Biology subjects

Shih, Y.-C.

Publications and source records attributed to Shih, Y.-C..

9 recordsLinked to original sources

bioRxiv2025

Late onset of striatal projection neuron hyperexcitability in Fmr1-/y mice

AbstractFragile X Syndrome (FXS), the most common genetic cause of intellectual disability and autism spectrum disorder (ASD), results from silencing of the FMR1 gene and consequent loss of Fragile X Messenger Ribonucleoprotein (FMRP). FMRP deficiency disrupts neural development, leading to behavioral and motor deficits associated with striatal dysfunction. While structural and functional abnormalities in striatal projection neurons (SPNs) have been observed in adult Fmr1 knockout (KO) mice, their developmental onset and contribution to early FXS pathophysiology remain unknown. In this study, we examined the postnatal maturation of SPN in the dorsomedial striatum (DMS) of Fmr1 KO mice, assessing glutamatergic synaptic inputs and intrinsic excitability. During postnatal development, Fmr1 deficient SPNs in DMS display normal synaptic and intrinsic properties, consistent with typical maturation. In contrast, by P60, SPNs of mice exhibit pronounced hyperexcitability, characterized by increased membrane resistance, reduced rheobase, and slower action potential kinetics. These perturbations affect both Dopamine 1 receptor-expressing (D1-SPN) and D2 receptor-expressing (D2-SPN) SPNs, though some action potential dynamics are selectively impaired in D1-SPNs. Chronic aripiprazole treatment, a widely prescribed therapy for FXS-related symptoms, fails to normalize SPN excitability, highlighting its limited efficacy in addressing core SPN dysfunction. Our findings reveal a late-onset hyperexcitability in DMS SPNs of Fmr1 KO mice, suggesting a progressive emergence of striatal neuron abnormalities over development. These results underscore the importance of developmental timing in FXS pathophysiology and emphasize the need for targeted interventions to address striatal circuit dysfunction.

neuroscience↗

bioRxiv2025

The Filterprep: A Simple and Efficient Approach for High-Yield, High-Purity Plasmid DNA Purification

Plasmid DNA purification remains a fundamental yet resource-intensive step in molecular biology and biotechnology. Conventional protocols often yield plasmids with suboptimal purity, while commercial kits, though efficient, are costly and use proprietary formulations that limit transparency and customization. Here, we present Filterprep, a hybrid method combining classical ethanol precipitation with a single spin-column cleanup step, enabling rapid recovery of high-purity plasmid DNA with yields notably higher than those obtained using commercial kits, in approximately 40 minutes. Filterprep offers a transparent, cost-effective, and scalable alternative, simplifying workflows and reducing hands-on time without compromising DNA quality. The purified plasmids are compatible with a variety of downstream applications, including mammalian cell transfection, protein expression, and reporter assays. With its balance of efficiency and practicality, Filterprep is well suited for high-throughput laboratories and resource-limited settings.

biochemistry↗

bioRxiv2024

Early Postnatal Dysfunction of mPFC PV Interneurons in Shank3B-/- Mice

Anterior cingulate cortex (ACC) dysfunction is implicated in the cognitive and social deficits associated with autism spectrum disorder (ASD), yet the developmental trajectory of ACC circuit maturation in ASD remains poorly understood. Here, we examined the postnatal development of glutamatergic synaptic connectivity and intrinsic excitability in layer 2/3 pyramidal neurons (PYR) and Parvalbumin-expressing interneurons (PVIN) in the ACC of mice harboring a deletion in SHANK3 (Shank3B-/-), a well-established genetic cause of autism. We found that ACC PVINs in Shank3B-/- mice exhibit reduced excitability and in vivo hypoactivity as early as postnatal day 15 (P15) despite receiving normal levels of glutamatergic input. This early PVIN hypoexcitability is associated with decreased feedforward inhibition from the mediodorsal thalamus and reduced hyperpolarization-activated (Ih) currents mediated by hyperpolarization-activated cyclic nucleotide gated (HCN) channels. In contrast, PYRs display normal excitability and synaptic input at this stage but already exhibit reduced Ih currents, indicating an early emergence of HCN channel dysfunction in both PYR and PVIN. By adulthood, both neuron populations undergo marked phenotypic changes, characterized by reduced glutamatergic synaptic input and divergent alterations in excitability. Together, these findings reveal a distinct sequence of early PVIN dysfunction followed by cell-type specific circuit reorganization within ACC layer 2/3 of Shank3B-/- mice and identify HCN channelopathy and impaired PVIN-mediated inhibition as early pathogenic features of SHANK3-related neurodevelopmental disorders.

