Biology subjects

Rupp, A.

Publications and source records attributed to Rupp, A..

8 recordsLinked to original sources

bioRxiv2025

Neuronal SEL1L-HRD1 ERAD regulates one-carbon metabolism and is essential for motor function and survival

Hypomorphic variants in the SEL1L-HRD1 ER-associated degradation (ERAD) complex have been linked to severe neurological syndromes in children, including neurodevelopmental delay, intellectual disability, motor dysfunction, and early death. Despite this association, its physiological importance and underlying mechanisms in neurons remain poorly understood. Here, we show that neuronal SEL1L-HRD1 ERAD is essential for maintaining one-carbon metabolism, motor function, and overall viability. Neuron-specific deletion of Sel1L in mice (Sel1LSynCre) resulted in growth retardation, severe motor impairments, and early mortality by 9 weeks of age--mirroring core clinical features observed in affected patients--despite preserved neuronal numbers and only modest ER stress. Multi-omics analyses, including single-nucleus RNA sequencing and metabolomics, revealed significant dysregulation of one-carbon metabolism in ERAD-deficient brains. This included activation of the serine, folate, and methionine pathways, accompanied by elevated levels of S-adenosylmethionine and related metabolites, likely resulted from induction of the integrated stress response (ISR). Together, these findings uncover a previously unappreciated role for neuronal SEL1L-HRD1 ERAD in coordinating ER protein quality control with metabolic adaptation, providing new insight into the molecular basis of ERAD-related neurodevelopmental disease. SummaryUsing a neuron-specific Sel1L knockout mouse model, we demonstrate that Sel1L deficiency activates integrated stress responses, rewires one-carbon metabolism, and impairs motor function and survival.

cell biology↗

bioRxiv2025

Combined MEG and EEG suggest a limbic source network of the P3 in retrosplenial cortex, insula, and hippocampus

The event-related P3 is evoked by most task-relevant or salient stimuli, but its neural sources remain controversial. Here we reevaluate the role of hippocampus, unambiguously demonstrated in intracranial recordings, and retro-splenial cortex as sources of the P3 in magneto- and electroencephalography. Observers detected rare visual targets of a deviant shape and ignored rare non-targets of a deviant color. Source analysis was based on noise-normalized minimum-norm estimates in an individual, MRI-based source space. Critically, the cortical source space was extended to include the cornu ammonis of the hippocampus. Source analysis at the P3 peak showed strong sources in retrosplenial cortex and a weaker source in hippocampus. Activity in left somatosensory cortex was related to the button presses. Subsequent activity was observed in insula and anterior mid-cingulate cortex. Further simulation studies explored the spread of these sources and the plausibility of their combination to explain the data, and demonstrate that the combination of magneto- and electroencephalography increased the specificity of the source estimate. Overall, these data support an interpretation of the P3 as physiological indicator of activity in the limbic system for target and distractor stimuli.

neuroscience↗

bioRxiv2025

A single dorsal vagal complex circuit mediates the aversive and anorectic responses to GLP1R agonists

GLP-1 receptor agonists (GLP1RAs) effectively reduce feeding to treat obesity, although nausea and other aversive side effects of these drugs can limit their use. Brainstem circuits that promote satiation and that mediate the physiologic control of body weight can be distinguished from those that cause aversion. It remains unclear whether brainstem Glp1r neurons contribute to the normal regulation of energy balance and whether GLP1RAs control appetite via circuits distinct from those that mediate aversive responses, however. Hence, we defined roles for AP and NTS Glp1r-expressing neurons (APGlp1r and NTSGlp1r neurons, respectively) in the physiologic control of body weight, the GLP1RA-dependent suppression of food intake, and the GLP1RA-mediated stimulation of aversive responses. While silencing non-aversive NTSGlp1r neurons interfered with the physiologic restraint of feeding and body weight, restoring NTSGlp1r neuron Glp1r expression on an otherwise Glp1r-null background failed to enable long-term body weight suppression by GLP1RAs. In contrast, selective Glp1r expression in APGlp1r neurons restored both aversive responses and long-term body weight suppression by GLP1RAs. Thus, while non-aversive NTSGlp1r neurons control physiologic feeding, aversive APGlp1r neurons mediate both the anorectic and weight loss effects of GLP1RAs, dictating the functional inseparability of these pharmacologic GLP1RA responses at a circuit level.

neuroscience↗

bioRxiv2024

Cell-type-specific cholinergic control of granular retrosplenial cortex with implications for angular velocity coding across brain states

Cholinergic receptor activation enables the persistent firing of cortical pyramidal neurons, providing a key cellular basis for theories of spatial navigation involving working memory, path integration, and head direction encoding. The granular retrosplenial cortex (RSG) is important for spatially-guided behaviors, but how acetylcholine impacts RSG neurons is unknown. Here, we show that a transcriptomically, morphologically, and biophysically distinct RSG cell-type - the low-rheobase (LR) neuron - has a very distinct expression profile of cholinergic muscarinic receptors compared to all other neighboring excitatory neuronal subtypes. LR neurons do not fire persistently in response to cholinergic agonists, in stark contrast to all other principal neuronal subtypes examined within the RSG and across midline cortex. This lack of persistence allows LR neuron models to rapidly compute angular head velocity (AHV), independent of cholinergic changes seen during navigation. Thus, LR neurons can consistently compute AHV across brain states, highlighting the specialized RSG neural codes supporting navigation.

