Alessandra Berry

Early disruption of the mother -infant relationship: effects on brain plasticity and implications for psychopathology

Early environmental manipulations can impact on the developing nervous system, contributing to shape individual differences in physiological and behavioral responses to environmental challenges. In particular, it has been shown that disruptions in the mother-infant relationship result in neuroendocrine, neurochemical and behavioural changes in the adult organism, although the basic mechanisms underlying such changes have not been completely elucidated. Recent data suggest that neurotrophins might be among the mediators capable of transducing the effects of external manipulations on brain development. Nerve growth factor and brain-derived neurotrophic factor are known to play a major role during brain development, while in the adult animal they are mainly responsible for the maintenance of neuronal function and structural integrity. Changes in the levels of neurotrophic factors during critical developmental stages might result in long-term changes in neuronal plasticity and lead to increased vulnerability to aging and to psychopathology.

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.

Glucocorticoid-Related Molecular Signaling Pathways Regulating Hippocampal Neurogenesis

Stress and glucocorticoid hormones regulate hippocampal neurogenesis, but the molecular mechanisms underlying their effects are unknown. We, therefore, investigated the molecular signaling pathways mediating the effects of cortisol on proliferation, neuronal differentiation, and astrogliogenesis, in an immortalized human hippocampal progenitor cell line. In addition, we examined the molecular signaling pathways activated in the hippocampus of prenatally stressed rats, characterized by persistently elevated glucocorticoid levels in adulthood. In human hippocampal progenitor cells, we found that low concentrations of cortisol (100 nM) increased proliferation (+16%), decreased neurogenesis into microtubule-associated protein 2 (MAP2)-positive neurons (−24%) and doublecortin (Dcx)-positive neuroblasts (−21%), and increased differentiation into S100β-positive astrocytes (+23%). These effects were dependent on the mineralocorticoid receptor (MR) as they were abolished by the MR antagonist, spironolactone, and mimicked by the MR-agonist, aldosterone. In contrast, high concentrations of cortisol (100 μM) decreased proliferation (−17%) and neuronal differentiation into MAP2-positive neurons (−22%) and into Dcx-positive neuroblasts (−27%), without regulating astrogliogenesis. These effects were dependent on the glucocorticoid receptor (GR), blocked by the GR antagonist RU486, and mimicked by the GR-agonist, dexamethasone. Gene expression microarray and pathway analysis showed that the low concentration of cortisol enhances Notch/Hes-signaling, the high concentration inhibits TGFβ-SMAD2/3-signaling, and both concentrations inhibit Hedgehog signaling. Mechanistically, we show that reduced Hedgehog signaling indeed critically contributes to the cortisol-induced reduction in neuronal differentiation. Accordingly, TGFβ-SMAD2/3 and Hedgehog signaling were also inhibited in the hippocampus of adult prenatally stressed rats with high glucocorticoid levels. In conclusion, our data demonstrate novel molecular signaling pathways that are regulated by glucocorticoids in vitro, in human hippocampal progenitor cells, and by stress in vivo, in the rat hippocampus.

Social deprivation stress is a triggering factor for the emergence of anxiety- and depression-like behaviours and leads to reduced brain BDNF levels in C57BL/6J mice.

Stress is a main risk factor that can trigger psychiatric disorders, including anxiety and major depression. Neurotrophins, such as Brain-Derived Neurotrophic Factor (BDNF), have been identified as neuroendocrine effectors involved in the response to stress and in the neurobehavioural changes associated with depression. Aim of this paper was to study the relationship between neuroendocrine activation (circulating corticosterone and brain BDNF levels) and a wide array of depression- and anxiety-like behaviours (anhedonia, behavioural despair, generalised and social anxiety) resulting from exposure to chronic stress. To this end, 3-month-old C57BL/6J male mice were exposed to either chronic disruption of the social structure (SS), to a stable social structure (SG) or to social deprivation (SD), a condition lacking social stimuli. Results show that, despite not developing anhedonia (decreased preference for a sucrose solution), SD mice were characterised by increased emotionality and hypothalamic-pituitary-adrenal axis reactivity in addition to reduced BDNF levels. By contrast, SG and SS mice showed increased anhedonia accompanied by no alterations in the behavioural and neuroendocrine profile. The results here reported indicate that mice exposed to different social housing conditions use different behavioural strategies to cope with external challenges. In addition they suggest that social deprivation might represent a stressful condition triggering the emergence of both anxiety- and depression-like behaviours and clearly indicate BDNF as a main neurobiological variable mediating these responses.

