Biology subjects

Kiehn, O.

Publications and source records attributed to Kiehn, O..

6 recordsLinked to original sources

bioRxiv2026

A uniform tissue-clearing framework and mesoSPIM-ultra enable cm-scale single-neuron tracing

Tissue-clearing and light-sheet microscopy have transformed volumetric imaging of intact organs, yet limited mechanistic understanding of dehydration-based clearing continues to constrain rational protocol design and broader applicability. Here, we define the cardinal chemical and physical principles underlying dehydration-based tissue-clearing and establish a new pipeline for large-volume imaging. To maximize imaging performance, we developed the "mesoSPIM-ultra", an upgraded mesoSPIM platform with a temperature-controlled sample chamber, a large field-of-view (FoV) camera and specialized optics to achieve long-working-distance, high-resolution imaging of cleared samples. We applied this approach to investigate the projectome of Chx10+ neurons, a cell population with complex axonal morphologies along the entire mouse spinal-cord and brain, and implicated in ipsilateral orienting behaviors. By combining behavioral analysis with post-hoc single-neuron reconstructions, we revealed previously inaccessible branching architectures and long-range projections extending from the brainstem to the spinal cord. Together, our work establishes a mechanistic foundation for tissue-clearing and scalable imaging.

neuroscience↗

bioRxiv2024

A hypothalamus-brainstem circuit governs the prioritization of safety over essential needs

Animals continously adapt their behavior to balance survival and fulfilling essential needs. This balancing act involves prioritization of safety over the pursuit of other needs. However, the specific deep brain circuits that regulate safety-seeking behaviors in conjuction with motor circuits remain poorly understood. Here we identify a class of glutamatergic neurons in the lateral hypothalamic area (LHA) that target the midbrain locomotor-promoting pedunculopontine nucleus (PPN). Upon activation, this LHA-PPN pathway orchestrates context-dependent locomotion, prioritizing safety-directed movement over other essential needs such as foraging or mating. Remarkably, the neuronal activity of these circuits correlates directly with safety-seeking behavior. These circuits may respond to both intrinsic and external cues, playing a pivotal role in ensuring survival. Our findings uncover a circuit motif within the lateral hypothalamus that when recruited, prioritizes critical needs through the recruitment of an appropriate motor action.

neuroscience↗

bioRxiv2023

Spinal inhibitory neurons degenerate before motor neurons and excitatory neurons in a mouse model of ALS

Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of somatic motor neurons. Major focus has been directed to motor neuron intrinsic properties as a cause for degeneration while less attention has been given to the contribution of spinal interneurons. In the present work, we applied multiplexing detection of transcripts and machine learning-based image analysis to investigate the fate of multiple spinal interneuron populations during ALS progression in the SOD1G93A mouse model. The analysis showed that spinal inhibitory interneurons are affected early in disease, before motor neurons death, and are characterized by a slow progressive degeneration, while excitatory interneurons are affected later with a steep progression. Moreover, we report differential vulnerability within inhibitory and excitatory subpopulations, with interneurons directly projecting onto motor neurons being preferentially affected. Our study reveals a strong interneuron involvement in ALS development with interneuron specific degeneration. This points to differential involvement of diverse spinal neuronal circuits that eventually may be determining for motor neuron degeneration. TeaserA new approach to study the motor neuron disorder Amyotrophic Lateral Sclerosis shows the early and differential dysregulation of spinal interneurons.

neuroscience↗

bioRxiv2020

Locomotor deficits in ALS mice are paralleled by loss of V1-interneuron-connections onto fast motor neurons

ALS is characterized by progressive inability to execute movements. Motor neurons innervating fast-twitch muscle fibers exhibit preferential degeneration. The reason for differential vulnerability of fast motor neurons, and its consequence on motor output is not known. Here, we show that fast motor neurons receive more inhibitory synaptic inputs than slow motor neurons, and loss of inhibitory synapses onto fast motor neurons precedes disease progression in the SOD1G93A mouse model of ALS. Loss of inhibitory synapses on fast motor neurons is accounted for by a loss of synapses from inhibitory V1 spinal interneurons. Deficits in V1-motor neuron connectivity appear prior to motor neuron death and are paralleled by development of specific SOD1G93A locomotor deficits. These distinct SOD1G93A locomotor deficits are phenocopied by silencing of inhibitory V1 spinal interneurons in wild-type mice. Silencing inhibitory V1 spinal interneurons does not exacerbate SOD1G93A locomotor deficits, suggesting phenotypic pathway interaction. Our study identifies a potential cell non-autonomous source of motor neuronal vulnerability in ALS, and links ALS-induced changes in locomotor phenotypes to inhibitory V1 interneurons.

neuroscience↗

bioRxiv2019

Brainstem Neurons that Command Left/Right Locomotor Asymmetries

Descending command neurons instruct spinal networks to execute basic locomotor functions, such as which gait and what speed. The command functions for gait and speed are symmetric, implying that a separate unknown system directs asymmetric movements--the ability to move left or right. Here we report the discovery that Chx10-lineage reticulospinal neurons act to control the direction of locomotor movements in mammals. Chx10 neurons exhibit ipsilateral projection, and can decrease spinal limb-based locomotor activity ipsilaterally. This circuit mechanism acts as the basis for left or right locomotor movements in freely moving animals: selective unilateral activation of Chx10 neurons causes ipsilateral movements whereas inhibition causes contralateral movements. Spontaneous forward locomotion is thus transformed into an ipsilateral movement by braking locomotion on the ipsilateral side. We identify sensorimotor brain regions that project onto Chx10 reticulospinal neurons, and demonstrate that their unilateral activation can impart left/right directional commands. Together these data identify the descending motor system which commands left/right locomotor asymmetries in mammals.

neuroscience↗

bioRxiv2019

Nimodipine prevents the development of spasticity after spinal cord injury

Spasticity, one of the most frequent comorbidities of spinal cord injury (SCI), disrupts motor recovery and quality of life. Despite major progress in neurorehabilitative and pharmacological approaches, no curative treatment for spasticity exists. Here, we show in a mouse model of chronic SCI that treatment with nimodipine -- an FDA-approved L-type calcium channel blocker -- starting in the acute phase of SCI completely prevents the development of spasticity measured as increased muscle tone and spontaneous spasms. The aberrant muscle activities are permanently blocked even after termination of the treatment. Constitutive and conditional silencing in neuronal subtypes of CaV 1.3 channels shows that preventive effect of nimodipine on spasticity after SCI is mediated by the neuronal CaV 1.3 channels. This study identifies a potentially curative treatment protocol with a specific target for the prevention of spasticity after SCI.

pathology↗