Edmar Miyoshi

Impaired learning in a spatial working memory version and in a cued version of the water maze in rats with MPTP-induced mesencephalic dopaminergic lesions

A lesion in the substantia nigra pars compacta (SNc) of rats induced by intra-nigral administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) caused specific loss of dopamine and its nonconjugated metabolites in the dorsal striatum and in the prefrontal cortex (PFC), but not in the hippocampus or the ventral striatum (nucleus accumbens). This lesion did not alter the motor performance of the rats or learning of a spatial reference memory task in the water maze but impaired learning of a spatial working memory task and also of a cued version of the water maze. The results are discussed by relating the selective memory deficits observed in these water maze tasks to the PFC, dorsal striatum, and hippocampus. Some parallels between the memory deficits in these SNc-lesioned rats and Parkinsons disease patients are also discussed.

Memory disruption in rats with nigral lesions induced by MPTP: a model for early Parkinson's disease amnesia

Intra-nigral administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) caused a lesion in the substantia nigra, compact part (SNc) and a specific loss of dopamine and its metabolites in the striatum of rats. The animals were then tested in the two-way active avoidance task. MPTP-treated animals presented lower learning scores in the training and test sessions, an effect that was not caused by motor impairment or by a decreased sensitivity to footshock since their reaction time to the footshock (unconditioned stimulus - UCS) was not reduced. These lower scores were also not attributable to lower acoustic sensitivity or to a slowing in the association of the sound cue (conditioned stimulus - CS) with the UCS since the reaction time to the CS in the active avoidance response did not differ between MPTP-treated and control groups. Therefore, these results are more properly attributable to an impairment of the memory acquisition and retention processes. In addition, this study is presented as a model of early Parkinsons Disease amnesia and is discussed in terms of the importance of the nigrostriatal pathway to memory acquisition and storage processes.

Evidence for the substantia nigra pars compacta as an essential component of a memory system independent of the hippocampal memory system.

The aim of the present study was to test if the nigrostriatal pathway is an essential component for a water maze cued task learning and if it works independently of the hippocampal memory system. This hypothesis was tested using an animal model of Parkinsons disease in which male Wistar rats were lesioned in the substantia nigra pars compacta (SNc) by the intranigral infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), thus causing a partial depletion of striatal dopamine. SNc-lesioned and sham-operated animals were implanted bilaterally with guide cannulae above the dorsal hippocampus in order to be tested after the administration of 0.4 microl 2% lidocaine or saline into this structure. The animals were tested in a spatial or in a cued version of the water maze, memory tasks previously reported to model hippocampal-dependent spatial/relational and striatal-dependent S-R learning, respectively. Hippocampal inactivation, but not SNc lesion, impaired learning and memory in the spatial version of the water maze. An opposite situation was observed with the cued version. No significant interaction was observed between the SNc lesion and hippocampal inactivation conditions affecting scores in the spatial or in the cued version of the water maze. These results suggest that the nigrostriatal pathway is an essential part of the memory system that processes S-R learning and that it works independently of the hippocampal memory system that processes spatial/relational memories.

l-Dopa restores striatal dopamine level but fails to reverse MPTP-induced memory deficits in rats

The objective of the present investigation was to test the effects of benserazide/L-dopa treatment in a model of learning and memory deficits associated with early Parkinsons disease. Intra-nigral administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) caused a lesion in the substantia nigra, compact part and a specific loss of dopamine (DA) and its metabolites in the striatum of rats and a memory impairment in the two-way active avoidance task. The administration of benserazide/L-dopa (50 and 200 mg/kg) to the MPTP-lesioned rats restored the striatal level of DA, but did not reverse the MPTP-induced learning and memory impairment. As this treatment caused a large increase of DA levels in extrastriatal brain regions of the MPTP-lesioned animals, this study suggests that benserazide/L-dopa therapy was not effective in improving the observed learning impairment because this treatment appears to tilt the balance between DA levels in the striatum and in the extrastriatal regions, such as frontal cortex and limbic structures, resulting in a cognitive deficit.

