Biology subjects

Schmidt, M. E.

Publications and source records attributed to Schmidt, M. E..

8 recordsLinked to original sources

bioRxiv2026

Remembering touch: Somatosensory cortex supports long-term memory for dynamic vibrotactile patterns.

The neural substrates of tactile long-term memory (LTM) in humans remain poorly understood, as relatively few neuroimaging studies have addressed this question. Here, we asked whether retrieval of tactile stimulation engages modality-specific representations in the primary and secondary somatosensory cortices (S1 and S2), alongside domain-general retrieval networks. Participants learned 16 tactile trajectories, each presented for 1.2 s on the left thumb through sequential activation of 10 vibrating dots on a Braille-like display. Three learning sessions within one week were followed by a recognition test during functional magnetic resonance imaging (fMRI). In the final sample (n = 26), we contrasted BOLD responses during successful recognition of learned stimuli with those during correct rejection of novel stimuli. Successful recognition was associated with increased activity in contralateral S1 and S2, alongside activation in the hippocampus as well as frontal and parietal regions implicated in memory retrieval. A psychophysiological interaction analysis (PPI) further revealed increased task-dependent connectivity between the hippocampus and contralateral S1 and S2 during successful recognition. Together, these findings suggest that tactile long-term memory retrieval relies on coordinated hippocampal-somatosensory interactions and may engage long-term memory representations in somatosensory cortex.

neuroscience↗

bioRxiv2025

Mesoscale developmental rivalry in human extrastriate visual cortex

In humans and non-human primates, the extrastriate visual cortex contains fine-scale columns selectively responsive to motion, disparity, and color. However, the developmental interplay between these functional modules remains poorly understood. Using high-resolution fMRI, we compared the mesoscale organization of extrastriate cortex in 16 individuals with normal vision and 15 participants with amblyopia (PwA) caused by strabismus (n=8) or anisometropia (n=7). In controls, the cortical territory occupied by disparity-selective columns exhibited a competitive relationship with that of motion- and color-selective columns. Consistent with this pattern, PwA showed a reduction in disparity-selective responses accompanied by enhanced motion- and color-selective activity, as well as expansion of the cortical territory allocated to them. Our results show that the mesoscale modules of the human visual system are rivals in development allowing intact functions to usurp those that are compromised.

neuroscience↗

bioRxiv2025

Unraveling the mesoscale functional connectivity of the human primary visual cortex using high-resolution functional MRI.

Despite their importance for visual perception, functional connectivity between ocular dominance columns (ODCs)in the human primary visual cortex (V1) remains largely unknown. Using high- resolution functional MRI (fMRI), we localized ODCs and assessed their resting-state functional connectivity (rs-FC) in 12 human adults. Consistent with anatomical studies in animals, we found stronger rs-FC in the middle compared to deep and superficial cortical depths and selectively stronger rs- FC between ODCs with alike compared to unalike ocular polarity. Beyond what was known from animal models, and consistent with human perceptual biases, intra- and interhemispheric rs-FC was stronger in peripheral (compared to central) and in dorsal (compared to ventral) V1 subregions. Lastly, rs-FC patterns correlated with ODC maps, suggesting that ODC maps can be predicted from rs-FC patterns within V1. These results highlight the heterogeneity in rs-FC between ODCs across cortical depths and V1 subfields, underscoring their likely association with human perceptual features.

neuroscience↗

bioRxiv2023

Immunologic changes are detectable in the peripheral blood transcriptome of clinically asymptomatic Chagas cardiomyopathy patients

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, is a neglected parasitic disease that affects approximately 6 million individuals worldwide. Of those infected, 20-30% will go on to develop chronic Chagas cardiomyopathy (CCC), and ultimately many of these individuals will progress to advanced heart failure. The mechanism by which this progression occurs is poorly understood, as few studies have focused on early CCC. In this study, we sought to understand the physiologic changes associated with T. cruzi infection and the development of CCC. We analyzed gene expression in the peripheral blood of asymptomatic Chagas patients with early structural heart disease, Chagas patients without any signs or symptoms of disease, and Chagas-negative patients with and without early structural heart disease. Our analysis shows that early CCC was associated with a downregulation of various peripheral immune response genes, with gene expression changes suggestive of reduced antigen presentation and T cell activation. Notably, these genes and processes were distinct from those of early cardiomyopathy in Chagas-negative patients, suggesting that the processes mediating CCC may be unique from those mediating progression to other cardiomyopathies. This work highlights the importance of the immune response in early CCC, providing insight into the early pathogenesis of this disease. The changes we have identified may serve as biomarkers of progression and could inform strategies for the treatment of CCC in its early stages, before significant cardiac damage has occurred.

immunology↗

bioRxiv2023

Flicker light stimulation induces thalamocortical hyperconnectivity with LGN and higher-order thalamic nuclei

