Topic: substantia nigra pars compacta

How does the activity of midbrain dopamine (DA) neurons influence behavior? A prominent, but incompletely tested, hypothesis is that the activity of ventral tegmental area (VTA) DA neurons generates downstream representations of state values in ventral striatum (NAc), while substantia nigra pars compacta DA activity generates action values in the dorsal striatum. To test this model, we performed Neuropixels recordings in a trial-and-error probabilistic learning task where mice continuously adapted their choices to obtain a reward of optogenetic stimulation of VTA DA neurons (paired with an aud

Neuromodulatory signals are powerful and prevalent influences on behavior. For example, dopaminergic inputs to the dorsolateral striatum are correlated with action selection and invigoration, and the loss of dopaminergic drive in Parkinson's disease manifests in deficits of movement timing and initiation. While the role of dopamine in the cortex-basal ganglia-thalamaus (C-BG-T) loop has been explored within the framework of reinforcement learning, computational models of how dopamine might influence fast-timescale movement generation have not been explored to the same extent. Here, we propose

Parkinson's disease is a motor and cognitive neurodegenerative disorder associated to the progressive loss of Substantia Nigra pars compacta dopaminergic neurons. One cause of the disease is associated with the spreading of α-synuclein aggregates. Recent findings indicate that extracellular α-synuclein oligomers represent the most neurotoxic species and reduce the firing discharge of midbrain neurons, impair network synchronization, up-regulate Cav2.2 Ca channels and neurotransmitter release in cortical neurons. Here we combined conventional electrophysiology (current-clamp) and diamond multi

In neuroscience, progress in understanding brain function, pathologies and neuroanatomy are often interdependent. Forebrain and cortical brain regions are mostly defined, however, midbrain to hindbrain regions are not as well characterized. Earlier this century, we discovered a structure at the transition between the midbrain to hindbrain regions, in rats, that we named the tail of the ventral tegmental area (tTVA), also known as the rostromedial tegmental nucleus (RMTg). The tVTA is now thought to be the primary inhibitory center of midbrain dopaminergic systems, inhibiting dopamine neurons o

Among symptoms characterizing Parkinson’s disease (PD), freezing of gait (FoG) can become particularly disabling for patients. Anxiety levels have been linked to the severity of FoG, yet in this circumstance, levodopa treatment lacks effectiveness. A better understanding of the neural circuit mechanisms underlying FoG is required for a more targeted approach towards its treatment. To this end, we developed a viral vector (AAV2/9-CreON-A53T-αSyn) mouse model restricting synucleinopathy to local circuit elements, i.e. selected neuron subtypes within specific brain regions in vivo. We validated t

The expression of the transmembrane neuronal gap junction protein connexin 36 (Cx36) was investigated in the reticulo-thalamic nucleus (RT) and in the CA3 region of hippocampus in a rat model of Parkinson’s disease (PD). We compared the Cx36 expression in a rat model of PD (the hemiparkinsonian rats with PD cholinopathy - unilateral lesion of the substantia nigra pars compacta (SNpc) with bilateral lesion of the pedunculopontine nucleus (PPT)) versus control rats.A total of 12 adult male Wistar rats were divided in control group (n = 6) and PD group (n = 6). We performed a fluorescence immunoh

Inactivating mutations in the PRKN gene encoding the ubiquitin ligase PARKIN are a leading cause of Autosomal Recessive Juvenile Parkinsonism (ARJP), a neurodegenerative disease characterized by early dysfunction and death of dopaminergic neurons in the substantia nigra pars compacta (SNc). Harnessing this mutation to create an early-onset Parkinson’s disease (PD) mouse model would provide a unique opportunity to clarify the mechanisms involved in the neurodegenerative process and lay the groundwork for the development of neuroprotective strategies. By using CRISPR/Cas9 technology, we created

Parkinson's disease (PD) is a multifaceted neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons, predominantly within the substantia nigra pars compacta (SNc) region. Dysregulation of FoxO1 has been implicated in various neurodegenerative diseases, including Alzheimer's disease and PD, yet the precise underlying mechanisms remain largely elusive. In this study, we investigated the impact of α-synuclein pre-formed fibrils (PFF) treatment on BV-2 microglial cells to elucidate alterations in molecular properties and neuronal degeneration. Surprisingly, our find

Background: Parkinson's disease (PD) is characterized by the formation of proteinaceous aggregates of α-synuclein (α-syn) in cell bodies and neurites of Substantia Nigra pars compacta (SNpc) dopaminergic neurons, eventually causing cell death. Interestingly, defective activity or mutations in GBA1, the gene encoding the lysosomal enzyme Glucocerebrosidase (GCase), are the strongest risk factor to develop PD. Based on this evidence, reverting the cytological and molecular abnormalities caused by GCase mutations or enhancing the activity of the wild type enzyme may represent a feasible therapeut

The degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) is a hallmark of Parkinson’s disease (PD). Nevertheless, little is known about the molecular signals that are altered in the prodromal phase in the adult striatum. To address this, we have used spatial transcriptomics and single-nucleus RNA sequencing to characterize the molecular events in mouse models of prodromal PD. We have used two different PD models: a) a progressive dopamine degeneration model of mitochondrial dysfunction (MitoPark mice), and b) a mild toxin model based on a low-dose unilateral 6-hydr

The pathway descending from the superior colliculus (SC) to the dopaminergic (DA) neurons within the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) is involved in controlling an animal’s orienting movements based on sensory integration. Most studies to date have focused only on the dominant, ipsilateral branch of this pathway, although there are both monosynaptic and polysynaptic contralateral connections descending from the SC to the ventral midbrain. Therefore, we set out to characterise the responses of DA neurons in the VTA/SNc to lateralized retinal stimulation and