Learning processing in the basal ganglia: a mosaic of broken mirrors.

In the present review we propose a model to explain the role of the basal ganglia in sensorimotor and cognitive functions based on a growing body of behavioural, anatomical, physiological, and neurochemical evidence accumulated over the last decades. This model proposes that the body and its surrounding environment are represented in the striatum in a fragmented and repeated way, like a mosaic consisting of the fragmented images of broken mirrors. Each fragment forms a functional unit representing articulated parts of the body with motion properties, objects of the environment which the subject can approach or manipulate, and locations the subject can move to. These units integrate the sensory properties and movements related to them. The repeated and widespread distribution of such units amplifies the combinatorial power of the associations among them. These associations depend on the phasic release of dopamine in the striatum triggered by the saliency of stimuli and will be reinforced by the rewarding consequences of the actions related to them. Dopamine permits synaptic plasticity in the corticostriatal synapses. The striatal units encoding the same stimulus/action send convergent projections to the internal segment of the globus pallidus (GPi) and to the substantia nigra pars reticulata (SNr) that stimulate or hold the action through a thalamus-frontal cortex pathway. According to this model, this is how the basal ganglia select actions based on environmental stimuli and store adaptive associations as nondeclarative memories such as motor skills, habits, and memories formed by Pavlovian and instrumental conditioning.

Both the dorsal hippocampus and the dorsolateral striatum are needed for rat navigation in the Morris water maze

The multiple memory systems theory proposes that the hippocampus and the dorsolateral striatum are the core structures of the spatial/relational and stimulus-response (S-R) memory systems, respectively. This theory is supported by double dissociation studies showing that the spatial and cue (S-R) versions of the Morris water maze are impaired by lesions in the dorsal hippocampus and dorsal striatum, respectively. In the present study we further investigated whether adult male Wistar rats bearing double and bilateral electrolytic lesions in the dorsal hippocampus and dorsolateral striatum were as impaired as rats bearing single lesions in just one of these structures in learning both versions of the water maze. Such a prediction, based on the multiple memory systems theory, was not confirmed. Compared to the controls, the animals with double lesions exhibited no improvement at all in the spatial version and learned the cued version very slowly. These results suggest that, instead of independent systems competing for holding control over navigational behaviour, the hippocampus and dorsal striatum both play critical roles in navigation based on spatial or cue-based strategies.

Microdialysis study of striatal dopamine in MPTP-hemilesioned rats challenged with apomorphine and amphetamine

Motor impairments of Parkinsons disease (PD) appear only after the loss of more than 70% of the DAergic neurons of the substantia nigra pars compacta (SNc). An earlier phase of this disease can be modeled in rats that received a unilateral infusion of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) into the SNc. Though these animals do not present gross motor impairments, they rotate towards the lesioned side when challenged with DAergic drugs, like amphetamine and apomorphine. The present study aimed to test whether these effects occur because the drugs disrupt compensatory mechanisms that keep extracellular levels of dopamine in the striatum (DA(E)) unchanged. This hypothesis was tested by an in vivo microdialysis study in awake rats with two probes implanted in the right and left striatum. Undrugged rats did not present turning behaviour and their basal DA(E) did not differ between the lesioned and sham-lesioned sides. However, after apomorphine treatment, DA(E) decreased in both sides, but to a larger extent in the lesioned side at the time the animals started ipsiversive turning behaviour. After amphetamine challenge, DA(E) increased in both sides, becoming significantly higher in the non-lesioned side at the time the animals started ipsiversive turning behaviour. These results are in agreement with the hypothesis that absence of gross motor impairments in this rat model of early phase PD depends on maintenance of extracellular DA by mechanisms that may be disrupted by events demanding its alteration to higher or lower levels.

