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Nature Communications May 2024Serotonin is a neuromodulator that affects multiple behavioral and cognitive functions. Nonetheless, how serotonin causes such a variety of effects via brain-wide...
Serotonin is a neuromodulator that affects multiple behavioral and cognitive functions. Nonetheless, how serotonin causes such a variety of effects via brain-wide projections and various receptors remains unclear. Here we measured brain-wide responses to optogenetic stimulation of serotonin neurons in the dorsal raphe nucleus (DRN) of the male mouse brain using functional MRI with an 11.7 T scanner and a cryoprobe. Transient activation of DRN serotonin neurons caused brain-wide activation, including the medial prefrontal cortex, the striatum, and the ventral tegmental area. The same stimulation under anesthesia with isoflurane decreased brain-wide activation, including the hippocampal complex. These brain-wide response patterns can be explained by DRN serotonergic projection topography and serotonin receptor expression profiles, with enhanced weights on 5-HT1 receptors. Together, these results provide insight into the DR serotonergic system, which is consistent with recent discoveries of its functions in adaptive behaviors.
Topics: Animals; Optogenetics; Dorsal Raphe Nucleus; Male; Serotonergic Neurons; Mice; Serotonin; Magnetic Resonance Imaging; Prefrontal Cortex; Mice, Inbred C57BL; Brain; Ventral Tegmental Area; Hippocampus; Receptors, Serotonin
PubMed: 38755120
DOI: 10.1038/s41467-024-48489-6 -
Scientific Reports May 2024Safe and effective pain management is a critical healthcare and societal need. The potential for acute liver injury from paracetamol (ApAP) overdose; nephrotoxicity and...
Safe and effective pain management is a critical healthcare and societal need. The potential for acute liver injury from paracetamol (ApAP) overdose; nephrotoxicity and gastrointestinal damage from chronic non-steroidal anti-inflammatory drug (NSAID) use; and opioids' addiction are unresolved challenges. We developed SRP-001, a non-opioid and non-hepatotoxic small molecule that, unlike ApAP, does not produce the hepatotoxic metabolite N-acetyl-p-benzoquinone-imine (NAPQI) and preserves hepatic tight junction integrity at high doses. CD-1 mice exposed to SRP-001 showed no mortality, unlike a 70% mortality observed with increasing equimolar doses of ApAP within 72 h. SRP-001 and ApAP have comparable antinociceptive effects, including the complete Freund's adjuvant-induced inflammatory von Frey model. Both induce analgesia via N-arachidonoylphenolamine (AM404) formation in the midbrain periaqueductal grey (PAG) nociception region, with SRP-001 generating higher amounts of AM404 than ApAP. Single-cell transcriptomics of PAG uncovered that SRP-001 and ApAP also share modulation of pain-related gene expression and cell signaling pathways/networks, including endocannabinoid signaling, genes pertaining to mechanical nociception, and fatty acid amide hydrolase (FAAH). Both regulate the expression of key genes encoding FAAH, 2-arachidonoylglycerol (2-AG), cannabinoid receptor 1 (CNR1), CNR2, transient receptor potential vanilloid type 4 (TRPV4), and voltage-gated Ca channel. Phase 1 trial (NCT05484414) (02/08/2022) demonstrates SRP-001's safety, tolerability, and favorable pharmacokinetics, including a half-life from 4.9 to 9.8 h. Given its non-hepatotoxicity and clinically validated analgesic mechanisms, SRP-001 offers a promising alternative to ApAP, NSAIDs, and opioids for safer pain treatment.
Topics: Animals; Male; Mice; Acetaminophen; Amidohydrolases; Analgesics; Arachidonic Acids; Benzoquinones; Glycerides; Periaqueductal Gray; Transcriptome
PubMed: 38750093
DOI: 10.1038/s41598-024-61791-z -
Frontiers in Endocrinology 2024The brain regulates multiple physiological processes in fish. Despite this, knowledge about the basic structure and function of distinct brain regions in non-model fish...
