RESUMEN
Huntington disease (HD) is a progressive neurodegenerative disorder characterized by emotional, cognitive, and motor dysfunctions. Aggregation of huntingtin is a hallmark of HD and, therefore, a crucial parameter for the evaluation of HD animal models. We investigated here the regional, cellular, and subcellular distribution of N-terminal huntingtin aggregates and associated neuropathological changes in the forebrain of a rat transgenic for HD (tgHD). The tgHD rat brain showed enormously enlarged lateral ventricles and a similar atrophy of cortical and subcortical areas as known in HD patients. Huntingtin aggregates of varying size and forms were regionally identified in neuronal nuclei, cytoplasm, dendrites, dendritic spines, axons, and synaptic terminals, closely resembling the results described earlier for human HD brains and in established HD mouse models. Huntingtin aggregates in mitochondria support mitochondrial dysfunction as contributing to the disease pathogenesis. Dark cell degeneration was reminiscent of results in HD individuals and HD mouse models. Interestingly, huntingtin aggregates were especially well accumulated in two interacting limbic forebrain systems, the ventral striatopallidum and the extended amygdala, which may contribute to the early onset of emotional changes observed in the tgHD rat. In conclusion, the tgHD rat model reflects to a remarkable extent the cellular and subcellular neuropathological key features as observed in human HD and HD mouse brains and hints of changes in limbic forebrain systems, which may elucidate the emotional dysfunction in the tgHD rat and affective disturbances in HD patients.
Asunto(s)
Encéfalo/patología , Enfermedad de Huntington/patología , Cuerpos de Inclusión/patología , Proteínas del Tejido Nervioso/metabolismo , Neuronas/patología , Proteínas Nucleares/metabolismo , Amígdala del Cerebelo/metabolismo , Amígdala del Cerebelo/patología , Animales , Animales Modificados Genéticamente , Ganglios Basales/metabolismo , Ganglios Basales/patología , Encéfalo/metabolismo , Núcleo Celular/metabolismo , Núcleo Celular/patología , Citoplasma/metabolismo , Citoplasma/patología , Dendritas/metabolismo , Dendritas/patología , Modelos Animales de Enfermedad , Humanos , Proteína Huntingtina , Enfermedad de Huntington/genética , Enfermedad de Huntington/metabolismo , Cuerpos de Inclusión/metabolismo , Ratones , Microscopía Electrónica de Transmisión , Mitocondrias/metabolismo , Mitocondrias/patología , Degeneración Nerviosa/metabolismo , Degeneración Nerviosa/patología , Proteínas del Tejido Nervioso/genética , Neuronas/metabolismo , Proteínas Nucleares/genética , Terminales Presinápticos/metabolismo , Terminales Presinápticos/patología , Ratas , Ratas Sprague-DawleyRESUMEN
The lateral habenular complex is part of the habenular nuclei, a distinct structure in the dorsal diencephalon of all vertebrates. In contrast to the bewildering diversity of behaviors, in which the lateral habenular complex is thought to be involved, there is an astonishing lack of information concerning its cellular organization, its neuronal circuits, and the neurophysiological mechanisms, which may provide the physiological and molecular basis for its diverse biological functions. This problem may be due to an unexpected heterogeneity of the lateral habenular complex. Recently, a detailed subnuclear organization has been described (Andres et al. [1999] J Comp Neurol 407:130-150), which provides the base for a subsequent physiological and behavioral analysis of this area. Available criteria, however, can be applied to semithin sections only. To facilitate further investigations, the present work aimed to elaborate novel morphologic and immunocytochemical criteria that can be applied to conventional cryostat or Vibratome sections to allow identification and delineation of subnuclei of the lateral habenular complex. Consequently, the regional, cellular, and subcellular localization of approximately 30 different neuroactive molecules was investigated. Of these candidate molecules, gamma-aminobutyric acid-B receptor protein, Kir3.2 potassium channel protein, tyrosine hydroxylase, and neurofilament heavy chain proved to be suitable markers. Our observation suggests that the habenular subnuclei express distinct immunocytochemical characteristics. These features may be used to identify and delineate the subnuclei on conventional cryostat or Vibratome sections. From our results, it is expected that the further functional analysis of the lateral habenular complex will be facilitated considerably.