Projects

Tryp-to-Brain

Growing awareness suggests the gut microbiome contributes to gastrointestinal and behavioral symptoms of autism spectrum disorder (ASD). The mechanisms by which gut microbiota influence ASD symptoms are unclear. Tryptophan (Trp), an essential amino acid absorbed and metabolized in the GI tract, is the sole substrate for serotonin synthesis, occurring primarily in the gut (90%) and the central nervous system (10%). Altered Trp metabolite concentrations are linked to neurological disorders, including ASD, with studies noting Trp deficiency in autistic patients. Hyperserotonemia is a biomarker for ASD, traditionally studied in the CNS, although 5-HT is primarily produced from Trp in the GI tract. Research suggests ASD pathogenesis may begin in fetal life, influenced by maternal nutrition during pregnancy. We hypothesize that prenatal diet impacts brain development and ASD risk. Our goal is to understand how prenatal Trp availability affects offspring cognition, neural systems (serotonergic, GABAergic, glutamatergic), GI functions, and microbiota using an Nf1+/- mouse model of ASD. Pregnant Nf1+/- and wild-type mice will receive a diet enhanced in Trp (TRP+, 1.5%), or a control diet (0.7%) from embryonic day 1 to weaning. Offspring will undergo behavior analyses and molecular approaches. This longitudinal study will use the same animals to correlate behavior, neurophysiology, GI, and microbiome changes. Understanding the impact of prenatal Trp availability on ASD can inform dietary guidelines for pregnant women, potentially reducing ASD risk. This research could lead to early interventions that improve the quality of life for individuals with ASD and their families, fostering greater societal inclusion and support. 

prenatal diet | tryptophan | gut-brain axis | autism spectrum disorder 

2022-2024

Unlocking Tryp in TSC

Tuberous sclerosis complex (TSC) is a neurological disorder characterized by brain abnormalities, such as cortical tubers, leading to severe epilepsy and autism spectrum disorder (ASD). While cortical lesions are a hallmark of TSC, the specific cortical alterations contributing to the symptomatology remain unknown. Tryptophan (Tryp) is an essential amino acid and a precursor for biologically important compounds, including the neurotransmitter serotonin (5-HT). Dietary Tryp intake influences 5-HT production, potentially impacting behavior and cognition, suggesting therapeutic benefits. Alterations in Tryp and 5-HT are implicated in several neurological disorders, including ASD and TSC. However, the specific role of Tryp in managing neurological function and autistic manifestations in TSC is not fully understood. This study investigated ASD-like behavior and its correlation with cortical neurophysiology alterations in the Tsc2 +/- mouse model. Additionally, we hypothesized that Tryp supplementation could address ASD manifestations and explored the impact of a Tryp-enriched diet. We aim to identify specific cortical alterations related to TSC-associated epilepsy and autistic features, providing insights for new therapeutic interventions.

tuberous sclerosis complex | tryptophan metabolism | serotonin pathway | epilepsy | autism spectrum disorder

Mariana Lapo Pais

2021-2025

Edible flowers for ASD 

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairment in social interaction and communication, associated with repetitive and/or restricted behaviors and interests. The pathophysiology of ASD has not yet been fully elucidated, but it is known that the interaction of environmental and genetic factors influences it. Treatment is also not delimited and, therefore, new therapeutic alternatives have gained space, especially the brain-intestine axis, as it has been discovered that the gastrointestinal tract plays an important role in the development of ASD.  The objective of the study is to investigate the effects of Tagetes erecta dry extract (rich in lutein) on neurobehavioral and intestinal changes in different animal models of ASD (valproic acid and NF1). To this end, experiments will be carried out on two models of autism, the valproic acid model (carried out in Brazil) and the NF1 neurofibromatosis model (carried out in Portugal), with the animals being treated from weaning until P60 with food-enriched with 0.3 % of Tageres erecta extract, when behavioral tests will be carried out, and subsequently sacrificed for tissue collection (serum, colon, ileum, cortex, hippocampus and cerebellum) and biochemical, immunohistochemical, intestinal permeability and serotonin dosage tests. Partial results point to effects on social interaction (females), anxiety-like behavior (males), and memory (females and males).

autism spectrum disorder | tagetes erecta | gut-brain axis

Joanna Sievers

2024

Plasticity recovery in neurodevelopmental disorders by cell-selective and systems-level GABAergic manipulation 

Neurodevelopmental disorders, including autism spectrum disorders (ASD) and schizophrenia, require effective treatments. Neural plasticity impairment is commonly associated with these diseases, leading to altered neural circuitry and excitation/inhibition (E/I) imbalances, resulting in suboptimal brain connectivity and behavioral issues. Current therapeutic approaches, such as pharmacological and brain stimulation therapies, have failed or shown poor outcomes due to a lack of circuit selectivity. Effective treatment must target specific neural circuits and cell types to restore impaired circuits and achieve lasting cognitive improvements. Our lab focuses on neurofibromatosis type 1 (NF1), characterized by E/I imbalances and GABA neurotransmitter changes. NF1 mice exhibit memory and learning deficits linked to increased inhibitory neurotransmission, particularly via PV fast-spiking interneurons. We hypothesize that inhibiting PV-neurons in NF1 will enhance plasticity, allowing input-specific synaptic connections to be strengthened and maintained. We propose combining PV-neuron inhibition with transcranial direct current stimulation (tDCS) to enhance its effectiveness.

We anticipate two major advances: identifying disease-related circuits to encourage targeted therapies in neurodevelopmental disorders and improving tDCS-based interventions. This approach may benefit a range of conditions with plasticity-related neuropsychiatric implications, such as ASD, schizophrenia, epilepsy, and depression.

visual system | neurofibromatosis type 1 | excitation-inhibition | brain stimulation

Amount 10 000€

2021