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International Journal of Molecular... Apr 2024Adenosine A receptor (AR) antagonists are the leading nondopaminergic therapy to manage Parkinson's disease (PD) since they afford both motor benefits and...
Adenosine A receptor (AR) antagonists are the leading nondopaminergic therapy to manage Parkinson's disease (PD) since they afford both motor benefits and neuroprotection. PD begins with a synaptic dysfunction and damage in the striatum evolving to an overt neuronal damage of dopaminergic neurons in the substantia nigra. We tested if AR antagonists are equally effective in controlling these two degenerative processes. We used a slow intracerebroventricular infusion of the toxin MPP in male rats for 15 days, which caused an initial loss of synaptic markers in the striatum within 10 days, followed by a neuronal loss in the substantia nigra within 30 days. Interestingly, the initial loss of striatal nerve terminals involved a loss of both dopaminergic and glutamatergic synaptic markers, while GABAergic markers were preserved. The daily administration of the AR antagonist SCH58261 (0.1 mg/kg, i.p.) in the first 10 days after MPP infusion markedly attenuated both the initial loss of striatal synaptic markers and the subsequent loss of nigra dopaminergic neurons. Strikingly, the administration of SCH58261 (0.1 mg/kg, i.p. for 10 days) starting 20 days after MPP infusion was less efficacious to attenuate the loss of nigra dopaminergic neurons. This prominent AR-mediated control of synaptotoxicity was directly confirmed by showing that the MPTP-induced dysfunction (MTT assay) and damage (lactate dehydrogenase release assay) of striatal synaptosomes were prevented by 50 nM SCH58261. This suggests that AR antagonists may be more effective to counteract the onset rather than the evolution of PD pathology.
Topics: Animals; Adenosine A2 Receptor Antagonists; Rats; Male; Disease Models, Animal; Parkinson Disease; Receptor, Adenosine A2A; Corpus Striatum; Dopaminergic Neurons; Pyrimidines; Triazoles; Substantia Nigra; Neuroprotective Agents; Rats, Sprague-Dawley
PubMed: 38732120
DOI: 10.3390/ijms25094903 -
Scientific Reports May 2024Asymptomatic Leucine-Rich Repeat Kinase 2 Gene (LRRK2) carriers are at risk for developing Parkinson's disease (PD). We studied presymptomatic substantia nigra pars...
Asymptomatic Leucine-Rich Repeat Kinase 2 Gene (LRRK2) carriers are at risk for developing Parkinson's disease (PD). We studied presymptomatic substantia nigra pars compacta (SNc) regional neurodegeneration in asymptomatic LRRK2 carriers compared to idiopathic PD patients using neuromelanin-sensitive MRI technique (NM-MRI). Fifteen asymptomatic LRRK2 carriers, 22 idiopathic PD patients, and 30 healthy controls (HCs) were scanned using NM-MRI. We computed volume and contrast-to-noise ratio (CNR) derived from the whole SNc and the sensorimotor, associative, and limbic SNc regions. An analysis of covariance was performed to explore the differences of whole and regional NM-MRI values among the groups while controlling the effect of age and sex. In whole SNc, LRRK2 had significantly lower CNR than HCs but non-significantly higher volume and CNR than PD patients, and PD patients significantly lower volume and CNR compared to HCs. Inside SNc regions, there were significant group effects for CNR in all regions and for volumes in the associative region, with a trend in the sensorimotor region but no significant changes in the limbic region. PD had reduced volume and CNR in all regions compared to HCs. Asymptomatic LRRK2 carriers showed globally decreased SNc volume and CNR suggesting early nigral neurodegeneration in these subjects at risk of developing PD.
Topics: Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Male; Female; Middle Aged; Melanins; Magnetic Resonance Imaging; Parkinson Disease; Substantia Nigra; Aged; Heterozygote; Adult; Case-Control Studies
PubMed: 38729969
DOI: 10.1038/s41598-024-59074-8 -
Journal of Parkinson's Disease 2024Parkinson's disease (PD) is characterized by alpha-synuclein (α-Syn) pathology, neurodegeneration and neuroinflammation. Human leukocyte antigen (HLA) variants...
BACKGROUND
Parkinson's disease (PD) is characterized by alpha-synuclein (α-Syn) pathology, neurodegeneration and neuroinflammation. Human leukocyte antigen (HLA) variants associated with PD and α-Syn specific CD4+ T lymphocytes in PD patients highlight the importance of antigen presentation in PD etiology. The class II transactivator (CIITA) regulates major histocompatibility complex class II (MHCII) expression. Reduced Ciita levels significantly increase α-Syn pathology, nigrostriatal neurodegeneration and behavioral deficits in α-Syn-induced rat PD models.
