Biology subjects

Tai, L.-H.

Publications and source records attributed to Tai, L.-H..

6 recordsLinked to original sources

bioRxiv2025

Genetic changes linked to two different syndromic forms of autism enhance reinforcement learning in adolescent male but not female mice

Autism Spectrum Disorder (ASD) is characterized by restricted and repetitive behaviors and social differences, both of which may manifest, in part, from underlying differences in corticostriatal circuits and reinforcement learning. Here, we investigated reinforcement learning in developing mice with mutations in either Tsc2 or Shank3, both high-confidence ASD risk genes associated with major syndromic forms of ASD. Using an odor-based two-alternative forced choice (2AFC) task, we tested early adolescent mice of both sexes and found male Tsc2 and Shank3B heterozygote (Het) mice showed enhanced learning performance compared to their wild type (WT) siblings. No gain of function was observed in females. Using a novel reinforcement learning (RL) based computational model to infer learning rate as well as policy-level task engagement and disengagement, we found that the gain of function in males was driven by an enhanced positive learning rate in both Tsc2 and Shank3B Het mice. The gain of function in Het males was absent when mice were trained with a probabilistic reward schedule. These findings in two ASD mouse models reveal a convergent learning phenotype that shows similar sensitivity to sex and environmental uncertainty. These data can inform our understanding of both strengths and challenges associated with autism, while providing further evidence that sex and experience of uncertainty modulate autism-related phenotypes. Significance StatementReinforcement learning is a foundational form of learning that is widely used in behavioral interventions for autism. Here, we measured reinforcement learning in developing mice carrying genetic mutations linked to two different syndromic forms of autism. We found that males showed strengths in reinforcement learning compared to their wild type siblings, while females showed no differences. This gain of function in males was no longer observed when uncertainty was introduced into the reward schedule for correct choices. These findings support a model in which diverse genetic changes interact with sex to generate common phenotypes underlying autism. Our data further support the idea that autism risk genes may produce strengths as well as challenges in behavioral function.

neuroscience↗

bioRxiv2024

The adolescent frontal cortex shows stronger population-level encoding of information than the adult during a putative sensitive period

Adolescence is commonly claimed to be a sensitive period for brain development, but it is not clear how experience at this stage can have such strong impacts. We hypothesized that enhanced sensitivity to experience during adolescence may manifest as stronger encoding of task-related information in the dorsomedial prefrontal cortex (dmPFC). To enable optical access to task-related layer 2/3 neural activity in the developing mouse dmPFC, we imaged mice under a 2-photon microscope while they learned an auditory go/no-go task. We found adolescent mice (postnatal day P30-45) learned the task to criterion faster than adult mice (P60-75). When we compared neural activity in expert mice with comparable performance between the two age groups, we found that a similar fraction of single cells encoded task variables in the two groups. However, task information could be better decoded from the adolescent dmPFC population activity than the adult, even when we controlled for differences in head-fixed running. Adolescents also showed greater noise correlation than adults and shuffling to remove this noise correlation suggested noise correlation contributed to gain of function in adolescent compared to adult brain. We suggest a working model for adolescent brain function in which greater noise correlation supports greater capacity for distributed encoding of information driving, for better or for worse, increased sensitivity to experiences at this stage of life.

neuroscience↗

bioRxiv2024

Adolescent and adult mice use both incremental reinforcement learning and short term memory when learning concurrent stimulus-action associations

Computational modeling has revealed that human research participants use both rapid working memory (WM) and incremental reinforcement learning (RL) (RL+WM) to solve a simple instrumental learning task, relying on WM when the number of stimuli is small and supplementing with RL when the number of stimuli exceeds WM capacity. Inspired by this work, we examined which learning systems and strategies are used by adolescent and adult mice when they first acquire a conditional associative learning task. In a version of the human RL+WM task translated for rodents, mice were required to associate odor stimuli (from a set of 2 or 4 odors) with a left or right port to receive reward. Using logistic regression and computational models to analyze the first 200 trials per odor, we determined that mice used both incremental RL and stimulus-insensitive, one-back strategies to solve the task. While these one-back strategies may be a simple form of short-term or working memory, they did not approximate the boost to learning performance that has been observed in human participants using WM in a comparable task. Adolescent and adult mice also showed comparable performance, with no change in learning rate or softmax beta parameters with adolescent development and task experience. However, reliance on a one-back perseverative, win-stay strategy increased with development in males in both odor set sizes. Our findings advance a simple conditional associative learning task and new models to enable the isolation and quantification of reinforcement learning alongside other strategies mice use while learning to associate stimuli with rewards within a single behavioral session. These data and methods can inform and aid comparative study of reinforcement learning across species. Author summaryHere we studied the strategies and mechanisms mice use to learn a simple two choice odor based task in a single session. Using a set size manipulation and computational models we find evidence that mice use incremental reinforcement learning as well as several short-term (one-back) strategies to earn water reward. Our data and models clarify how mice learn a simple task and establish methods by which mouse and human reinforcement learning may be isolated for cross-species comparison of learning.

