Biology subjects

Le Pichon, C.

Publications and source records attributed to Le Pichon, C..

4 recordsLinked to original sources

bioRxiv2022

Local production of reactive oxygen species drives vincristine-induced axon degeneration

Neurological side effects arising from chemotherapy, such as severe pain and cognitive impairment, are a major concern for cancer patients. These major side effects can lead to reduction or termination of chemotherapy medication in patients, negatively impacting their prognoses. With cancer survival rates improving dramatically, addressing side effects of cancer treatment has become pressing. Here, we use iPSC-derived human neurons to investigate the molecular mechanisms that lead to neurotoxicity induced by vincristine, a common chemotherapeutic used to treat solid tumors. Our results uncover a novel mechanism by which vincristine causes a local increase in mitochondrial proteins that produce reactive oxygen species (ROS) in the axon. Vincristine triggers a cascade of axon pathology, causing mitochondrial dysfunction that leads to elevated axonal ROS levels and SARM1-dependent axon degeneration. Importantly, we show that the neurotoxic effect of increased axonal ROS can be mitigated by the small molecule mdivi-1 and antioxidants glutathione and mitoquinone, identifying a novel therapeutic avenue to treat the neurological effects of chemotherapy.

neuroscience↗

bioRxiv2022

The Human Motoneuron Expression Signature is Defined by ALS-Related Genes

The mammalian spinal cord functions as a community of glial and neuronal cell types to accomplish sensory processing, autonomic control, and movement; conversely, the dysfunction of these cell types following spinal cord injury or disease states can lead to chronic pain, paralysis, and death. While we have made great strides in understanding spinal cellular diversity in animal models, it is crucial to characterize human biology directly to uncover specialized features of basic function and to illuminate human pathology. Here, we present a cellular taxonomy of the adult human spinal cord using single nucleus RNA-sequencing with spatial transcriptomics and antibody validation. We observed 29 glial clusters, including rare cell types such as ependymal cells, and 35 neuronal clusters, which we found are organized principally by anatomical location. To demonstrate the potential of this resource for understanding human disease, we analyzed the transcriptome of spinal motoneurons that are prone to degeneration in amyotrophic lateral sclerosis (ALS) and other diseases. We found that, compared with all other spinal neurons, human motoneurons are defined by genes related to cell size, cytoskeletal structure, and ALS, thereby supporting a model of a specialized motoneuron molecular repertoire that underlies their selective vulnerability to disease. We include a publicly available browsable web resource with this work, in the hope that it will catalyze future discoveries about human spinal cord biology.

neuroscience↗

bioRxiv2022

Medullary kappa-opioid receptor neurons inhibit pain and itch through a descending circuit

In perilous and stressful situations, the ability to suppress pain can be critical for survival. The rostral ventromedial medulla (RVM) contains neurons that robustly inhibit nociception at the level of the spinal cord through a top-down modulatory pathway. Although much is known about the role of the RVM in the inhibition of pain, the precise ability to directly manipulate pain-inhibitory neurons in the RVM has never been achieved. We now expose a cellular circuit that inhibits nociception and itch in mice. Through a combination of molecular, tracing, and behavioral approaches, we found that RVM neurons containing the kappa-opioid receptor (KOR) inhibit itch and nociception. With chemogenetic inhibition, we uncovered that these neurons are required for stress-induced analgesia. Using intersectional chemogenetic and pharmacological approaches, we determined that RVMKOR neurons inhibit nociception and itch through a descending circuit. Lastly, we identified a dynorphinergic pathway arising from the periaqueductal gray (PAG) that modulates nociception within the RVM. These discoveries highlight a distinct population of RVM neurons capable of broadly and robustly inhibiting itch and nociception.

neuroscience↗

bioRxiv2020

Ventral arkypallidal neurons modulate accumbal firing to promote reward consumption.

A pause in firing of nucleus accumbens shell (NAcSh) neurons is critical for reward consumption; however, the substrate driving this pause is unknown. While ventral pallidal (VP) activity encodes reward value, the specific roles of VP subpopulations in computation and expression of this value are poorly understood. Here, we establish that inhibitory input from the VP is crucial for reward-related inhibition of NAc firing. A sparse, non-canonical subpopulation of VP neurons, the so-called "ventral arkypallidal (vArky)" neurons makes inhibitory synaptic contacts throughout the NAcSh, and drives inhibition of NAcSh neurons in vivo. Moreover, endogenous calcium activity of vArky neurons predicted subsequent reward consumption behavior, while optogenetically activating this pathway increased reward consumption by amplifying hedonic value of reward. Classically, the VP is considered downstream of the NAc; however, our results challenge this view and establish that vArky neurons in the VP promote reward consumption via potent modulation of NAcSh firing.

neuroscience↗