Continuous high-frequency deep brain stimulation of the anterior insula modulates autism-like behavior in a valproic acid-induced rat model

Abstract

Background Until now, the treatment of patients with autism spectrum disorder (ASD) remain a difficult problem. The insula is involved in empathy and sensorimotor integration, which are often impaired in individuals with ASD. Deep brain stimulation, modulating neuronal activity in specific brain circuits, has recently been considered as a promising intervention for neuropsychiatric disorders. Valproic acid (VPA) is a potential teratogenic agent, and prenatal exposure can cause autism-like symptoms including repetitive behaviors and defective sociability. Herein, we investigated the effects of continuous high-frequency deep brain stimulation in the anterior insula of rats exposed to VPA and explored cognitive functions, behavior, and molecular proteins connected to autism spectrum disorder. Methods VPA-exposed offspring were bilaterally implanted with electrodes in the anterior insula (Day 0) with a recovery period of 1 week. (Day 0–7). High-frequency deep brain stimulation was applied from days 11 to 29. Three behavioral tests, including three-chamber social interaction test, were performed on days 7, 13, 18, 25 and 36, and several rats were used for analysis of immediate early genes and proteomic after deep brain stimulation intervention. Meanwhile, animals were subjected to a 20 day spatial learning and cognitive rigidity test using IntelliCage on day 11. Results Deep brain stimulation improved the sociability and social novelty preference at day 18 prior to those at day 13, and the improvement has reached the upper limit compared to day 25. As for repetitive/stereotypic-like behavior, self- grooming time were reduced at day 18 and reached the upper limit, and the numbers of burried marbles were reduced at day 13 prior to those at day 18 and day 25. The improvements of sociability and social novelty preference were persistent after the stimulation had ceased. Spatial learning ability and cognitive rigidity were unaffected. We identified 35 proteins in the anterior insula, some of which were intimately linked to autism, and their expression levels were reversed upon administration of deep brain stimulation. Conclusions Autism-like behavior was ameliorated and autism-related proteins were reversed in the insula by deep brain stimulation intervention, these findings reveal that the insula may be a potential target for DBS in the treatment of autism, which provide a theoretical basis for its clinical application., although future studies are still warranted.

Artemisinin reduces PTSD-like symptoms, improves synaptic plasticity, and inhibits apoptosis in rats subjected to single prolonged stress

“…As described previously ( Xiao et al, 2022 ), the experimental arena comprised a topless rectangular box (120 cm × 60 cm × 40 cm) divided into three chambers of equal volumes (left, middle, and right). The chambers were connected by two doors (20 cm × 10 cm) on either wall of the middle volume.…”

“…As described previously (Xiao et al, 2022), the experimental arena comprised a topless rectangular box (120 cm × 60 cm × 40 cm) divided into three chambers of equal volumes (left, middle, and right). The chambers were connected by two doors In this study, we constructed a schematic of the PTSD model through the SPS procedure in rats, AR or saline administration modality and the four behavioral paradigms of MWM, EPM, OFT, and SIT.…”

Brain-derived neurotrophic factor from microglia regulates neuronal development in the medial prefrontal cortex and its associated social behavior

“…MG-BDNF is implicated in learning-dependent neural plasticity [ 29 ] and may modify social circuit formation in brain regions other than the mPFC, even in adulthood [ 62 ]. For example, the high-frequency deep brain stimulation in the anterior insula, which is a well-known brain region regulating social behavior, improves the impairment of sociability and social novelty preference, but not spatial learning abilities and cognitive rigidity, in valproic acid-exposed rats [ 63 ]. Previous studies have also reported that microglia are related to mPFC circuit formation and cognitive maturation in adolescence [ 24 ]; thus, normalizing MG-BDNF after p45–p50 may be sufficient to restore sociability.…”

Systematic review and meta-analysis: multimodal functional and anatomical neural alterations in autism spectrum disorder

“…Accumulating evidence shows that the insula is a critically impaired region in ASD [11,[24][25][26], dysfunction of which could relate to many behavioral and cognitive symptoms of ASD (e.g., mentalizing and empathizing) [8,44,45]. A recent experiment on an autism rat model demonstrated that cognitive impairment and repetitive/stereotypic-like behaviors might be attributable to the dysregulation of synaptic and associated receptor proteins in the insula [46]. Task-based functional meta-analyses demonstrated decreased activation in the insula in ASD during social cognitive and cognitive control [8,10].…”