Biology subjects

Moratalla, R.

Publications and source records attributed to Moratalla, R..

3 recordsLinked to original sources

bioRxiv2024

GBA1 MUTATIONS ALTER THE PHENOTYPE AND BEHAVIOUR OF DOPAMINERGIC NEURONS IN PARKINSON DISEASE, INFLUENCING VGLUT2 AND CRYAB EXPRESSION

Mutations in the GBA1 gene are major risk factors for Parkinso[n]s disease (PD), but their role in PD pathology is not fully understood. The impact of GBA1 mutations was investigated in dopamine (DA) neurons obtained from induced pluripotent stem cells (iPSCs) derived from PD patients carrying the N370S or L444P GBA1 mutation. DA neurons co-expressing TH and VGLUT2 were detected in the cultures, and their number and/or expression of VGLUT2/SLC17A6 mRNA was markedly reduced in both N370S and L444P cultures compared to controls. A significant increase in the firing rate of N370S neurons was found, whereas evoked dopamine release was stronger from neurons carrying either mutation. Furthermore, mutant neurons accumulated abundant degenerative structures, and there was a significant accumulation of -synuclein aggregates in N370S neurons. Notably, a significant upregulation of the chaperone CRYAB/HSPB5/alpha-crystallin-B was found early in DA neuron differentiation and in the substantia nigra of PD patients. Our findings indicate that N370S and L444P GBA1 mutations impair midbrain DA neurons expressing VGLUT2, and provoke molecular, functional and structural changes, possibly involved in PD pathology.

neuroscience↗

bioRxiv2023

Serotonergic and dopaminergic neurons in the dorsal raphe are differentially altered in a mouse model for Parkinson's disease.

Parkinsons disease (PD) is characterized by motor impairments caused by degeneration of dopamine neurons in the substantia nigra pars compacta. In addition to these symptoms, PD patients often suffer from non-motor co-morbidities including sleep and psychiatric disturbances, which are thought to depend on concomitant alterations of serotonergic and noradrenergic transmission. A primary locus of serotonergic neurons is the dorsal raphe nucleus (DRN), providing brain-wide serotonergic input. Here, we identified electrophysiological and morphological parameters to classify serotonergic and dopaminergic neurons in the murine DRN under control conditions and in a PD model, following striatal injection of the catecholamine toxin, 6-hydroxydopamine (6-OHDA). Electrical and morphological properties of both neuronal populations were altered by 6-OHDA. In serotonergic neurons, most changes were reversed when 6-OHDA was injected in combination with desipramine, a noradrenaline reuptake inhibitor, protecting the noradrenergic terminals. Our results show that the depletion of both noradrenaline and dopamine in the 6-OHDA mouse model causes changes in the DRN neural circuitry.

neuroscience↗

bioRxiv2023

Dissociable control of motivation and reinforcement by distinct ventral striatal dopamine receptors

Dopamine release in striatal circuits, including the nucleus accumbens (NAc), tracks separable features of reward such as motivation and reinforcement. However, the cellular and circuit mechanisms by which dopamine receptors transform dopamine release into distinct constructs of reward remain unclear. Here, we show that dopamine D3 receptor (D3R) signaling in the NAc drives motivated behavior by regulating local NAc microcircuits. Furthermore, D3Rs co-express with dopamine D1 receptors (D1Rs), which regulate reinforcement, but not motivation. Paralleling dissociable roles in reward function, we report non-overlapping physiological actions of D3R and D1R signaling in NAc neurons. Our results establish a novel cellular framework wherein dopamine signaling within the same NAc cell type is physiologically compartmentalized via actions on distinct dopamine receptors. This structural and functional organization provides neurons in a limbic circuit with the unique ability to orchestrate dissociable aspects of reward-related behaviors that are relevant to the etiology of neuropsychiatric disorders.

neuroscience↗