OBJECTIVE
Characterize immune profiles associated with enhanced PD-like pathology observed in rats expressing lower Ciita levels (DA.VRA4) compared to the background strain (DA).
METHODS
To model PD, we combined rAAV-mediated α-Syn overexpression in the substantia nigra with striatal injection of α-Syn preformed fibrils. Immune profiles in brain and blood were analyzed by flow cytometry and multiplexed ELISA in naïve rats, 4- and 8 weeks post rAAV injection.
RESULTS
Flow cytometry showed Ciita-dependent regulation of MHCII on microglia, brain macrophages and circulating myeloid cells. The MHCII-dependent microglial response was highest at 4 weeks post rAAV injection, whereas the MHCII levels in circulating myeloid cells was highest at 8 weeks. There was no major infiltration of macrophages or T lymphocytes into the CNS in response to α-Syn and only subtle Ciita- and/or α-Syn-dependent changes in the T lymphocyte compartment. Lower Ciita levels were consistently associated with higher TNF levels in serum.
CONCLUSIONS
Ciita regulates susceptibility to PD-like pathology through minor but detectable changes in resident and peripheral immune cells and TNF levels, indicating that mild immunomodulatory therapies could have therapeutic effects in PD.
Topics: Animals; alpha-Synuclein; Rats; Disease Models, Animal; Trans-Activators; Parkinson Disease; Nuclear Proteins; Substantia Nigra; Male; Dependovirus; Microglia
PubMed: 38728204
DOI: 10.3233/JPD-240062 -
Journal of Parkinson's Disease 2024Previous studies have demonstrated the importance of the locus coeruleus (LC) in sleep-wake regulation. Both essential tremor (ET) and Parkinson's disease (PD) share...
BACKGROUND
Previous studies have demonstrated the importance of the locus coeruleus (LC) in sleep-wake regulation. Both essential tremor (ET) and Parkinson's disease (PD) share common sleep disorders, such as poor quality of sleep (QoS). LC pathology is a feature of both diseases. A question arises regarding the contribution of LC degeneration to the occurrence of poor QoS.
OBJECTIVE
To evaluate the association between LC impairment and sleep disorders in ET and PD patients.
METHODS
A total of 83 patients with ET, 124 with PD, and 83 healthy individuals were recruited and divided into ET/PD with/without poor QoS (Sle/NorET and Sle/NorPD) subgroups according to individual Pittsburgh Sleep Quality Index (PSQI) score. Neuromelanin-sensitive magnetic resonance imaging (NM-MRI) and free-water imaging derived from diffusion MRI were performed. Subsequently, we evaluated the association between contrast-to-noise ratio of LC (CNRLC) and free-water value of LC (FWLC) with PSQI scores in ET and PD groups.
RESULTS
CNRLC was significantly lower in ET (p = 0.047) and PD (p = 0.018) than in healthy individuals, whereas no significant difference was found in FWLC among the groups. No significant differences were observed in CNR/FWLC between patients with/without sleep disorders after multiple comparison correction. No correlation was identified between CNR/FWLC and PSQI in ET and PD patients.
CONCLUSIONS
LC degeneration was observed in both ET and PD patients, implicating its involvement in the pathophysiology of both diseases. Additionally, no significant association was observed between LC integrity and PSQI, suggesting that LC impairment might not directly relate to overall QoS.
Topics: Humans; Essential Tremor; Locus Coeruleus; Female; Male; Parkinson Disease; Aged; Middle Aged; Sleep Wake Disorders; Magnetic Resonance Imaging; Nerve Degeneration; Sleep Quality; Melanins
PubMed: 38728202
DOI: 10.3233/JPD-240001 -
Behavioural Brain Research Jun 2024Neurotoxins have been extensively investigated, particularly in the field of neuroscience. They induce toxic damage, oxidative stress, and inflammation on neurons,...