Non‐motor Function of the Midbrain Dopaminergic Neurons

The roles of the nigrostriatal pathway are far beyond the simple control of motor functions. The tonic release of dopamine in the dorsal and ventral striatum controls the choice of proper actions toward a given environmental situation. In the striatum, a specific action is triggered by a specific stimulus associated with it. When the subject faces a novel and salient stimulus, the phasic release of dopamine allows synaptic plasticity in the cortico-striatal synapses. Neurons of different regions of cortical areas make synapses that converge to the same medium spine neurons of the striatum. The convergent associations form functional units encoding body parts, objects, locations, and symbolic representations of the subjects world. Such units emerge in the striatum in a repetitive manner, like a mosaic of broken mirrors. The phasic release of dopamine allows the association of units to encode an action of the subject directed to an object or location with the outcome of this action. Reinforced stimulus-action-outcome associations will affect future decision making when the same stimulus (object, location, idea) is presented to the subject in the future. In the absence of a minimal amount of striatal dopamine, no action is initiated as seen in Parkinsons disease subjects. The abnormal and improper association of these units leads to the initiation of unpurposeful and sometimes repetitive actions, as those observed in dyskinetic patients. The association of an excessive reinforcement of some actions, like drug consumption, leads to drug addiction. Improper associations of ideas and unpleasant outcomes may be related to traumatic and depressive symptoms common in many diseases, including Parkinsons disease. The same can be said about the learning and memory impairments observed in demented and nondemented Parkinsons disease patients.

Abnormal Cerebrovascular Reactivity in Patients with Parkinson’s Disease

Background. Orthostatic hypotension (OH) is an important nonmotor manifestation of Parkinsons disease (PD). Changes in cerebrovascular reactivity may contribute to this manifestation and can be monitored using transcranial Doppler. Objective. To identify possible changes in cerebrovascular reactivity in patients with OH. Methods. Twenty-two individuals were selected and divided into three groups: with and without OH and controls. Transcranial Doppler was used to assess basal mean blood flow velocity, postapnea mean blood flow velocity, percentage increase in mean blood flow velocity, and cerebrovascular reactivity as measured by the breath-holding index. Results. PD patients had lower values of basal velocity (p = 0.019), postapnea velocity (p = 0.0015), percentage increase in velocity (p = 0.039), and breath-holding index (p = 0.04) than the controls. Patients with OH had higher values of basal velocity (p = 0.09) and postapnea velocity (p = 0.19) but lower values of percentage increase in velocity (p = 0.22) and breath-holding index (p = 0.32) than patients without OH. Conclusions. PD patients present with abnormalities in a compensatory mechanism that regulates cerebral blood flow. OH could be an indicator of these abnormalities.

Effects of Hypericum perforatum on turning behavior in an animal model of Parkinson's disease

A Doenca de Parkinson e uma doenca neurodegenerativa relacionada a idade, caracterizada pela morte lenta e progressiva de neuronios dopaminergicos da substância negra pars compacta. O Hypericum perforatum (H. perforatum) e um fitoterapico utilizado como antidepressivo, apresentando propriedades antioxidantes, anti-inflamatorias e nootropicas. Neste trabalho, avaliaram-se os efeitos do tratamento com H. perforatum no comportamento rotatorio de ratos no modelo da doenca de Parkinson induzido pela administracao unilateral de 6-OHDA no feixe prosencefalico medial. Ratos Wistar machos foram tratados com H. perforatum (100, 200 ou 400 mg/kg, v.o.) por 35 dias (do 28o dia antes ate o 7o dia apos a lesao). As rotacoes ipsilaterais e contralaterais a lesao foram registradas no 7o, 14o e 21o dias apos a cirurgia. As tres doses de H. perforatum utilizadas reduziram o numero de rotacoes contralaterais, indicando um possivel efeito neuroprotetor da planta. Porem, o H. perforatum nao impediu a reducao na expressao da enzima tirosina hidroxilase no estriado lesionado, quantificada por Western blot. Propomos que o H. perforatum possa bloquear o aumento da expressao dos receptores dopaminergicos no estriado lesionado com 6-OHDA. Entretanto, estudos adicionais sao necessarios para identificar o mecanismo exato pelo qual o H. perforatum reduziu o numero de rotacoes contralaterais. Os resultados do presente estudo sugerem o H. perforatum como um potencial agente terapeutico para a doenca de Parkinson.