The brain regulates multiple physiological processes in fish. Despite this, knowledge about the basic structure and function of distinct brain regions in non-model fish species remains limited due to their diversity and the scarcity of common biomarkers. In the present study, four major brain parts, the telencephalon, diencephalon, mesencephalon and rhombencephalon, were isolated in largemouth bass, . Within these parts, nine brain regions and 74 nuclei were further identified through morphological and cytoarchitectonic analysis. Transcriptome analysis revealed a total of 7153 region-highly expressed genes and 176 region-specifically expressed genes. Genes related to growth, reproduction, emotion, learning, and memory were significantly overexpressed in the olfactory bulb and telencephalon (OBT). Feeding and stress-related genes were in the hypothalamus (Hy). Visual system-related genes were predominantly enriched in the optic tectum (OT), while vision and hearing-related genes were widely expressed in the cerebellum (Ce) region. Sensory input and motor output-related genes were in the medulla oblongata (Mo). Osmoregulation, stress response, sleep/wake cycles, and reproduction-related genes were highly expressed in the remaining brain (RB). Three candidate marker genes were further identified for each brain regions, such as neuropeptide FF () for OBT, pro-melanin-concentrating hormone () for Hy, vesicular inhibitory amino acid transporter () for OT, excitatory amino acid transporter 1 () for Ce, peripherin () for Mo, and isotocin neurophysin () for RB. Additionally, the distribution of seven neurotransmitter-type neurons and five types of non-neuronal cells across different brain regions were analyzed by examining the expression of their marker genes. Notably, marker genes for glutamatergic and GABAergic neurons showed the highest expression levels across all brain regions. Similarly, the marker gene for radial astrocytes exhibited high expression compared to other markers, while those for microglia were the least expressed. Overall, our results provide a comprehensive overview of the structural and functional characteristics of distinct brain regions in the largemouth bass, which offers a valuable resource for understanding the role of central nervous system in regulating physiological processes in teleost.
Topics: Animals; Bass; Biomarkers; Brain; Neurons; Gene Expression Profiling; Transcriptome; Telencephalon
PubMed: 38745953
DOI: 10.3389/fendo.2024.1385575 -
Scientific Reports May 2024Parkinson's disease (PD) is a complex neurodegenerative disorder without a cure. The onset of PD symptoms corresponds to 50% loss of midbrain dopaminergic (mDA) neurons,...
Parkinson's disease (PD) is a complex neurodegenerative disorder without a cure. The onset of PD symptoms corresponds to 50% loss of midbrain dopaminergic (mDA) neurons, limiting early-stage understanding of PD. To shed light on early PD development, we study time series scRNA-seq datasets of mDA neurons obtained from patient-derived induced pluripotent stem cell differentiation. We develop a new data integration method based on Non-negative Matrix Tri-Factorization that integrates these datasets with molecular interaction networks, producing condition-specific "gene embeddings". By mining these embeddings, we predict 193 PD-related genes that are largely supported (49.7%) in the literature and are specific to the investigated PINK1 mutation. Enrichment analysis in Kyoto Encyclopedia of Genes and Genomes pathways highlights 10 PD-related molecular mechanisms perturbed during early PD development. Finally, investigating the top 20 prioritized genes reveals 12 previously unrecognized genes associated with PD that represent interesting drug targets.
Topics: Parkinson Disease; Humans; Dopaminergic Neurons; RNA-Seq; Induced Pluripotent Stem Cells; Mesencephalon; Gene Regulatory Networks; Mutation; Cell Differentiation; Multiomics; Single-Cell Gene Expression Analysis
PubMed: 38744869
DOI: 10.1038/s41598-024-61844-3 -
Brain Stimulation 2024Transcranial direct current stimulation (tDCS) is a noninvasive neuromodulation method that can modulate many brain functions including learning and memory. Recent...
