humans, respiratory and emotional hypersensitivity to CO2 marks separation anxiety and panic disorders, and is enhanced by early-life adversities. Mice exposed to the repeated cross-fostering paradigm (RCF) of interference with maternal environment show heightened separation anxiety and hyperventilation to 6% CO2-enriched air.

Social threat exposure in juvenile mice promotes cocaine-seeking by altering blood clotting and brain vasculature.

Childhood maltreatment is associated with increased severity of substance use disorder and frequent relapse to drug use following abstinence. However, the molecular and neurobiological substrates that are engaged during early traumatic events and mediate the greater risk of relapse are poorly understood and knowledge of risk factors is to date extremely limited. In this study, we modeled childhood maltreatment by exposing juvenile mice to a threatening social experience (social stressed, S-S).

Treatment Approaches in Rodent Models for Autism Spectrum Disorder.

Recent years have seen an impressive amount of research devoted to the developing of therapies to treat autism spectrum disorder (ASD). This work has been largely based on rodent models, employing a multitude of genetic and environmental manipulations. Unfortunately, the task of identifying suitable treatments for ASD is extremely challenging, due to a variety of problems specific to the research in this field.

Unstable Maternal Environment Affects Stress Response in Adult Mice in a Genotype-Dependent Manner.

Early postnatal events exert powerful effects on development, inducing persistent functional alterations in different brain network, such as the catecholamine prefrontal-accumbal system, and increasing the risk of developing psychiatric disorders later in life. However, a vast body of literature shows that the interaction between genetic factors and early environmental conditions is crucial for expression of psychopathologies in adulthood. We evaluated the long-lasting effects of a repeated cross-fostering (RCF) procedure in 2 inbred strains of mice (C57BL/6J, DBA/2), known to show a different susceptibility to the development and expression of stress-induced psychopathologies.

Early handling and repeated cross-fostering have opposite effect on mouse emotionality.

Early life events have a crucial role in programming the individual phenotype and exposure to traumatic experiences during infancy can increase later risk for a variety of neuropsychiatric conditions, including mood and anxiety disorders. Animal models of postnatal stress have been developed in rodents to explore molecular mechanisms responsible for the observed short and long lasting neurobiological effects of such manipulations. The main aim of this study was to compare the behavioral and hormonal phenotype of young and adult animals exposed to different postnatal treatments.

Response, use and habituation to a mouse house in C57BL/6J and BALB/c mice.

Animal welfare depends on the possibility to express species-specific behaviours and can be strongly compromised in socially and environmentally deprived conditions. Nesting materials and refuges are very important resources to express these behaviours and should be considered as housing supplementation items. We evaluated the effects of one item of housing supplementation in standard settings in laboratory mice.

Early social enrichment rescues adult behavioral and brain abnormalities in a mouse model of fragile X syndrome.

Converging lines of evidence support the use of environmental stimulation to ameliorate the symptoms of a variety of neurodevelopmental disorders. Applying these interventions at very early ages is critical to achieve a marked reduction of the pathological phenotypes. Here we evaluated the impact of early social enrichment in Fmr1-KO mice, a genetic mouse model of fragile X syndrome (FXS), a major developmental disorder and the most frequent monogenic cause of autism.

Evaluation of social and nonsocial behaviors mediated by opioids in mouse pups.

The experimental approach to carry out a behavioral study involving opioids in mouse pups needs equipments and procedures different from those used for adult animals. Pups are immature at birth and only slowly acquire all the potentialities that characterize adult con-specifics. The standard and abnormal development of behavioral systems and their neural correlates can be followed during the first postnatal weeks, using appropriate methodologies that exploit characteristic pups' capabilities.

Region specific up-regulation of oxytocin receptors in the opioid oprm1 (-/-) mouse model of autism.

Autism spectrum disorders (ASDs) are characterized by impaired communication, social impairments, and restricted and repetitive behaviors and interests. Recently, altered motivation and reward processes have been suggested to participate in the physiopathology of ASDs, and μ-opioid receptors (MORs) have been investigated in relation to social reward due to their involvement in the neural circuitry of reward. Mice lacking a functional MOR gene (Oprm1 (-/-) mice) display abnormal social behavior and major autistic-like core symptoms, making them an animal model of autism.