Cortical spreading depression (SD) is a self-propagating wave of depolarization that is thought to be an underling mechanism of migraine aura. Growing evidence demonstrates that cortical SD triggers ...neurogenic meningeal inflammation and contributes to migraine headaches via subsequent activation of trigeminal afferents. Although direct and indirect evidence shows that cortical SD activates the trigeminal ganglion (peripheral pathway) and the trigeminal nucleus caudalis (TNC, the first central site of the trigeminal nociceptive pathway), it is not yet known whether cortical SD activates the high-order trigeminal nociceptive pathway in the brain. To address this, we induced unilateral cortical SD in rats, and then examined brain activity using voxel-based statistical parametric mapping analysis of FDG-PET imaging. The results show that approximately 40h after the induction of unilateral cortical SD, regional brain activity significantly increased in several regions, including ipsilateral TNC, contralateral ventral posteromedial (VPM) and posterior thalamic nuclei (Po), the trigeminal barrel-field region of the primary somatosensory cortex (S1BF), and secondary somatosensory cortex (S2). These results suggest that cortical SD is a noxious stimulus that can activate the high-order trigeminal nociceptive pathway even after cortical SD has subsided, probably due to prolonged meningeal inflammation.
•Unilateral cortical SD was induced in rat brain to extract migraine pain pathway.•Voxel-based SPM analysis of small animal FDG-PET imaging was conducted.•Brain activity increased in the ipsilateral TNC, contralateral VPM/Po and S1BF.•Activation of high-order trigeminal pathway existed after cortical SD has subsided.•Cortical SD induced prolonged neurogenic inflammation might be involved.
It is believed that depression impedes and motivation enhances functional recovery after neuronal damage such as spinal-cord injury and stroke. However, the neuronal substrate underlying such ...psychological effects on functional recovery remains unclear. A longitudinal study of brain activation in the non-human primate model of partial spinal-cord injury using positron emission tomography (PET) revealed a contribution of the primary motor cortex (M1) to the recovery of finger dexterity through the rehabilitative training. Here, we show that activity of the ventral striatum, including the nucleus accumbens (NAc), which plays a critical role in processing of motivation, increased and its functional connectivity with M1 emerged and was progressively strengthened during the recovery. In addition, functional connectivities among M1, the ventral striatum and other structures belonging to neural circuits for processing motivation, such as the orbitofrontal cortex, anterior cingulate cortex and pedunculopontine tegmental nucleus were also strengthened during the recovery. These results give clues to the neuronal substrate for motivational regulation of motor learning required for functional recovery after spinal-cord injury.
Patients with damage to the primary visual cortex (V1) can respond correctly to visual stimuli in their lesion-affected visual field above the chance level, an ability named blindsight. Here, we ...present a protocol for making an animal model of blindsight in macaque monkeys. We describe the steps to perform pre-lesion training of monkeys on a visual task, followed by lesion surgery, post-lesion training, and evaluation of blindsight. This animal model can be used to investigate the source of visual awareness.
For complete details on the use and execution of this protocol, please refer to Yoshida et al. (2008)1 and Takakuwa et al. (2021).2
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•A protocol for making a "blindsight" model in macaque moneys•Lesion surgery to remove most parts of V1 by aspiration•Train monkeys and evaluate task performance to assess "blindsight" ability•Post-mortem assessment to confirm the extent of V1 lesion and influence in the LGN
Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.
Patients with damage to the primary visual cortex (V1) can respond correctly to visual stimuli in their lesion-affected visual field above the chance level, an ability named blindsight. Here, we present a protocol for making an animal model of blindsight in macaque monkeys. We describe the steps to perform pre-lesion training of monkeys on a visual task, followed by lesion surgery, post-lesion training, and evaluation of blindsight. This animal model can be used to investigate the source of visual awareness.
