Biology subjects

Abel, T. J.

Publications and source records attributed to Abel, T. J..

7 recordsLinked to original sources

bioRxiv2026

Adenosylhomocysteinase drives epigenetic and metabolic reprogramming in ZFTA-RELA ependymoma

Supratentorial ependymomas (ST-EPNs) are aggressive pediatric brain tumors predominantly driven by the recurrent ZFTA-RELA fusion, an oncogenic chromatin regulator that establishes an aberrant transcriptional program. Although metabolic pathways modulate epigenetic regulation by controlling the availability of metabolic cofactors, how ZFTA-RELA coordinates metabolic reprogramming with epigenetic regulation is not well understood. Here, we show that ZFTA-RELA-positive ependymomas exhibit enhanced methionine dependency, elevated adenosyl homocysteinase (AHCY) expression, and epigenetically control aspartate metabolism for tumor growth. Mechanistically, ZFTA-RELA upregulates AHCY, increasing cellular methylation potential which promotes H3K4me3-dependent expression of CAD, the first enzyme complex of de novo pyrimidine biosynthesis, while simultaneously enforcing H3K27me3 mediated repression of ASNS, which encodes asparagine synthetase. Through this coordinated epigenetic program, aspartate utilization is directed toward pyrimidine biosynthesis while endogenous asparagine production is limited. Restricting S-adenosylmethionine availability or genetically or pharmacologically inhibiting AHCY reverses these epigenetic states, leading to CAD downregulation, ASNS upregulation, impaired nucleotide synthesis, and suppression of tumor growth in vitro and in vivo. Similarly, EZH2 inhibition also restores ASNS expression and suppresses tumor proliferation. These findings suggest that ZFTA-RELA EPN maintain ASNS-low phenotype which conditionally make them dependent on extracellular asparagine. We further show that enhanced de novo pyrimidine synthesis not only supports nucleotide production but also provides UDP-sugars required for N-glycosylation and stabilization of the asparagine transporter SLC1A5, thereby promoting extracellular asparagine uptake and tumor proliferation. Collectively, our findings identify AHCY as a critical metabolic regulator of epigenetic and metabolic reprogramming that drives pyrimidine synthesis and establishes extracellular asparagine dependency, revealing actionable metabolic vulnerabilities in ZFTA-RELA-positive ST-EPNs.

cancer biology↗

bioRxiv2024

A hierarchy of processing complexity and timescales for natural sounds in human auditory cortex

Efficient behavior is supported by humans ability to rapidly recognize acoustically distinct sounds as members of a common category. Within auditory cortex, there are critical unanswered questions regarding the organization and dynamics of sound categorization. Here, we performed intracerebral recordings in the context of epilepsy surgery as 20 patient-participants listened to natural sounds. We built encoding models to predict neural responses using features of these sounds extracted from different layers within a sound-categorization deep neural network (DNN). This approach yielded highly accurate models of neural responses throughout auditory cortex. The complexity of a cortical sites representation (measured by the depth of the DNN layer that produced the best model) was closely related to its anatomical location, with shallow, middle, and deep layers of the DNN associated with core (primary auditory cortex), lateral belt, and parabelt regions, respectively. Smoothly varying gradients of representational complexity also existed within these regions, with complexity increasing along a posteromedial-to-anterolateral direction in core and lateral belt, and along posterior-to-anterior and dorsal-to-ventral dimensions in parabelt. When we estimated the time window over which each recording site integrates information, we found shorter integration windows in core relative to lateral belt and parabelt. Lastly, we found a relationship between the length of the integration window and the complexity of information processing within core (but not lateral belt or parabelt). These findings suggest hierarchies of timescales and processing complexity, and their interrelationship, represent a functional organizational principle of the auditory stream that underlies our perception of complex, abstract auditory information.

neuroscience↗

bioRxiv2024

Functional Heterogeneity of Voice-Encoding Cortex Revealed by Clinical Language Mapping

