Search bioRxiv⌕ Search

bioRxiv · 10.1101/2024.09.20.614117

Stimulation of otolith irregular fibers produces a rostro-caudal gradient in activity in the vestibular nuclear complex (VNC), but not the vestibulocerebellum (VeCb)

Abstract

The vestibular system is important for posture, balance, motor control, and spatial orientation. Each of the vestibular end organs have specialized neuroepithelia with both regular and irregular afferents. In otolith organs, the utricle and saccule, afferents most responsive to linear jerk (jerk - derivative of acceleration) are located in the striola and project centrally to the vestibular nuclear complex (VNC) as well as the uvula and nodulus of the vestibulocerebellum (VeCb). The pattern of central neuronal activation attributed to otolith irregular afferents is relatively unknown. To address this gap, c-Fos was used as a marker of neuronal activity to map the distribution of active neurons throughout the rostro-caudal extent of the VNC and VeCb. Immunohistochemistry for c-Fos was performed to assess activation of VNC and VeCb neurons in response to a linear jerk stimulus delivered in the naso-occipital plane. Activated neurons were distributed throughout the VNC, including the lateral vestibular nucleus (LVe), magnocellular medial vestibular nucleus (MVeMC), parvocellular medial vestibular nucleus (MVePC), spinal vestibular nucleus (SpVe), and superior vestibular nucleus (SuVe). Notably, after stimulation, the MVePC exhibited the greatest number of c-Fos labeled nuclei. Significant increases in c-Fos labeling were found in mid-rostrocaudal and caudal regions of the VNC in the LVe, MVe, and SpVe. Additionally, c-Fos labeling was observed across all regions of the VeCb after jerk stimulation. Significant increases in the number of labeled nuclei were found throughout the rostro-caudal extent of the nodulus and uvula. However, jerk stimulated increases in activity for the paraflocculus were restricted to the caudal VeCb. The distribution of neuronal activity suggests that regions receiving the greatest direct otolith input exhibit the most substantial changes in response to otolith derived, irregular fiber stimulation. HighlightsO_LINuclei with descending projections (LVe, MVePC, and SpVe) demonstrated the greatest change in activity after naso-occipital jerk stimulation. C_LIO_LINaso-occipital jerk stimulation preferentially activates caudal VNC neurons C_LIO_LINaso-occipital jerk stimulation activates neurons throughout the VeCb C_LIO_LIJerk stimulation in the naso-occipital plane has the greatest effects on activity in VNC and VeCb regions with the greatest inputs from afferents originating in gravity receptors C_LI

Explore related subjects

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Holt, A. G., King, S., Naqvi, D., Braun, R. D., Bauer, D. S., Anderson, M., King, W. M.. 2024-09-21. Stimulation of otolith irregular fibers produces a rostro-caudal gradient in activity in the vestibular nuclear complex (VNC), but not the vestibulocerebellum (VeCb). https://doi.org/10.1101/2024.09.20.614117

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

Isogenic forebrain organoids uncover early neurodevelopmental alterations and imbalances in neuronal function leading to hyperexcitation in Gaucher disease