The thalamus is primarily known as a relay for sensory information; however, it also critically contributes to higher-order cortical processing and coordination. Thalamocortical hyperconnectivity is associated with hallucinatory phenomena that occur in various psychopathologies (e.g., psychosis, migraine aura) and altered states of consciousness (ASC, e.g., induced by psychedelic drugs). However, the exact functional contribution of thalamocortical hyperconnectivity in forming hallucinatory experiences is unclear. Flicker light stimulation (FLS) can be used as an experimental tool to induce transient visual hallucinatory phenomena in healthy participants. Here, we use FLS in combination with fMRI to test how FLS modulates thalamocortical connectivity between specific thalamic nuclei and visual areas. We show that FLS induces thalamocortical hyperconnectivity between LGN, early visual areas and proximal upstream areas of ventral and dorsal visual streams (e.g., hV4, VO1, V3a). Further, an exploratory analysis indicates specific higher-order thalamic nuclei, such as anterior and mediodorsal nuclei, to be strongly affected by FLS. Here, the connectivity changes to upstream cortical visual areas directly reflect a frequency-dependent increase in experienced visual phenomena. Together these findings contribute to the identification of specific thalamocortical interactions in the emergence of visual hallucinations. HighlightsO_LIFlicker light stimulation (FLS) induces thalamocortical hyperconnectivity between the first-order thalamic LGN and early visual cortices, likely due to entrainment. C_LIO_LIThalamocortical connectivity between LGN and upstream visual areas, but not V1, is associated with the intensity of visual hallucinations. C_LIO_LIThalamocortical connectivity changes with higher-order thalamic nuclei, such as anterior and mediodorsal nuclei, show strongest modulation by flicker frequency, which corresponds to the intensity of visual hallucinations. C_LI

neuroscience↗

bioRxiv2021

Rescue of aberrant huntingtin palmitoylation ameliorates mutant huntingtin-induced toxicity

Huntington disease (HD) is a neurodegenerative disorder caused by a CAG expansion in the HTT gene that codes for an elongated polyglutamine tract in the huntingtin (HTT) protein. HTT is subject to multiple post-translational modifications (PTMs) that regulate its cellular function. Mutating specific PTM sites within mutant HTT (mHTT) in HD mouse models can modulate disease phenotypes, highlighting the key role of HTT PTMs in the pathogenesis of HD. These findings have led to increased interest in developing small molecules to modulate HTT PTMs in order to decrease mHTT toxicity. However, the therapeutic efficacy of pharmacological modulation of HTT PTMs in preclinical HD models remains largely unknown. HTT is palmitoylated at cysteine 214 by the huntingtin-interacting protein 14 (HIP14 or ZDHHC17) and 14-like (HIP14L or ZDHHC13) acyltransferases. Here, we assessed if HTT palmitoylation should be regarded as a therapeutic target to treat HD by (1) investigating palmitoylation dysregulation in rodent and human HD model systems, (2) measuring the impact of mHTT-lowering therapy on brain palmitoylation, and (3) evaluating if HTT palmitoylation can be pharmacologically modulate. We show that palmitoylation of mHTT and some HIP14/HIP14L-substrates is decreased early in multiple HD mouse models, and that aging further reduces HTT palmitoylation. Lowering mHTT in the brain of YAC128 mice is not sufficient to rescue aberrant palmitoylation. However, we demonstrate that mHTT palmitoylation can be normalized in COS-7 cells, in YAC128 cortico-striatal primary neurons and HD patient-derived lymphoblasts using an acyl-protein thioesterase (APT) inhibitor. Moreover, we show that modulating palmitoylation reduces mHTT aggregation and mHTT-induced cytotoxicity in COS-7 cells and YAC128 neurons. HighlightsO_LIPalmitoylation of mHTT is reduced in multiple transgenic HD mouse models C_LIO_LIHTT palmitoylation decreases with increasing polyQ length in HD patient cells C_LIO_LImHTT-lowering in mouse brains does not rescue aberrant palmitoylation C_LIO_LImHTT palmitoylation in HD patient-derived cells can be rescued via APT inhibition C_LIO_LIPromoting palmitoylation reduces mHTT aggregation and cytotoxicity in vitro C_LI

neuroscience↗

bioRxiv2019

The interaction of aging and oxidative stress contributes to pathogenesis in mouse and human Huntington disease neurons

Huntington disease (HD) is a fatal, inherited neurodegenerative disorder caused by a mutation in huntingtin (HTT). While mutant HTT is present ubiquitously throughout life, HD onset typically occurs in mid-life. Oxidative damage accumulates in the aging brain and is a feature of HD. We sought to interrogate the roles and interaction of age and oxidative stress in HD using primary Hu97/18 mouse neurons, neurons differentiated from HD patient induced pluripotent stem cells (iPSCs), and mice. We find that primary neurons must be matured in culture for canonical stress responses to occur. Furthermore, when aging is accelerated in mature HD neurons, mutant HTT accumulates and sensitivity to oxidative stress is selectively enhanced. Furthermore, we observe HD-specific phenotypes in iPSC-derived neurons and mouse brains that have undergone accelerated aging. These findings suggest a role for aging in HD pathogenesis and interaction between biological age of HD neurons and sensitivity to exogenous stress.

neuroscience↗

bioRxiv2017

Identification of a novel caspase cleavage site in huntingtin that regulates mutant huntingtin clearance.

Huntington disease (HD) is a progressive neurodegenerative disease that initially affects the striatum leading to changes in behavior and loss of motor coordination. It is caused by an expansion in the polyglutamine repeat at the N-terminus of huntingtin (HTT) that leads to aggregation of mutant HTT. The loss of wildtype function, in combination with the toxic gain of function mutation, initiates various cell death pathways. Wildtype and mutant HTT are regulated by different post-translational modifications that can positively or negatively regulate their function or toxicity. In particular, we have previously shown that caspase cleavage of mutant HTT at amino acid position aspartate 586 (D586) by caspase-6 is critical for the pathogenesis of the disease in an HD mouse model. Herein, we describe the identification of a new caspase cleavage site at position D572 that is mediated by caspase-1. Inhibition of caspase-1 also inhibits cleavage at D586 through inhibition of caspase-6. Inhibition of caspase cleavage at D572 significantly decreases mutant HTT aggregation and significantly increased the turnover of soluble mutant HTT. This suggests that caspase-1 may be a viable target to inhibit caspase cleavage of mutant HTT at both D572 and D586 to promote mutant HTT clearance.

neuroscience↗