OBJECTIVE: To establish an efficient protocol for directed differentiation of human induced pluripotent stem cells (hiPSCs) into functional midbrain dopaminergic progenitor cells (DAPs) in vitro. METHODS: hiPSCs were induced to differentiate into DAPs in two developmental stages. In the first stage (the first 13 days), hiPSCs were induced into intermediate cells morphologically similar to primitive neuroepithelial cells (NECs) in neural induction medium containing a combination of small molecule compounds. In the second stage, the intermediate cells were further induced in neural differentiation medium until day 28 to obtain DAPs. After CM-DiI staining, the induced DAPs were stereotactically transplanted into the right medial forebrain bundle (MFB) of rat models of Parkinson's disease (PD). Eight weeks after transplantation, the motor behaviors of PD rats was evaluated. Immunofluorescence assay of brain sections of the rats was performed at 2 weeks after transplantation to observe the survival, migration and differentiation of the transplanted cells in the host brain microenvironment. RESULTS: hiPSCs passaged stably on Matrigel showed a normal diploid karyotype, expressed the pluripotency markers OCT4, SOX2, and Nanog, and were positive for alkaline phosphatase. The primitive neuroepithelial cells obtained on day 13 formed dense cell colonies in the form of neural rosettes and expressed the neuroepithelial markers (SOX2, Nestin, and PAX6, 91.3%-92.8%). The DAPs on day 28 highly expressed the specific markers (TH, FOXA2, LMX1A and NURR1, 93.3-96.7%). In rat models of PD, the hiPSCs-DAPs survived and differentiated into TH⁺, FOXA2⁺ and Tuj1⁺ neurons at 2 weeks after transplantation. Eight weeks after transplantation, the motor function of PD rats was significantly improved as shown by water maze test (P < 0.0001) and apomorphine-induced rotation test (P < 0.0001) compared with rats receiving vehicle injection. CONCLUSION HiPSCs can be effectively induced to differentiate into DAPs capable of differentiating into functional neurons both in vivo and in vitro. In rat models of PD, the transplanted hiPSCs-DAPs can survive for more than 8 weeks in the MFB and differentiate into multiple functional neurocytes to ameliorate neurological deficits of the rats, suggesting the potential value of hiPSCs-DAPs transplantation for treatment of neurological diseases.
Humans ; Rats ; Animals ; Induced Pluripotent Stem Cells ; Cell Differentiation/physiology* ; Neurons ; Parkinson Disease ; Mesencephalon ; Cells, Cultured

Wernekink commissure syndrome is a rare midbrain syndrome with bilateral cerebellar dysfunction,eye movement disorder,and palatal myoclonus.Few cases of this syndrome have been reported in China,let alone those combined with hallucinations and involuntary groping.This paper reports the diagnosis and treatment of a case of Wernekink commissure syndrome with hallucinations and involuntary groping,aiming to enrich the knowledge about this disease for clinicians.
Humans ; Mesencephalon ; Ocular Motility Disorders/diagnosis* ; Spinal Cord ; Syndrome ; Hallucinations

Itch is an unpleasant sensation that provokes the desire to scratch. While acute itch serves as a protective system to warn the body of external irritating agents, chronic itch is a debilitating but poorly-treated clinical disease leading to repetitive scratching and skin lesions. However, the neural mechanisms underlying the pathophysiology of chronic itch remain mysterious. Here, we identified a cell type-dependent role of the anterior cingulate cortex (ACC) in controlling chronic itch-related excessive scratching behaviors in mice. Moreover, we delineated a neural circuit originating from excitatory neurons of the ACC to the ventral tegmental area (VTA) that was critically involved in chronic itch. Furthermore, we demonstrate that the ACC→VTA circuit also selectively modulated histaminergic acute itch. Finally, the ACC neurons were shown to predominantly innervate the non-dopaminergic neurons of the VTA. Taken together, our findings uncover a cortex-midbrain circuit for chronic itch-evoked scratching behaviors and shed novel insights on therapeutic intervention.
Mice ; Animals ; Gyrus Cinguli/physiology* ; Pruritus/pathology* ; Mesencephalon ; Cerebral Cortex/pathology* ; Neurons/pathology*

Humans ; Mesencephalon ; Neural Pathways ; Pain ; Spinal Cord

Humans ; Locomotion ; Mesencephalon ; Midbrain Reticular Formation ; Parkinson Disease

Corpus Striatum ; Dopaminergic Neurons ; Humans ; Mesencephalon ; Parkinson Disease/drug therapy* ; Pars Compacta ; Substantia Nigra

