Biology subjects

Rudolph, S.

Publications and source records attributed to Rudolph, S..

8 recordsLinked to original sources

bioRxiv2026

Neural Activation of Human Primary Intestinal Enteroendocrine L-cells

Intestinal enteroendocrine L-cells play a central role in metabolic homeostasis by secreting the gut hormones GLP-1 and PYY, but whether and how neural signals regulate human L-cell function remains poorly understood. This gap reflects the limited availability of human model systems enriched for mature L-cells. Here, we establish a differentiation strategy that generates human donor-derived ileal organoids with markedly increased L-cell abundance, enabling functional interrogation of L-cell physiology in their basal state. Using this system, we show that cholinergic and adrenergic stimuli activate L-cells, triggering calcium influx and secretion of GLP-1 and PYY. Pharmacological analysis reveals that cholinergic regulation of human L-cells is mediated predominantly through M3 muscarinic receptors, while adrenergic regulation is mediated through the {beta}1 adrenergic receptor. Neurotransmitter-evoked activation also initiates gap junction-dependent calcium waves that propagate across the intestinal epithelium; however, disruption of epithelial coupling by abolishing calcium propagation does not impair hormone secretion. Together, these findings identify L-cells as integrative hubs that couple neural signals to gut hormone secretion and epithelial calcium waves, providing mechanistic insight into the gut-brain axis and how the nervous system regulates intestinal endocrine function in human intestine.

cell biology↗

bioRxiv2026

Hippocampal CA2 modulates trace fear conditioning through circuit-specific control of CA1

Forming associations between temporally separated events depends on pathways linking the CA1, the subiculum (SUB), and the entorhinal cortex. The degree to which this process requires the CA2, which shares extensive connectivity with these regions, remains unknown. Using trace fear conditioning (TFC), where mice learn to associate a tone and shock separated by a temporal gap, we showed that the dCA2 contributes to TFC. Interestingly, whereas chronic dCA2 inhibition decreased cue-associated freezing, acute dCA2[->]dCA1 projection inhibition increased freezing. Combined with differential effects on cFos expression, this suggests that global and projection-specific perturbations of the dCA2 have distinct effects on TFC and hippocampal activity states. Fiber photometry revealed that dCA2[->]dCA1 activity shifted from tone responsiveness during conditioning to expected shock activation during recall, consistent with learning-associated activity remodeling. Together, these findings identify the dCA2 as a contributor to TFC and implicate dCA2[->]dCA1 signaling in shaping fear expression across learning and recall.

neuroscience↗

bioRxiv2026

MNRR1 is required for Triple Negative Breast Cancer growth and metastasis and can be targeted by repurposed drugs.

Despite progress in recent decades, breast cancers remain the most diagnosed malignancies, and second leading cause of cancer death, in women. Although improved screening and systemic and endocrine adjuvant approaches have contributed to major declines in breast cancer mortality, current standard of care drugs are extremely toxic, and many women continue to be overtreated. Although nearly two-thirds of breast cancers are hormone-responsive, aggressive subtypes, particularly Triple Negative Breast Cancer (TNBC), still lack safe oral medications. Recently the roles that mitochondria play in TNBC carcinogenesis, metastasis, and resistance to treatment have garnered a great deal of attention. Contrary to the popular dogma that cancer cells are powered by glycolysis, metastatic breast cancer cells have enhanced mitochondrial function. Our work identified that Mitochondrial Nuclear Retrograde Regulator 1 (MNRR1; also, CHCHD2, PARK22), a key coordinator of mitochondrial-nuclear crosstalk that is physically present in both compartments, is overexpressed in TNBC cells and is an important regulator of metastasis signaling. We have identified Heat Shock Factor 1 (HSF1) as the main transcription factor that activates the MNRR1 promoter in TNBC cell lines. In the mitochondria, MNRR1 protein facilitates ATP production and inhibits apoptosis, whereas in the nucleus it regulates the transcription of stress-responsive genes including several required for epithelial to mesenchymal transition (EMT), metabolic flexibility, and cell growth. Thus, each of the bi-organellar functions of MNRR1 constitutes processes regarded as hallmarks of cancer. For reasons that are not yet fully understood, MNRR1 levels display a significant and robust ancestry bias, showing increased expression in tumor samples from Non-Hispanic Black (NHB) women when compared to disease-matched tumors from Non-Hispanic White (NHW) patients. It is possible that increased levels of MNRR1 may underlie the aggressive metastatic phenotype observed in many NHB patients. In further support of this observation, loss of MNRR1 function, either genetically or by use of inhibitors, reduces TNBC growth and metastasis. MNRR1 therefore is an attractive therapeutic target that could be exploited for design of novel therapies or as adjuncts to existing ones.