neuroscience↗

bioRxiv2024

Reduction of right-hemispheric auditory cortex activity in response to speech in more experienced paediatric cochlear implant users

In case of severe hearing loss early in life or congenital deafness, cochlear implants (CIs) represent the method of choice to restore hearing and enable language acquisition. While speech intelligibility has been shown to improve during the first year after implantation to then reach a plateau, the underlying neuroplastic changes are poorly understood. Here, we longitudinally compared the cortical processing of speech stimuli in a case-control design with two groups of pre-lingually deafened CI users (4.4 vs. 25.8 months of CI experience) and an age-matched control group with normal hearing (NH; mean group ages [~]9 years). In two experiments, participants were presented with running speech and vowel sequences while fNIRS and EEG data were obtained simultaneously. Despite trends in this direction, cortical activity did not increase significantly with more CI experience and did not approach the higher levels observed in the NH controls. However, in the speech experiment, the less experienced CI group showed an abnormal shift of activity to the right hemisphere not observed in the other two groups. These results hence imply that adaptation to CI-based hearing is not characterised by a gradual increase of activity in left-hemispheric language network, but a reduction of abnormal activity elsewhere.

neuroscience↗

bioRxiv2023

The auditory P2 evoked by speech sounds consists of two separate subcomponents

The P2 component of the auditory evoked potential is commonly thought to reflect acoustic stimulus properties as well as prior exposure to the materials, rather than change-related cortical activity. Here, we challenge this view by showing that the P2 is strongly increased in response to voice pitch changes with a stepwise pattern compared to changes in dynamic pitch contours typical for natural speech, and also reflects the magnitude of these pitch changes. Furthermore, it is demonstrated that neither the P2 nor any other component are affected by the harmonicity of the materials. Despite no prior exposure, artificially created inharmonic versions of the speech materials elicited similar activity throughout auditory cortex. This suggests that so-called harmonic template neurons observed in animal studies are either absent or do not exist in sufficient number in human auditory cortex to detect their activity extracranially. Crucially, both morphology and source reconstructions of the EEG data showed that the P2 appears to consist of two separate subcomponents. Whereas source activity for the "P2a" was strongest in right auditory cortex, the subsequent "P2b" included generators spread across auditory cortex and association areas, bilaterally. The two subcomponents thus likely reflect processing at different stages of the auditory pathway.

neuroscience↗

bioRxiv2020

Cortical activity evoked by voice pitch changes: a combined fNIRS and EEG study

Numerous studies have investigated the cortical representation and time course of responses to auditory signals with and without pitch. However, little is known regarding the responses evoked by pitch changes. To study the spatial as well as temporal characteristics of cortical activity elicited by voice pitch changes, combined functional near-infrared spectroscopy (fNIRS) and electroencephalography (EEG) data were obtained from normal-hearing listeners presented with continuous vowel sequences in which the prosodic contours either varied between the individual vowels or were the same throughout. The fNIRS topographies and the EEG source reconstructions indicated additional right-hemispheric activity anterior to the primary auditory cortex and in the superior temporal sulcus for sequences with variable prosody. Additionally, the time courses of the fNIRS signals showed that activity was more sustained in response to sequences with changing prosodic contours. The EEG data revealed a similar pattern for the P2 amplitude, which was smaller during the second half for blocks with fixed prosody, whereas the P1 was consistently larger for sequences with variable prosody. Moreover, the sources of the P2, but not the P1, were lateralised to the right, suggesting that the hemispheric asymmetry in the processing of voice pitch changes develops over time.

neuroscience↗

bioRxiv2020

Auditory cortex activity measured with functional near-infrared spectroscopy is susceptible to masking by cortical blood stealing

To validate the use of functional near-infrared spectroscopy (fNIRS) in auditory perception experiments, combined fNIRS and electroencephalography (EEG) data were obtained from normal-hearing subjects passively listening to speech-like stimuli without linguistic content. The fNIRS oxy-haemoglobin (HbO) results were found to be inconsistent with the deoxy-haemoglobin (HbR) and EEG data, as they were dominated by pronounced cerebral blood stealing in anterior- to-posterior direction. This large-scale bilateral gradient in the HbO data masked the right-lateralised neural activity in the auditory cortex that was clearly evident in the HbR data and EEG source reconstructions. When the subjects were subsequently split into subgroups with more positive or more negative HbO responses in the right auditory cortex, the former group surprisingly showed smaller event-related potentials, less activity in frontal cortex, and increased EEG alpha power, all indicating reduced attention and vigilance. These findings thus suggest that positive HbO responses in the auditory cortex may not necessarily be a favourable result when investigating auditory perception using fNIRS. More generally, the results show that the interpretation of fNIRS HbO signals can be misleading and demonstrate the benefits of combined fNIRS-EEG analyses in resolving this issue.

neuroscience↗