Biology subjects

Diem, S.

Publications and source records attributed to Diem, S..

4 recordsLinked to original sources

bioRxiv2024

Chronic potentiation of metabotropic glutamate receptor 2 with a nanobody accelerates amyloidogenesis in Alzheimer's disease.

Immunotherapy of Alzheimers disease (AD) is a promising approach to reduce the accumulation of amyloid-beta (A{beta}), a critical event in the onset of the disease. Targeting the group II metabotropic glutamate receptors, mGlu2 and mGlu3, could be important in controlling A{beta} production, although their respective contribution remains unclear due to the lack of selective tools. Here, we show that enhancing mGlu2 receptor activity increases A{beta}1-42 peptide production whereas activation of mGlu3 has no effect. We show that such a difference likely results from the direct interaction of APP with mGlu3, but not with mGlu2 receptors, that prevents APP amyloidogenic cleavage and A{beta}1-42 peptides production. We then show that chronic treatments of the AD model 5xFAD mice with a brain-penetrating mGlu2-potentiating nanobody accelerated amyloid aggregation and exacerbated memory deficits, but had no effect in control mice. Our results confirm that a selective mGluR2 activation exacerbates AD disease development, suggesting that therapeutic benefices could be obtained with blockers of this receptor. Our study also provides the proof-of-concept that chronic administration of nanobodies targeting neuroreceptors can be envisioned to treat brain diseases.

neuroscience↗

bioRxiv2021

Upregulation of breathing rate during running exercise by central locomotor circuits

While respiratory adaptation to exercise is compulsory to cope with the increased metabolic supply to body tissues and with the necessary clearing of metabolic waste, the neural apparatus at stake remains poorly identified. Using viral tracing, ex vivo and in vivo optogenetic and chemogenetic interference strategies in mice, we unravel interactive locomotor and respiratory networks nodes that mediate the respiratory rate increase that accompanies a running exercise. We show that the mesencephalic locomotor region (MLR) and the lumbar spinal locomotor pattern generator (lumbar CPG), which respectively initiate and execute the locomotor behavior, access the respiratory network through distinct entry points. The MLR directly projects onto the inspiratory rhythm generator, the preBotzinger complex (preBotC), and can trigger a moderate increase of respiratory frequency, prior to, or even in the absence of, locomotion. In contrast, the lumbar CPG projects onto the retrotrapezoid nucleus (RTN) that in turn contacts the preBotC to enforce, during effective locomotion, higher respiratory frequencies. These data expand, on the one hand, the functional implications of the MLR beyond locomotor initiation to a bona fide respiratory modulation. On the other hand, they expand the adaptive respiratory ambitions of the RTN beyond chemoception to "locomotor- ception".

neuroscience↗

bioRxiv2021

An executive center for the intake of liquids

It has long been known that orofacial movements for feeding can be triggered, coordinated, and often rhythmically organized at the level of the brainstem, without input from higher centers. We uncover two nuclei that can organize the movements for ingesting fluids in mammals. These neuronal groups, defined by unique transcriptional codes and developmental origins, IRtPhox2b and Peri5Atoh1, are located, respectively, in the intermediate reticular formation of the medulla and around the motor nucleus of the trigeminal nerve. They are premotor to all jaw-opening and tongue muscles. Stimulation of either, in awake animals, opens the jaw, while IRtPhox2b alone also protracts the tongue. Moreover, stationary stimulation of IRtPhox2b entrains a rhythmic alternation of tongue protraction and retraction, synchronized with jaw opening and closing, that mimics lapping. Finally, fiber photometric recordings show that IRtPhox2b is active during volitional lapping. Our study identifies one of the long hypothesized subcortical nuclei underpinning a stereotyped feeding behavior.

neuroscience↗

bioRxiv2020

Independent respiratory and locomotor rhythms in running mice

Examining whether and how the rhythms of limb and breathing movements interact is highly informative about the mechanistic origin of hyperpnoea to exercise. However, studies have failed to reveal regularities. In particular, whether breathing frequency is inherently proportional to limb velocity and/or imposed by a synchronization of breaths to strides is still unclear. Here, we examined the specifications of respiratory changes during running in mice, the premier model for investigating, in a standardized manner, complex integrative tasks including adaptive breathing. We show that respiratory rate increases during running to a fixed and stable value, irrespective of trotting velocities and of inclination. Yet, respiratory rate was further enhanced during gallop. We also demonstrate the absence of temporal coordination of breaths to strides at any speed, intensity or gait. Our work thus highlights a hardwired mechanism that sets respiratory frequency independently of limb movements but in relation with the engaged locomotor program.

neuroscience↗