Nadia Francia

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.

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.

Spatial memory deficits in middle-aged mice correlate with lower exploratory activity and a subordinate status : role of hippocampal neurotrophins

The aim of the present work was to relate age‐related individual differences in cognitive function with behavioural strategies employed in social and non‐social challenges. To this purpose, the behaviour of adult (5‐month‐old) and middle‐aged (13‐month‐old) CD‐1 mice was scored in the social interaction, plus‐maze, Morris water maze (MWM) and open‐field tests. In addition, brain levels of nerve growth factor and brain‐derived neurotrophic factor (BDNF) were analysed and correlated with the behaviours scored. Compared to adults, middle‐aged mice showed greater anxiety in both non‐social and social situations, spending less time in the open arms of the plus‐maze and performing more freezing behaviour in response to aggression. Based upon their behaviour in the social interaction test, adult and middle‐aged subjects were classified as dominant or subordinate and their behaviour in the open field, plus‐maze and MWM tests subjected to factor analysis, taking into account age and social status. Results highlighted meaningful differences in exploratory strategies as a function of social status only in middle‐aged subjects. In particular, middle‐aged dominants were, overall, more explorative than same‐aged subordinates, spending less time in peripheral areas and approaching more readily a novel object. Interestingly, in middle‐aged mice, superior performance in the MWM task was associated with exploratory strategies exploited by dominants. At adulthood, BDNF hippocampal levels, but not specific behaviours, were positively correlated with the ability to learn a spatial task. Overall, data indicate that, in middle‐aged subjects individual differences in exploratory strategies, rather than neurotrophin levels, are able to predict the degree of impairment in a spatial learning task.

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.

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.

Neurobehavioural effects of hypergravity conditions in the adult mouse.

To evaluate the behavioural response to a hypergravity condition in CD-1 mice, young adult subjects of both sexes were exposed to 2 g for a single 60 min rotational session. Motion sickness (MS) and ethological-type scoring of different activities were used to evaluate the behavioural response. Nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) levels were also assessed. Behavioural scores indicated a transient mild sickness associated with hypergravity, with reduction in spontaneous activity. In males kaolin consumption (a MS index) increased following rotation while females consumed more kaolin irrespective of whether they have been rotated or simply exposed to the noise and vibration of the rotational apparatus. In males, hypothalamic NGF levels were markedly increased after rotation while no major changes were observed in central BDNF expression. These results indicate mice may represent a suitable MS model.

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 occured 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.

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.

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.

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.