Biology subjects

Zimmer, L.

Publications and source records attributed to Zimmer, L..

6 recordsLinked to original sources

bioRxiv2026

CM/Pf contribution to mesocircuit dynamics underlying awareness in non-human primates

BackgroundIn acute disorders of consciousness following severe brain injury, the heterogeneity and multiplicity of brain lesions make it difficult to infer a direct causal link between lesion patterns and impaired consciousness. As a result, neuroimaging analyses performed in intensive care settings can inform theories of consciousness mainly through correlational, rather than causal, evidence. The mesocircuit hypothesis proposes that interactions between the thalamus, basal ganglia, and cortex support the neural mechanisms underlying awareness. Among its key components, the intralaminar thalamic nuclei are thought to play a central role, yet their respective contributions to mesocircuit dynamics remain poorly understood. MethodsIn two macaque monkeys, we combined causal perturbations of three thalamic nuclei (the centromedian-parafascicular complex (CM/Pf), central lateral nucleus (CL), and mediodorsal nucleus (MD)) with a cue-guided behavioural task requiring the processing of multisensory information. Electrical microstimulation was first used to compare the behavioural consequences of perturbing each target. Reversible pharmacological inactivation using muscimol was subsequently performed in the CM/Pf and CL. Finally, the large-scale metabolic effects of CM/Pf inactivation (muscimol) and disinhibition (bicuculline) were assessed using [18F]FDG PET imaging. ResultsPerturbation of the intralaminar nuclei disrupted behavioural performance, with the strongest and most reproducible effects observed following CM/Pf manipulation. CM/Pf inactivation reduced correct responses and increased omissions and wrong responses, particularly under conditions requiring greater behavioural engagement. Importantly, these deficits occurred without evidence of major wakefulness impairment, as animals remained responsive throughout testing and showed no substantial increase in eye-closure probability. In contrast, CL perturbation produced weaker behavioural effects, suggesting distinct functional contributions of the two intralaminar nuclei. [18F]FDG PET imaging revealed that CM/Pf disinhibition increased glucose metabolism across thalamic, striatal, pallidal, and frontal cortical territories, whereas CM/Pf inactivation induced a broadly reciprocal pattern of metabolic pattern. These findings identify the CM/Pf as a major modulator of both thalamo-striatal and thalamo-cortical components of the mesocircuit. ConclusionsOur results show that a unilateral intralaminar nucleus perturbation is not sufficient to affect wakefulness, suggesting that this function is mediated by a bilateral network at the thalamus level within the mesocircuit. The CM/Pf emerged as the intralaminar nucleus exerting the strongest influence on goal directed behaviours requiring the mesocircuit dynamics. Our findings also support the existence of partially distinct intralaminar pathways contributing differentially to global state regulation of awareness-related functions, and identify the CM/Pf as a key thalamo-striatal hub within the mesocircuit.

neuroscience↗

bioRxiv2025

Multiomic profiling of a unique in-transit melanoma cohort identifies melanoma differentiation as predictor of tumor progression and therapy response

Melanoma patients with in-transit metastasis (ITM), a stage of disease where melanoma has metastasized to sites in between the primary lesion and draining lymph node, vary significantly in their clinical outcomes, but the biology driving differential outcomes in ITM is poorly understood. To elucidate the mechanisms of differential outcomes, we utilized multimodal molecular profiling (WES, RNA-seq, highly multiplexed immunofluorescence, spatial transcriptomics) in 1) evolutionary analysis of longitudinal tumor samples and 2) identifying prognostic tumor intrinsic and microenvironmental features in a unique cohort of patients with unresectable ITM. Among other findings, we observed a persistent dedifferentiated AXL/NGFR clonal lineage pre-existing and following immune checkpoint blockade in in-transit and distant metastases. Concordantly, we found that low pigmentation and high T cell exhaustion signatures were independently associated with distant progression. Our findings highlight tumor cell state and immune dysfunction as key predictors and potential biomarkers of metastatic risk in ITM. STATEMENT OF SIGNIFICANCEWhat drives distant progression in melanoma is unclear. Analyzing tumor and immune features in a rare in-transit melanoma patient cohort, we identify biological signals highlighting how immune and tumor states observable in pre-distant metastasis melanomas shape long-term outcomes, and nominate potential prognostic biomarkers.

cancer biology↗

bioRxiv2024

Induction of hemodynamic traveling waves by glial-related vasomotion in a rat model of neuroinflammation: implications for functional neuroimaging

