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The objective of the study was to identify brain structures that mediate reward as evidenced by positive reinforcing effects of stimuli on behavior. Testing by intracerebral self-stimulation enabled monkeys to inform whether activation of ~2900 sites in 74 structures of 4 sensorimotor pathways and 4 modulatory loop pathways was positive, negative or neutral. Stimulation was rewarding at 30% of sites, negative at 17%, neutral at 52%. Virtually all (99%) structures yielded some positive or negative sites, suggesting a ubiquitous distribution of pathways transmitting valence information. Mapping of sites to structures with dense versus sparse dopaminergic (DA) or noradrenergic (NA) innervation showed that stimulation of DA-pathways was rewarding or neutral. Stimulation of NA-pathways was not rewarding. Stimulation of association areas was generally rewarding; stimulation of purely sensory or motor structures was generally negative. Reward related more to structures' sensorimotor function than to density of DA-innervation. Stimulation of basal ganglia loop pathways was rewarding except in lateral globus pallidus, an inhibitory structure in the negative feedback loop; stimulation of the cerebellar loop was rewarding in anterior vermis and the spinocerebellar pathway; and stimulation of the hippocampal CA1 loop was rewarding. While most positive sites were in the DA reward system, numerous sites in sparsely DA-innervated posterior cingulate and parietal cortices may represent a separate reward system. DA-density represents concentrations of plastic synapses that mediate acquisition of new synaptic connections. DA-sparse areas may represent innate, genetically programmed reward-associated pathways. Implications of findings in regard to response habituation and addiction are discussed., (© 2021 Wiley Periodicals LLC.)

Background: Neuroprotection for Parkinson's disease (PD) remains elusive. Biomarkers hold the promise of removing roadblocks to therapy development. The National Institute of Neurological Disorders and Stroke has therefore established the Parkinson's Disease Biomarkers Program to promote discovery of PD biomarkers for use in phase II and III clinical trials., Methods: Using a novel consortium design, the Parkinson's Disease Biomarker Program is focused on the development of clinical and laboratory-based biomarkers for PD diagnosis, progression, and prognosis. Standardized operating procedures and pooled reference samples were created to allow cross-project comparisons and assessment of batch effects. A web-based Data Management Resource facilitates rapid sharing of data and biosamples across the research community for additional biomarker projects., Results: Eleven consortium projects are ongoing, seven of which recruit participants and obtain biosamples. As of October 2014, 1,082 participants have enrolled (620 PD, 101 with other causes of parkinsonism, 23 essential tremor, and 338 controls), 1,040 of whom have at least one biosample. Six thousand eight hundred ninety-eight total biosamples are available from baseline, 6-, 12-, and 18-month visits: 1,006 DNA, 1,661 RNA, 1,419 whole blood, 1,382 plasma, 1,200 serum, and 230 cerebrospinal fluid (CSF). Quality control analysis of plasma, serum, and CSF samples indicates that almost all samples are high quality (24 of 2,812 samples exceed acceptable hemoglobin levels)., Conclusions: By making samples and data widely available, using stringent operating procedures based on existing standards, hypothesis testing for biomarker discovery, and providing a resource that complements existing programs, the Parkinson's Disease Biomarker Program will accelerate the pace of PD biomarker research. © 2015 International Parkinson and Movement Disorder Society., (© 2015 International Parkinson and Movement Disorder Society.)

Abnormal subgranular zone (SGZ) neurogenesis is proposed to contribute to Alzheimer's disease (AD)-related decreases in hippocampal function. Our goal was to examine hippocampal neurogenesis in the PDAPP mouse, a model of AD with age-dependent accumulation of amyloid-beta(42) (Abeta(42))-containing plaques that is well studied with regard to AD therapies. A secondary goal was to determine whether altered neurogenesis in the PDAPP mouse is associated with abnormal maturation or number of mature cells. A tertiary goal was to provide insight into why hippocampal neurogenesis appears to be increased in AD post-mortem tissue and decreased in most AD mouse models. We report an age-dependent decrease in SGZ proliferation in homozygous PDAPP mice. At 1 year of age, PDAPP mice also had new dentate gyrus granule neurons with abnormal maturation and fewer dying cells relative to control mice. In contrast to decreased SGZ cell birth, PDAPP mice had increased birth of immature neurons in the outer portion of the granule cell layer (oGCL), providing insight into why some studies link AD with increased neurogenesis. However, these ectopic oGCL cells were still rare compared with SGZ proliferating cells, emphasizing that the primary characteristic of PDAPP mice is decreased neurogenesis. The decrease in SGZ neurogenesis was not associated with an age-dependent loss of dentate granule neurons. The altered neurogenesis in the PDAPP mouse may contribute to the age-related cognitive deficits reported in this model of AD and may be a useful adjunct target for assessing the impact of AD therapies., (J. Comp. Neurol. 495:70-83, 2006. (c) 2006 Wiley-Liss, Inc.)

