Partial selectivity of 6-OHDA induced neuronal degeneration after intratissular injection in the brain with special reference to the nigro-striatal dopamine system

1975 ◽  
Vol 37 (3) ◽  
pp. 219-227 ◽  
Author(s):  
F. Javoy
Author(s):  
Yoshihisa Fujita ◽  
Sho Yagishita ◽  
Haruo Kasai ◽  
Shin Ishii

AbstractGeneralization enables applying past experience to similar but nonidentical situations. Therefore, it may be essential for adaptive behaviors. Recent neurobiological observation indicates that the striatal dopamine system achieves generalization and subsequent discrimination by updating corticostriatal synaptic connections in differential response to reward and punishment. To analyze how the computational characteristics in this system affect behaviors, we proposed a novel reinforcement learning model with multilayer neural networks in which the synaptic weights of only the last layer are updated according to the prediction error. We set fixed connections between the input and hidden layers so as to maintain the similarity of inputs in the hidden-layer representation. This network enabled fast generalization, and thereby facilitated safe and efficient exploration in reinforcement learning tasks, compared to algorithms which do not show generalization. However, disturbance in the network induced aberrant valuation. In conclusion, the unique computation suggested by corticostriatal plasticity has the advantage of providing safe and quick adaptations to unknown environments, but on the other hand has the potential defect which can induce maladaptive behaviors like delusional symptoms of psychiatric disorders.Author summaryThe brain has an ability to generalize knowledge obtained from reward- and punishment-related learning. Animals that have been trained to associate a stimulus with subsequent reward or punishment respond not only to the same stimulus but also to resembling stimuli. How does generalization affect behaviors in situations where individuals are required to adapt to unknown environments? It may enable efficient learning and promote adaptive behaviors, but inappropriate generalization may disrupt behaviors by associating reward or punishment with irrelevant stimuli. The effect of generalization here should depend on computational characteristics of underlying biological basis in the brain, namely, the striatal dopamine system. In this research, we made a novel computational model based on the characteristics of the striatal dopamine system. Our model enabled fast generalization and showed its advantage of providing safe and quick adaptation to unknown environments. By contrast, disturbance of our model induced abnormal behaviors. The results suggested the advantage and the shortcoming of generalization by the striatal dopamine system.


Author(s):  
Mariko Nakata ◽  
Masayuki Shimoda ◽  
Shinya Yamamoto

Abstract Irradiation with ultraviolet (UV) light on the cortical surface can induce a focal brain lesion (UV lesion) in rodents. In the present study, we investigated the process of establishing a UV lesion. Rats underwent UV irradiation (365 nm wavelength, 2.0 mWh) over the dura, and time-dependent changes in the cortical tissue were analyzed histologically. We found that the majority of neurons in the lesion started to degenerate within 24 hours and the rest disappeared within 5 days after irradiation. UV-induced neuronal degeneration progressed in a layer-dependent manner. Moreover, UV-induced terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positivity and heme oxygenase-1 (HO-1) immunoreactivity were also detected. These findings suggest that UV irradiation in the brain can induce gradual neural degeneration and oxidative stress. Importantly, UV vulnerability may vary among cortical layers. UV-induced cell death may be due to apoptosis; however, there remains a possibility that UV-irradiated cells were degenerated via processes other than apoptosis. The UV lesion technique will not only assist in investigating brain function at a targeted site but may also serve as a pathophysiological model of focal brain injury and/or neurodegenerative disorders.


