Use of assistance and therapy dogs for children with autism spectrum disorders: a critical review of the current evidence.

BACKGROUND: Autism spectrum disorders (ASD) are characterized by deficits in social reciprocity and communication, and by unusually restricted, repetitive behaviors. Intervention strategies based on the exploitation of the emotional aspects of human-dog relationships hold the potential to overcome the difficulty of subjects with ASD to relate and interact effectively with others, targeting core symptoms of this disorder. METHODS: This review summarizes the results of six published studies on the effects of brief interactions with dogs and the effects of introducing dogs in families with a child diagnosed with ASD, with an emphasis on social behaviors and language use. Furthermore, the possible mechanisms responsible for the beneficial effects observed are discussed. CONCLUSIONS: Although the studies described here are encouraging, further research with better designs and using larger samples is needed to strengthen translation of such interventions to the clinic. In addition, potential applications of analyzing child-dog interactions are highlighted to screen for early signs of the disorder.

Evaluation of gene, protein and neurotrophin expression in the brain of mice exposed to space environment for 91 days.

Effects of 3-month exposure to microgravity environment on the expression of genes and proteins in mouse brain were studied. Moreover, responses of neurobiological parameters, nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF), were also evaluated in the cerebellum, hippocampus, cortex, and adrenal glands. Spaceflight-related changes in gene and protein expression were observed. Biological processes of the up-regulated genes were related to the immune response, metabolic process, and/or inflammatory response. Changes of cellular components involving in microsome and vesicular fraction were also noted. Molecular function categories were related to various enzyme activities. The biological processes in the down-regulated genes were related to various metabolic and catabolic processes. Cellular components were related to cytoplasm and mitochondrion. The down-regulated molecular functions were related to catalytic and oxidoreductase activities. Up-regulation of 28 proteins was seen following spaceflight vs. those in ground control. These proteins were related to mitochondrial metabolism, synthesis and hydrolysis of ATP, calcium/calmodulin metabolism, nervous system, and transport of proteins and/or amino acids. Down-regulated proteins were related to mitochondrial metabolism. Expression of NGF in hippocampus, cortex, and adrenal gland of wild type animal tended to decrease following spaceflight. As for pleiotrophin transgenic mice, spaceflight-related reduction of NGF occurred only in adrenal gland. Consistent trends between various portions of brain and adrenal gland were not observed in the responses of BDNF to spaceflight. Although exposure to real microgravity influenced the expression of a number of genes and proteins in the brain that have been shown to be involved in a wide spectrum of biological function, it is still unclear how the functional properties of brain were influenced by 3-month exposure to microgravity.

Animal-assisted interventions as innovative tools for mental health.

There is a growing interest for the potential health benefits of human-animal interactions. Although scientific evidence on the effects is far from being consistent, companion animals are used with a large number of human subjects, ranging from children to elderly people, who benefit most from emotional support. Based on a comprehensive review of the literature, this paper examines the potential for domesticated animals, such as dogs, for providing emotional and physical opportunities to enrich the lives of many frail subjects. In particular, we focus on innovative interventions, including the potential use of dogs to improve the life of emotionally-impaired children, such as those affected by autism spectrum disorders. Overall an ever increasing research effort is needed to search for the mechanism that lie behind the human-animal bond as well as to provide standardized methodologies for a cautious and effective use of animal-assisted interventions.

A novel BDNF polymorphism affects plasma protein levels in interaction with early adversity in rhesus macaques.

Early stressful events can increase vulnerability for psychopathology, although knowledge on the effectors is still limited. In this report we describe the characterization of a single nucleotide polymorphism (SNP) in rhesus macaques, which results in a Val to Met transition in the pro-BDNF domain, similar to a well described variant in the human gene. Further, we tested the hypothesis that peripheral levels of BDNF, which is involved in the response to stress and in the pathophysiology of anxiety and depression, might be differentially affected in a non-human primate model of early adverse rearing in a genotype-dependent manner. Males and females rhesus macaques reared either with their mothers (MR), in peer-only groups (PR), or in a "surrogate/peer-reared" (SPR) condition with limited peer interactions, were used as experimental subjects. BDNF levels were determined at baseline on postnatal days (PND) 14, 30 and 60 by means of specific ELISA procedure. Data indicate that BDNF levels were increased as a result of peer-rearing and that this increase was moderated by the presence of the SNP. Overall these data indicate that a SNP, which results in a Val to Met transition in the pro-BDNF domain, is present in rhesus macaques and is able to affect BDNF peripheral levels, thus making this primate model a fundamental tool to study gene by environment interactions involving the BDNF gene.

