Subthalamic nucleus lesions induce deficits as well as benefits in the hemiparkinsonian rat
J. M. HendersonLucy AnnettLawrence J. RyanWesley ChiangSeiko HidakaEduardo M. TorresStephen B. Dunnett
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Abstract Lesions of the subthalamic nucleus can restore some imbalances in motor output of the basal ganglia induced by nigrostriatal dopamine depletion, and have been proposed as a potential therapy for Parkinson's disease. Although there is substantial supporting evidence from experimental studies in both rats and primates, there is less information on the effects of subthalamic lesions alone. In order to characterize potential side effects, the present study evaluates the behavioural effects of unilateral excitotoxic lesions of the subthalamic nucleus in rats that have previously received either unilateral saline or 6‐hydroxydopamine injections into the nigrostriatal bundle on the same side. The 6‐hydroxydopamine lesions induced ipsilateral orientation asymmetries in head position and body axis bias, rotational asymmetries following injections of direct or indirect dopamine agonists, neglect of contralateral stimuli, and a reduction in the numbers of pellets retrieved with the contralateral paw in a skilled reaching task. Subsequent excitotoxic lesions of the subthalamic nucleus reduced (but did not abolish) rotational asymmetries, had no effects on the measures of neglect and skilled paw‐reaching, and produced contralateral orientation biases in head turning and body axis curling. Rats that received subthalamic lesions alone exhibited de novo impairments comprising contralateral biases in the orientation tests. These results support a neuromodulatory role of the subthalamic nucleus in regulating motor outputs of the basal ganglia, and caution that there may be distinct side effects of the lesion by itself. Whereas some impairments attributable to dopamine depletion may be alleviated by subthalamic manipulations, other symptoms are not, or may even be aggravated.Keywords:
Subthalamic Nucleus
Nigrostriatal pathway
Medial forebrain bundle
A major challenge in the field of neuroscience is to link behavior with specific neuronal circuitries and cellular events. One way of facing this challenge is to identify unique cellular markers and thus have the ability to, through various mouse genetics tools, mimic, manipulate and control various aspects of neuronal activity to decipher their correlation to behavior. The Vesicular Glutamate Transporter 2 (VGLUT2) packages glutamate into presynaptic vesicles for axonal terminal release. In this thesis, VGLUT2 was used to specifically target cell populations within the basal ganglia of mice with the purpose of investigating its connectivity, function and involvement in behavior. The motor and limbic loops of the basal ganglia are important for processing of voluntary movement and emotions. During such physiological events, dopamine plays a central role in modulating the activity of these systems.The brain reward system is mainly formed by dopamine projections from the ventral tegmental area (VTA) to the ventral striatum. Certain dopamine neurons within the VTA exhibit the ability to co-release dopamine and glutamate. In paper I, glutamate and dopamine co-release was targeted and our results demonstrate that the absence of VGLUT2 in dopamine neurons leads to perturbations of reward consumption and reward-associated memory, probably due to reduced DA release observed in the striatum as detected by in vivo chronoamperometry.In papers II and IV, VGLUT2 in a specific subpopulation within the subthalamic nucleus (STN) was identified and targeted. Based on the described role of the STN in movement control, we hypothesized that the mice would be hyperlocomotive. As shown in paper II, this was indeed the case. In paper IV, a putative reward-related phenotype was approached and we could show reduced operant-self administration of sugar and altered dopamine release levels suggesting a role for the STN in reward processes.In paper III, we investigated and identified age- and sex-dimorphisms in dopamine kinetics in the dorsal striatum of one of the most commonly used mouse lines worldwide, the C57/Bl6J. Our results point to the importance of taking these dimorphisms into account when utilizing the C57/Bl6J strain as model for neurological and neuropsychiatric disorders.
