To date, numerous case-control studies have shown the complexity of the pathogenesis of Parkinson's disease (PD). In terms of genetic factors, several susceptibility genes are known to contribute to the development of PD, including alpha-synuclein (SNCA), leucine-rich repeat kinase 2 (LRRK2), and glucocerebrosidase (GBA). In addition, numerous recent epidemiological studies have shown that several environmental factors are either risk factors for PD or protective factors against PD. Risk factors identified include herbicides and pesticides (e.g., paraquat, rotenone, and maneb), metals (e.g., manganese and lead), head trauma, and well water. In contrast, smoking and coffee/caffeine consumption are known to be protective against PD. A recent finding in this field is that environmental-genetic interactions contribute more to the pathogenesis of PD than do genetic factors or environmental factors alone. In this review, I will discuss how these interactions promote the development of PD.
alpha-Synuclein ; Case-Control Studies ; Craniocerebral Trauma ; Glucosylceramidase ; Herbicides ; Manganese ; Metals ; Paraquat ; Parkinson Disease ; Pesticides ; Phosphotransferases ; Risk Factors ; Rotenone ; Smoke ; Smoking ; Water wells

Consciousness has become a legitimate theme of neuroscientific discourse over the last two decades. Neuroscientific investigation seeking neural correlates of consciousness (NCC) has ranged from the neuronal level to the system level. Regarding system level studies, there is a large body of evidence supporting the idea that functional connectivity studies can help in examining NCC. Functional connectivity studies have suggested the involvement of the thalamo-cortical, frontoparietal, and other cortico-cortical connectivity under anesthetic-induced unconsciousness and in disorders of consciousness. Likewise, effective connectivity has been used to investigate the causal interactions among elements of functional connectivity in various consciousness states, and provided a deeper understanding of NCC. Moreover, as an extended version of connectivity studies, complex network methods have also been used for studies on NCC. In this review, we focused on the aspect of the brain system level of NCC including functional and effective connectivity networks from methodological perspectives. In addition, as for states of consciousness, anesthetic-induced unconsciousness and disorders of consciousness are the main subjects. This review discusses what we have learned from recent studies about the exploration of human brain connectivity on consciousness and its neural correlates.
Brain ; Consciousness ; Humans ; Neurons ; Unconsciousness

Movement defects in obesity are associated with peripheral muscle defects, arthritis, and dysfunction of motor control by the brain. Although movement functionality is negatively correlated with obesity, the brain regions and downstream signaling pathways associated with movement defects in obesity are unclear. A dopaminergic neuronal pathway from the substantia nigra (SN) to the striatum is responsible for regulating grip strength and motor initiation through tyrosine hydroxylase (TH) activity-dependent dopamine release. We found that mice fed a high-fat diet exhibited decreased movement in open-field tests and an increase in missteps in a vertical grid test compared with normally fed mice. This motor abnormality was associated with a significant reduction of TH in the SN and striatum. We further found that phosphorylation of c-Jun N-terminal kinase (JNK), which modulates TH expression in the SN and striatum, was decreased under excess-energy conditions. Our findings suggest that high calorie intake impairs motor function through JNK-dependent dysregulation of TH in the SN and striatum.
Animals ; Arthritis ; Brain ; Diet, High-Fat* ; Dopamine ; Dopaminergic Neurons* ; Hand Strength ; JNK Mitogen-Activated Protein Kinases ; Mesencephalon* ; Mice ; Obesity ; Phosphorylation ; Substantia Nigra ; Tyrosine 3-Monooxygenase

