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 ; Locomotion ; Mesencephalon ; Midbrain Reticular Formation ; Parkinson Disease

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

Humans ; Mesencephalon ; Neural Pathways ; Pain ; Spinal Cord

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

PURPOSE: Mild traumatic brain injury (TBI) is common but accurate diagnosis and its clinical consequences have been a problem. Maxillofacial trauma does have an association with TBI. Neuron-specific enolase (NSE) has been developed to evaluate neuronal damage. The objective of this study was to investigate the accuracy of NSE serum levels to detect mild brain injury of patients with sustained maxillofacial fractures during motor vehicle accidents. METHODS: Blood samples were drawn from 40 healthy people (control group) and 48 trauma patients who had sustained isolated maxillofacial fractures and mild brain injury in motor vehicle accidents. Brain injuries were graded by Glasgow Coma Scale. In the trauma group, correlations between the NSE serum value and different facial fracture sites were also assessed. RESULTS: The NSE serum level (mean ± SD, ng/ml) in the 48 patients with maxillofacial fractures and mild TBI was 13.12 ± 9.68, significantly higher than that measured in the healthy control group (7.72 ± 1.82, p < 0.001). The mean NSE serum level (ng/ml) in the lower part of the facial skeleton (15.44 with SD 15.34) was higher than that in the upper facial part (12.42 with SD 7.68); and the mean NSE level (ng/ml) in the middle-and lower part (11.97 with SD 5.63) was higher than in the middle part (7.88 with SD 2.64). CONCLUSION An increase in NSE serum levels can be observed in patients sustained maxillofacial fractures and mild brain injury.
Accidents, Traffic ; Adult ; Aged ; Biomarkers ; blood ; Brain Injuries, Traumatic ; diagnosis ; Craniocerebral Trauma ; Female ; Humans ; Male ; Maxillary Fractures ; Maxillofacial Injuries ; Mesencephalon ; injuries ; Middle Aged ; Motorcycles ; Phosphopyruvate Hydratase ; blood ; Predictive Value of Tests ; Young Adult

The neuroimaging has been applied in the study of pathophysiology in major depressive disorder (MDD). In this review article, several kinds of methodologies of neuroimaging would be discussed to summarize the promising biomarkers in MDD. For the magnetic resonance imaging (MRI) and magnetoencephalography field, the literature review showed the potentially promising roles of frontal lobes, such as anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DLPFC) and orbitofrontal cortex (OFC). In addition, the limbic regions, such as hippocampus and amygdala, might be the potentially promising biomarkers for MDD. The structures and functions of ACC, DLPFC, OFC, amygdala and hippocampus might be confirmed as the biomarkers for the prediction of antidepressant treatment responses and for the pathophysiology of MDD. The functions of cognitive control and emotion regulation of these regions might be crucial for the establishment of biomarkers. The near-infrared spectroscopy studies demonstrated that blood flow in the frontal lobe, such as the DLPFC and OFC, might be the biomarkers for the field of near-infrared spectroscopy. The electroencephalography also supported the promising role of frontal regions, such as the ACC, DLPFC and OFC in the biomarker exploration, especially for the sleep electroencephalogram to detect biomarkers in MDD. The positron emission tomography (PET) and single-photon emission computed tomography (SPECT) in MDD demonstrated the promising biomarkers for the frontal and limbic regions, such as ACC, DLPFC and amygdala. However, additional findings in brainstem and midbrain were also found in PET and SPECT. The promising neuroimaging biomarkers of MDD seemed focused in the fronto-limbic regions.
Amygdala ; Biomarkers ; Brain Stem ; Depression ; Depressive Disorder, Major ; Electroencephalography ; Frontal Lobe ; Gyrus Cinguli ; Hippocampus ; Magnetic Resonance Imaging ; Magnetoencephalography ; Mesencephalon ; Neuroimaging ; Positron-Emission Tomography ; Prefrontal Cortex ; Spectroscopy, Near-Infrared ; Tomography, Emission-Computed ; Tomography, Emission-Computed, Single-Photon