Psychiatric vulnerability: suggestions from animal models and role of neurotrophins.

Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are well-studied neurotrophins involved in the neurogenesis, differentiation, growth and maintenance of selected peripheral and central populations of neuronal cells during development and at adulthood. Neurotrophins, in concert to hypothalamic-pituitary-adrenal (HPA) axis, play a key role in modulating brain plasticity and behavioral coping, especially during ontogenetic critical periods, when developing brain is particularly sensitive to external stimulations. Indeed, early life events, such psychophysical stress, affect NGF and BDNF levels, and induce dysregulation of the HPA axis. Thus, early life experiences can affect brain development, contributing to shape interindividual differences in vulnerability to stress or psychiatric disorders. At adulthood, intermale aggressive interactions in mice, representing a psychosocial stressful condition, has been shown to markedly alter NGF and BDNF levels both in plasma as well as in selected brain areas, including the hypothalamus and hippocampus. These results have been extended to humans, showing that blood NGF levels are enhanced in psychological contexts mainly associated to anxiety and fear, such as first skydiving experience. Recent studies indicate a role for neurotrophins also in vulnerability and resilience to stress-related neuropsychiatric disorders. Overall, these findings suggest a role of neurotrophins as factors mediating both short- and long-term experience effects on brain structure and function.

Early life stress as a risk factor for mental health: role of neurotrophins from rodents to non-human primates.

Early adverse events can enhance stress responsiveness and lead to greater susceptibility for psychopathology at adulthood. The epigenetic factors involved in transducing specific features of the rearing environment into stable changes in brain and behavioural plasticity have only begun to be elucidated. Neurotrophic factors, such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), are affected by stress and play a major role in brain development and in the trophism of specific neuronal networks involved in cognitive function and in mood disorders. In addition to the central nervous system, these effectors are produced by peripheral tissues, thus being in a position to integrate the response to external challenges. In this paper we will review data, obtained from animal models, indicating that early maternal deprivation stress can affect neurotrophin levels. Maladaptive or repeated activation of NGF and BDNF, early during postnatal life, may influence stress sensitivity at adulthood and increase vulnerability for stress-related psychopathology.

Changes in plasma levels of BDNF and NGF reveal a gender-selective vulnerability to early adversity in rhesus macaques.

Early stressful events can increase vulnerability for psychopathology, although knowledge on the effectors is still limited. Here we tested the hypothesis that peripheral levels of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), which are involved in the response to stress and in the pathophysiology of anxiety and depression, might be affected in a non-human primate model of adverse rearing. Males and females rhesus macaques reared with their mothers (MR) or in peer-only groups (PR) were used as experimental subjects. BDNF, NGF, adrenocorticotropic hormone (ACTH), cortisol and growth hormone (GH) were determined at baseline on postnatal days (PND) 14, 30 and 60 by means of specific ELISA and RIA procedures. In addition, behavior was assessed on PND 7, 14, 21, 30 (Brazelton test) and 60 (home cage observation). Data indicate gender differences in basal levels of BDNF throughout development. Peer-rearing increased significantly BDNF levels only in females. In addition, while all peer-reared subjects showed high levels of stereotypies and self-directed behaviors, behavioral passivity was selectively increased in females. By contrast, NGF levels were increased in response to peer-rearing only in males, and correlated positively with other "classic" endocrine responses to stress, such as cortisol and GH. Our data identify BDNF and NGF as neuroendocrine markers underlying differential responses to maternal deprivation in males and females rhesus macaques. The selective changes in BDNF levels in females could help explain the greater vulnerability to mood disorders of this gender reported in humans.

A mouse model of neurobehavioural response to altered gravity conditions: an ontogenetical study.

To determine the influence of gravity during critical periods of development is important in the perspective of long-term spaceflight and exploration, data coming from this kind of studies providing insight into basical biological phenomena underlying the development of the nervous system and its plasticity. Aim of the present study was to evaluate neurobehavioural responses to hypergravity exposure in CD-1 mice at different stage of development. Early adolescent (postnatal day 28, PND 28), adolescent (PND 42) and young-adult (PND 60) male and female mice were exposed to acute 2g rotational-generated hypergravity. Motion sickness index and behavioural performances pre, during and after rotation were recorded, and long-lasting effects on exploratory behaviour (hole-board test) and emotional/anxiety-like responses (plus-maze test) were investigated. Furthermore, in order to correlate behavioural changes with alterations in central levels of neurotrophins, brain amounts of Nerve Growth Factor (NGF) and Brain Derived Neurotrophic Factor (BDNF) were also assessed on PND 90, following a re-exposure to hypergravity. Age and sex differences were observed, females being more vulnerable than males to motion sickness, and susceptibility to hypergravity increasing with age of exposure. Moreover, mice showed a general reduction in spontaneous activity during the rotation, while recovery time after rotation became progressively longer with increasing age of the experimental subjects. Long-term effects on exploratory behaviour and emotional/anxiety-like response were also observed, behavioural profiles mainly changing in those animals experiencing hypergravity as young-adults. Finally, major changes in brain levels of NGF and BDNF were detected in mice firstly exposed as young-adults.

