Biology subjects

Masana, M.

Publications and source records attributed to Masana, M..

6 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

Hippocampal Egr1-dependent neuronal ensemblesnegatively regulate motor learning

Motor skills learning is classically associated with brain regions including cerebral and cerebellar cortices and basal ganglia. Less is known about the role of the hippocampus in the acquisition and storage of motor skills. Here we show that mice receiving a long-term training in the accelerating rotarod display marked transcriptional changes in the striatum and hippocampus when compared with short-term trained mice. We identify Egr1 as a modulator of gene expression in the hippocampus during motor learning. Using mice in which neural ensembles are permanently labeled in an Egr1 activity-dependent fashion we identify ensembles of Egr1-expressing pyramidal neurons in CA1 activated in short- and long-term trained mice in the rotarod task. When Egr1 is downregulated or these neuronal ensembles are depleted, motor learning is improved whereas their chemogenetic stimulation impairs motor learning performance. Thus, Egr1 organizes specific CA1 neuronal ensembles during the accelerating rotarod task that limit motor learning.

neuroscience↗

bioRxiv2020

RTP801 Is A Key Modulator For Motor Learning

RTP801/REDD1 is a stress-regulated protein whose upregulation is necessary and sufficient to trigger neuronal death in in vitro and in vivo models of Parkinsons and Huntingtons diseases and is up regulated in compromised neurons in human postmortem brains of both neurodegenerative disorders. Indeed, in both Parkinsons and Huntingtons disease mouse models, RTP801 knockdown alleviates motor-learning deficits. Here, we investigated the physiological role of RTP801 in neuronal plasticity. RTP801 is found in rat, mouse and human synapses. The absence of RTP801 enhanced excitatory synaptic transmission in both neuronal cultures and brain slices from RTP801 knock-out (KO) mice. Indeed, RTP801 KO mice showed improved motor learning, which correlated with lower spine density but increased basal filopodia and mushroom spines in the motor cortex layer V. This paralleled with higher levels of synaptosomal GluA1 and TrkB receptors in homogenates derived from KO mice motor cortex, proteins that are associated with synaptic strengthening. Altogether, these results indicate that RTP801 has an important role modulating neuronal plasticity in motor learning.

neuroscience↗

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↗

bioRxiv2020

SYNAPTIC RTP801 CONTRIBUTES TO MOTOR LEARNING DYSFUNCTION IN HUNTINGTON DISEASE

RTP801/REDD1 is a stress responsive protein that mediates mutant huntingtin (mhtt) toxicity in cellular models and is up regulated in Huntingtons disease (HD) patients putamen. Here, we investigated whether RTP801 is involved in motor impairment in HD by affecting striatal synaptic plasticity. Ectopic mhtt was over expressed in cultured rat primary neurons. The protein levels of RTP801 were assessed in homogenates and crude synaptic fractions from human postmortem HD brains and mouse models of HD. Striatal RTP801 expression was knocked down with adeno-associated viral particles containing a shRNA in the R6/1 mouse model of HD and motor learning was then tested. Ectopic mhtt elevated RTP801 in synapses of cultured neurons. RTP801 was also up regulated in striatal synapses from HD patients and mouse models. Knocking down RTP801 in the R6/1 mouse striatum prevented motor learning impairment. RTP801 silencing normalized the Ser473 Akt hyperphosphorylation by downregulating Rictor and it induced synaptic elevation of calcium permeable GluA1 subunit and TrkB receptor levels, suggesting an enhancement in synaptic plasticity. These results indicate that mhtt-induced RTP801 mediates motor dysfunction in a HD murine model, revealing a potential role in the human disease. These findings open a new therapeutic framework focused on the RTP801/Akt/mTOR axis.

neuroscience↗