Increased numbers of orexin/hypocretin neurons in a genetic rat depression model.

The Flinders Sensitive Line (FSL) rat is a genetic animal model of depression that displays characteristics similar to those of depressed patients including lower body weight, decreased appetite and reduced REM sleep latency. Hypothalamic neuropeptides such as orexin/hypocretin, melanin-concentrating hormone (MCH) and cocaine and amphetamine regulated transcript (CART), that are involved in the regulation of both energy metabolism and sleep, have recently been implicated also in depression. We therefore hypothesized that alterations in these neuropeptide systems may play a role in the development of the FSL phenotype with both depressive like behavior, metabolic abnormalities and sleep disturbances. In this study, we first confirmed that the FSL rats displayed increased immobility in the Porsolt forced swim test compared to their control strain, the Flinders Resistant Line (FRL), which is indicative of depressive-like behavior. We then examined the number of orexin-, MCH- and CART-immunopositive neurons in the hypothalamus using stereological analyses. We found that the total number of orexin-positive neurons was higher in the hypothalamus of female FSL rats compared to female FRL rats, whereas no changes in the MCH or CART populations could be detected between the strains. Chronic treatment with the selective serotonin reuptake inhibitor (SSRI) escitalopram reduced immobility only in the FRL rats where it also increased the number of MCH positive neurons compared to untreated rats. These findings support the view that orexin may be involved in depression and strengthen the notion that the "depressed" brain responds differently to pharmacological interventions than the normal brain.

A point mutation in the dynein heavy chain gene leads to striatal atrophy and compromises neurite outgrowth of striatal neurons.

The molecular motor dynein and its associated regulatory subunit dynactin have been implicated in several neurodegenerative conditions of the basal ganglia, such as Huntington's disease (HD) and Perry syndrome, an atypical Parkinson-like disease. This pathogenic role has been largely postulated from the existence of mutations in the dynactin subunit p150(Glued). However, dynactin is also able to act independently of dynein, and there is currently no direct evidence linking dynein to basal ganglia degeneration. To provide such evidence, we used here a mouse strain carrying a point mutation in the dynein heavy chain gene that impairs retrograde axonal transport. These mice exhibited motor and behavioural abnormalities including hindlimb clasping, early muscle weakness, incoordination and hyperactivity. In vivo brain imaging using magnetic resonance imaging showed striatal atrophy and lateral ventricle enlargement. In the striatum, altered dopamine signalling, decreased dopamine D1 and D2 receptor binding in positron emission tomography SCAN and prominent astrocytosis were observed, although there was no neuronal loss either in the striatum or substantia nigra. In vitro, dynein mutant striatal neurons displayed strongly impaired neuritic morphology. Altogether, these findings provide a direct genetic evidence for the requirement of dynein for the morphology and function of striatal neurons. Our study supports a role for dynein dysfunction in the pathogenesis of neurodegenerative disorders of the basal ganglia, such as Perry syndrome and HD.