neuroscience↗

bioRxiv2023

Nucleus accumbens dopamine release reflects Bayesian inference during instrumental learning

Dopamine release in the nucleus accumbens has been hypothesized to signal reward prediction error, the difference between observed and predicted reward, suggesting a biological implementation for reinforcement learning. Rigorous tests of this hypothesis require assumptions about how the brain maps sensory signals to reward predictions, yet this mapping is still poorly understood. In particular, the mapping is non-trivial when sensory signals provide ambiguous information about the hidden state of the environment. Previous work using classical conditioning tasks has suggested that reward predictions are generated conditional on probabilistic beliefs about the hidden state, such that dopamine implicitly reflects these beliefs. Here we test this hypothesis in the context of an instrumental task (a two-armed bandit), where the hidden state switches repeatedly. We measured choice behavior and recorded dLight signals reflecting dopamine release in the nucleus accumbens core. Model comparison among a wide set of cognitive models based on the behavioral data favored models that used Bayesian updating of probabilistic beliefs. These same models also quantitatively matched the dopamine measurements better than non-Bayesian alternatives. We conclude that probabilistic belief computation contributes to instrumental task performance in mice and is reflected in mesolimbic dopamine signaling.

animal behavior and cognition↗

bioRxiv2020

An easily adopted murine model of distal pancreatectomy for investigating immunotherapy efficacy in resectable pancreatic adenocarcinoma

BackgroundAlthough surgery provides the greatest therapeutic benefit to eligible pancreatic ductal adenocarcinoma (PDAC) patients it does not significantly improve survival for the majority of patients. Unfortunately our understanding of the therapeutic benefit of combining surgery with different treatment modalities including promising immunotherapeutics is limited by the current lack of easily adopted surgical models. The purpose of this study was to develop a surgically resectable model of PDAC in immunocompetent mice for use in preclinical investigations. Materials and MethodsSurgically resectable orthotopic tumors were generated by injecting Pan02 cells into the tail of the pancreas. Fifteen days post implantation the primary tumors and tail of the pancreas were resected by laparotomy while preserving the spleen. Splenic function, tumor growth, immune phenotyping and survival were assessed following surgical resection of the primary tumor mass. ResultsAs expected orthotopic tumor implants recapitulated many of the major histological hallmarks of PDAC including disrupted lobular structure and vascular invasion. Preservation of splenic immune cell viability and function was not associated with improved survival following surgery alone. However, pre-operative vaccination with GVAX was associated with improved survival which was not impacted by surgery. ConclusionThis represents the first murine model of surgically resectable murine model of PDAC which recapitulates known pathological hallmarks of human disease in an immune competent model while allowing spleen preservation. This relatively simple and easily adopted approach provides an ideal platform to examine the efficacy of potential immunotherapy combinations for PDAC surgery patients.

cancer biology↗

bioRxiv2017

Sepsis Increases Perioperative Metastases In A Murine Model

BackgroundCancer surgery can promote tumour metastases and worsen prognosis, but the effects of perioperative complications such as sepsis, blood loss, and hypothermia on subsequent cancer metastases have not been addressed.\n\nObjectiveTo evaluate the effect of common perioperative factors on postoperative tumour metastases in murine models of cancer surgery. We hypothesize that perioperative blood loss, hypothermia, and sepsis facilitate tumour metastases in these murine models.\n\nMethodsPrior to surgery, pulmonary metastases were established by intravenous challenge of CT26LacZ colon cancer cells in Balb/c mice or B16LacZ melanoma cells in C57Bl/6 mice. Surgical stress was generated through partial hepatectomy (PH) or left nephrectomy (LN). Sepsis was induced by puncturing the cecum to express stool into the abdomen. Hemorrhagic shock was induced by removal of 30% of total blood volume via saphenous vein. Hypothermia was induced by removing the heating apparatus during surgery and lowering core body temperatures to 30{degrees}C. Lung tumour burden was quantified 3 days following surgery.\n\nResultsSurgically stressed mice subjected to Stage 3 hemorrhagic shock or hypothermia did not show an additional increase in lung tumour burden. In contrast, surgically stressed mice subjected to intraoperative sepsis demonstrated an additional 2-fold increase in the number of tumour metastases. Furthermore, natural killer (NK) cell function, as assessed by YAC-1 tumour cell lysis, was significantly attenuated in surgically stressed mice subjected to intraoperative sepsis. Both NK cell-mediated cytotoxic function and lung metastases were improved with perioperative administration of polyI:C, which is a ligand for toll-like receptor (TLR)-3\n\nConclusionsPerioperative sepsis, but not hemorrhagic shock or hypothermia, enhances the prometastatic effect of surgery in murine models of cancer. Identification of the mechanisms underlying perioperative immune suppression will be critical in the development of immunomodulation strategies that aim to attenuate perioperative metastatic disease.

cancer biology↗