BackgroundCerebral hemodynamics are crucial for brain homeostasis and serve as a key proxy for brain activity. Although this process involves coordinated interaction between vessels, neurons and glial cells, its dysregulation in neuroinflammation is not well understood. MethodsWe used in vivo mesoscopic functional ultrasound imaging to monitor cerebral blood volume changes during neuroinflammation in male rats injected with lipopolysaccharide (LPS) in the visual cortex, under resting-state or visual stimulation, combined to advanced ex vivo techniques for glial cell reactivity analysis. FindingsCortical neuroinflammation induced large oscillatory hemodynamic traveling waves in the frequency band of vasomotion ([~]0.1 Hz) in both anesthetized and awake rats. Vasomotor waves traveled through large distances between adjacent penetrating vessels, spanning the entire cortex thickness, and even extending to subcortical areas. Moreover, vasomotion amplitude correlated with microglial morphology changes and was significantly reduced by astrocytic toxins, suggesting that both microglia and astrocytes are involved in the enhancement of vasomotion during neuroinflammation. Notably, functional connectivity was increased under this oscillatory state and functional hyperemia was exacerbated. InterpretationThese findings reveal new spatiotemporal properties of cerebral vasomotion and suggest this is a major component of brain hemodynamics in pathological states. Moreover, reactive microglia and astrocytes are participating to increased vasomotion during neuroinflammation. For the field of functional neuroimaging, our results advocate for considering 0.1 Hz hemodynamic oscillations as an important complement to traditional measurements, particularly in neuroinflammatory conditions. Indeed, brain hemodynamics may provide insights not only into neuronal activity but also glial reactivity. FundingSupported by ANR ("LabCom-NI2D") and Auvergne-Rhone-Alpes Region ("BI2D").

neuroscience↗

bioRxiv2024

Nitration of a ribosomal pentapeptide generates a noncanonical precursor for nonribosomal peptide synthesis

Peptide natural products possess a fascinating array of complex structures and diverse functions. Central to this is a repertoire of modified amino acid building blocks, which stem from fundamentally different biosynthesis pathways for peptides of nonribosomal and ribosomal origins. Given these origins, integration of nonribosomal and ribosomal pathways have previously been thought unlikely. Now, we demonstrate that ribosomal biosynthesis generates a key noncanonical 3-nitrotyrosine building block for the nonribosomal synthesis of rufomycin. In this pathway, a biarylitide-type ribosomal peptide is nitrated by a modified cytochrome P450 crosslinking enzyme, with the nitrated residue liberated by the actions of a dedicated protease found within the rufomycin gene cluster before being incorporated into rufomycin by the rufomycin nonribosomal peptide synthetase. This resolves the enigmatic origins of 3-nitrotyrosine within rufomycin biosynthesis and demonstrates unexpected integration of ribosomal peptide synthesis as a mechanism for the generation of noncanonical building blocks within nonribosomal synthesis pathways.

biochemistry↗

bioRxiv2022

Genomic heterogeneity and ploidy identify patients with intrinsic resistance to PD-1 blockade in metastatic melanoma

While the introduction of immune checkpoint blockade (ICB) has dramatically improved clinical outcomes for patients with advanced melanoma, a significant proportion of patients develop resistance to therapy, and mechanisms of resistance are poorly elucidated in most cases. Further, while combination ICB has higher response rates and improved progression free survival compared to single agent therapy in the front line setting, there is significantly increased toxicity with combination ICB, and biomarkers to identify patients who would disproportionately benefit from combination therapy vs aPD-1 ICB are poorly characterized. To understand resistance mechanisms to single vs combination ICB therapy, we analyze whole-exome-sequencing (WES) of pre-treatment tumor and matched normals of 4 cohorts (n=140) of previously ICB-naive aPD-1 ICB treated patients. We find that high intratumoral genomic heterogeneity and low ploidy identify patients with intrinsic resistance to aPD-1 ICB. Comparing to a melanoma cohort from a pre-targeted therapy and ICB time period ("untreated" cohort), we find that genomic heterogeneity specifically predicts response and survival in the ICB treated cohorts, but not in the untreated cohort, while ploidy is also prognostic of overall survival in the "untreated" (by targeted therapy or ICB) group. To establish clinically actionable predictions, we optimize a simple decision tree using genomic ploidy and heterogeneity to identify with high confidence (90% PPV) a subset of patients with intrinsic resistance to and significantly worse survival on aPD1 ICB treatment. We then validate this model in independent cohorts, and further show that a significant proportion of patients predicted to have intrinsic resistance to single agent aPD-1 ICB respond to combination ICB, which suggests that nominated patients may benefit disproportionately from combination ICB. We further show that the features and predictions of the model are independent of known clinical features and previously nominated molecular biomarkers. These findings highlight the clinical and biological importance of genomic heterogeneity and ploidy, and sets a concrete framework towards clinical actionability, broadly advancing precision medicine in oncology.

cancer biology↗

bioRxiv2022

Your turn, my turn. Neural synchrony in mother-infant proto-conversation.

Even before infants utter their first words, they engage in highly coordinated vocal exchanges with their caregivers. During these so-called proto-conversations, caregiver-infant dyads use a presumably universal communication structure - turn-taking, which has been linked to favourable developmental outcomes. However, little is known about potential mechanisms involved in early turn-taking. Previous research pointed to interpersonal synchronisation of brain activity between adults and preschool-aged children during turn-taking. Here, we assessed caregivers and infants at 4-6 months of age (N=55) during a face-to-face interaction. We used functional-near infrared spectroscopy hyperscanning to measure dyads brain activity and microcoded their turn-taking. We also measured infants inter-hemispheric connectivity as an index for brain maturity and later vocabulary size and attachment security as developmental outcomes potentially linked to turn-taking. The results showed that more frequent turn-taking was related to interpersonal neural synchrony, but the strength of the relation decreased over the course of the proto-conversation. Importantly, turn-taking was positively associated with infant brain maturity and later vocabulary size, but not with later attachment security. Taken together, these findings shed light on mechanisms facilitating preverbal turn-taking and stress the importance of emerging turn-taking for child brain and language development.

neuroscience↗