Biology subjects

Streng, M. L.

Publications and source records attributed to Streng, M. L..

4 recordsLinked to original sources

bioRxiv2024

Early and widespread engagement of the cerebellum during hippocampal epileptiform activity

Despite research illustrating the cerebellum may be a critical circuit element in processes beyond motor control, and growing evidence for a role of the cerebellum in a range of neurological disorders, including the epilepsies, remarkably little is known about cerebellar engagement during seizures. We therefore implemented a novel method for repeated widefield calcium imaging of the cerebellum in awake, chronically epileptic mice. We found widespread changes in cerebellar Purkinje cell activity during temporal lobe seizures. Changes were noted in the anterior and posterior cerebellum (lobules IV-VII), along the midline (vermis), and both ipsilaterally and contralaterally (in the simplex and Crus I) to the seizure focus. This was true for both overtly behavioral seizures and for hippocampal seizures that remained electrographic only -- arguing against cerebellar modulation simply reflecting motor components. Moreover, even brief interictal spikes produced widespread alterations in cerebellar activity. Perhaps most remarkably, changes in the cerebellum also occurred prior to any noticeable change in the hippocampal electrographic recordings. Together these results underscore the relevance of the cerebellum with respect to seizure networks, warranting a more consistent consideration of the cerebellum in epilepsy.

neuroscience↗

bioRxiv2023

Mesoscale Ca2+ imaging reveals networks of Purkinje cell dendritic and somatic modulation, with divergent roles of activity versus correlation during behavior

A major challenge in cerebellar physiology is determining how the stereotypic, conserved circuitry of the cerebellar cortex, with its dominant parasagittal and transverse architectures, underlies its fundamental computations and contributions to behavior. To interrogate Purkinje cell dynamics at this parasagittal and transverse spatial scale, we implemented a novel approach for awake, chronic, wide-field Ca2+ imaging of the cerebellar cortex. We observe two functionally and spatially distinct Purkinje cell networks, reflecting their dendritic and somatic activities, respectively. Both dendritic and somatic networks exhibit bilateral, widespread activation during behavior, but with diverse patterns of spatial correlations occurring primarily along the parasagittal and transverse directions, consistent with the main geometry of the cerebellar cortex. Somatic network correlation dynamics are robustly modulated by prediction errors, and even reflect ultimate behavioral outcomes. These results provide a novel link between cerebellar structure and function, with the correlation dynamics of Purkinje cell activity a key feature.

neuroscience↗

bioRxiv2022

To be and not to be: Wide-field Ca2+ imaging reveals neocortical functional segmentation combines stability and flexibility

The stability and flexibility of the functional parcellation of the cerebral cortex is fundamental to how familiar and novel information is both represented and stored. We leveraged new advances in Ca2+ sensors and microscopy to understand the dynamics of functional segmentation in the dorsal cerebral cortex. We performed wide-field Ca2+ imaging in head-fixed mice and used spatial Independent Component Analysis (ICA) to identify independent spatial sources of Ca2+ fluorescence. The imaging data were evaluated over multiple timescales and discrete behaviors including resting, walking, and grooming. When evaluated over the entire dataset, a set of template independent components (ICs) were identified that were common across behaviors. Template ICs were present across a range of timescales, from days to 30 seconds, although with lower occurrence probability at shorter timescales, highlighting the stability of the functional segmentation. Importantly, unique ICs emerged at the shorter duration timescales that could act to transiently refine the cortical network. When data were evaluated by behavior, both common and behavior-specific ICs emerged. Each behavior is composed of unique combinations of common and behavior-specific ICs. These observations suggest that cerebral cortical functional segmentation exhibits considerable spatial stability over time and behaviors while retaining the flexibility for task-dependent reorganization.

neuroscience↗

bioRxiv2021

Distinct fastigial output channels and their impact on temporal lobe seizures

Despite being canonically considered a motor control structure, the cerebellum is increasingly recognized for important roles in processes beyond this traditional framework, including seizure suppression. Excitatory fastigial neurons project to a large number of downstream targets, and it is unclear if this broad targeting underlies seizure suppression, or if a specific output may be sufficient. To address this question, we used the intrahippocampal kainic acid mouse model of temporal lobe epilepsy, male and female animals, and a dual-virus approach to selectively label and manipulate fastigial outputs. We examined fastigial neurons projecting to the superior colliculus, medullary reticular formation, and central lateral nucleus of the thalamus, and found that these comprise largely non-overlapping populations of neurons which send collaterals to unique sets of additional thalamic and brainstem regions, creating distinct, somewhat overlapping, "output channels". We found that neither optogenetic stimulation of superior colliculus nor reticular formation output channels attenuated hippocampal seizures. In contrast, on-demand stimulation of fastigial neurons targeting the central lateral nucleus robustly inhibited seizures. Our results indicate that fastigial control of hippocampal seizures does not require simultaneous modulation of many fastigial output channels. Rather, selective modulation of the fastigial output channel to the central lateral thalamus, specifically, is sufficient for seizure control. This may provide a means for more selective therapeutic interventions, which provide seizure control while minimizing unwanted side effects. More broadly, our data highlight the concept of specific cerebellar output channels, whereby discrete cerebellar nucleus neurons project to specific aggregates of downstream targets, with distinct functional outcomes. Significance statementThe cerebellum has an emerging relationship with non-motor systems and may represent a powerful target for therapeutic intervention in temporal lobe epilepsy. We find that fastigial neurons project to numerous brain regions via largely segregated output channels, and that excitation of fastigial neurons projecting to the central lateral nucleus of the thalamus, but not the superior colliculus or reticular formation, is sufficient to attenuate hippocampal seizures. These findings illustrate an important conceptual framework: fastigial neurons project to aggregates of downstream targets via distinct output channels, which cannot be predicted simply by somatic location within the nucleus, and these channels have distinct functional outcomes. This nuanced appreciation of fastigial outputs may provide a path for therapeutic interventions with minimized side effects.

neuroscience↗