Repeated acute exposures to hypergravity during early development subtly affect CD-1 mouse neurobehavioural profile.

Exposure to altered gravitational environment, especially during critical ontogenetic phases, may induce persistent nervous system modifications and behavioural anomalies. This study evaluated the effects of hypergravity exposure on the development of the nervous system and assessed the relevance of parity in the mother's responses to altered gravitational stimuli. CD-1 mouse pups of both sexes delivered by primiparous and biparous dams were exposed to 1h of 2 G rotationally induced hypergravity from PND2 to PND9. Sensorimotor responses and somatic growth were daily measured (PND2-PND15), ultrasonic vocalisations recorded on PNDs 2, 5 and 9, and homing behaviour evaluated on PND12. In addition, spatial orientation ability was assessed in a T-maze on PND18, while mice exploratory behaviour and locomotor activity were evaluated in an open-field test (PND21). Long-term effects of hypergravity exposure on both spatial learning (Morris water-maze test) and brain levels of NGF and BDNF were also investigated at adulthood. Rotation per se induced a delay in somatic growth, sensorimotor responses and ultrasonic vocalisation profile, while hypergravity highlighted sex differences in open-field behaviour. Strategies to solve a spatial learning task, rather than learning per se, were affected by early exposure to rotation, while hypergravity selectively altered behavioural profile in the reversal phase of the test. Early exposure to rotation per se also decreased hypothalamic BDNF levels, while hypergravity reduced NGF levels in the frontal cortex. Previous maternal experience did not interact with hypergravity exposure, while differences between offspring of primiparous and biparous dams were observed in sensorimotor development and exploratory behaviour.

Prolonged prenatal exposure to low-level ozone affects aggressive behaviour as well as NGF and BDNF levels in the central nervous system of CD-1 mice.

The long-term effects on isolation-induced aggressive behaviour and central NGF and BDNF levels of gestational exposures to ozone (O(3)) were evaluated in adult CD-1 mice. Females were exposed to O(3), at the dose of 0.0, 0.3 or 0.6 ppm from 30 days prior the formation of breeding pairs until gestational day 17. Litters were fostered at birth to untreated dams and, at adulthood, male offspring underwent five successive daily encounters (15 min each) with a standard opponent of the same strain, sex, weight and age. The encounters on day 1, 3 and 5 were videotaped and agonistic and non-agonistic behavioural items finely scored. O(3)-exposed mice showed a significant increase in freezing and defensive postures, a decrease in nose-sniffing behaviour and reduced progressively the aggressive behavioural profile displayed on day 1. Reduced NGF levels in the hippocampus and increased BDNF in the striatum were also found upon O(3) exposure.

Effects of acute hypergravity exposure and parity on maternal behavior in CD-1 mice.

We assessed the behavioral response to acute hypergravity exposure in lactating mother mice, Mus musculus of the outbred CD-1 strain. Primiparous or terziparous dams were exposed with their litters to a centrifugal force equivalent to 2G hypergravity for 1 h daily from postnatal day 2 (P2) to P9. We made detailed behavioral observations before, during and after the rotation on selected days to identify elements of the maternal behavioral repertoire vulnerable to 2G challenge. Licking and nest building were reduced during rotation while mothers sniffed and snouted their pups more. Nursing and total time in physical contact with pups were relatively stable. The effects of rotation were most pronounced on P2, dams appearing to habituate to the treatment with repeated exposure. Dam parity had a limited effect on the behavioral response to rotation, primiparous mothers tending to spend longer nursing their pups during the rotation and showing a greater tendency to lick and nest-build in post-rotation. Differences between parity groups diminished over days. Body weight was decreased in rotated primiparous dams and their pups gained less weight than stationary controls. Ultrasonic vocalization (USV) rates recorded on P2, P5 and P9 seemed to indicate delayed behavioral development in rotated pups.

Cognitive and emotional alterations in periadolescent mice exposed to 2 g hypergravity field.