OBJECTIVE: The provisional diagnosis of progressive supranuclear palsy (PSP) depends on a combination of typical clinical features and specific MRI findings, such as atrophy of the tegmentum in the midbrain. Atrophy of the superior cerebellar peduncle (SCP) distinguishes PSP from other types of parkinsonism. Histological factors affect the conventional fluid-attenuated inversion recovery (FLAIR) signals, such as the extent of neuronal loss and gliosis. METHODS: We investigated patients with PSP to verify the percentage of patients with various PSP phenotypes presenting a high signal intensity in the SCP. Three interviewers, who were not informed about the clinical data, visually inspected the presence or absence of a high signal intensity in the SCP on the FLAIR images. We measured the pixel value in the SCP of each patient. Clinical characteristics were evaluated using the Mann-Whitney test, followed by the χ² test. RESULTS: Ten of the 51 patients with PSP showed a high signal intensity in the SCP on FLAIR MRI. Higher pixel values were observed within the SCP of patients with a high signal intensity in the SCP than in patients without a high signal intensity (p < 0.001). The sensitivity and specificity of the high signal intensity in the SCP of patients with PSP was 19.6% and 100%, respectively. This finding was more frequently observed in patients with PSP with Richardson's syndrome (PSP-RS) (25.7%) than other phenotypes (6.2%). CONCLUSION: The high signal intensity in the SCP on FLAIR MRI might be an effective diagnostic tool for PSP-RS.
Atrophy ; Diagnosis ; Gliosis ; Humans ; Magnetic Resonance Imaging ; Mesencephalon ; Neurodegenerative Diseases ; Neurons ; Parkinsonian Disorders ; Phenotype ; Sensitivity and Specificity ; Supranuclear Palsy, Progressive

The role of the microbiome in health and human disease has emerged at the forefront of medicine in the 21st century. Over the last 2 decades evidence has emerged to suggest that inflammation-derived oxidative damage and cytokine induced toxicity may play a significant role in the neuronal damage associated with Parkinson's disease (PD). Presence of pro-inflammatory cytokines and T cell infiltration has been observed in the brain parenchyma of patients with PD. Furthermore, evidence for inflammatory changes has been reported in the enteric nervous system, the vagus nerve branches and glial cells. The presence of α-synuclein deposits in the post-mortem brain biopsy in patients with PD has further substantiated the role of inflammation in PD. It has been suggested that the α-synuclein misfolding might begin in the gut and spread “prion like” via the vagus nerve into lower brainstem and ultimately to the midbrain; this is known as the Braak hypothesis. It is noteworthy that the presence of gastrointestinal symptoms (constipation, dysphagia, and hypersalivation), altered gut microbiota and leaky gut have been observed in PD patients several years prior to the clinical onset of the disease. These clinical observations have been supported by in vitro studies in mice as well, demonstrating the role of genetic (α-synuclein overexpression) and environmental (gut dysbiosis) factors in the pathogenesis of PD. The restoration of the gut microbiome in patients with PD may alter the clinical progression of PD and this alteration can be accomplished by carefully designed studies using customized probiotics and fecal microbiota transplantation.
Animals ; Anti-Bacterial Agents ; Biopsy ; Brain ; Brain Stem ; Cytokines ; Deglutition Disorders ; Dysbiosis ; Enteric Nervous System ; Fecal Microbiota Transplantation ; Gastrointestinal Microbiome ; Humans ; In Vitro Techniques ; Inflammation ; Mesencephalon ; Mice ; Microbiota ; Neuroglia ; Neurons ; Parkinson Disease ; Probiotics ; Vagus Nerve

The habenula (Hb) is small but important brain structure, anatomically and functionally links the forebrain with the midbrain to modulate various neuropsychiatric functions associated with drug addiction and emotion-associated dysfunctions. Several reports suggested that the dysfunction of Hb-related functions affected the Hb structurally and functionally. However, the technical limitation has awaited the solid conclusion of whether Hb change due to depression is likely to occur in certain subnuclei of the Hb. To probe this possibility, we developed 3-dimensional reconstruction methods for the high-resolution volumetric analysis of Hb and the mRNA levels at the given volume in normal or lipopolysaccharide (LPS)-mediated mouse model of depression. Notably, we discovered that the volume reduction was prominent in medial Hb but not in lateral Hb after LPS treatments. On the other hand, the RNA expression levels of known Hb regional markers such as Tac1 (dorsal part of medial Hb), ChAT (ventral part of medial Hb), and Tacr1 (medial and lateral Hb) were all decreased in all Hb subnuclei in LPS-injected mice. Accordingly, accurate volumetry with marker labeling was not feasible. Collectively, these established 3D analyses of mouse Hb successfully and precisely determine the volume-based changes of small brain structure, which should be applicable in a wider range of mouse models or pathological specimens.
Animals ; Brain ; Depression ; Gene Expression ; Habenula ; Hand ; Mesencephalon ; Mice ; Prosencephalon ; RNA ; RNA, Messenger ; Substance-Related Disorders

The habenula is a small and bilateral nucleus above dorsal thalamus, which contains several different types of neurons. The habenula has extensive connections with the forebrain, septum and monoaminergic nuclei in the midbrain and brainstem. Habenula is known as an 'anti-reward' nucleus, which can be activated by aversive stimulus and negative reward prediction errors. Accumulating researchs have implicated that the habenula is involved in several behaviors crucial to survival. Meanwhile, the roles of the habenula in neuropsychiatric diseases have received increasing attention. This review summaries the studies regarding the roles of habenula and the related circuits in neuropathic pain, depression, drug addiction and schizophrenia, and discusses the possibility to use the habenula as a treatment target.
Depressive Disorder ; Habenula ; Humans ; Mental Disorders ; pathology ; Mesencephalon ; Neurons ; metabolism ; Reward