1994 ◽  
Vol 31 (1) ◽  
pp. 48-54 ◽  
Author(s):  
J. F. Edwards ◽  
R. W. Storts ◽  
J. R. Joyce ◽  
J. M. Shelton ◽  
C. S. Menzies

Two, 8-month-old Rambouillet half-sister ewes with signs of visual loss and decreased mentation were examined. Ewe No. 1 was necropsied at 10 months of age, and alter being held under observation for a further 6 months, ewe No. 2 was necropsied at 16 months of age. At that time, the ewe was blind and severely depressed. Both ewes had deposition of an autofluorescent lipopigment, identified as ceroid-lipofuscin, in neurons of the brain, spinal cord, eye, and dorsal root ganglia. The disease process was progressive and characterized by deposition of lipopigment with neuronal degeneration and severe fibrillary aslrogliosis. This progressive loss of neurons in the older ewe led to severe retinal degeneration. No pigment was observed in cells outside of the nervous system and eye. Controlled breeding studies have shown that this disease has an autosomal, recessive inheritance. The disease referred to here as juvenile-onset neuronal ceroid-lipofuscinosis of Rambouillet sheep is unlike the majority of the hereditary ceroid-lipofuscinoses that occur in human beings and animals in that only the nervous system is affected. Therefore, this disease could serve as an excellent model for the study of lipopigment deposition that affects the nervous system as a result of various disease states and during aging.


Author(s):  
Marlaina R. Stocco ◽  
Ahmed A. El-Sherbeni ◽  
Bin Zhao ◽  
Maria Novalen ◽  
Rachel F. Tyndale

Abstract Rationale Cytochrome P450 2D (CYP2D) enzymes metabolize many addictive drugs, including methamphetamine. Variable CYP2D metabolism in the brain may alter CNS drug/metabolite concentrations, consequently affecting addiction liability and neuropsychiatric outcomes; components of these can be modeled by behavioral sensitization in rats. Methods To investigate the role of CYP2D in the brain in methamphetamine-induced behavioral sensitization, rats were pretreated centrally with a CYP2D irreversible inhibitor (or vehicle) 20 h prior to each of 7 daily methamphetamine (0.5 mg/kg subcutaneous) injections. In vivo brain microdialysis was used to assess brain drug and metabolite concentrations, and neurotransmitter release. Results CYP2D inhibitor (versus vehicle) pretreatment enhanced methamphetamine-induced stereotypy response sensitization. CYP2D inhibitor pretreatment increased brain methamphetamine concentrations and decreased the brain p-hydroxylation metabolic ratio. With microdialysis conducted on days 1 and 7, CYP2D inhibitor pretreatment exacerbated stereotypy sensitization and enhanced dopamine and serotonin release in the dorsal striatum. Day 1 brain methamphetamine and amphetamine concentrations correlated with dopamine and serotonin release, which in turn correlated with the stereotypy response slope across sessions (i.e., day 1 through day 7), used as a measure of sensitization. Conclusions CYP2D-mediated methamphetamine metabolism in the brain is sufficient to alter behavioral sensitization, brain drug concentrations, and striatal dopamine and serotonin release. Moreover, day 1 methamphetamine-induced neurotransmitter release may be an important predictor of subsequent behavioral sensitization. This suggests the novel contribution of CYP2D in the brain to methamphetamine-induced behavioral sensitization and suggests that the wide variation in human brain CYP2D6 may contribute to differential methamphetamine responses and chronic effects.


Science ◽  
2021 ◽  
Vol 372 (6537) ◽  
pp. eabf4740
Author(s):  
K. Schmack ◽  
M. Bosc ◽  
T. Ott ◽  
J. F. Sturgill ◽  
A. Kepecs

Hallucinations, a central symptom of psychotic disorders, are attributed to excessive dopamine in the brain. However, the neural circuit mechanisms by which dopamine produces hallucinations remain elusive, largely because hallucinations have been challenging to study in model organisms. We developed a task to quantify hallucination-like perception in mice. Hallucination-like percepts, defined as high-confidence false detections, increased after hallucination-related manipulations in mice and correlated with self-reported hallucinations in humans. Hallucination-like percepts were preceded by elevated striatal dopamine levels, could be induced by optogenetic stimulation of mesostriatal dopamine neurons, and could be reversed by the antipsychotic drug haloperidol. These findings reveal a causal role for dopamine-dependent striatal circuits in hallucination-like perception and open new avenues to develop circuit-based treatments for psychotic disorders.


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