Rapid rescue of despair behaviors by sonogenetic neuromodulation of the mPFC-DRN pathway.

Environmental factors, including maternal medications, have been implicated in shaping early brain development []. Some antiepileptic drugs (AEDs), such as Levetiracetam (LEV), are considered non-teratogenic and safe for use during pregnancy []. However, other medications that can pass maternal and fetal barriers might increase the risk of neurodevelopmental and/or psychiatric disorders []. For example, valproate (VPA), an AED, is a well-known teratogen that passes the barriers and reaches the fetal brain [–]. exposure to VPA, especially in the first trimester, is associated with increased risk of congenital malformations, such as neural tube closure defects, and neurodevelopmental disorders, including autism spectrum disorder (ASD)[, ]. Despite its known teratogenic effects, VPA treatment may be continued during pregnancy when it is the only effective treatment for seizure control in patients who do not respond to other AEDs []. Since the use of VPA is unavoidable in some cases of pregnancies of epileptic patients, understanding the mechanism by which VPA disrupts neurodevelopment is crucial to develop strategies to mitigate the risk. exposure to VPA is a common environmentally induced animal model of autism spectrum disorder (ASD) []. Rodents prenatally exposed to VPA display ASD-like behavioral phenotypes such as reduced sociability and repetitive hyperactivity combined with reduced exploratory activity [–]. This animal model also provides a tool to study the neurobiology of VPA-induced ASD and VPA-induced structural malformations in the nervous system. Findings show that VPA results in dysregulated differentiation of neural progenitor cells [] and excitation/inhibition imbalance []. Additionally, the expression level of collagens was increased in the medial prefrontal cortex of rats prenatally exposed to VPA []. A possible mechanism that might induce these changes is through epigenetic effect of VPA as a histone deacetylase inhibitor (HDACi) []. However, animal models are limited in understanding the VPA-induced ASD pathophysiology and the effects of VPA on the developing human brain due to interspecies differences []. Human induced pluripotent stem cell (iPSC)- and embryonic stem cell (ESC)-derived neural organoids provide an in vitro model system to investigate the mechanisms of environmental exposures in neurodevelopment [, , ] and developmental defects in ASD [, ] in a human-specific tissue context. Various neural organoid protocols have been developed, including regionalized protocols such as dorsal forebrain organoids (DFOs), which recapitulate important features of the cellular, molecular, and cytoarchitectural features of specific regions of the human brain [, ]. Human neural organoids have been utilized to study the effects VPA exposure and its potential link to ASD [–]. Independent studies have shown that VPA treatment altered ventricular zone (VZ)-like structures and progenitors, and impaired differentiation in neural organoids [–]. While these studies have provided insights into the cellular and transcriptional changes induced by VPA exposure, they have not investigated how microenvironment components, such as extracellular matrix (ECM) are altered in a human tissue context.