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Author(s): Lilascharoen, Varoth | Advisor(s): Lim, Byungkook | Abstract: The external segment of the globus pallidus (GPe), a subcortical nucleus centrally located in the indirect pathway of the basal ganglia, plays a pivotal role in processing and broadcasting information received from the striatum and the subthalamic nucleus through its widespread projections across major basal ganglia nuclei. One of the largest neuronal populations of the GPe expresses the Ca2+-binding protein parvalbumin (PV) and projects to multiple nuclei of the basal ganglia and the thalamus and has been shown to be involved in movement disability in Parkinson’s disease (PD). However, most studies to date considered GPe PV neurons as a homogeneous population. We found that the GPe PV neurons can be further subdivided into two non-overlapping populations based on their projections to either the substantia nigra pars reticulata (SNr) or the parafascicular thalamus (PF) and their intrinsic electrophysiological properties. We further investigated the circuit-specific roles of these subpopulations in locomotion and reversal learning as well as their contributions to the impairments of motor and cognitive flexibility in a PD mouse model. Our findings establish the behavioral significance of two distinct GPe PV neuronal populations embedded in discrete neural pathways and their differential contributions to specific subdomains of Parkinsonian-like behaviors.
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Medium spiny neuron
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Parkinson's disease is a neurological disorder characterized by the manifestation of motor symptoms, such as akinesia, muscle rigidity and tremor at rest. These symptoms are classically attributed to the degeneration of dopamine neurons in the pars compacta of substantia nigra (SNc), which results in a marked dopamine depletion in the striatum. It is well established that dopamine neurons in the SNc innervate not only the striatum, which is the main target, but also other basal ganglia nuclei including the two segments of globus pallidus and the subthalamic nucleus. The role of dopamine and its depletion in the striatum is well known, however, the role of dopamine depletion in the pallidal complex and the subthalamic nucleus in the genesis of their abnormal neuronal activity and in parkinsonian motor deficits is still not clearly determined. Based on recent experimental data from animal models of Parkinson's disease in rodents and non-human primates and also from parkinsonian patients, this review summarizes current knowledge on the role of dopamine in the modulation of basal ganglia neuronal activity and also the role of dopamine depletion in these nuclei in the pathophysiology of Parkinson's disease.
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Subthalamic Nucleus
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Pars reticulata
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Medial forebrain bundle
Subthalamic Nucleus
Nigrostriatal pathway
Hydroxydopamine
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Subthalamic Nucleus
Medium spiny neuron
Pars reticulata
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Basal ganglia and cerebellum have been implicated in critical roles related to control of voluntary motor movements for action selection and cognition. Basal ganglia primarily receive inputs from cortical areas as well as thalamic regions, and their functional architecture is parallel in nature which link several brain regions like cortex and thalamus. Striatum, substantia nigra, pallidum form different neuronal populations in basal ganglia circuit which were functionally distinct supporting sensorimotor, cognitive and emotional-motivational brain functions. In this paper, we have modelled and simulated basal ganglia neurons as well as basal ganglia circuit using integrate and fire neurons. Firing behaviour of subthalamic nucleus and global pallidus externa show how they modulate spike transmission in the circuit and could be used to model circuit dysfunctions in Parkinson's disease.
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Action selection
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Subthalamic Nucleus
Ventral pallidum
Medium spiny neuron
Putamen
Pars reticulata
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Abstract A distinct population of dopamine neurons in the substantia nigra pars lateralis (SNL) has a unique projection to the most caudolateral (tail) region of the striatum. Here, using two electrochemical techniques to measure basal dopamine and electrically evoked dopamine release in anesthetized rats, we characterized this pathway, and compared it with the ‘classic’ nigrostriatal pathway from neighboring substantia nigra pars compacta (SNc) dopamine neurons to the dorsolateral striatum. We found that the tail striatum constitutes a distinct dopamine domain compared with the dorsolateral striatum, with consistently lower basal and evoked dopamine, and diverse dopamine release kinetics. Importantly, electrical stimulation of the SNL and SNc evoked dopamine release in entirely separate striatal regions; the tail and dorsolateral striatum, respectively. Furthermore, we showed that stimulation of the subthalamic nucleus (STN) evoked dopamine release exclusively in the tail striatum, likely via the SNL, consistent with previous anatomical evidence of STN afferents to SNL dopamine neurons. Our work identifies the STN as an important modulator of dopamine release in a novel dopamine pathway to the tail striatum, largely independent of the classic nigrostriatal pathway, which necessitates a revision of the basal ganglia circuitry with the STN positioned as a central integrator of striatal information. image
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