Autism

Autism is a debilitating, pervasive neurodevelopmental disorder of unknown etiology, characterized by a spectrum of symptoms of social deficits, inflexible behaviors, and abnormal communication, in addition to frequent reports of sensory abnormalities and anxiety. There is currently no empirically based consensus on the causes of symptoms, their remarkable heterogeneity, and no global treatment. In most current theories, neural hypo-function is proposed to prevent autistic patients from properly acquiring, processing and responding to social and emotional information. However, mainly due to methodology, empirical research results are still controversial, and deserve further investigation. Importantly, excessive neural processing has been shown to occur in the autistic brain in response to specific sensory or social stimulation, supporting the notion of neural hyper-function in autism.
In support of neural hyper-function in autism, our laboratory has demonstrated in the valproic acid (VPA) rat model of autism that the primary sensory and frontal cortices, as well the amygdala microcircuits are hyper-plastic and hyper-reactive [1,4]. In parallel, we reported excessive behavioral fear expression, over-generalization of fear responses, and resistance to fear extinction in the VPA rat compared to controls [2]. Together with the full range of autistic symptoms and neural microcircuitry abnormalities found in humans, this data inspired the hypothesis of autism as an Intense World Syndrome [3].
The experimentally based and common neuropathology proposed in the Intense World Theory is hyper-functioning of elementary brain modules, the local neural microcircuits, which are characterized by hyper-reactivity and hyper-plasticity. Such hyper-functional microcircuits are proposed to easily become autonomous, leading to runaway information processing, over-specialization in tasks and a hyper-preference syndrome. The proposed core cognitive consequences are hyper-perception, hyper-attention, hyper-memory, functions mediated by the neocortex, and hyper-emotionality, mediated by the hyper-functionality of the limbic system. These four dimensions could potentially explain the full spectrum of symptoms in autism, depending on the severity of the microcircuit pathology in different brain regions. The degree of hyper-functionality in different brain regions could vary in each child depending on genetic personality traits, on unique epigenetic events, and unique sequence of postnatal experiences.

Approach

Hyper-emotionality Project

In our current investigations we try to address if autism is characterized by disproportionately stronger emotional responses to stimulation, due to limbic hyper-functionality. This would lead to abnormally high stress or fear responses to unexpected events, as well as to otherwise neutral or pleasant stimulation. Using the VPA rat model of autism, we are currently investigating if hyper-reactivity in the amygdala and related output systems occurs during social experiences. This for instance, is characterized by exaggerated neural responses and deregulated hypothalamic-pituitary axis (HPA) neuroendrocrine function. In turn, rearing animals in an environment with more predictable events should ameliorate behavioral and physiological markers of hyper-emotionality in adulthood, while sporadic over-stimulation should exacerbate autistic symptoms.

Contact

monica.favre@epfl.ch

References

M. R. Favre; D. La Mendola; J. Meystre; D. Christodoulou; M. Cochrane et al. : Predictable enriched environment prevents development of hyper-emotionality in the VPA rat model of autism; Frontiers in Neuroscience. 2015. DOI : 10.3389/fnins.2015.00127.
M. R. Favre; T. R. Barkat; D. Lamendola; G. Khazen; H. Markram et al. : General developmental health in the VPA-rat model of autism; Frontiers In Behavioral Neuroscience. 2013. DOI : 10.3389/fnbeh.2013.00088.
G. T. Silva; J.-V. Le Bé; I. Riachi; T. Rinaldi; K. Markram et al. : Enhanced long-term microcircuit plasticity in the valproic Acid animal model of autism; Frontiers in synaptic neuroscience. 2009. DOI : 10.3389/neuro.19.001.2009.
T. Rinaldi; C. Perrodin; H. Markram : Hyper-connectivity and hyper-plasticity in the medial prefrontal cortex in the valproic Acid animal model of autism; Frontiers in neural circuits. 2008. DOI : 10.3389/neuro.04.004.2008.
T. Rinaldi; G. Silberberg; H. Markram : Hyperconnectivity of Local Neocortical Microcircuitry Induced by Prenatal Exposure to Valproic Acid; Cereb Cortex. 2008. DOI : 10.1093/cercor/bhm117.
K. Markram; T. Rinaldi; D. La Mendola; C. Sandi; H. Markram : Abnormal fear conditioning and amygdala processing in an animal model of autism; Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2008. DOI : 10.1038/sj.npp.1301453.
T. Rinaldi; K. Kulangara; K. Antoniello; H. Markram : Elevated NMDA receptor levels and enhanced postsynaptic long-term potentiation induced by prenatal exposure to valproic acid; Proc Natl Acad Sci U S A. 2007. DOI : 10.1073/pnas.0704391104.
H. Markram; T. Rinaldi; K. Markram : The intense world syndrome – an alternative hypothesis for autism; Front. Neurosci.. 2007. DOI : 10.3389/neuro.01.1.1.006.2007.