Neurotoxins have been extensively investigated, particularly in the field of neuroscience. They induce toxic damage, oxidative stress, and inflammation on neurons, triggering neuronal dysfunction and neurodegenerative diseases. Here we demonstrate the neuroprotective effect of a silicon (Si)-based hydrogen-producing agent (Si-based agent) in a juvenile neurotoxic mouse model induced by 6-hydroxydopamine (6-OHDA). The Si-based agent produces hydrogen in bowels and functions as an antioxidant and anti-inflammatory agent. However, the effects of the Si-based agent on neural degeneration in areas other than the lesion and behavioral alterations caused by it are largely unknown. Moreover, the neuroprotective effects of Si-based agent in the context of lactation and use during infancy have not been explored in prior studies. In this study, we show the neuroprotective effect of the Si-based agent on 6-OHDA during lactation period and infancy using the mouse model. The Si-based agent safeguards against the degradation and neuronal cell death of dopaminergic neurons and loss of dopaminergic fibers in the striatum (STR) and ventral tegmental area (VTA) caused by 6-OHDA. Furthermore, the Si-based agent exhibits a neuroprotective effect on the length of axon initial segment (AIS) in the layer 2/3 (L2/3) neurons of the medial prefrontal cortex (mPFC). As a result, the Si-based agent mitigates hyperactive behavior in a juvenile neurotoxic mouse model induced by 6-OHDA. These results suggest that the Si-based agent serves as an effective neuroprotectant and antioxidant against neurotoxic effects in the brain, offering the possibility of the Si-based agent as a neuroprotectant for nervous system diseases.
Topics: Animals; Neuroprotective Agents; Oxidopamine; Mice; Silicon; Disease Models, Animal; Dopaminergic Neurons; Female; Hydrogen; Male; Neurotoxicity Syndromes; Corpus Striatum; Ventral Tegmental Area; Mice, Inbred C57BL
PubMed: 38723675
DOI: 10.1016/j.bbr.2024.115040 -
Cell Reports May 2024The locomotor role of dopaminergic neurons is traditionally attributed to their ascending projections to the basal ganglia, which project to the mesencephalic locomotor...
The locomotor role of dopaminergic neurons is traditionally attributed to their ascending projections to the basal ganglia, which project to the mesencephalic locomotor region (MLR). In addition, descending dopaminergic projections to the MLR are present from basal vertebrates to mammals. However, the neurons targeted in the MLR and their behavioral role are unknown in mammals. Here, we identify genetically defined MLR cells that express D or D receptors and control different motor behaviors in mice. In the cuneiform nucleus, D-expressing neurons promote locomotion, while D-expressing neurons stop locomotion. In the pedunculopontine nucleus, D-expressing neurons promote locomotion, while D-expressing neurons evoke ipsilateral turns. Using RNAscope, we show that MLR dopamine-sensitive neurons comprise a combination of glutamatergic, GABAergic, and cholinergic neurons, suggesting that different neurotransmitter-based cell types work together to control distinct behavioral modules. Altogether, our study uncovers behaviorally relevant cell types in the mammalian MLR based on the expression of dopaminergic receptors.
Topics: Animals; Locomotion; Mesencephalon; Mice; Dopaminergic Neurons; Dopamine; Receptors, Dopamine D1; Receptors, Dopamine D2; Mice, Inbred C57BL; Cholinergic Neurons; GABAergic Neurons; Male
PubMed: 38722743
DOI: 10.1016/j.celrep.2024.114187 -
Neuroscience and Biobehavioral Reviews Jul 2024The mesopontine tegmentum, comprising the pedunculopontine tegmentum (PPN) and the laterodorsal tegmentum (LDT), is intricately connected to various regions of the basal... (Review)
Review
The mesopontine tegmentum, comprising the pedunculopontine tegmentum (PPN) and the laterodorsal tegmentum (LDT), is intricately connected to various regions of the basal ganglia, motor systems, and limbic systems. The PPN and LDT can regulate the activity of different brain regions of these target systems, and in this way are in a privileged position to modulate motivated behaviours. Despite recent findings, the PPN and LDT have been largely overlooked in discussions about the neural circuits associated with reward and aversion. This review aims to provide a timely and comprehensive resource on past and current research, highlighting the PPN and LDT's connectivity and influence on basal ganglia and limbic, and motor systems. Seminal studies, including lesion, pharmacological, and optogenetic/chemogenetic approaches, demonstrate their critical roles in modulating reward/aversive behaviours. The review emphasizes the need for further investigation into the associated cellular mechanisms, in order to clarify their role in behaviour and contribution for different neuropsychiatric disorders.
Topics: Reward; Humans; Animals; Tegmentum Mesencephali; Basal Ganglia; Avoidance Learning; Neural Pathways
PubMed: 38718986
DOI: 10.1016/j.neubiorev.2024.105702 -
JASA Express Letters May 2024A long-standing quest in audition concerns understanding relations between behavioral measures and neural representations of changes in sound intensity. Here, we...
A long-standing quest in audition concerns understanding relations between behavioral measures and neural representations of changes in sound intensity. Here, we examined relations between aspects of intensity perception and central neural responses within the inferior colliculus of unanesthetized rabbits (by averaging the population's spike count/level functions). We found parallels between the population's neural output and: (1) how loudness grows with intensity; (2) how loudness grows with duration; (3) how discrimination of intensity improves with increasing sound level; (4) findings that intensity discrimination does not depend on duration; and (5) findings that duration discrimination is a constant fraction of base duration.
