Biology subjects

Hsu, T.-T.

Publications and source records attributed to Hsu, T.-T..

4 recordsLinked to original sources

bioRxiv2025

Abnormal synaptic proteomes, impaired neural ensembles, and defective behaviors in autism mouse models are ameliorated by dietary intervention with nutrient mixtures

Autism spectrum disorders (ASD) are a group of heterogeneous, behaviorally defined neurodevelopmental conditions influenced by both genetic and environmental factors. Here, we show that nutrients--an important environmental factor--can modulate synaptic proteomes, reconfigure neural ensembles, and improve social behaviors in ASD mouse genetic models. We analyzed Tbr1+/- mice, a well-established model of ASD, using proteomic approaches and in vivo calcium imaging. Synaptic and metabolic proteomes were found to be sensitive to Tbr1 haploinsufficiency. Our results also revealed that Tbr1 haploinsufficiency promotes hyperactivation and hyperconnectivity of basolateral amygdala (BLA) neurons, enhancing the activity correlation between individual neurons and their corresponding ensembles. Zinc, branched-chain amino acids (BCAA), and serine--all nutrients known to regulate synapse formation and activity--were then combined into supplement cocktails and administered to Tbr1+/- mice. This treatment altered synaptic and metabolic proteomes and normalized the activity and connectivity of the BLA in Tbr1+/- mice during social interactions. We further show that although a low dose of individual nutrients did not alter social behaviors, treatment with supplement cocktails containing low-dose individual nutrients improved social behaviors and associative memory of Tbr1+/- mice, implying a synergistic effect of combining low-dose zinc, BCAA, and serine. Moreover, the supplement cocktails also improved social behaviors in Nf1+/- and Cttnbp2+/M120I mice, two additional ASD mouse models. Thus, our findings reveal aberrant neural connectivity in the BLA of Tbr1+/- mice and indicate that dietary supplementation with zinc, BCAA, and/or serine offers a safe and accessible approach to mitigate neural connectivity and social behaviors across multiple ASD models.

neuroscience↗

bioRxiv2025

Shared Alteration of Whole-Brain Connectivity and Olfactory Deficits in Multiple Autism Mouse Models

Autism spectrum disorder (ASD) is a disconnection condition influenced by both heterogeneous genetic and environmental factors, yet it remains unclear whether common connectivity deficits exist. Here, we demonstrate that different ASD-linked mutations lead to distinct circuit abnormalities but share deficits in the piriform cortex and olfactory discrimination. Using advanced artificial intelligence, we developed a whole-brain mapping platform to analyze the distribution of the Thy1-YFP projection neurons in three ASD mouse models (Tbr1+/-, Nf1+/-, Vcp+/R95G). Our analysis revealed changes in axonal patterns and neuronal distribution, indicating deficits in projection neuron differentiation and maintenance. Notably, the piriform cortex consistently exhibited reduced YFP+ cells and signals and impaired functionality across all models. Visual and somatosensory cortices were also affected, but the patterns varied. These findings highlight that the sensory regions, especially the piriform cortex, are susceptible to ASD-related mutations, strengthening the notion that different sensory experiences are common in ASD. HighlightsO_LIAI-powered whole-mouse brain quantification accelerates neural connectivity study. C_LIO_LIAutism-linked mutations lead to various circuit abnormalities of Thy1-YFP neurons. C_LIO_LIMultiple sensory regions all exhibit circuit deficits among the three autism models. C_LIO_LIAbnormalities of olfaction and piriform cortex circuits are common in autism models. C_LI

neuroscience↗

bioRxiv2023

Tbr1 autism mouse model displays altered structural and functional amygdalar connectivity and abnormal whole-brain synchronization

Autism spectrum disorders (ASD) are considered neural dysconnectivity syndromes. To better understand ASD and uncover potential treatments, it is imperative to know and dissect the connectivity deficits under conditions of autism. Here, we apply a whole-brain immunostaining and quantification platform to demonstrate impaired structural and functional connectivity and aberrant whole-brain synchronization in a Tbr1+/- autism mouse model. We express a channelrhodopsin variant oChIEF fused with Citrine at the basolateral amygdala (BLA) to outline the axonal projections of BLA neurons. By activating the BLA under blue light theta-burst stimulation (TBS), we then evaluate the effect of BLA activation on C-FOS expression at a whole brain level to represent neural activity. We show that Tbr1 haploinsufficiency almost completely disrupts contralateral BLA axonal projections and results in mistargeting in both ipsilateral and contralateral hemispheres, thereby globally altering BLA functional connectivity. Based on correlated C-FOS expression among brain regions, we further show that Tbr1 deficiency severely disrupts whole-brain synchronization in the absence of salient stimulation. Tbr1+/- and wild-type (WT) mice exhibit opposing responses to TBS-induced amygdalar activation, reducing synchronization in WT mice but enhancing it in Tbr1+/- mice. Whole-brain modular organization and inter-module connectivity are also affected by Tbr1 deficiency and amygdalar activation. Following BLA activation by TBS, the synchronizations of the whole brain and the default mode network, a specific subnetwork highly relevant to ASD, are enhanced in Tbr1+/- mice, implying a potential ameliorating effect of amygdalar stimulation on brain function. Indeed, TBS-mediated BLA activation increases nose-to-nose social interactions of Tbr1+/- mice, strengthening evidence for the role of amygdalar connectivity in social behaviors. Our high-resolution analytical platform reveals the inter- and intra-hemispheric connectopathies arising from ASD. Our study emphasizes the defective synchronization at a whole-brain scale caused by Tbr1 deficiency and implies a potential beneficial effect of deep brain stimulation at the amygdala for TBR1-linked autism.

neuroscience↗

bioRxiv2021

Sex-biased response to and brain cell infection by SARS-CoV-2 in a highly susceptible human ACE2 transgenic model

The COVID-19 pandemic is caused by SARS-CoV-2 infection. Human angiotensin-converting enzyme II (hACE2) has been identified as the receptor enabling SARS-CoV-2 host entry. To establish a mouse model for COVID-19, we generated transgenic mouse lines using the (HS4)2-pCAG-hACE2-HA-(HS4)2 transgene cassette, which expresses HA-tagged hACE2 under control of the CAG promoter and is flanked by HS4 insulators. Expression levels of the hACE2 transgene are respectively higher in lung, brain and kidney of our CAG-hACE2 transgenic mice and relatively lower in duodenum, heart and liver. The CAG-hACE2 mice are highly susceptibility to SARS-CoV-2 infection, with 100 PFU of SARS-CoV-2 being sufficient to induce 87.5% mortality at 9 days post-infection and resulting in a sole (female) survivor. Mortality was 100% at the higher titer of 1000 PFU. At lower viral titers, we also found that female mice exposed to SARS-CoV-2 infection suffered much less weight loss than male mice, implying sex-biased responses to SARS-CoV-2 infection. We subjected neuronal cultures to SARS-CoV-2 pseudovirus infection to ascertain the susceptibilities of neurons and astrocytes. Moreover, we observed that expression of SARS-CoV-2 Spike protein alters the synaptic responses of cultured neurons. Our transgenic mice may serve as a model for severe COVID-19 and sex-biased responses to SARS-CoV-2 infection, aiding in the development of vaccines and therapeutic treatments for this disease.

microbiology↗