Parkinson's disease (PD) is a chronic neurodegenerative disease that is up to 90% idiopathic and occurs randomly in the population, possibly due to environmental factors. It is characterized by the progressive loss of dopaminergic neurons in the brain region called substantia nigra pars compacta (SNpc). This results in a range of motor and non-motor symptoms that severely impact the life quality of the affected individual. Studies have shown that gut dysbiosis in Parkinson's disease precedes neuronal degeneration, and our laboratory found that one of the environmental factors, dim light at nig

Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and caudoputamen (Cp), leading to motor and non-motor symptoms. Neuroinflammation, oxidative stress, and imbalance in purinergic signaling significantly contribute to its progression. Current treatments fail to halt disease progression, necessitating novel approaches. Repetitive transcranial magnetic stimulation (rTMS) has shown promise in alleviating PD symptoms, but its underlying mechanisms remain unclear. We investigated the effects of prolonged intermitten

Parkinson’s disease is caused by the selective loss of the dopaminergic neurons of the Substantia Nigra pars compacta and, consequently, striatal dopamine depletion. In Parkinson’s disease therapy, dopamine loss is counteracted by the administration of the dopamine precursor L-DOPA, which is initially effective in ameliorating motor symptoms, but over time it leads to a burdening side effect of uncontrollable jerky movements, termed L-DOPA-induced dyskinesia. To date, no efficient treatment for dyskinesia exists. The dopaminergic and serotonergic systems are intrinsically linked, and a role ha

Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons in the substantia nigra pars compacta, leading to striatal dopamine deficiency. The A2A and D2 receptors form heteromeric complexes in striatal neurons that play an important modulatory role in fine-tuning motor control.The aim of this study was to assess, for the first time, the proportion of individual A2AR, of individual D2R and of A2AR-D2R heteromers (A2A-D2Het) present in a primate 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) PD model, with and without showing dyskinesias. This h

Parkinson's disease (PD) is a complex neurodegenerative movement disorder. The central pathological feature of PD is the progressive loss of dopaminergic neurons in the substantia nigra pars compacta, that project to the dorsal striatum. The resulting dopamine deficiency in this area dysregulates the striatal neural net, causing the motor deficits of PD patients. However, the process leading dopamine's depletion into neural deficits and how it can reflect on cortical activity is still largely unknown. This project's goal is to investigate the electrophysiological and functional changes affecti

Parkinson’s disease (PD) is characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Among other factors, microglia are thought to take part in the chronic neuroinflammatory scenario that contributes to the process of neuronal death. However, the factors that maintain the overreactive response of microglia in PD remain mysterious. As we wanted to simulate the chronic neuroinflammatory scenario taking place in PD, we evaluated the response of microglial cells after repetitive pro-inflammatory stimuli induced by LPS and IFN-g in vitro. In contrast w

Alpha-synuclein (ASYN) is a presynaptic neuronal protein related genetically and neuropathologically to Parkinson's disease (PD). However, the role of ASYN in the selective degeneration of specific neuronal populations such as the loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNc) remains elusive. Since previous strategies for viral overexpression of ASYN in animals are not cell-type specific, we generated novel adeno-associated viral vectors (AAV) to Cre-dependently express human wild-type ASYN (ASYN-WT) or ASYN with pathogenic A53T or A30P mutations. This strategy allo

The neurodegenerative process in Parkinson’s disease involves exacerbated inflammation with the participation of astrocytes. The P2Y1 receptor (P2Y1R) is a purinergic receptor predominantly expressed in astrocytes, regulating their activity, proliferation, and glutamate release. Therefore, our investigation explores whether the P2Y1R contributes to dopaminergic neuron degeneration, potentially via astrocytic involvement. To study dopaminergic degeneration, we injected 9 µg 6-hydroxydopamine into the right striatum (STR) of male Sprague-Dawley rats aged 6-8 weeks (ethical approval: 167/2019). D

Parkinson’s disease (PD) is the second most common neurodegenerative disorder. The disease is mainly characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the abnormal accumulation and aggregation of alpha-synuclein (alpha-syn) in the form of Lewy bodies and Lewy neurites. Even if recent studies allowed for an increased understanding of the role of alpha-syn misfolding and aggregation in PD pathogenesis, many other aspects influence disease onset and progression; among them, evidence suggests neuroinflammation as a key factor of PD casca

Physiological levels of reactive oxygen species (ROS) are required for the proper regulation of biological functions and cell signaling. However, ROS overproduction and inadequate scavenging lead to oxidative stress and consequent damage to macromolecules. Recent evidence has demonstrated the incontrovertible involvement of oxidative stress in the onset and progression of different central nervous system (CNS) disorders, including neurodegenerative events. For instance, redox disbalance together with α-synuclein aggregation and neuroinflammation, contributes to the loss of dopaminergic neurons

Aims: Parkinson's disease (PD), a chronic neurological disorder affecting motor functions, is characterized by damage to dopaminergic neurons in the substantia nigra pars compacta (SNc). This study investigates the therapeutic properties of bacterial melanin (BM), known for enhancing brain trophic effects, inhibiting inflammation, and mitigating gliosis—a key aspect in PD development.Methods: To assess rat brain morpho-functional states, we conducted histochemical and morphometric studies on SNc cellular structures post-rotenone intoxication and under BM influence. Experiments involved intact