BACKGROUND
Transcranial direct current stimulation (tDCS) is a noninvasive neuromodulation method that can modulate many brain functions including learning and memory. Recent evidence suggests that tDCS memory effects may be caused by co-stimulation of scalp nerves such as the trigeminal nerve (TN), and not the electric field in the brain. The TN gives input to brainstem nuclei, including the locus coeruleus that controls noradrenaline release across brain regions, including hippocampus. However, the effects of TN direct current stimulation (TN-DCS) are currently not well understood.
HYPOTHESIS
In this study we tested the hypothesis that stimulation of the trigeminal nerve with direct current manipulates hippocampal activity via an LC pathway.
METHODS
We recorded neural activity in rat hippocampus using multichannel silicon probes. We applied 3 min of 0.25 mA or 1 mA TN-DCS, monitored hippocampal activity for up to 1 h and calculated spikes-rate and spike-field coherence metrics. Subcutaneous injections of xylocaine were used to block TN, while intraperitoneal and intracerebral injection of clonidine were used to block the LC pathway.
RESULTS
We found that 1 mA TN-DCS caused a significant increase in hippocampal spike-rate lasting 45 min in addition to significant changes in spike-field coherence, while 0.25 mA TN-DCS did not. TN blockage prevented spike-rate increases, confirming effects were not caused by the electric field in the brain. When 1 mA TN-DCS was delivered during clonidine blockage no increase in spike-rate was observed, suggesting an important role for the LC-noradrenergic pathway.
CONCLUSION
These results support our hypothesis and provide a neural basis to understand the tDCS TN co-stimulation mechanism. TN-DCS emerges as an important tool to potentially modulate learning and memory.
Topics: Animals; Hippocampus; Rats; Male; Trigeminal Nerve; Rats, Sprague-Dawley; Transcranial Direct Current Stimulation; Locus Coeruleus
PubMed: 38740183
DOI: 10.1016/j.brs.2024.05.005 -
Addiction Biology May 2024Synthetic opioids such as fentanyl contribute to the vast majority of opioid-related overdose deaths, but fentanyl use remains broadly understudied. Like other...
Synthetic opioids such as fentanyl contribute to the vast majority of opioid-related overdose deaths, but fentanyl use remains broadly understudied. Like other substances with misuse potential, opioids cause lasting molecular adaptations to brain reward circuits, including neurons in the ventral tegmental area (VTA). The VTA contains numerous cell types that play diverse roles in opioid use and relapse; however, it is unknown how fentanyl experience alters the transcriptional landscape in specific subtypes. Here, we performed single nuclei RNA sequencing to study transcriptional programs in fentanyl-experienced mice. Male and female C57/BL6 mice self-administered intravenous fentanyl (1.5 μg/kg/infusion) or saline for 10 days. After 24 h abstinence, VTA nuclei were isolated and prepared for sequencing on the 10× platform. We identified different patterns of gene expression across cell types. In dopamine neurons, we found enrichment of genes involved in growth hormone signalling. In dopamine-glutamate-GABA combinatorial neurons, and some GABA neurons, we found enrichment of genes involved in Pi3k-Akt signalling. In glutamate neurons, we found enrichment of genes involved in cholinergic signalling. We identified transcriptional regulators for the differentially expressed genes in each neuron cluster, including downregulated transcriptional repressor Bcl6, and upregulated transcription factor Tcf4. We also compared the fentanyl-induced gene expression changes identified in mouse VTA with a published rat dataset in bulk VTA, and found overlap in genes related to GABAergic signalling and extracellular matrix interaction. Together, we provide a comprehensive picture of how fentanyl self-administration alters the transcriptional landscape of the mouse VTA that serves as the foundation for future mechanistic studies.
Topics: Animals; Ventral Tegmental Area; Mice; Fentanyl; Male; Female; Analgesics, Opioid; Mice, Inbred C57BL; Dopaminergic Neurons; Self Administration; GABAergic Neurons; Neurons; Opioid-Related Disorders
PubMed: 38735880
DOI: 10.1111/adb.13403 -
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