Machuca-Marquez, P. | Search bioRxiv

bioRxiv2021

Vestibular CCK neurons drive motion-induced malaise

Travel can induce motion sickness (MS) in susceptible individuals. MS is an evolutionary conserved mechanism caused by mismatches between motion-related sensory information and past visual and motion memory, triggering a malaise accompanied by hypolocomotion, hypothermia, hypophagia and nausea. Vestibular nuclei (VN) are critical for the processing of movement input from the inner ear. Motion-induced activation of VN neurons recapitulates MS-related signs. However, the genetic identity of VN neurons mediating MS- related autonomic and aversive responses remains unknown. Here, we identify a central role of cholecystokinin (CCK)-expressing VN neurons in motion-induced malaise. Moreover, we show that CCK VN inputs onto the parabrachial nucleus activate Calca- expressing neurons and are sufficient to establish avoidance to novel food, which is prevented by CCK-A receptor antagonism. These observations provide greater insight into the neurobiological regulation of MS by identifying the neural substrates of MS and providing potential targets for treatment. SIGNIFICANCE STATEMENTWe live in an age where travel is paramount. However, one of the most disabling conditions inherent to traveling is motion sickness (MS). While studies have underscored the role of the vestibular system in the development of MS, the neuronal populations involved in motion-induced malaise remain largely unknown. Here, we describe the vestibular pathways eliciting MS responses, and identify a key role for cholecystokinin (CCK)-expressing vestibular neurons. We reveal that a vestibulo-parabrachial (PBN) CCKergic projection is sufficient to induce conditioned taste aversion, likely through the activation of calcitonin gene-related peptide-expressing PBN neurons. Finally, we underscore the role of CCK-A receptor signaling as a novel druggable target to treat MS, providing novel insight on the neurobiological substrates of MS.

neuroscience↗

bioRxiv2019

Defined neuronal populations drive fatal phenotype in Leigh Syndrome

Dysfunctions of the mitochondrial energy-generating machinery cause a series of progressive, untreatable and usually fatal diseases collectively known as mitochondrial disease. High energy-requiring organs such as the brain are especially affected, leading to developmental delay, ataxia, respiratory failure, hypotonia, seizures and premature death. While neural affectation is a critical component of the pathology, only discrete neuronal populations are susceptible. However, their molecular identity and their contribution to the disease remain unknown. Mice lacking the mitochondrial Complex I subunit NDUFS4 (Ndufs4KO mice) recapitulate the classical signs of Leigh Syndrome (LS), the most common presentation of mitochondrial disease with predominant CNS affectation. Here, we identify the critical role of two genetically-defined neuronal populations driving the fatal phenotype in Ndufs4KO mice. Selective inactivation of Ndufs4 in Vglut2-expressing glutamatergic neurons causes brainstem inflammation, motor and respiratory deficits, and early death. On the other hand, Ndufs4 deletion in GABAergic neurons leads to basal ganglia inflammation without motor or respiratory involvement, but accompanied by severe refractory epileptic seizures preceding premature death. These results provide novel insight in the cell type-specific contribution to LS pathology and open new avenues to understand the underlying cellular mechanisms of mitochondrial disease.

neuroscience↗