Regions in the superior temporal sulcus and gyrus have been heavily implicated in voice-selective responses in human auditory cortex. Despite an apparent specialization for the encoding of human voice, research outside the auditory domain suggests that these areas likely participate in additional neural processes including speech processing and production. The aim of the current study was to combine results of electrophysiological recording and clinical stimulation mapping procedures in patients undergoing stereoelectroencephalography (sEEG) to explore potential functional heterogeneity in voice-encoding cortex. Both channels that demonstrated voice-encoding properties and channels critically implicated in language functioning were heavily concentrated in the left STG/S. Analysis of functional overlap revealed channels in the posterior STG/S that appear to be involved in both voice encoding and language. Strength of voice encoding in these functionally diverse sites was not significantly different from sites that were implicated in voice encoding alone. Our findings add to prior observations of functional heterogeneity in the STG/S and contribute to proposed models of speech perception. We discuss these results in the context of the utility of electrophysiological methods in mapping cortical networks and identifying regions essential for functioning.

neuroscience↗

bioRxiv2024

Intracranial Mapping of Response Latencies and Task Effects for Spoken Syllable Processing in the Human Brain

Prior lesion, noninvasive-imaging, and intracranial-electroencephalography (iEEG) studies have documented hierarchical, parallel, and distributed characteristics of human speech processing. Yet, there have not been direct, intracranial observations of the latency with which regions outside the temporal lobe respond to speech, or how these responses are impacted by task demands. We leveraged human intracranial recordings via stereo-EEG to measure responses from diverse forebrain sites during (i) passive listening to /bi/ and /pi/ syllables, and (ii) active listening requiring /bi/-versus-/pi/ categorization. We find that neural response latency increases from a few tens of ms in Heschls gyrus (HG) to several tens of ms in superior temporal gyrus (STG), superior temporal sulcus (STS), and early parietal areas, and hundreds of ms in later parietal areas, insula, frontal cortex, hippocampus, and amygdala. These data also suggest parallel flow of speech information dorsally and ventrally, from HG to parietal areas and from HG to STG and STS, respectively. Latency data also reveal areas in parietal cortex, frontal cortex, hippocampus, and amygdala that are not responsive to the stimuli during passive listening but are responsive during categorization. Furthermore, multiple regions--spanning auditory, parietal, frontal, and insular cortices, and hippocampus and amygdala--show greater neural response amplitudes during active versus passive listening (a task-related effect). Overall, these results are consistent with hierarchical processing of speech at a macro level and parallel streams of information flow in temporal and parietal regions. These data also reveal regions where the speech code is stimulus-faithful and those that encode task-relevant representations. New & NoteworthyWe leverage direct, intracranial electroencephalography recordings to document speech information flow through diverse sites in the human forebrain, including areas where reported electrode coverage has historically been limited. Our data are consistent with hierarchical processing of speech at a macro level and parallel streams of information flow in temporal and parietal regions. They also reveal regions in the auditory pathway where stimulus-faithful speech codes are transformed to behaviorally relevant representations of speech content.

neuroscience↗

bioRxiv2022

Auditory cortical responses to speech are shaped by statistical learning of short-term speech input regularities