Gaucher disease is a rare lysosomal storage disorder caused by autosomal recessive mutations in the GBA1 gene, encoding the lysosomal enzyme glucocerebrosidase. Gaucher disease is classified in 3 different subtypes depending on the presence and severity of neurological involvement, with type 2 resulting in fatal early-onset neuropathology and patients exhibiting developmental delays, seizures and early death. Studies investigating disease mechanisms of neuronopathic Gaucher disease are mainly based on animal models and focus predominantly on late neuronal phenotypes. Here, we established healthy control and Gaucher disease patient-derived iPSC lines and engineered them to obtain isogenic control and disease lines. Using these lines, we generated cortical and subpallial brain organoids in which we identified early-onset lipid dysregulation in form of glucosylceramide accumulation, highly elevated glucosylsphingosine, and a later increase in ganglioside levels, recapitulating clinical findings. Furthermore, single-cell transcriptomic profiling uncovered novel phenotypes in both cortical and subpallial forebrain organoids. Subpallial alterations consisted of an early increase in migrating interneurons in subpallial organoids, which upregulated cholesterol metabolism. Cortical alterations showed early upregulation of mitochondrial genes and a downregulation of proliferation, with a subsequent switch from GABAergic to glutamatergic neuron fate with a striking increase in gene expression related to the synaptic assembly. Functional assays demonstrated a marked hyperexcitability of cortical organoids and reduced response to GABA-A receptor blockage in Gaucher disease. Additional 2D neuronal network models confirmed the organoid data and showed that both glutamatergic and GABAergic neurons contribute to the phenotype, with hyperexcitability of Gaucher glutamatergic neurons and incapacity of Gaucher GABAergic neurons to balance the excessive excitation. This alteration represents a clinically significant phenotype as many patients exhibit an excitation/inhibition imbalance leading to treatment-resistant seizures, hastening their decline. In conclusion, our defined human models of Gaucher disease identify novel and clear phenotypes that can be used for drug screening or aid in development of new therapeutic strategies to ameliorate Gaucher disease.

neuroscience↗

Oxytocin and Vasopressin Immunoreactivity Differs Across Auditory Brainstem Nuclei in Rodents with Distinct Social Systems

Oxytocin (OT) and vasopressin (AVP) are neuropeptide hormones involved in regulating animal social behavior and a broad spectrum of physiological processes. Although their distributions are well documented in neuroendocrine regions of the forebrain and midbrain, their expression in the hindbrain remains poorly understood. Here, we used immunohistochemistry to quantify OT and AVP immunoreactive puncta within three auditory brainstem nuclei, the lateral superior olive (LSO), the medial superior olive (MSO), and the medial nucleus of the trapezoid body (MNTB) in six wild-caught rodent species differing in sociality. We also quantified the volume of these nuclei and examined variation in total brain volume across species and sociality. OT and AVP puncta count differed among species and social groups. Group-living species exhibited higher OT and AVP puncta counts than monogamous and solitary species in the LSO and MNTB. In the MSO, OT puncta counts did not differ among social groups, whereas AVP puncta counts were higher in group-living than in monogamous and solitary species. Total brain volume and the volumes of the MNTB and MSO differed among species, but not across social groups, whereas LSO volume did not differ among species or sociality. These findings revealed sociality-related variation in OT and AVP immunoreactive puncta within auditory brainstem circuits and suggest that neuropeptide signaling within early auditory brainstem pathways may contribute to the neural integration of social and auditory information.

neuroscience↗

Connexin 40 deficiency alters the temporal profile of postictal oxygen dynamics following focal seizures.

Epilepsy is increasingly recognized as a disorder involving both neuronal and vascular dysfunction. While connexin signaling has been implicated in epileptogenesis, the contribution of vascular connexins to seizure associated cerebrovascular pathology remains poorly understood. Connexin40 (Cx40) is an endothelial gap junction protein that plays a crucial role in vascular communication and blood-flow regulation. Seizures induce dynamic changes in cerebral perfusion and oxygenation, including prolonged postictal hypoperfusion/hypoxia. To determine whether Cx40 influences postictal hypoxia following focal seizures, we examined seizure characteristics and postictal oxygen dynamics in Cx40 knockout (Cx40-/-) mice using an established focal hippocampal seizure model. Electrically kindled seizures were elicited in wild-type and Cx40-/- mice, and local hippocampal tissue oxygenation was continuously monitored before and after seizure induction. Seizure duration did not differ between genotypes, indicating comparable seizure severity. Interestingly, Cx40 deletion altered the temporal pattern of postictal oxygen recovery, producing greater early hypoxia and a delayed secondary rebound in pO2 despite similar peak oxygen levels and overall hypoxic burden. These findings demonstrate that loss of Cx40 selectively alters the temporal profile of postictal oxygen dynamics without affecting seizure duration. Taken together, the results suggest that endothelial gap junctional communication contributes to postictal vascular recovery and identify Cx40 as a potential modulator of seizure associated neurovascular dysfunction.

neuroscience↗