The development of the nervous system is a dynamic process where epigenetic factors play a fundamental role. Both ground-based and space research indicate that exposure to an altered gravitational environment affects rodent neurobehavioral profile and stage of development as well as duration of exposure appear to be critical for the observed effects. The behavioral profile of adolescent (28-day-old) male and female CD-1 mice upon acute 2 g exposure was characterized and emotional/anxiety responses (plus-maze), as well as spatial learning performance (Morris water-maze), were assessed respectively 24 and 48 h after hypergravity exposure. Behavioral observation indicated a transient mild sickness associated with hypergravity, with a decrease in spontaneous activity. Rotation per se induced an increase in emotional/anxious responses and a deterioration of spatial learning acquisition, while hypergravity specifically improved flexibility of spatial orientation.

Neurobehavioral coping to altered gravity: endogenous responses of neurotrophins.

An altered gravitational environment represents a unique challenge for biological systems that have evolved against gravitational background. Ground-based and space research indicates that the developing nervous system is potentially affected by exposure to hyper/microgravity. With the construction of the orbiting International Space Station long-term research on the nervous system will be possible. With this perspective, we started ground-based studies to characterize mouse behavioral responses to rotation-induced 2 g hypergravity, using a custom-made centrifuge device. Brain levels of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) as well as NGF and BDNF expression and mast cell distribution in heart and lung, were evaluated and correlated with the changes in mouse behavior upon hypergravity exposure. Hypergravity strongly affected the spontaneous activity of the animals, selectively modifying mouse behavioral repertoire. Such changes were mainly related to variations in brain levels of NGF, while BDNF was slightly affected, thus confirming a role for these neurotrophins in neuronal plasticity underlying experience-induced neurobehavioral changes. Moreover, gender differences were observed in both behavioral and neurobiological responses to hypergravity. These results indicate that changes in the gravitational environment might represent a useful tool to investigate the neurobiological and behavioral responses to stressors and may provide insights into the mechanisms underlying development and plasticity of nervous system in brain, heart, and lung.

Effects of acute and repeated daily exposure to hypergravity on spatial learning in mice.

Studies in humans have revealed that exposure to altered gravity may lead to impairments in cognitive functions. The objective of this study was to test whether mice exposed to hypergravity using a centrifuge apparatus showed learning impairments in a spatial learning task. Mice rotating at 1G or at 2G acceleration gravity and non-rotating controls were tested for reactivity to a spatial change after either a single 1 h or five repeated 1 h daily rotations in the centrifuge. While no differences among groups were found in the performance after single exposure to altered gravity, 5 days of repeated exposures to 1G or 2G gravity conditions significantly affected mouse ability to discriminate a new spatial arrangement. Additionally, this effect was stronger in the animals repeatedly exposed to 2G rather than to 1G conditions.

Short-term hypergravity influences NGF and BDNF expression, and mast cell distribution in the lungs and heart of adult male mice.

In this study we investigate the effects of short-term hypergravity on lung and heart neurotrophins and mast cell distribution. Our results showed that brain derived-neurotrophic factor (BDNF) protein and mRNA expression are increased in the lungs of mice exposed to hypergravity while in the heart hypergravity causes a marked reduction in BDNF mRNA expression, and a decrease in BDNF protein. Compared to controls, nerve growth factor (NGF) protein was expressed more in the heart of rotated mice. These observations demonstrate that altered hypergravity can affect, though differentially, the local expression of NGF and BDNF proteins and their mRNAs in the lung and heart and indicates that short-term exposure to hypergravity causes a marked increase in BDNF, but not in NGF in the lungs of adult mice. Moreover, mast cells, which are NGF-producing cells and implicated in cardiac and respiratory activity, increased in number in proximity to blood vessels in the heart and in lung airway epithelium of rotated mice. This study indicates that hypergravity influences cardiovascular and respiratory tissue and suggests a neurotrophin involvement in the reaction to this environmental exposure.

Neurobehavioural responses to hypergravity environment in the CD-1 mouse.

Behavioural responses of CD-1 mice exposed to 2 g hypergravity (HG; 60 or 120 min) were investigated during adolescence and at adulthood. To characterise motion sickness (MS), pica behaviour, a reliable MS index measured through kaolin consumption, and spontaneous activity were evaluated before, during and after HG exposure. Short- and/or long-lasting effects on emotional responses, exploratory behaviour and spatial learning performances were also investigated and brain levels of nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) assessed. An increased pica behaviour during post rotational days and a reduction in spontaneous activity during rotation indicated a mild sickness associated with HG, and susceptibility to MS was sex and age related. Short- and long-lasting effects of exposure were also observed, rotated mice showing altered emotional/anxiety behavioural profiles and impaired spatial learning performances. Moreover, central NGF levels were markedly increased after rotation, while minor changes were observed in BDNF levels.