Speech perception presents an exemplary model of how neurobiological systems flexibly adjust when input departs from the norm. Dialects, accents, and even head colds can negatively impact comprehension by shifting speech from listeners expectations. Comprehension improves with exposure to shifted speech regularities, but there is no neurobiological model of this rapid learning. We used electroencephalography to examine human auditory cortical responses to utterances that varied only in fundamental frequency (F0, perceived as voice pitch) as we manipulated the statistical distributions of speech acoustics across listening contexts. Participants overtly categorized speech sampled across two acoustic dimensions that signal /b/ from /p/ (voice onset time [VOT] and F0) to model typical English speech regularities or an expectation-violating accent. These blocks were interleaved with passive exposure to two F0-distinguished test stimuli presented in an oddball ratio to elicit a cortical mismatch negativity (MMN) response. F0 robustly influenced speech categorization when short-term regularities aligned with English but F0 exerted no influence in the context of the accent. The short-term regularities modulated event-related potentials evoked by F0-distinguished test stimuli across both N1 and P3 temporal windows and, for P3 amplitude, there was a strong correlation with perceptual down-weighting of F0. The influence of the short-term regularities persisted to impact MMN in interleaved passive listening blocks when regularities mirrored English but were absent when regularities conveyed the accent. Thus, cortical response is modulated as a function of statistical regularities of the listening context, likely reflecting both early dimension encoding and later categorization. Significance StatementSpeech perception is a quintessential example of how neurobiological systems flexibly adjust when input departs from the norm. Perception is well-tuned to native-language speech patterns. Yet it adjusts when speech diverges from expectations, as with a foreign accent. We observe that the effectiveness of specific cues in speech, like the pitch of a voice, in signaling phonemes like /b/ versus /p/ is dynamically re-weighted when speech violates native-language expectations. We find that this re-weighting is mirrored in cortical responses that reflect both early acoustic dimension encoding and also in later responses linked to phoneme categorization. The results implicate dynamic adjustments in the mapping of speech to cortical representations, as modulated by statistical regularities experienced across local speech input.

neuroscience↗

bioRxiv2021

Categorical encoding of voice in human superior temporal cortex

The ability to recognize abstract features of voice during auditory perception is a complex, yet poorly understood, feat of human audition. For the listener, this occurs in near-automatic fasion to seamlessly extract complex cues from a highly variable auditory signal. Voice perception depends on specialized regions of auditory cortex, including superior temporal gyrus (STG) and superior temporal sulcus (STS). However, the nature of voice encoding at the cortical level remains poorly understoood. We leverage intracerebral recordings across human auditory cortex during presentation of voice and non-voice acoustic stimuli to examine voice encoding in auditory cortex, in eight patient-participants undergoing epilepsy surgery evaluation. We show that voice-selectivity increases along the auditory hierarchy from supratemporal plane (STP) to the STG and STS. Results show accurate decoding of vocalizations from human auditory cortical activity even in the complete absence of linguistic content. These findings show an early, less-selective temporal window of neural activity in the STG and STS followed by a sustained, strongly voice-selective window. We then developed encoding models that demonstrate divergence in the encoding of acoustic features along the auditory hierarchy, wherein STG/STS responses were best explained by voice category as opposed to the acoustic features of voice stimuli. This is in contrast to neural activity recorded from STP, in which responses were accounted for by acoustic features. These findings support a model of voice perception that engages categorical encoding mechanisms within STG and STS. Significance StatementVoice perception occurs via specialized networks in higher order auditory cortex, yet how voice features are encoded remains a central unanswered question. With human intracerebral recordings of auditory cortex, we provide evidence for categorical encoding of voice in STG and STS and occurs in the absence of linguistic content. This selectivity strengthens after an initial onset response and cannot be explained by simple acoustic features. Together, these data support the existence of sites within STG and STS that are specialized for voice perception.

neuroscience↗

bioRxiv2017

Surgically disconnected temporal pole exhibits resting functional connectivity with remote brain regions

Functional connectivity, as measured by resting-state fMRI, has proven a powerful method for studying brain systems in the context of behavior, development, and disease states. However, the relationship of functional connectivity to structural connectivity remains unclear. If functional connectivity relies on structural connectivity, then anatomical isolation of a brain region should eliminate functional connectivity with other brain regions. We tested this by measuring functional connectivity of the surgically disconnected temporal pole in resection patients (N=5; mean age 37; 2F, 3M). Functional connectivity was evaluated based on coactivation of whole-brain fMRI data with the average low-frequency BOLD signal from disconnected tissue in each patient. In sharp contrast to our prediction, we observed significant functional connectivity between the disconnected temporal pole and remote brain regions in each disconnection case. These findings raise important questions about the neural bases of functional connectivity measures derived from the fMRI BOLD signal.

neuroscience↗