Biology subjects

Garcia-Garcia, E.

Publications and source records attributed to Garcia-Garcia, E..

4 recordsLinked to original sources

bioRxiv2024

Differential contribution of direct and indirect pathways from dorsolateral and dorsomedial striatum to motor symptoms in Huntington's disease mice

The alterations in the basal ganglia circuitry associated with motor symptoms in Huntingtons Disease (HD) have been extensively investigated. Yet, the specific contribution of the direct and indirect striatal output pathways from the dorsolateral (DLS) and dorsomedial striatum (DMS) to the motor dysfunction is still not fully understood. Here, using the symptomatic R6/1 male mouse model of HD, strong functional connectivity alterations between DMS and DLS regions with the rest of brain were observed by fMRI, particularly pronounced in the DLS. Then, we systematically evaluated how the selective optogenetic stimulation of the direct and indirect pathways from DLS and DMS influences locomotion, exploratory behavior, and motor learning. In wild type (WT) mice, optogenetic stimulation of the direct pathway from DLS and the indirect pathway from DMS elicited subtle locomotor enhancements, while exploratory behavior remained unaltered. Additionally, stimulation of the indirect pathway from DLS improved the performance in the accelerated rotarod task. In contrast, in HD mice, optogenetic stimulation of the distinct striatal pathways did not modulate these behaviors. Overall, this study points to deficits in the integration of neuronal activity in HD mice, while it contributes to deeper understanding of the complexity of motor control by the diverse striatal subcircuits.

neuroscience↗

bioRxiv2022

Altered M2 Cortex - Superior Colliculus visual perception circuit in Huntington's Disease

The premotor cortical area -M2 cortex in rodents- connection to the striatum is involved in movement and prominently affected in Huntingtons Disease (HD). M2 cortex also projects to the superior colliculus (SC), implicated in oculomotor functions (i.e. saccades) and visual perception. Here, we investigated the contribution of M2 cortex - SC circuit to HD physiopathology in male mice. Using fMRI, we observed that M2 cortex functional connectivity with the SC was the most prominently affected circuit in the symptomatic R6/1 HD mouse model. Structural alterations were also detected by tractography and viral tracing. HD mice showed decreased defensive behavioral responses towards an unexpected visual stimuli, such as a moving robo-beetle, and decreased locomotion upon unexpected flash of light. Additionally, optogenetic M2 cortex - SC stimulation promoted avoidance responses towards the robo-beetle in WT, but not HD mice. Though, DWI measurements in vivo and ex vivo electrophysiological responses to optogenetic and electrical stimuli in the SC suggested preserved brain structure. Finally, GCamp6f fluorescence recordings with fiber photometry indicated that aberrant M2 cortex engagement might be the underlying mechanism of visual perception alterations in HD. Collectively, our findings point to a key role of M2 cortex - SC circuit alterations in HD pathophysiology.

neuroscience↗

bioRxiv2020

Drosophila Hedgehog can act as a morphogen in the absence of regulated Ci processing

SummaryExtracellular Hedgehog (Hh) proteins induce transcriptional changes in target cells by inhibiting the proteolytic processing of full-length Drosophila Ci or mammalian Gli proteins to nuclear transcriptional repressors and by activating the full-length proteins, which are otherwise held inactive by cytoplasmic binding partners and subject to accelerated degradation following activation. We used Ci variants expressed at physiological levels to investigate the contributions of these mechanisms to dose-dependent Hh signaling at the anteroposterior (AP) border of Drosophila wing imaginal discs. Ci variants that cannot be processed supported a normal pattern of graded target gene activation and the development of adults with normal wing morphology when supplemented by constitutive Ci repressor, showing that Hh can signal normally in the absence of regulated processing. The full-length Ci-155 protein profile of these variants revealed a linear gradient of Hh-stimulated degradation, allowing derivation of a spatial profile of inhibition of processing of normal C-155 by Hh. The processing-resistant Ci variants were also significantly activated in the absence of Hh by elimination of Cos2, acting through association with the CORD domain of Ci, or PKA, revealing separate inhibitory roles of these two components in addition to their well-established roles in promoting Ci-155 processing.Competing Interest StatementThe authors have declared no competing interest.View Full Text

developmental biology↗

bioRxiv2020

M2 Cortex-Dorsolateral striatum stimulation reverses motor symptoms and synaptic deficits in Huntington's Disease

Huntingtons disease (HD) is a neurological disorder characterized by motor disturbances. HD pathology is most prominent in the striatum, the central hub of basal ganglia. The cortex is the main striatal afference and progressive cortico-striatal disconnection characterizes HD. We mapped cortico-striatal dysfunction in HD mice to ultimately modulate the activity of selected cortico-striatal circuits to ameliorate motor symptoms and recover synaptic plasticity. Multimodal MRI in vivo suggested prominent functional network deficits in fronto-striatal compared to motor-striatal pathways, which were accompanied by reduced glutamate levels in the striatum of HD mice. Moreover, optogenetically-stimulated glutamate release from fronto-striatal terminals was reduced in HD mice and electrophysiological responses in striatal neurons were blunted. Remarkably, repeated M2 Cortex-dorsolateral striatum optogenetic stimulation normalized motor behavior in HD mice and evoked a sustained increase of synaptic plasticity. Overall, these results reveal that the selective stimulation of fronto-striatal pathways can become an effective therapeutic strategy in HD.

neuroscience↗