neuroscience↗

bioRxiv2024

Striatal output regulates the postnatal maturation of cortical circuits

The dorsomedial prefrontal cortex (dmPFC) is interconnected with the basal ganglia (BG) through large-scale circuit loops that regulate critical motor and cognitive functions. In mice, these circuits undergo extensive postnatal maturation with marked changes in neural activity and expansion of synaptic connectivity. While cortical activity is known to regulate the development of downstream striatal circuits, the role of the basal ganglia in cortical maturation remains unknown. Here, we used mesoscale two-photon microscopy and whole-cell electrophysiology to examine whether striatal output during early postnatal development impacts the activity and maturation of upstream dmPFC circuits. We found that ablating spiny projection neurons of the direct or indirect pathways of the striatum during the first two postnatal weeks causes bidirectional changes in dmPFC neural activity, similar to observations in mature circuits. In addition, these manipulations alter the maturation of synaptic connectivity of dmPFC layer 2/3 pyramidal neurons, shifting the balance of excitation and inhibition of cortical circuits. These findings demonstrate that striatal output modulates the activity of cortical circuits during early postnatal development and suggest a regulatory role of the basal ganglia in the establishment of cortical circuits.

neuroscience↗

bioRxiv2024

A mediating framework in resting-state connectivity between the medial prefrontal cortex and anterior cingulate in mild cognitive impairment

Mild cognitive impairment (MCI) is recognized as the prodromal phase of dementia, a condition that can be either maintained or reversed through timely medical interventions to prevent cognitive decline. Considerable studies using functional magnetic resonance imaging (fMRI) have indicated that altered activity in the medial prefrontal cortex (mPFC) serves as an indicator of various cognitive stages of aging. However, the impacts of intrinsic functional connectivity in the mPFC as a mediator on cognitive performance in individuals with and without MCI have not been fully understood. In this study, we recruited 42 MCI patients and 57 healthy controls, assessing their cognitive abilities and functional brain connectivity patterns through neuropsychological evaluations and resting-state fMRI, respectively. The MCI patients exhibited poorer performance on multiple neuropsychological tests compared to the healthy controls. At the neural level, functional connectivity between the mPFC and the anterior cingulate cortex (ACC) was significantly weaker in the MCI group and correlated with multiple neuropsychological test scores. The result of the mediation analysis further demonstrated that functional connectivity between the mPFC and ACC notably mediated the relationship between the MCI and semantic working memory. These findings suggest that altered mPFC-ACC connectivity may have a plausible causal influence on cognitive decline and provide implications for early identifications of neurodegenerative diseases and precise monitoring of disease progression.

neuroscience↗

bioRxiv2024

Invariant Neural Representation of Parts of Speech in the Human Brain

Elucidating the internal representation of language in the brain has major implications for cognitive science, brain disorders, and artificial intelligence. A pillar of linguistic studies is the notion that words have defined functions, often referred to as parts of speech. Here we recorded invasive neurophysiological responses from 1,801 electrodes in 20 patients with pharmacologically-resistant epilepsy while they were presented with two-word phrases consisting of an adjective and a noun. We observed neural signals that distinguished between these two parts of speech. The representation of parts of speech showed invariance across visual and auditory presentation modalities, robustness to word properties like length, order, frequency, and semantics, and even generalized across different languages. The selective signals were circumscribed within a small region in the left lateral orbitofrontal cortex. This selective, invariant, and localized representation of parts of speech extends classic fronto-temporal language models, providing a target for mechanistic and causal tests of how the brain represents basic building blocks of language, and introduces a systematic approach to elucidate the orchestration of more complex aspects of language.

neuroscience↗

bioRxiv2023

Late onset and regional heterogeneity of synaptic deficits in cortical PV interneurons of Shank3B-/- mice

