Biology subjects

Shi, T.-T.

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

3 recordsLinked to original sources

bioRxiv2026

Valine Engages a Prefrontal mGluR5 Allosteric Site to Preserve Social Behavior

Branched-chain amino acid metabolism is linked to neurodevelopmental disorders, but whether a defined amino acid directly modulates cortical receptor signaling to control behavior is unknown. Here, we show that valine is uniquely required for sociability through medial prefrontal cortex (mPFC) circuitry. Partial dietary valine restriction, but not comparable leucine or isoleucine restriction, or mPFC-restricted acceleration of BCAA catabolism through Bckdk loss, disrupts social interaction, and local valine supplementation rescues behavior. LiP-SMap, surface plasmon resonance, cryo-EM, and mutagenesis identify metabotropic glutamate receptor 5 (mGluR5) as a direct valine target and reveal a valine-selective allosteric pocket distinct from the glutamate site. Valine is signaling-biased: it drives {beta}-arrestin-linked output yet has little standalone Gq efficacy, instead potentiating glutamate-evoked mGluR5 signaling to recruit endocannabinoid/CB1 feedback, gate inhibitory transmission, and preserve mPFC-dependent social behavior. Together, these findings identify valine as a diet-derived allosteric ligand that links amino acid availability to cortical circuit control of social behavior.

neuroscience↗

bioRxiv2026

Microglial pruning of extinction-ensemble synapses preserves fear memory

Fear extinction suppresses learned fear without erasing the original memory, yet how competing fear and extinction ensembles are selectively updated remains unknown. Here, we show that microglia preserve fear memory by selectively editing extinction-ensemble synapses during retrieval. In medial prefrontal cortex, microglial processes, but not somata, expand, ramify, and tighten their engagement with extinction-ensemble dendrites and spines, where they preferentially engulf excitatory postsynaptic material and bias spine remodeling toward elimination. This selectivity is instructed by local find-me, eat-me, and dont-eat-me cues: purinergic signaling recruits microglial processes, phosphatidylserine exposure licenses engulfment of extinction-ensemble synapses, and CD47-SIRP protects fear ensembles from removal. Weakening microglial recruitment or engulfment, or removing this protection, accelerates extinction without impairing fear acquisition. These findings identify microglial processes as active gatekeepers of ensemble competition and reveal a neuroimmune mechanism that preserves fear memory by limiting extinction. In BriefDuring memory updating, microglial processes selectively engage extinction-ensemble synapses rather than globally pruning active circuits. Local recruitment, engulfment, and protection cues determine this choice, allowing microglia to preserve fear memory by limiting extinction. HighlightsO_LIExtinction retrieval selectively recruits microglial processes to extinction ensembles. C_LIO_LIMicroglia preferentially engulf excitatory postsynaptic material from extinction ensembles. C_LIO_LILocal "find-me," "eat-me," and "dont-eat-me" cues determine synapse selection. C_LIO_LIDisrupting microglial pruning facilitates extinction without impairing fear learning. C_LI

neuroscience↗

bioRxiv2022

A minimally-invasive method for serial cerebrospinal fluid collection and injection in rodents with high survival rates

Cerebrospinal fluid (CSF) is a clear fluid surrounding and nourishing the brain and spinal cord. Molecular profiling of the CSF is a common diagnostic approach for central nervous system (CNS) diseases, including infectious diseases, autoimmune disorders, brain hemorrhage and traumatic brain injury, CNS tumors, and Alzheimers disease1-10. Rodent models are critical for investigating CNS disease mechanisms and therapeutics, however, both collecting CSF and injecting materials into CSF in small animals are technically challenging and often result in high rates of postoperative mortality. Here, we present an easy-to-practice and cost-effective protocol with minimum instrument requirements to access the CSF in live rodents for collection and infusion purposes. By introducing a metal needle tool bent at a unique angle and length, we could steadily reach the CSF via the foramen magnum. Compared with prior methods, this protocol requires neither the operator to discern the changes in resistance from solid tissues while puncturing the needle, nor surgical opening of the skin and muscle covering the rodent neck. Using this method, we frequently obtain 5-15 L of CSF from mice and 70-120 L from rats to enable diverse downstream analyses including mass spectrometry. Due to the minimal invasiveness, this procedure allows iterative CSF collection from the same animal every few days - a major improvement over prior protocols that require extensive surgical operations. Moreover, we demonstrate that this method could be used for injecting desired solutions including dyes into mouse CSF with high success rates. Our method shortens the time required for CSF collection or injection to 3-5 minutes. Notably, we could reach near 100% postoperative recovery rates in both mice and rats even with repetitive collections. Together, we establish an efficient and minimally-invasive protocol for collecting CSF and inoculating reagents into the CSF in live rodents to enable various longitudinal studies at the forefronts of CNS investigation.

neuroscience↗