α-Synuclein (α-Syn) is a small presynaptic protein and its mutant forms (e.g. A53T) are known to be directly associated with Parkinson's disease (PD). Pathophysiological mechanisms underlying α-Syn-mediated neurodegeneration in PD still remain to be explored. However, several studies strongly support that overexpression of mutant α-Syn causes reduced release of dopamine (DA) in the brain, and contributes to motor deficits in PD. Using a favorable genetic model Drosophila larva, we examined whether reduced DA release is enough to induce key PD symptoms (i.e. locomotion deficiency and DA neurodegeneration), mimicking a PD gene α-Syn. In order to reduce DA release, we expressed electrical knockout (EKO) gene in DA neurons, which is known to make neurons hypo-excitable. EKO led to a decrease in a DA neuronal marker signal (i.e., TH – tyrosine hydroxylase) and locomotion deficits in Drosophila larva. In contrast, acute and prolonged exposure to blue light (BL, 470 nm) was sufficient to activate channelrhodopsin 2 (ChR2) and rescue PD symptoms caused by both α-Syn and EKO. We believe this is for the first time to confirm that locomotion defects by a genetic PD factor such as α-Syn can be rescued by increasing DA neuronal excitability with an optogenetic approach. Our findings strongly support that PD is a failure of DA synaptic transmission, which can be rescued by optogenetic activation of ChR2.
alpha-Synuclein* ; Brain ; Dopamine ; Dopaminergic Neurons ; Drosophila ; Drosophila melanogaster ; Larva ; Locomotion ; Models, Genetic ; Neurons ; Optogenetics* ; Parkinson Disease ; Synaptic Transmission ; Tyrosine

Human studies of brain stimulation have demonstrated modulatory effects on the perception of pain. However, whether the primary somatosensory cortical activity is associated with antinociceptive responses remains unknown. Therefore, we examined the antinociceptive effects of neuronal activity evoked by optogenetic stimulation of primary somatosensory cortex. Optogenetic transgenic mice were subjected to continuous or pulse-train optogenetic stimulation of the primary somatosensory cortex at frequencies of 15, 30, and 40 Hz, during a tail clip test. Reaction time was measured using a digital high-speed video camera. Pulse-train optogenetic stimulation of primary somatosensory cortex showed a delayed pain response with respect to a tail clip, whereas no significant change in reaction time was observed with continuous stimulation. In response to the pulse-train stimulation, video monitoring and local field potential recording revealed associated paw movement and sensorimotor rhythms, respectively. Our results show that optogenetic stimulation of primary somatosensory cortex at beta and gamma frequencies blocks transmission of pain signals in tail clip test.
Animals ; Brain ; Humans ; Mice ; Mice, Transgenic ; Neurons ; Optogenetics ; Pain Perception* ; Reaction Time ; Somatosensory Cortex* ; Tail*

Translationally controlled tumor protein (TCTP) is a cytosolic protein with microtubule stabilization and calcium-binding activities. TCTP is expressed in most organs including the nervous system. However, detailed distribution and functional significance of TCTP in the brain remain unexplored. In this study, we investigated the global and subcellular distributions of TCTP in the mouse brain. Immunohistochemical analyses with anti-TCTP revealed that TCTP was widely distributed in almost all regions of the brain including the cerebral cortex, thalamus, hypothalamus, hippocampus, and amygdala, wherein it was localized in axon tracts and axon terminals. In the hippocampus, TCTP was prominently localized to axon terminals of the perforant path in the dentate gyrus, the mossy fibers in the cornu ammonis (CA)3 region, and the Schaffer collaterals in the CA1 field, but not in cell bodies of granule cells and pyramidal neurons, and in their dendritic processes. Widespread distribution of TCTP in axon tracts and axon terminals throughout the brain suggests that TCTP is likely involved in neurotransmitter release and/or maintaining synaptic structures in the brain, and that it might have a role in maintaining synaptic functions and synaptic configurations important for normal cognitive, stress and emotional functions.
Amygdala ; Animals ; Axons* ; Brain ; Cell Body ; Cerebral Cortex ; Cognition ; Cytosol ; Dentate Gyrus ; Hippocampus ; Hypothalamus ; Immunohistochemistry ; Mice* ; Microtubules ; Nervous System ; Neurons* ; Neurotransmitter Agents ; Perforant Pathway ; Presynaptic Terminals* ; Pyramidal Cells ; Thalamus

