Faculty Bibliography

We examined the degeneration of neocortical neurons in normal aging and Alzheimer's disease (AD) using terminal transferase (TdT)-mediated deoxyuridine triphosphate (d-UTP)-biotin nick-end labeling (TUNEL), a method that identifies DNA strand breaks and constitutes a positive marker for dying neurons. TUNEL was positive in neurons, glia, and microglial cells in AD but not in younger or age-matched cognitively characterized controls. Neuronal labeling in AD was most conspicuous in cortical layer III in the early stages of the disease and became more widespread as the disease progressed. In addition, we observed TUNEL of lamina III neurons in a subset of older subjects who had normal cognition but abundant neocortical senile plaques. In concert, the availability of a direct marker of dying neurons allows for specific correlations of cell death with other neuropathological markers as well as clinical variables. Observations from the present study suggest that the death of cortical neurons precedes the symptomatic stage of AD and evolves in parallel with the clinical progression of the disease and that there appears to be an association between the degree of cell death and the severity of senile plaques.

Neurons in the nucleus basalis of Meynert (NBM) were analyzed morphometrically in 21 rhesus monkeys ranging in age from 9 to 33 years. Numbers of cholinergic neurons were similar across all ages at several NBM levels in either Nissl-stained paraffin sections or sections processed immunocytochemically for nerve growth factor receptor (p75LNGFr). Size of NBM neurons was larger in aged monkeys than young monkeys at all NBM levels, particularly in the most posterior subdivision. A subset of monkeys were behaviorally characterized shortly before death, and partial correlation analyses indicated that increased age was associated with declines in recognition memory, visuospatial orientation, and reaction time. Controlling for age, spatial memory and concurrent discrimination abilities were associated with lower cell number in intermediate NBM. Numbers of neurons in anterior NBM did not correlate with any behavioral measure. These observations indicate that numbers of NBM cholinergic neurons are stable with age, that NBM neurons become hypertrophic in older animals, and that morphometric indices of cholinergic neurons are associated with cognitive function.

Using in situ hybridization histochemistry, we studied the distribution of neurons that express preproopiomelanocortin (pre-POMC), preprodynorphin (pre-PDYN), and preproenkephalin (pre-PENK) gene transcripts within the human hypothalamus and surrounding structures. Of the three opioid systems, pre-POMC neurons have the most restricted distribution. Pre-POMC cells are most numerous in the infundibular nucleus and retrochiasmatic area of the mediobasal hypothalamus; a few labeled cells are present within the boundaries of the ventromedial nucleus and infundibular stalk. Pre-POMC message was not found in the limited samples of structures adjacent to the hypothalamus. In contrast to neurons that express pre-POMC, neurons expressing pre-PDYN and pre-PENK are more widely represented throughout the hypothalamus and extrahypothalamic structures. However, pre-PDYN and pre-PENK cells differ from one another in distribution. Pre-PDYN message is especially abundant in neurons of the tuberal and mammillary regions, with a distinct population of labeled cells in the premammillary nucleus and dorsal posterior hypothalamus. Pre-PDYN gene expression also is found in neurons of the dorsomedial nucleus, ventromedial nucleus, caudal magnocellular portion of the paraventricular nucleus, dorsolateral supraoptic nucleus, tuberomammillary nucleus, caudal lateral hypothalamus, and retrochiasmatic area. In structures immediately adjacent to the hypothalamus, pre-PDYN neurons were observed in the caudate nucleus, putamen, cortical nucleus of the amygdala, and bed nucleus of the stria terminalis. Pre-PENK neurons occur in varying numbers in all hypothalamic nuclei except the mammillary bodies. The chiasmatic region is particularly rich in pre-PENK neurons, with the highest packing density in the intermediate nucleus [the intermediate nucleus (Braak and Braak [1987] Anat. Embryol. 176:315-330) has also been termed the sexually dimorphic nucleus of the preoptic area (SDA-POA; Swaab and Fliers [1985] Science 228:1112-1115) or the interstitial nucleus of the anterior hypothalamus 1 (Allen et al. [1989] J. Neurosci. 9:497-506)], dorsal suprachiasmatic nucleus, medial preoptic area, and rostral lateral hypothalamic area. Pre-PENK neurons are numerous in the infundibular nucleus, ventromedial nucleus, dorsomedial nucleus, caudal parvicellular portion of the paraventricular nucleus, tuberomammillary nucleus, lateral hypothalamus, and retrochiasmatic area. Only a few lightly labeled cells were found in the periphery of the supraoptic nucleus and lateral tuberal nucleus. In areas adjacent to the hypothalamus, cells that contain pre-PENK message occur in the nucleus basalis of Meynert, central nucleus of amygdala, bed nucleus of the stria terminalis, caudate nucleus, and putamen.(ABSTRACT TRUNCATED AT 400 WORDS)

We studied the distribution of messenger ribonucleic acids coding for vasopressin and oxytocin in the human hypothalamus by means of hybridization histochemistry. Numerous large and medium-sized neurons contain vasopressin messenger ribonucleic acid in the paraventricular nucleus, supraoptic nucleus, and accessory magnocellular nucleus. Small, lightly labeled vasopressin neurons also were detected in the suprachiasmatic nucleus. In addition, a relatively sparse band of mostly ovoid, medium-sized vasopressin neurons mingle with unlabeled neurons of the lateral hypothalamic area; these cells extend dorsoventrally from the region ventral to the stria terminalis to the ventrolateral hypothalamus, sometimes transgressing the boundaries of nearby nuclei. We did not detect vasopressin gene expression in neurons of the bed nucleus of the stria terminalis proper, although some of the dorsal-most labeled neurons of the lateral hypothalamus extend into the region of the caudal bed nucleus. Some lateral hypothalamic neurons also encroach upon other extrahypothalamic structures, such as the zona incerta. The nucleus basalis of Meynert complex was, with only rare exceptions, devoid of cells containing vasopressin messenger ribonucleic acid. Oxytocin messenger ribonucleic acid is found in the supraoptic nucleus, paraventricular nucleus, accessory magnocellular nucleus and, less frequently, in neurons of the lateral hypothalamus. In the hypothalamic magnocellular nuclei, oxytocin neurons are somewhat smaller than vasopressin neurons. Vasopressin cells outnumber oxytocin cells in the supraoptic nucleus, but their numbers are comparable in the paraventricular nucleus. As with vasopressin neurons, lateral hypothalamic oxytocin cells loosely span several diencephalic nuclei and encroach occasionally upon adjacent regions. These results confirm that the organization of vasopressin and oxytocin neurons in the human hypothalamus is largely comparable to that in nonhuman species and demonstrate the utility of hybridization histochemistry for elucidating the chemoarchitecture of the human brain.