Alzheimer's disease is characterized by neuronal degeneration in the cerebral cortex and hippocampus and subcortical neuronal degeneration in such nuclei as the locus coeruleus (LC). Transgenic mice overexpressing mutant human amyloid precursor protein V717F, PDAPP mice, develop several Alzheimer's disease-like lesions. The present study sought to determine whether there is also loss of LC noradrenergic neurons or evidence of degenerative changes in these animals. PDAPP hemizygous and wild-type littermate control mice were examined at 23 months of age, at a time when there are numerous amyloid-beta (Abeta) plaques in the neocortex and hippocampus. Tissue sections were stained immunohistochemically with an antibody against tyrosine hydroxylase (TH) to identify LC neurons. Computer imaging procedures were used to count the TH-immunoreactive somata in sections through the rostral-caudal extent of the nucleus. There was no loss of LC neurons in the hemizygous mice. In a second experiment, homozygous PDAPP and wild-type mice were examined, at 2 months and 24 months of age. Again there was no age-related loss of neurons in the homozygous animals. In the portion of the LC where neurons reside that project to the cortex and hippocampus, however, the neurons were decreased in size selectively in the 24-month-old transgenic animals. These data indicate that overt LC cell loss does not occur following abundant overexpression of Abeta peptide. However, the selective size reduction of the LC neuronal population projecting to cortical and hippocampal regions containing Abeta-related neuropathology implies that these cells may be subjected to a retrograde-mediated stress., (Copyright 2005 Wiley-Liss, Inc.)

The dopaminergic neurons in the ventral substantia nigra (SN) are significantly more vulnerable to degeneration in Parkinson's disease (PD) than the dopaminergic neurons in the ventral tegmental area (VTA). The ventral SN neurons also contain significantly more neuromelanin pigment than the dopaminergic neurons in the VTA. In vitro data indicate that neuromelanin pigment is formed from the excess cytosolic catecholamine that is not accumulated into synaptic vesicles by the vesicular monoamine transporter-2 (VMAT2). By using quantitative immunohistochemical methods in human postmortem brain, we sought to examine the relative contents of VMAT2 within neurons that contain different amounts of neuromelanin pigment. The immunostaining intensity (ISI) was measured for VMAT2 and also for the rate-limiting enzyme for the synthesis of dopamine, tyrosine hydroxylase (TH). ISI measures were taken from the ventral SN region where neurons are most vulnerable to degeneration in PD, nigrosome-1 (N1); from the ventral SN region where cells are moderately vulnerable to degeneration in PD, the matrix (M); and from VTA neurons near the exit of the third nerve (subregion III). The data indicate that 1) subregion III neurons have significantly higher levels of VMAT2 ISI compared with N1 neurons (more than twofold) and M neurons (45%); 2) there is an inverse relationship between VMAT2 ISI and neuromelanin pigment in the N1 and III neurons; 3) there is an inverse relationship between VMAT2 ISI and the vulnerability to degeneration in PD in the N1, M, and III subregions; and 4) neurons with high VMAT2 ISI also have high TH ISI. These data support the hypothesis that midbrain dopaminergic neurons that synthesize greater amounts of dopamine have more vesicular storage capacity for action potential-induced release of transmitter and that the ventral SN neurons accumulate the most neuromelanin pigment, in part because they have the least VMAT2 protein., (Copyright 2004 Wiley-Liss, Inc.)

Transgenic mice overexpressing mutant human amyloid precursor protein (PDAPP mice) develop several Alzheimer's disease (AD)-like lesions including an age-related accumulation of amyloid-beta (Abeta)-containing neuritic plaques. Although aged, heterozygous PDAPP mice also exhibit synaptic and glial cell changes characteristic of AD pathology, no evidence of widespread neuronal loss has been observed. The present study sought to determine whether homozygous PDAPP mice, which express very high levels of Abeta peptide, exhibit AD-like cholinergic degenerative changes, and whether the changes parallel the deposition of Abeta plaques. Mice were examined at 2 and 4 months and at 1 and 2 years of age. There was an age-related increase in the density of Abeta plaques in the cortex and hippocampus of the PDAPP animals; at 4 months of age there were very few plaques, and at 2 years there was a very high density of plaques. There was an age-related reduction in the density of cholinergic nerve terminals in the cerebral cortex; at 2 months there was a normal density of nerve terminals, but as early as age 4 months there was an approximately 50% reduction. However, at age 2 years there was no difference in the number or size of basal forebrain cholinergic somata compared with 2-month-old PDAPP mice. These data indicated that the homozygous PDAPP mouse exhibits cholinergic nerve terminal degenerative pathology and that the cortical neurodegenerative changes occur before the deposition of Abeta-containing neuritic plaques., (Copyright 2003 Wiley-Liss, Inc.)