Boschen, Suelen L

Background/Goal: Parkinson’s disease (PD) disrupts dopaminergic transmission, leading to motor deficits and altered activity in the primary motor cortex (M1). While M1 modulation is critical for motor control, its response to dopaminergic degeneration and treatment remains unclear. This study aimed to characterize M1 neuronal activity and motor behavior in hemiparkinsonian rats using in vivo calcium imaging across naïve, lesioned, and levodopa-treated states. Methods: Thirteen Sprague Dawley rats were injected with GCaMP6f in the M1 and implanted with a GRIN lens and guide cannula targeting the medial forebrain bundle. Calcium imaging and motor behavior were assessed longitudinally using a single pellet reaching test (SPRT) before and after unilateral 6-hydroxydopamine (6-OHDA) lesioning and subsequent levodopa/carbidopa treatment. Dopaminergic lesion severity was quantified via tyrosine hydroxylase immunohistochemistry. Calcium event frequency and influx were analyzed with CNMF-E and statistical modeling. Results: Levodopa treatment improved fine motor performance as shown by a significant reduction in grasp errors (mean difference: −8.91, 95% CI: −16.66 to −1.16, p = 0.031) and increased reaching duration (mean difference: 4.13, 95% CI: 0.94 to 7.32, p = 0.019) compared to the lesioned state. M1 calcium activity showed modulation dependent on lesion severity: low-lesion rats exhibited reduced event frequency (mean difference: 0.04 Hz, 95% CI: 0.001 to 0.08, p = 0.045) and increased influx post-lesion (mean difference: −0.20 z·s, 95% CI: −0.38 to −0.02, p = 0.038), while high-lesion rats showed increased influx only after levodopa treatment (mean difference: −0.34 z·s, 95% CI: −0.52 to −0.16, p = 0.003). Correlation analyses revealed that calcium influx, but not frequency, was negatively correlated with lesion severity during levodopa treatment (Spearman r = −0.857, p = 0.024). Conclusion: M1 neuronal activity appears to be differentially modulated by dopaminergic degeneration and levodopa treatment in a lesion-dependent manner. These preliminary findings suggest dynamic cortical responses in PD and support the utility of calcium imaging for monitoring circuit-level changes in disease and therapy. Further research with larger cohorts and complementary methodologies will be necessary to validate and extend these observations.

Over the past 80 years, research on dopamine has undergone significant evolution, reshaping our understanding of its roles in the brain and the body [...]

Lewy body dementia (LBD) is an often misdiagnosed and mistreated neurodegenerative disorder clinically characterized by the emergence of neuropsychiatric symptoms followed by motor impairment. LBD falls within an undefined range between Alzheimer’s disease (AD) and Parkinson’s disease (PD) due to the potential pathogenic synergistic effects of tau, beta-amyloid (Aβ), and alpha-synuclein (αsyn). A lack of reliable and relevant animal models hinders the elucidation of the molecular characteristics and phenotypic consequences of these interactions. Here, the goal was to evaluate whether the viral-mediated overexpression of αsyn in adult hTau and APP/PS1 mice or the overexpression of tau in Line 61 hThy1-αsyn mice resulted in pathology and behavior resembling LBD. The transgenes were injected intravenously via the tail vein using AAV-PHP.eB in 3-month-old hThy1-αsyn, hTau, or APP/PS1 mice that were then aged to 6-, 9-, and 12-months-old for subsequent phenotypic and histological characterization. Although we achieved the widespread expression of αsyn in hTau and tau in hThy1-αsyn mice, no αsyn pathology in hTau mice and only mild tau pathology in hThy1-αsyn mice was observed. Additionally, cognitive, motor, and limbic behavior phenotypes were not affected by overexpression of the transgenes. Furthermore, our APP/PS1 mice experienced premature deaths starting at 3 months post-injection (MPI), therefore precluding further analyses at later time points. An evaluation of the remaining 3-MPI indicated no αsyn pathology or cognitive and motor behavioral changes. Taken together, we conclude that the overexpression of αsyn in hTau and APP/PS1 mice and tau in hThy1-αsyn mice does not recapitulate the behavioral and neuropathological phenotypes observed in LBD.

Abstract Although dopamine is commonly studied for its role in incentive motivation, cognition, and various neuropsychiatric disorders, evidence from Parkinson's disease (PD) patients that present auditory deficits suggest that dopamine is also involved in central auditory processing. It has been recently discovered that the subparafascicular thalamic nucleus (SPF) sends dopaminergic projections to the inferior colliculus (IC), an important convergence hub for the ascending and descending auditory pathways. In the present study, our aim was to provide neurochemical evidence that activation of SPF neurons evokes dopamine release in the IC of anesthetized rats using fast‐scan cyclic and paired pulse voltammetry in combination with carbon fiber microelectrodes. Electrical stimulation of the SPF (60 and 90 Hz) evoked dopamine release in the IC in a frequency‐dependent manner, with higher frequencies evoking greater amplitude dopamine responses. Optogenetic‐evoked dopamine responses were similar to the effects of electrical stimulation suggesting that electrical stimulation‐evoked dopamine release was not due to nonspecific activation of fibers of passage, but rather to activation of SPF cells projecting to the IC. Selective dopamine reuptake blockade enhanced the evoked dopamine response, while selective blockade of serotonin did not, confirming the selectivity of the neurochemical recordings to dopamine. Therefore, the SPF neuronal pathway functionally mediates dopamine release in the IC and thus may be involved in auditory processing deficits associated with PD.