The striatum plays important motor, associative and cognitive roles in brain functions. However, the rodent dorsolateral (the primate putamen) and dorsomedial (the primate caudate nucleus) striatum ...are not anatomically separated, making it difficult to distinguish their functions. By contrast, anatomical separation exists between the caudate nucleus and putamen in primates. Here, we successfully decreased dopamine D1 receptor (D1R) or D2R mRNA expression levels selectively in the marmoset caudate using shRNA knockdown techniques, as determined using positron emission tomography imaging with specific D1R and D2R ligands and postmortem in situ hybridization analysis. We then conducted a voxel-based correlation analysis between binding potential values of PET imaging and visual discrimination learning task performance in these genetically modified marmosets to find a critical role for the caudate D2R but no apparent role for the caudate D1R. This latter finding challenges the current understanding of the mechanisms underlying D1R activation in the caudate.
This study presents the early framework of selective cell tagging (SeCT) therapy, which is the concept of preferentially labeling specific cells in vivo with chemical moieties that can elicit a ...therapeutic response. Using glycosylated artificial metalloenzyme (GArM)-based protein labeling, this study reports two separate functional strategies. In one approach, early tumor onset can be suppressed by tagging cancer cells in living mice with an integrin-blocking cyclic-Arg-Gly-Asp (cRGD) moiety, thereby disrupting cell adhesion onto the extracellular matrix. In another approach, tumor growth in mice can be reduced by tagging with a cytotoxic doxorubicin moiety. Subsequent cell death occurs following internalization and drug release. Overall, experiments have shown that mouse populations receiving the mixture of SeCT labeling reagents exhibited a significant delay/reduction in tumor onset and growth compared with controls. Highlighting its adaptability, this work represents a foundational step for further development of SeCT therapy and its potential therapeutic applications.
Isolation-induced abnormal behaviors are useful animal models for assessing potential anti-psychotic drugs. This study examined the effect of MGS0028, a selective metabotropic glutamate 2/3 receptor ...agonist, on abnormal behaviors such as hyperactivity, aggression, and deficits of prepulse inhibition in isolation-reared mice. MGS0028 attenuated hyperactivity and aggressive behaviors in isolation-reared mice. The agonist also reversed isolation rearing–induced deficits of prepulse inhibition. On the other hand, MGS0028 did not affect locomotor activity and prepulse inhibition in group-reared mice. These results suggest that the metabotropic glutamate 2/3 receptor agonist, MGS0028, is a potential compound for the treatment of psychiatric disorders.
Dysfunction of glucose transporter 1 (GLUT1) proteins causes infantile epilepsy, which is designated as a GLUT1 deficiency syndrome (GLUT1DS; OMIM #606777). Patients with GLUT1DS display varied ...clinical phenotypes, such as infantile seizures, ataxia, severe mental retardation with learning disabilities, delayed development, hypoglycorrhachia, and other varied symptoms.
mutant mice mutagenized with N-ethyl-N-nitrosourea (ENU) carry a missense mutation in the
gene that results in amino acid substitution at the 324th residue of the GLUT1 protein. In this study, these mutants exhibited various phenotypes, including embryonic lethality of homozygotes, a decreased cerebrospinal-fluid glucose value, deficits in contextual learning, a reduction in body size, seizure-like behavior and abnormal electroencephalogram (EEG) patterns. During EEG recording, the abnormality occurred spontaneously, whereas the seizure-like phenotypes were not observed at the same time. In sleep-wake analysis using EEG recording, heterozygotes exhibited a longer duration of wake times and shorter duration of non-rapid eye movement (NREM) sleep time. The shortened period of NREM sleep and prolonged duration of the wake period may resemble the sleep disturbances commonly observed in patients with GLUT1DS and other epilepsy disorders. Interestingly, an
kinetic analysis of glucose utilization by positron emission tomography with 2-deoxy-2-fluorine-18fluoro-D-glucose imaging revealed that glucose transportation was reduced, whereas hexokinase activity and glucose metabolism were enhanced. These results indicate that a
mutant is a useful tool for elucidating the molecular mechanisms of GLUT1DS.This article has an associated First Person interview with the joint first authors of the paper.
