Valproic acid exposure affects social visual lateralization and asymmetric gene expression in zebrafish larvae.

Cerebral asymmetry is critical for typical brain function and development; at the same time, altered brain lateralization seems to be associated with neuropsychiatric disorders. Zebrafish are increasingly emerging as model species to study brain lateralization, using asymmetric development of the habenula, a phylogenetically old brain structure associated with social and emotional processing, to investigate the relationship between brain asymmetry and social behavior. We exposed 5-h post-fertilization zebrafish embryos to valproic acid (VPA), a compound used to model the core signs of ASD in many vertebrate species, and assessed social interaction, visual lateralization and gene expression in the thalamus and the telencephalon. VPA-exposed zebrafish exhibit social deficits and a deconstruction of social visual laterality to the mirror. We also observe changes in the asymmetric expression of the epithalamic marker leftover and in the size of the dorsolateral part of the habenula in adult zebrafish. Our data indicate that VPA exposure neutralizes the animals' visual field bias, with a complete loss of the left-eye use bias in front of their own mirror image, and alters brain asymmetric gene expression and morphology, opening new perspectives to investigate brain lateralization and its link to atypical social cognitive development.

Embryonic Valproate Exposure Alters Mesencephalic Dopaminergic Neurons Distribution and Septal Dopaminergic Gene Expression in Domestic Chicks.

In recent years, the role of the dopaminergic system in the regulation of social behavior is being progressively outlined, and dysfunctions of the dopaminergic system are increasingly associated with neurodevelopmental disorders, including autism spectrum disorder (ASD). To study the role of the dopaminergic (DA) system in an animal model of ASD, we investigated the effects of embryonic exposure to valproic acid (VPA) on the postnatal development of the mesencephalic DA system in the domestic chick. We found that VPA affected the rostro-caudal distribution of DA neurons, without changing the expression levels of several dopaminergic markers in the mesencephalon. We also investigated a potential consequence of this altered DA neuronal distribution in the septum, a social brain area previously associated to social behavior in several vertebrate species, describing alterations in the expression of genes linked to DA neurotransmission. These findings support the emerging hypothesis of a role of DA dysfunction in ASD pathogenesis. Together with previous studies showing impairments of early social orienting behavior, these data also support the use of the domestic chick model to investigate the neurobiological mechanisms potentially involved in early ASD symptoms.

Spontaneous Visual Preference for Face-Like Stimuli Is Impaired in Newly-Hatched Domestic Chicks Exposed to Valproic Acid During Embryogenesis.

Faces convey a great amount of socially relevant information related to emotional and mental states, identity and intention. Processing of face information is a key mechanism for social and cognitive development, such that newborn babies are already tuned to recognize and orient to faces and simple schematic face-like patterns since the first hours of life. Similar to neonates, also non-human primates and domestic chicks have been shown to express orienting responses to faces and schematic face-like patterns. More importantly, existing studies have hypothesized that early disturbances of these mechanisms represent one of the earliest biomarker of social deficits in autism spectrum disorders (ASD). We used VPA exposure to induce neurodevelopmental changes associated with ASD in domestic chicks and tested whether VPA could impact the expression of the animals' approach responses to schematic face-like stimuli. We found that VPA impairs the chicks' preference responses to these social stimuli. Based on the results shown here and on previous studies, we propose the domestic chick as animal model to investigate the biological mechanisms underlying face processing deficits in ASD.

A novel integrated approach to estimate the mitochondrial content of neuronal cells and brain tissues.

BACKGROUND: Mitochondria and their dynamics fuel most cellular processes both in physiological and pathological conditions. In the central nervous system, mitochondria sustain synaptic transmission and plasticity via multiple mechanisms which include their redistribution and/or expansion to higher energy demanding sites, sustaining activity changes and promoting morphological circuit adaptations. NEW METHOD: To be able to evaluate changes in mitochondrial number and protein phenotype, we propose a novel methodological approach where the simultaneous analysis of both mitochondrial DNA and protein content is performed on each individual microsample, avoiding non-homogeneous loss of material. RESULTS: We validated this method on neuronal-like cells and tissue samples and obtained estimates for the mitochondrial/genomic DNA ratio as well as for the abundance of protein counterparts. When the mitochondrial content per cell was evaluated in different brain areas, our results matched the known regional variation in aerobic-anaerobic metabolism. When long-term potentiation (LTP) was induced on hippocampal neurons, we detected increases in the abundance of mitochondria that correlated with the degree of synaptic enhancement. CONCLUSIONS: Our approach can be effectively used to study the mitochondrial content andits changes in different brain cells and tissues.