Neuroscience
-
In the recent past, the pathogenesis of Parkinson's disease (PD) has evolved from a neurodegenerative disorder considered entirely sporadic to a disease with an unequivocal genetic component. Indeed, different inherited forms of PD have been discovered and characterized, although the functional roles of the gene products identified are still under intense investigation. ⋯ Although most of the rodent models display neither obvious behavioral impairment nor evidence for neurodegeneration, remarkable abnormalities of dopamine-mediated neurotransmission and corticostriatal synaptic plasticity have been described, indicative of a fundamental distortion of network function within the basal ganglia. The picture emerging from a critical review of recent data on monogenic parkinsonisms suggests that mutations in PD genes might cause developmental rearrangements in the corticobasal ganglia circuitry, compensating the dopaminergic dysfunction observed both in mice and humans, in order to maintain proper motor function.
-
Schizophrenia is one of the most common psychiatric disorders, but despite progress in identifying the genetic factors implicated in its development, the mechanisms underlying its etiology and pathogenesis remain poorly understood. Development of mouse models is critical for expanding our understanding of the causes of schizophrenia. ⋯ We describe and compare the different approaches that are necessitated by diverse susceptibility alleles, and discuss their advantages and drawbacks. Finally, we discuss emerging mouse models, such as second-generation pathophysiology models based on innovative approaches that are facilitated by the information gathered from the current genetic mouse models.
-
Review
Functional interactions within striatal microcircuit in animal models of Huntington's disease.
Mutant huntingtin (mhtt) causes loss of synaptic plasticity and selective degeneration of striatal medium spiny neurons (MSNs), a core pathological feature of Huntington's disease (HD). However, projecting neurons become dysfunctional in the very early stages, long before death and this dysfunctional state may contribute to disease. Interneurons appear to be more resistant to the effects of mhtt and play important roles in supporting the activity of projecting neurons. ⋯ Electrophysiological studies provide crucial information on neuronal dysfunction and circuit changes that underlie or precede symptoms. Here we review recent papers in which HD models have been used to study various aspects of neuronal physiology of corticostriatal pathway. We will also discuss advantages and limitations of rodent models compared to primate models and current challenges of therapies aimed at rescuing striatal function in HD.
-
Research involving animal models of drug addiction can be viewed as a sort of reverse psychiatry. Contrary to clinicians who seek to treat addicted people to become and remain abstinent, researchers seek to make drug-naïve animals addicted to a drug with known addictive properties in humans. The goals of this research are to better understand the neuroscience of drug addiction and, ultimately, to translate this knowledge into effective treatments for people with addiction. ⋯ In fact, it appears that resilience to cocaine addiction is the norm in rats. As in human cocaine users, only few individual rats would be vulnerable. This conclusion has several important implications for future research on the neuroscience of cocaine addiction and on preclinical medication development.
-
Major limitations to the pharmacotherapy of Parkinson's disease (PD) are the motor complications resulting from L-DOPA treatment. Abnormal involuntary movements (dyskinesia) affect a majority of the patients after a few years of L-DOPA treatment and can become troublesome and debilitating. Once dyskinesia has debuted, an irreversible process seems to have occurred, and the movement disorder becomes almost impossible to eliminate with adjustments in peroral pharmacotherapy. ⋯ The application of classical 6-hydroxydopamine (6-OHDA) lesion procedures to produce rodent models of dyskinesia has provided the field with more dynamic tools, since the versatility of toxin doses and injection coordinates allows for mimicking different stages of PD. This article will review models developed in non-human primate and rodents to reproduce motor complications induced by dopamine replacement therapy. The recent breakthroughs represented by mouse models and the relevance of rodents in relation to non-human primate models will be discussed.