Why dopamine-containing neurons of the brain's substantia nigra pars compacta die in Parkinson's disease has been an enduring mystery. Our studies suggest that the unusual reliance of these neurons on L-type Ca(v)1.3 Ca2+ channels to drive their maintained, rhythmic pacemaking renders them vulnerable to stressors thought to contribute to disease progression. The reliance on these channels increases with age, as juvenile dopamine-containing neurons in the substantia nigra pars compacta use pacemaking mechanisms common to neurons not affected in Parkinson's disease. These mechanisms remain latent in adulthood, and blocking Ca(v)1.3 Ca2+ channels in adult neurons induces a reversion to the juvenile form of pacemaking. Such blocking ('rejuvenation') protects these neurons in both in vitro and in vivo models of Parkinson's disease, pointing to a new strategy that could slow or stop the progression of the disease.

Among the most widely used models of Parkinson’s disease (PD) are those that employ toxins, especially 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Depending on the protocol used, MPTP yields large variations in nigral cell loss, striatal dopamine loss and behavioral deficits. Motor deficits do not fully replicate those seen in PD. Nonetheless, MPTP mouse models mimic many aspects of the disease and are therefore important tools for understanding PD. In this review, we will discuss the ability of MPTP mouse models to replicate the pathophysiology of PD, the mechanisms of MPTP-induced neurotoxicity, strain differences in susceptibility to MPTP, and the models’ roles in testing therapeutic approaches.

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The circuitry important for voluntary movement is influenced by dopamine from the substantia nigra and regulated by the nigrostriatal system. The basal ganglia influence the pyramidal tract and other motor systems, such as the mesopontine nuclei and the rubrospinal tract. Although the neuroanatomical substrates underlying motor control are similar for humans and rodents, the behavioral repertoire mediated by those circuits is not. The principal aim of this review is to evaluate how injury to dopamine-mediated pathways in rodents gives rise to motor dysfunction that mimics human Parkinsonism. We will examine the behavioral tests in common use with rodent models of Parkinson's disease and critically evaluate the appropriateness of each test for detecting motor impairment. We will show how tests of motor performance must be guided by a thorough understanding of the clinical symptoms accompanying the disease, the circuitry mediating dopamine deficits in rodents, and familiarity with the rodent behavioral repertoire. We will explain how investigations in rodents of skilled forepaw actions, including placing, grooming, or foot faults, have clear correlates in Parkinson's disease, and are, therefore, the most sensitive ways of detecting motor impairment following dopamine loss from the basal ganglia of rodents.

Parkinson's disease (PD) is a progressive neurodegenerative disorder whose etiology is not understood. This disease occurs both sporadically and through inheritance of single genes, although the familial types are rare. Over the past decade or so, experimental and clinical data suggest that PD could be a multifactorial, neurodegenerative disease that involves strong interactions between the environment and genetic predisposition. Our understanding of the pathophysiology and motor deficits of the disease relies heavily on fundamental research on animal models and the last few years have seen an explosion of toxin-, inflammation-induced and genetically manipulated models. The insight gained from the use of such models has strongly advanced our understanding of the progression and stages of the disease. The models have also aided the development of novel therapies to improve symptomatic management, and they are critical for the development of neuroprotective strategies. This review critically evaluates these in vivo models and the roles they play in mimicking the progression of PD.

We examined the structural plasticity of excitatory synapses from corticostriatal and thalamostriatal pathways and their postsynaptic targets in adult Sprague-Dawley rats to understand how these striatal circuits change in L-DOPA-induced dyskinesias (LIDs). We present here detailed electron and light microscopic analyses that provide new insight into the nature of the structural and synaptic remodeling of medium spiny neurons in response to LIDs. Numerous studies have implicated enhanced glutamate signaling and persistent long-term potentiation as central to the behavioral sensitization phenomenon of LIDs. Moreover, experience-dependent alterations in behavior are thought to involve structural modifications, specifically alterations in patterns of synaptic connectivity. Thus, we hypothesized that in the striatum of rats with LIDs, one of two major glutamatergic pathways would form new or altered contacts, especially onto the spines of medium spiny neuron (MSNs). Our data provide compelling evidence for a dramatic rewiring of the striatum of dyskinetic rats and that this rewiring involves corticostriatal but not thalamostriatal contacts onto MSNs. There is a dramatic increase in corticostriatal contacts onto spines and dendrites that appear to be directly linked to dyskinetic behaviors, since they were not seen in the striatum of animals that did not develop dyskinesia. There is also an aberrant increase in spines receiving more than one excitatory contact(i.e., multisynaptic spines) in the dyskinetic animals compared with the 6-hydroxydopamine-treated and control rats. Such alterations could substantially impair the ability of striatal neurons to gate cortically driven signals and contribute to the loss of bidirectional synaptic plasticity.

The striatum can be divided into dorsal (caudate-putamen) and ventral parts. In the ventral division, the nucleus accumbens, which subserves adaptive and goal-directed behaviors, is further subdivided into shell and core. Accumbal neurons show different types of experience-dependent plasticity: those in the core seem to discriminate the motivational value of conditioned stimuli, features that rely on the integration of information and enhanced synaptic plasticity at the many spines on these cells, whereas shell neurons seem to be involved with the release of predetermined behavior patterns in relation to unconditioned stimuli, and the behavioral consequences of repeated administration of addictive drugs. In the core, the principal neurons are medium sized and densely spiny, but in the medial shell, these same neurons are much smaller and their dendrites, significantly less spiny, suggesting that morphological differences could mediate unique neuroadaptations associated with each region. This review is focused on evaluating the structural differences in nucleus accumbens core and shell neurons and discusses how such different morphologies could underlie distinguishable behavioral processes.

Our knowledge of the organization of the nucleus accumbens has been greatly advanced in the last two decades, but only now are we beginning to understand the complex neural circuitry that underlies the mix of behaviors attributed to this nucleus. Superimposed on the neurochemically defined territories of the shell and core are four or more conduits for information flow. Each of these behaviorally relevant pathways can be characterized by the spatial distribution of inputs to its central unit: the GABAergic projection neuron, a spiny cell that also contains the opioid peptides, enkephalin or dynorphin. In this review, current models of accumbal circuits will be examined and, with the aid of recent anatomical findings, further extended to shed light on how functionally diverse information is processed in this nucleus. However complex, accumbal wiring is not fixed, and, as we will show, psychostimulants, dopamine-deleting lesions, and chronic blockade of dopaminergic receptors can alter the anatomical substrate, synaptology, and neurotrophic factors that govern circuits through the shell and core.