cancer biology↗

bioRxiv2024

Neocortical long-range inhibition promotes cortical synchrony and sleep

Sleep and wakefulness are associated with distinct cortical patterns of rhythmic activity. During low-arousal states such as slow wave sleep, synchronous low-frequency rhythms dominate activity across widespread cortical regions. Although inhibitory neurons are increasingly recognized as key players of cortical state, the in vivo circuit mechanisms coordinating synchronized activity across local and distant neocortical networks remain poorly understood. Here, we show that somatostatin and chondrolectin co-expressing cells (Sst-Chodl), a sparse and genetically distinct class of neocortical GABAergic inhibitory neurons, are selectively active during low-arousal states and largely silent during periods of high arousal. In contrast to most neocortical inhibitory neurons, Sst-Chodl cells, despite being extremely sparse, exert widespread influence across the neocortex via long-range axons that simultaneously target multiple regions. Selective activation of Sst-Chodl cells is sufficient to promote multi-region cortical synchronization characteristic of low-arousal states and to induce sleep. Together, these findings show that long-range Sst-Chodl inhibitory neurons not only track behavioral state but can actively promote sleep-like cortical activity and sleep behavior, highlighting an important contribution of cortical circuits to sleep regulation alongside established subcortical mechanisms.

neuroscience↗

bioRxiv2021

Candelabrum cells are molecularly distinct, ubiquitous interneurons of the cerebellar cortex with specialized circuit properties

To understand how the cerebellar cortex transforms mossy fiber (MF) inputs into Purkinje cell (PC) outputs, it is vital to delineate the elements of this circuit. Candelabrum cells (CCs) are enigmatic interneurons of the cerebellar cortex that have been identified based on their morphology, but their electrophysiological properties, synaptic connections, and function remain unknown. Here we clarify these properties using electrophysiology, snRNA sequencing, in situ hybridization, and serial electron microscopy. We find that CCs are the most abundant PC layer interneuron. They are GABAergic, molecularly distinct, and present in all cerebellar lobules. Their high resistance renders CC firing highly sensitive to synaptic inputs. CCs are excited by MFs and granule cells, and strongly inhibited by PCs. CCs in turn inhibit molecular layer interneurons, which leads to PC disinhibition. Thus, inputs, outputs and local signals all converge onto CCs to allow them to assume a unique role in controlling cerebellar output.

neuroscience↗

bioRxiv2021

Purkinje cell outputs selectively inhibit a subset of unipolar brush cells in the input layer of the cerebellar cortex

Circuitry of the cerebellar cortex is regionally and functionally specialized. Unipolar brush cells (UBCs), and Purkinje cell (PC) synapses made by axon collaterals in the granular layer, are both enriched in areas that control balance and eye-movement. Here we find a link between these specializations: PCs preferentially inhibit mGluR1-expressing UBCs that respond to mossy fiber inputs with long lasting increases in firing, but PCs do not inhibit mGluR1-lacking UBCs. PCs inhibit about 29% of mGluR1-expressing UBCs by activating GABAA receptors (GABAARs) and inhibit almost all mGluR1-expressing UBCs by activating GABABRs. PC to UBC synapses allow PC output to regulate the input layer of the cerebellar cortex in diverse ways. GABAAR-mediated feedback is fast, unreliable, noisy, and suited to linearizing input-output curves and decreasing gain. Slow GABABR-mediated inhibition allows elevated PC activity to sharpen the input-output transformation of UBCs, and allows dynamic inhibitory feedback of mGluR1-expressing UBCs.

neuroscience↗

bioRxiv2020

A transcriptomic atlas of the mouse cerebellum reveals regional specializations and novel cell types

The cerebellum is a well-studied brain structure with diverse roles in motor learning, coordination, cognition, and autonomic regulation. Nonetheless, a complete inventory of cerebellar cell types is presently lacking. We used high-throughput transcriptional profiling to molecularly define cell types across individual lobules of the adult mouse cerebellum. Purkinje and granule neurons showed considerable regional specialization, with the greatest diversity occurring in the posterior lobules. For multiple types of cerebellar interneurons, the molecular variation within each type was more continuous, rather than discrete. For the unipolar brush cells (UBCs)--an interneuron population previously subdivided into two discrete populations--the continuous variation in gene expression was associated with a graded continuum of electrophysiological properties. Most surprisingly, we found that molecular layer interneurons (MLIs) were composed of two molecularly and functionally distinct types. Both show a continuum of morphological variation through the thickness of the molecular layer, but electrophysiological recordings revealed marked differences between the two types in spontaneous firing, excitability, and electrical coupling. Together, these findings provide the first comprehensive cellular atlas of the cerebellar cortex, and outline a methodological and conceptual framework for the integration of molecular, morphological, and physiological ontologies for defining brain cell types.

genomics↗

bioRxiv2019

Cerebellum-specific deletion of the GABAA receptor δ subunit alters anxiety-like, social and maternal behaviors without affecting motor performance

GABAA receptors containing the {delta}GABAA subunit ({delta}GABAARs) are involved in many physiological and pathophysiological processes, such as sleep, pain, stress, anxiety-related behaviors, and postpartum depression. These extrasynaptically located, high affinity and slowly desensitizing receptors mediate tonic inhibition throughout the brain, including in granule cells (GCs) of the cerebellar input layer. However, the extent to which {delta}GABAARs control the excitability of the cerebellar input layer and ultimately regulate behavior is unknown. We therefore deleted {delta}GABAA subunits specifically from GCs and determined the behavioral consequences in mice. Deletion reduced tonic inhibition and increased input layer excitability, but remarkably, did not affect either locomotion or motor learning. Unexpectedly, {delta}GABAA deletion heightened anxiety-like behaviors, and caused female-specific alterations in social and maternal behavior. Our findings establish that the cerebellar input layer is critical for regulating diverse behaviors that are relevant to psychiatric and neurodevelopmental disorders but were previously not associated with the cerebellum.

neuroscience↗