Epilepsy and epileptiform patterns of cortical activity are highly prevalent in autism spectrum disorders (ASDs), but the neural substrates and pathophysiological mechanisms underlying the onset of cortical dysfunction in ASD remains elusive. Reduced cortical expression of Parvalbumin (PV) has been widely observed in ASD mouse models and human postmortem studies, suggesting a crucial role of PV interneurons (PVINs) in ASD pathogenesis. Shank3B-/- mice carrying a {Delta}13-16 deletion in SHANK3 exhibit cortical hyperactivity during postnatal development and reduced sensory responses in cortical GABAergic interneurons in adulthood. However, whether these phenotypes are associated with PVIN dysfunction is unknown. Using whole-cell electrophysiology and a viral-based strategy to label PVINs during postnatal development, we performed a developmental characterization of AMPAR miniature excitatory postsynaptic currents (mEPSCs) in PVINs and pyramidal (PYR) neurons of layer (L) 2/3 mPFC in Shank3B-/- mice. Surprisingly, reduced mEPSC frequency was observed in both PYR and PVIN populations, but only in adulthood. At P15, when cortical hyperactivity is already observed, both neuron types exhibited normal mEPSC amplitude and frequency, suggesting that glutamatergic connectivity deficits in these neurons emerge as compensatory mechanisms. Additionally, we found normal mEPSCs in adult PVINs of L2/3 somatosensory cortex, revealing region-specific phenotypic differences of cortical PVINs in Shank3B-/- mice. Together, these results demonstrate that loss of Shank3 alters PVIN function but suggest that PVIN glutamatergic synapses are a suboptimal therapeutic target for normalizing early cortical imbalances in SHANK3-associated disorders. More broadly, these findings underscore the complexity of interneuron dysfunction in ASDs, prompting further exploration of region and developmental stage specific phenotypes for understanding and developing effective interventions.

neuroscience↗

bioRxiv2022

Task-specific neural processes underlying conflict resolution during cognitive control

Cognitive control involves flexibly combining multiple sensory inputs with task-dependent goals during decision making. Several tasks have been proposed to examine cognitive control, including Stroop, Eriksen-Flanker, and the Multi-source interference task. Because these tasks have been studied independently, it remains unclear whether the neural signatures of cognitive control reflect abstract control mechanisms or specific combinations of sensory and behavioral aspects of each task. To address this question, here we recorded invasive neurophysiological signals from 16 subjects and directly compared the three tasks against each other. Neural activity patterns in the theta and high-gamma frequency bands differed between incongruent and congruent conditions, revealing strong modulation by conflicting task demands. These neural signals were specific to each task, generalizing within a task but not across tasks. These results highlight the complex interplay between sensory inputs, motor outputs, and task demands and argue against a universal and abstract representation of conflict.

neuroscience↗

bioRxiv2019

Sustained modulation of emotion-related fibers after 8 weeks of mindfulness-based stress reduction training

An 8-week mindfulness-based stress reduction (MBSR) program enables novices to learn and practice mindfulness meditation. A longitudinal study design has been used in prior research to investigate the effect of short-term mindfulness meditation training on brain structures. Many studies have demonstrated microstructural changes in the white matter by comparing baseline measurements with measurements obtained immediately after short-term meditation training. However, these studies did not clarify the evolution of the modulated microstructures several months after mindfulness meditation practice is discontinued. Therefore, in this study, we recruited 13 novice practitioners and administered an 8-week MBSR training program. We extended the span of the longitudinal study by adding a third measurement taken approximately 6 months after the second time point. Diffusion indices derived from diffusion spectrum imaging were used to quantify the temporal changes in modulation across three time points. The analysis identified four tract bundles that were significantly modulated after the 8-week MBSR training program, namely the callosal fibers connecting the bilateral amygdalae and bilateral hippocampi, right thalamic radiation of the auditory nerve, and right uncinate fasciculus. At the third time point, at which the participants had discontinued practice for approximately 6 months, the diffusion indices of the four tract bundles still presented a significant difference compared with the baseline. Our results indicate that the modulation of microstructural properties of the white matter tract induced by the 8-week MBSR program was sustained after completion of the program and support that neuroplasticity in brain connection persists after the discontinuation of meditation training.

neuroscience↗