Early life influences on emotional reactivity: evidence that social enrichment has greater effects than handling on anxiety-like behaviors, neuroendocrine responses to stress and central BDNF levels

During the early post-natal phases the brain is experience-seeking and provided by a considerable plasticity which allows a fine tuning between the external environment and the developing organism. Since the early work of Seymour Levine, an impressive amount of research has clearly shown that stressful experiences exert powerful effects on the brain and body development. These effects can last throughout the entire life span influencing brain function and increasing the risk for depression and anxiety disorders. The mechanisms underlying the effects of early stress on the developing organism have been widely studied in rodents through experimental manipulations of the post-natal environment, such as handling, which have been shown to exert important effects on the emotional phenotype and the response to stress. In the present paper we review the relevant literature and present some original data indicating that, compared to handling, which imposes an external manipulation on the mother-infant relationship, social enrichment, in the form of communal rearing, in mice has very profound effects on animals emotionality and the response to stress. These effects are also accompanied by important changes in central levels of brain-derived neurotrophic factor. The present data indicate that communal rearing has more pervasive effects than handling, strengthening previous data suggesting that it is a good animal model of reduced susceptibility to depression-like behavior. Overall, the availability of ever more sophisticated animal models represents a fundamental tool to translate basic research data into appropriate interventions for humans raised under traumatic or impoverished situations.

Deletion of the life span determinant p66Shc prevents age-dependent increases in emotionality and pain sensitivity in mice.

Oxidative stress has been implicated in the aging process. Previous studies have determined that mice with a targeted mutation of the p66(Shc) gene show reduced oxidative stress and extended life span. This study is the first behavioral characterization of mice carrying a deletion of p66(Shc). Four-, 11- and 24-months-old homozygous knockout and wild-type mice of the 129Sv/Ev strain underwent a battery of behavioral tests. Locomotion and exploratory activity were tested in the open-field test, emotional reactivity was assessed in the elevated plus-maze, while nociception was evaluated by means of the hot-plate test (50 degrees C). In addition, social behavior was assessed in a social interaction test. Our results indicate that pain sensitivity and emotional behavior in wild-type mice increase with age. Deletion of the p66 gene results in an increase in pain threshold and reduced emotionality, differences with wild-type subjects becoming more pronounced with age. Thus reduced oxidative stress throughout the life span is able to prevent some behavioral effects of aging, particularly in response to painful or emotionally arousing stimuli. These data are discussed in relation to recent views, indicating new and complex interactions between oxidative stress and emotional stress.

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.

Intracerebroventricular administration of brain-derived neurotrophic factor in adult rats affects analgesia and spontaneous behaviour but not memory retention in a Morris Water Maze task

The present study tested the effects of in vivo administration of brain-derived neurotrophic factor (BDNF) and of its antibody (anti-BDNF) in a Morris Water Maze (MWM) task. Adult male rats were trained for three days in a MWM. At the end of the last training trial, subjects were injected intracerebroventricularly with one of the following: (i) BDNF (24 microg); (ii) anti-BDNF (25 microg); or (iii) vehicle (PBS, injection volume 10 microl). On day 5, subjects were tested for memory retention, pain sensitivity and locomotor behaviour. No differences emerged in the MWM as a function of treatment, even with a reduced number of acquisition trials. Nonetheless, BDNF affected both pain threshold in the hot-plate test, as well as exploratory behaviour in the open field test.

NGF, Brain and Behavioral Plasticity

Nerve Growth Factor (NGF) was initially studied for its role as a key player in the regulation of peripheral innervations. However, the successive finding of its release in the bloodstream of male mice following aggressive encounters and its presence in the central nervous system led to the hypothesis that variations in brain NGF levels, caused by psychosocial stressor, and the related alterations in emotionality, could be functional to the development of proper strategies to cope with the stressor itself and thus to survive. Years later this vision is still relevant, and the body of evidence on the role of NGF has been strengthened and expanded from trophic factor playing a role in brain growth and differentiation to a much more complex messenger, involved in psychoneuroendocrine plasticity.

Delayed BDNF alterations in the prefrontal cortex of rats exposed to prenatal stress: Preventive effect of lurasidone treatment during adolescence

Psychiatric diseases may often represent the consequence of exposure to adverse events early in life. Accordingly, exposure to stress during gestation in rats has a strong impact on development and can cause long-term abnormalities in adult behavior. Considering that neuronal plasticity has emerged as a major vulnerability element in psychiatric disorders, we investigated the postnatal developmental profile of Brain-Derived Neurotrophic Factor expression (BDNF), an important mediator for long-term functional deterioration associated to mental illness, in male and female rats following exposure to prenatal stress (PNS). Since we found that the majority of alterations became fully manifest at early adulthood, we tried to prevent these abnormalities with an early pharmacological intervention. To address this point, we treated rats during adolescence with the multi-receptor antipsychotic lurasidone, which was proven to be effective in animal models of schizophrenia. Interestingly, we show that lurasidone treatment was able to prevent the reduction of BDNF expression in adult rats that were exposed to PNS. Collectively, our results provide further support to the notion that exposure to early life stress has a negative impact on neuronal plasticity and that pharmacological intervention during critical time windows may prove effective in preventing neuroplastic dysfunction, leading to long-term beneficial effects on brain function.