Temporo-cerebellar connectivity underlies timing constraints in audition
Abstract
The flexible and efficient adaptation to dynamic, rapid changes in the auditory environment likely involves generating and updating of internal models. Such models arguably exploit connections between the neocortex and the cerebellum, supporting proactive adaptation. Here we tested whether temporo-cerebellar disconnection is associated with the processing of sound at short-timescales. First, we identify lesion-specific deficits for the encoding of short timescale spectro-temporal non-speech and speech properties in patients with left posterior temporal cortex stroke. Second, using lesion- guided probabilistic tractography in healthy participants, we revealed bidirectional temporo-cerebellar connectivity with cerebellar dentate nuclei and crura I/II. These findings support the view that the encoding and modeling of rapidly modulated auditory spectro-temporal properties can rely on a temporo-cerebellar interface. We discuss these findings in view of the conjecture that proactive adaptation to a dynamic environment via internal models is a generalizable principle.
Data availability
There is restricted access to the data due to German legal regulations of patient protection.We have made all data which we can legally share accessible via figure share (link is included in the resource statement). We have provided all data (lesion data, scripts, behavioral data that allowed lesion-symptom mapping) in our figure share account for reproduction of the critical seed region for a tracking analysis.Anonymisation of MRI/DTI data is not allowed either through the ethics agreement nor the participants' consent. We cannot do anything about this as these are the legal regulations that we have to deal with. We have made a clear statement that we seek open dialogue about how we have analysed our data. Further, given the data that we have provided, any interested researcher can (1) approach us about our analysis, (2) can take a set of open source age-matched structural MRI/DTI data to replicated our results
Article and author information
Author details
Funding
Deutsche Forschungsgemeinschaft (DFG KO 2268/6-1)
- Sonja Kotz
Dissertation award University of Leipzig (none)
- Anika Stockert
Max-Planck-Gesellschaft (none)
- Sonja Kotz
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: The protocol of the current research was approved by the ethics committee of the University of Leipzig, Germany (Protocol Number: 953). All participants provided written, informed consent before the start of data collection.
Copyright
© 2021, Stockert et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 905
- views
-
- 153
- downloads
-
- 14
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Cell Biology
- Neuroscience
Reactive astrocytes play critical roles in the occurrence of various neurological diseases such as multiple sclerosis. Activation of astrocytes is often accompanied by a glycolysis-dominant metabolic switch. However, the role and molecular mechanism of metabolic reprogramming in activation of astrocytes have not been clarified. Here, we found that PKM2, a rate-limiting enzyme of glycolysis, displayed nuclear translocation in astrocytes of EAE (experimental autoimmune encephalomyelitis) mice, an animal model of multiple sclerosis. Prevention of PKM2 nuclear import by DASA-58 significantly reduced the activation of mice primary astrocytes, which was observed by decreased proliferation, glycolysis and secretion of inflammatory cytokines. Most importantly, we identified the ubiquitination-mediated regulation of PKM2 nuclear import by ubiquitin ligase TRIM21. TRIM21 interacted with PKM2, promoted its nuclear translocation and stimulated its nuclear activity to phosphorylate STAT3, NF-κB and interact with c-myc. Further single-cell RNA sequencing and immunofluorescence staining demonstrated that TRIM21 expression was upregulated in astrocytes of EAE. TRIM21 overexpressing in mice primary astrocytes enhanced PKM2-dependent glycolysis and proliferation, which could be reversed by DASA-58. Moreover, intracerebroventricular injection of a lentiviral vector to knockdown TRIM21 in astrocytes or intraperitoneal injection of TEPP-46, which inhibit the nuclear translocation of PKM2, effectively decreased disease severity, CNS inflammation and demyelination in EAE. Collectively, our study provides novel insights into the pathological function of nuclear glycolytic enzyme PKM2 and ubiquitination-mediated regulatory mechanism that are involved in astrocyte activation. Targeting this axis may be a potential therapeutic strategy for the treatment of astrocyte-involved neurological disease.
-
- Neuroscience
Alzheimer’s disease (AD) leads to progressive memory decline, and alterations in hippocampal function are among the earliest pathological features observed in human and animal studies. GABAergic interneurons (INs) within the hippocampus coordinate network activity, among which type 3 interneuron-specific (I-S3) cells expressing vasoactive intestinal polypeptide and calretinin play a crucial role. These cells provide primarily disinhibition to principal excitatory cells (PCs) in the hippocampal CA1 region, regulating incoming inputs and memory formation. However, it remains unclear whether AD pathology induces changes in the activity of I-S3 cells, impacting the hippocampal network motifs. Here, using young adult 3xTg-AD mice, we found that while the density and morphology of I-S3 cells remain unaffected, there were significant changes in their firing output. Specifically, I-S3 cells displayed elongated action potentials and decreased firing rates, which was associated with a reduced inhibition of CA1 INs and their higher recruitment during spatial decision-making and object exploration tasks. Furthermore, the activation of CA1 PCs was also impacted, signifying early disruptions in CA1 network functionality. These findings suggest that altered firing patterns of I-S3 cells might initiate early-stage dysfunction in hippocampal CA1 circuits, potentially influencing the progression of AD pathology.