Radial glial cells (RGCs) which function as neural stem cells are known to be non-excitable and their proliferation depends on the intracellular calcium (Ca²⁺) level. It has been well established that Inositol 1,4,5-trisphosphate (IP3)-mediated Ca²⁺ release and Ca²⁺ entry through various Ca²⁺ channels are involved in the proliferation of RGCs. Furthermore, RGCs line the ventricular wall and are exposed to a shear stress due to a physical contact with the cerebrospinal fluid (CSF). However, little is known about how the Ca²⁺ entry through mechanosensitive ion channels affects the proliferation of RGCs. Hence, we hypothesized that shear stress due to a flow of CSF boosts the proliferative potential of RGCs possibly via an activation of mechanosensitive Ca²⁺ channel during the embryonic brain development. Here, we developed a new microfluidic two-dimensional culture system to establish a link between the flow shear stress and the proliferative activity of cultured RGCs. Using this microfluidic device, we successfully visualized the artificial CSF and RGCs in direct contact and found a significant enhancement of proliferative capacity of RGCs in response to increased shear stress. To determine if there are any mechanosensitive ion channels involved, a mechanical stimulation by poking was given to individual RGCs. We found that a poking on radial glial cell induced an increase in intracellular Ca²⁺ level, which disappeared under the extracellular Ca²⁺-free condition. Our results suggest that the shear stress by CSF flow possibly activates mechanosensitive Ca²⁺ channels, which gives rise to a Ca²⁺ entry which enhances the proliferative capacity of RGCs.
Brain ; Calcium Channels* ; Calcium* ; Cerebrospinal Fluid ; Ependymoglial Cells* ; Inositol 1,4,5-Trisphosphate ; Ion Channels ; Lab-On-A-Chip Devices ; Microfluidics ; Neural Stem Cells

Myotonic dystrophy type 1 (DM1) is caused by CTG repeat expansion in the DMPK gene in chromosome 19q13.3. External ophthalmoplegia is a rare manifestation in DM1. We report a DM1 patient confirmed by the presence of 650 CTG triplet expansions in the DMPK gene and had limitation of adduction gaze bilaterally. Brain MRI showed bilateral medial rectus muscles atrophy. Our patient provides additional evidence of ocular motor muscle involvement in DM1.
Atrophy ; Brain ; Humans ; Magnetic Resonance Imaging ; Muscles ; Myotonia ; Myotonic Dystrophy* ; Ophthalmoplegia ; Paralysis* ; Triplets

The existence of Toxocara canis-specific antibodies has recently been reported in patients with atopic myelitis. Here, we report the case of a 35-year-old male patient admitted with a chief complaint of right lower limb hypoesthesia lasting for a month. The patient was diagnosed with eosinophilic pneumonia 3 months ago, and a spine MRI revealed the presence of myelitis in the cervicothoracic cord. After confirming the presence of hyper-IgE-emia and Toxocara canis antibodies, the patient was treated with steroids and albendazole treatment, which improved his symptoms. To our knowledge, this is the first case of Toxocara canis-associated myelitis with eosinophilic pneumonia.
Adult ; Albendazole ; Antibodies ; Eosinophils* ; Humans ; Hypesthesia ; Lower Extremity ; Magnetic Resonance Imaging ; Male ; Myelitis* ; Pulmonary Eosinophilia* ; Spine ; Steroids ; Toxocara canis ; Toxocara*

Ischemia can cause decreased cerebral neurovascular coupling, leading to a failure in the autoregulation of cerebral blood flow. This study aims to investigate the effect of varying degrees of ischemia on cerebral hemodynamic reactivity using in vivo real-time optical imaging. We utilized direct cortical stimulation to elicit hyper-excitable neuronal activation, which leads to induced hemodynamic changes in both the normal and middle cerebral artery occlusion (MCAO) ischemic stroke groups. Hemodynamic measurements from optical imaging accurately predict the severity of occlusion in mild and severe MCAO animals. There is neither an increase in cerebral blood volume nor in vessel reactivity in the ipsilateral hemisphere (I.H) of animals with severe MCAO. The pial artery in the contralateral hemisphere (C.H) of the severe MCAO group reacted more slowly than both hemispheres in the normal and mild MCAO groups. In addition, the arterial reactivity of the I.H in the mild MCAO animals was faster than the normal animals. Furthermore, artery reactivity is tightly correlated with histological and behavioral results in the MCAO ischemic group. Thus, in vivo optical imaging may offer a simple and useful tool to assess the degree of ischemia and to understand how cerebral hemodynamics and vascular reactivity are affected by ischemia.
Animals ; Arteries ; Blood Volume ; Cerebrovascular Circulation ; Hemodynamics* ; Homeostasis ; Infarction, Middle Cerebral Artery* ; Ischemia ; Middle Cerebral Artery* ; Neurons ; Neurovascular Coupling ; Optical Imaging ; Rodentia* ; Stroke