Numerous associations between brain-reactive antibodies and neurological or psychiatric symptoms have been proposed. Serum autoantibody against the muscarinic cholinergic receptor (mAChR) was ...increased in some patients with chronic fatigue syndrome (CFS) or psychiatric disease. We examined whether serum autoantibody against mAChR affected the central cholinergic system by measuring brain mAChR binding and acetylcholinesterase activity using positron emission tomography (PET) in CFS patients with positive CFS(+) and negative CFS(-) autoantibodies.
Five CFS(+) and six CFS(-) patients, as well as 11 normal control subjects underwent a series of PET measurements with N-(11)Cmethyl-3-piperidyl benzilate (11)C(+)3-MPB for the mAChR binding and N-(11)Cmethyl-4-piperidyl acetate (11)CMP4A for acetylcholinesterase activity. Cognitive function of all subjects was assessed by neuropsychological tests. Although the brain (11)C(+)3-MPB binding in CFS(-) patients did not differ from normal controls, CFS(+) patients showed significantly lower (11)C(+)3-MPB binding than CFS(-) patients and normal controls. In contrast, the (11)CMP4A index showed no significant differences among these three groups. Neuropsychological measures were similar among groups.
The present results demonstrate that serum autoantibody against the mAChR can affect the brain mAChR without altering acetylcholinesterase activity and cognitive functions in CFS patients.
Optogenetics is a powerful tool for controlling biological functions using light. Optical fibers have been extensively utilized in optical stimulation devices for optogenetics. However, the use of ...optical fibers results in a small photo-stimulation region. In this study, micro-LED array devices were developed to achieve large-area photo-stimulation in the brain of a large animal, such as macaque monkeys. Planar and linear micro-LED array devices were designed and fabricated to photo-stimulate the prefrontal cortex (PFC) and ventral tegmental area (VTA) of the brain and induce a neurochemical response. Device operation, optical intensity, and safety were first characterized using rats. Subsequently, the devices were used to photo-stimulate the brain of macaque monkeys. In addition, microdialysis in the PFC was performed. The devices detected modulated levels of dopamine in the brains. Thus, the photo-stimulation of both the PFC and VTA were successfully achieved, and the effectiveness of the developed micro-LED array devices was demonstrated. The study will help facilitate further studies on micro-LED array stimulation for system-wide optogenetic manipulation in large animals.
Using reverse microdialysis and polygraphic recordings in freely moving cats, we investigated the effects on sleep–waking states of application of excitatory and inhibitory amino acid agonists, ...cholinergic agonist and monoamines to the periaqueductal grey and adjacent mesopontine tegmentum. Single‐unit recordings during behavioural states were further used to determine the neuronal characteristics of these structures. We found that muscimol, a GABAA receptor agonist, induced a significant increase in paradoxical sleep (PS) only when applied to a dorsocaudal central tegmental field (dcFTC) located just beneath the ventrolateral periaqueductal grey. In this structure, both kainic and N‐methyl‐aspartic acids caused a dose‐dependent increase in wakefulness (W) and decrease in both slow‐wave sleep (SWS) and PS. Norepinephrine and epinephrine, and to a lesser extent histamine, also increased W and decreased SWS and PS, whereas serotonin, dopamine and carbachol, a cholinergic agonist, had no effect. Two types of neurones were recorded in this structure, those exhibiting a higher rate of tonic discharge during both W and PS compared with during SWS, and those showing a phasic increase in firing rate during both active W and PS. Both types of neurones showed a gradual increase in unit activity during PS. Our study demonstrated for the first time that the ventrolateral periaqueductal grey and dcFTC play different roles in behavioural state control, that the dcFTC neurones are critically involved in the inhibitory mechanisms of PS generation, playing a central part in its maintenance, and that these neurones are under the control of GABAergic, glutamatergic, adrenergic and histaminergic systems.
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