The influence of ovarian hormones on the recovery period following lateral hypothalamic lesions.

Following bilateral lesions of the lateral hypothalamus animals are rendered completely aphagic and adipsic (Anand and Brobeck, 1951; Teitelbaum and Stellar, 1954). If not maintained by intragastric feeding, rats will eventually die of starvation and dehydration. However, if the animals are kept alive a gradual recovery of food and water intake will occur. This recovery period has been extensively and carefully studied, and four distinct recovery stages have been identified (Teitelbaum, 1961; Teitelbaum and Epstein, 1962). The first stage of recovery is characterized by the animal\u27s refusal of all food and water. In the second stage wet and palatable foods are accepted, although not in sufficient quantities to maintain life. During the third phase, the animal is able to regulate its caloric intake on wet and palatable foods, but is unable to regulate its weight on dry food. Finally, in the fourth stage the lateral hypothalamic lesioned animal will accept dry food and water in sufficient amounts to maintain life

Recovery of function : some new thoughts on an old problem.

PsychologyDoctor of Philosophy (PhD

Neuropsychological Test Performance in African-American and White Patients with Alzheimer's Disease

Little information exists on the performance of black versus white patients with Alzheimer's disease on neuropsychological tests for dementia.In this study, we compared performance on the CERAD (Consortium to Establish a Registry for Alzheimer's Disease) neuropsychological battery between white (n equals 830) and black (n equals 158) patients with Alzheimer's disease enrolled in the CERAD study at 23 university medical centers in the United States. The black patients were older, had fewer years of formal education, and were more impaired in their activities of daily living than were the white patients. After controlling for these characteristics and for duration of the disease and severity of dementia, there were differences in the performance of black and white patients on several of the cognitive measures. Black patients scored lower than whites on tests of visual naming and constructional praxis and on the Mini-Mental State Examination. There were no statistical differences in performance on tests of fluency and word list memory. These findings suggest that cultural or experiential differences may modify performance on specific neuropsychological tests. These factors, in addition to age and educational background, should be considered when interpreting performance on neuropsychological tests in elderly black patients with dementia

Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis

Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR, and SPINK1 variants were associated with pancreatitis risk. We now report two significant genome-wide associations identified and replicated at PRSS1-PRSS2 (1×10-12) and x-linked CLDN2 (p < 1×10-21) through a two-stage genome-wide study (Stage 1, 676 cases and 4507 controls; Stage 2, 910 cases and 4170 controls). The PRSS1 variant affects susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous male) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men – male hemizygous frequency is 0.26, female homozygote is 0.07

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped using a whole-exome microarray. In stage 2, we tested associated variants (P<1×10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, an additional 14,997 samples were used to test the most significant stage 2 associations (P<5×10-8) using imputed genotypes. We observed 3 novel genome-wide significant (GWS) AD associated non-synonymous variants; a protective variant in PLCG2 (rs72824905/p.P522R, P=5.38×10-10, OR=0.68, MAFcases=0.0059, MAFcontrols=0.0093), a risk variant in ABI3 (rs616338/p.S209F, P=4.56×10-10, OR=1.43, MAFcases=0.011, MAFcontrols=0.008), and a novel GWS variant in TREM2 (rs143332484/p.R62H, P=1.55×10-14, OR=1.67, MAFcases=0.0143, MAFcontrols=0.0089), a known AD susceptibility gene. These protein-coding changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified AD risk genes. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to AD development

A novel Alzheimer disease locus located near the gene encoding tau protein

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this recordAPOE ε4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ε4+ (10 352 cases and 9207 controls) and APOE ε4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ε4 status. Suggestive associations (P<1 × 10-4) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ε4+: 1250 cases and 536 controls; APOE ε4-: 718 cases and 1699 controls). Among APOE ε4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10-9). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ε4+ subjects (CR1 and CLU) or APOE ε4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10-7) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P≤1.3 × 10-8), frontal cortex (P≤1.3 × 10-9) and temporal cortex (P≤1.2 × 10-11). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10-6) and temporal cortex (P=2.6 × 10-6). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ε4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted

Chronic, oral aluminum administration to rats: Cognition and cholinergic parameters

Administration of aluminum sulfate in the drinking water of male Sprague-Dawley rats for thirty days resulted in an impairment of both consolidation and extinction of a passive avoidance task. No impairment of performance was observed on an active avoidance task, radial arm maze or open field activity measure. Biochemical analysis indicated a slight (<10%) but significant increase in hippocampal muscarinic receptor number after aluminum treatment as determined by tritiated quinuclidinyl benzilate ( 3H-QNB) binding. No changes were found in choline acetyltransferase (ChAT) activity, phosphoinositide hydrolysis, 3H-QNB binding in the cortex or tritiated pirenzepine ( 3H-PZ) binding in the hippocampus or cortex. These results indicate that cholinergic degeneration was not the cause of the observed cognitive impairments

Growth, endocrinological and behavioral deficits after monosodium l-glutamate in the neonatal rat: possible involvement of arcuate dopamine neuron damage

(1) The syndrome induced by the systemic administration of monosodium l-glutamate (MSG) to neonatal rats was investigated. (2) Animals receiving five injections of 4 mg/g of MSG (MSG V) in the first 10 days of life showed, as adults, growth, endocrinological, and behavioral abnormalities, whereas those receiving one injection (MSG I) showed few of the characteristic symptoms associated with neonatal MSG treatment. (3) MSG V females were markedly hypoactive ten weeks after weaning as measured in circular photocell activity cages in the dark part of the rats' day-night cycle. (4) MSG V rats were extremely stunted and obese (as determined by the Lee index) but appeared normophagic. (5) A previously unreported aspect of MSG toxicity, tail automutilation, occurred in a large proportion of MSG I and MSG V animals, with the highest incidence in MSG V females. (6) MSG V animals were hypothyroid as measured by radioimmunological determinations of serum triiodothyronine (T 3) and free thyroxine index (FTI). In addition, MSG V females had smaller ovaries, uteri, and pituitaries when compared with saline-treated controls. (7) Histochemical examination of the hypothalamic arcuate area revealed a marked loss of dopaminergic perikarya in MSG V, but not MSG I animals; other catecholamine systems appeared intact. This raises the possibility that damage to the tubero-infundibular dopamine system may contribute to endocrinological and other deficits observed after neonatal MSG treatment