Fractionator analysis shows loss of neurons in the lateral geniculate nucleus of macaques infected with neurovirulent simian immunodeficiency virus

Abstract

Infection of macaques with neurovirulent strains of simian immunodeficiency virus (SIVmac) is an experimental model for the neurological manifestations of AIDS. Loss of neurons has been reported in the cerebral cortex following immunodeficiency viral infection, but thalamic structures which may contribute to electrophysiological changes and neurological deficits have not been examined. In this study, the lateral geniculate nucleus (LGN) of macaques inoculated with macrophage-tropic, neurovirulent virus SIVmac239 (R71 and 17E) was examined for neuron loss using the optical fractionator method. Estimates of the number of neurons in the P layers of the lateral geniculate nucleus of age-matched control macaques ranged from 1.0 to 1.3 x 10(6), while the number of neurons in SIV infected macaques ranged from 0.8 to 1.1 x 10(6), reflecting neuron loss of up to 28%. Neuron loss was not observed in the magnocellular layer. The total number of glia and glial density were unchanged. Loss of neurons in the lateral geniculate nucleus was correlated with the pattern of neuropathological changes. Neuron loss was most severe in animals with encephalitis concentrated in the brain stem and subcortical white matter and was less apparent in animals with diffuse encephalitis. Neuron loss in the lateral geniculate nucleus did not explain changes observed in the visual evoked potential, which was severely affected in two animals which showed a loss of 24 and 26%, while it was normal in a third animal which showed neuron loss of 28%.

Visual deficits in a mouse model of Batten disease are the result of optic nerve degeneration and loss of dorsal lateral geniculate thalamic neurons

“…In examining cell numbers within the superior colliculus, lateral geniculate nucleus, and suprachiasmatic nucleus, we observed a selective loss of the large projection neurons within the dorsal portion of the lateral geniculate (LGNd). Cellular insult within LGNd has been noted in other neurodegenerative diseases that have visual deterioration as one of the early hallmarks of the disease, including Creutzfeldt-Jakob disease, Huntington's disease, and Alzheimer's disease (Brown et al, 1986;de la Monte et al, 1988;Wong-Riley et al, 1997;Berman et al, 1998).…”

“…A similar selective loss of neurons in the LGN has been observed in an experimental model of Neuro-AIDS in which animals had an approximate 25% reduction in the cells of the parvocellular layer of the LGNd. Like the Cln3 −/− mice, functional impairment was limited as only a portion of these animals had a detectable change in their visual evoked potentials (Berman et al, 1998). In JNCL patients, photoreceptors in the peripheral portion of the retina appear to be among the first to manifest degeneration (Bensaoula et al, 2000).…”

Stereologic analysis of the lateral geniculate nucleus of the thalamus in normal and schizophrenic subjects

“…Several studies in non-human primates have utilized stereologic cell counting methods to estimate the number of neurons in the normal, young adult LGN either as a control for experimental manipulation (Berman et al, 1998;Boire et al, 2002), development (Willliams and Rakic, 1988), aging (Ahmad and Spear, 1993, or as a primary interest (Sunner and Rakic, 1996;Blasco et al, 1999). Despite differences in methodology and species examined, these studies are generally in agreement in estimating approximately 1.4 million neurons in the whole LGN; neuronal number in the pigtail monkey (1.79 million) was slightly higher (Blasco et al, 1999).…”

Rhesus Macaque Model of Chronic Opiate Dependence and Neuro-AIDS: Longitudinal Assessment of Auditory Brainstem Responses and Visual Evoked Potentials

“…The SIVmac239 (R71/E17) virus has been shown to cross the blood brain barrier shortly after inoculation (Sharma et al, 1992; Narayan et al, 1997) and productively replicates primarily in memory CD4+ T cells in the gut-associated lymphoid tissue (GALT) and spleen (Veazey et al, 1998; Veazey et al, 2000a, b). Our neuropathological and stereological studies, utilizing a cohort of SIV mac R71/17E inoculated Indian origin rhesus macaques have demonstrated many of the features of HIV-1 encephalopathy (Raghavan, et al, 1999; Marcario et al, 2004) as well as a significant loss of neurons in the lateral geniculate nucleus (Berman et al, 1998), the globus pallidus, and the substantia nigra (Marcario et al, 2004). Thus, our model not only closely mimics the natural disease course of HIV infection but also demonstrates many of the hallmarks associated with HIV-related neurological disease.…”