Topics: Animals; Rabbits; Loudness Perception; Inferior Colliculi; Acoustic Stimulation; Discrimination, Psychological; Auditory Perception; Neurons
PubMed: 38717467
DOI: 10.1121/10.0025874 -
Alzheimer's Research & Therapy May 2024The locus coeruleus (LC) and the nucleus basalis of Meynert (NBM) are altered in early stages of Alzheimer's disease (AD). Little is known about LC and NBM alteration in...
BACKGROUND
The locus coeruleus (LC) and the nucleus basalis of Meynert (NBM) are altered in early stages of Alzheimer's disease (AD). Little is known about LC and NBM alteration in limbic-predominant age-related TDP-43 encephalopathy (LATE) and frontotemporal dementia (FTD). The aim of the present study is to investigate in vivo LC and NBM integrity in patients with suspected-LATE, early-amnestic AD and FTD in comparison with controls.
METHODS
Seventy-two participants (23 early amnestic-AD patients, 17 suspected-LATE, 17 FTD patients, defined by a clinical-biological diagnosis reinforced by amyloid and tau PET imaging, and 15 controls) underwent neuropsychological assessment and 3T brain MRI. We analyzed the locus coeruleus signal intensity (LC-I) and the NBM volume as well as their relation with cognition and with medial temporal/cortical atrophy.
RESULTS
We found significantly lower LC-I and NBM volume in amnestic-AD and suspected-LATE in comparison with controls. In FTD, we also observed lower NBM volume but a slightly less marked alteration of the LC-I, independently of the temporal or frontal phenotype. NBM volume was correlated with the global cognitive efficiency in AD patients. Strong correlations were found between NBM volume and that of medial temporal structures, particularly the amygdala in both AD and FTD patients.
CONCLUSIONS
The alteration of LC and NBM in amnestic-AD, presumed-LATE and FTD suggests a common vulnerability of these structures to different proteinopathies. Targeting the noradrenergic and cholinergic systems could be effective therapeutic strategies in LATE and FTD.
Topics: Humans; Frontotemporal Dementia; Male; Locus Coeruleus; Alzheimer Disease; Female; Aged; Magnetic Resonance Imaging; Basal Nucleus of Meynert; Middle Aged; Neuropsychological Tests; Amnesia; Positron-Emission Tomography
PubMed: 38702802
DOI: 10.1186/s13195-024-01466-z -
Scientific Reports May 2024Dysfunction of central serotonergic neurons is known to cause depressive disorders in humans, who often show reproductive and/or glucose metabolism disorders. This study...
Dysfunction of central serotonergic neurons is known to cause depressive disorders in humans, who often show reproductive and/or glucose metabolism disorders. This study examined whether dorsal raphe (DR) serotonergic neurons sense high glucose availability to upregulate reproductive function via activating hypothalamic arcuate (ARC) kisspeptin neurons (= KNDy neurons), a dominant stimulator of gonadotropin-releasing hormone (GnRH)/gonadotropin pulses, using female rats and goats. RNA-seq and histological analysis revealed that stimulatory serotonin-2C receptor (5HT2CR) was mainly expressed in the KNDy neurons in female rats. The serotonergic reuptake inhibitor administration into the mediobasal hypothalamus (MBH), including the ARC, significantly blocked glucoprivic suppression of luteinizing hormone (LH) pulses and hyperglycemia induced by intravenous 2-deoxy-D-glucose (2DG) administration in female rats. A local infusion of glucose into the DR significantly increased in vivo serotonin release in the MBH and partly restored LH pulses and hyperglycemia in the 2DG-treated female rats. Furthermore, central administration of serotonin or a 5HT2CR agonist immediately evoked GnRH pulse generator activity, and central 5HT2CR antagonism blocked the serotonin-induced facilitation of GnRH pulse generator activity in ovariectomized goats. These results suggest that DR serotonergic neurons sense high glucose availability to reduce gluconeogenesis and upregulate reproductive function by activating GnRH/LH pulse generator activity in mammals.
Topics: Animals; Luteinizing Hormone; Female; Receptor, Serotonin, 5-HT2C; Rats; Serotonergic Neurons; Goats; Gonadotropin-Releasing Hormone; Glucose; Serotonin; Kisspeptins; Arcuate Nucleus of Hypothalamus; Dorsal Raphe Nucleus; Rats, Sprague-Dawley
PubMed: 38702366
DOI: 10.1038/s41598-024-58470-4