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A complementary Machine Learning disposition method was generated and tested for after develop inspections in lithography. For lithography coating defects, this new method showed twice the sensitivity and five times the specificity in a controlled experiment versus the baseline system. Applying the detection method along with process improvements, preventative measures and rework for splatter defects, reduced yield loss from splatters by over 30x. Herein we describe learnings on the use of image enhancement for training and disposition, an Explainable AI system to support understanding, and a process flow to train augmentation based on performance.

The continuing explosion of scientific interest in the hippocampus began in the 1950s, initiated in large part by the recognition of the importance of the observations of hippocampectomized monkeys made by Klüver and Bucy and the remarkable memory loss of patient H. M. following temporal lobe surgery. Subsequent to these studies, research and theories about the hippocampus grew exponentially in number and diversity. As yet, no theory of hippocampal function explains all of the phenomena discovered in the clinic or laboratory. In this article, experimental results that have been forgotten or ignored in most theories are presented. Adequate theories of hippocampal function must account for known, reliable postsurgical behavioral observations and consider the conditions under which anomalies are noted. Comprehensive theories will require new approaches in which the interactions of the hippocampus with the central nervous system are understood.

This study describes alterations in the nervous system resulting from chronic administration of the fluoroaluminum complex (AlF3) or equivalent levels of fluoride (F) in the form of sodium-fluoride (NaF). Twenty seven adult male Long-Evans rats were administered one of three treatments for 52 weeks: the control group was administered double distilled deionized drinking water (ddw). The aluminum-treated group received ddw with 0.5 ppm AlF3 and the NaF group received ddw with 2.1 ppm NaF containing the equivalent amount of F as in the AlF3 ddw. Tissue aluminum (Al) levels of brain, liver and kidney were assessed with the Direct Current Plasma (DCP) technique and its distribution assessed with Morin histochemistry. Histological sections of brain were stained with hematoxylin & eosin (H&E), Cresyl violet, Bielschowsky silver stain, or immunohistochemically for beta-amyloid, amyloid A, and IgM. No differences were found between the body weights of rats in the different treatment groups although more rats died in the AlF3 group than in the control group. The Al levels in samples of brain and kidney were higher in both the AlF3 and NaF groups relative to controls. The effects of the two treatments on cerebrovascular and neuronal integrity were qualitatively and quantitatively different. These alterations were greater in animals in the AlF3 group than in the NaF group and greater in the NaF group than in controls.

Contents: Preface. F.A. King, C.J. Yarbrough, Yerkes Primate Research Center: A Historical Perspective. Part I: Limbic System and Behavior. L.E. Jarrard, T.L. Davidson, The Hippocampus and Complex, Nonspatial Discrimination: Is Learning Still "Not Possible?" N.A. Schmajuk, H.T. Blair, Time, Space, and the Hippocampus. D.S. Olton, Repairing the Damaged Septohippocampal System. L.W. Means, Working Memory for Water-Escape Loci in Rodents. J.J. Chrobak, A.L. Vi, G. Buzsaki, Septal Regulation of the Hippocampal-Entorhinal Network: Memory Formation and Failure. A. Poplawsky, The Effects of Gangliosides or Nimodipine on Promoting Behavioral Recovery in Rats With Septal Damage. D.P. Kimble, J.P. Vicedomini, The Septohippocampal Connection: Some Behavioral and Anatomical Relationships. Part II: Plasticity in Behavior and Brain. M.G. Packard, C.L. Williams, L. Cahill, J.L. McGaugh, The Anatomy of a Memory Modulatory System: From Periphery to Brain. T.L. Petit, Structure and Plasticity of the Hebbian Synapse: The Cascading Events for Memory Storage. F.H. Gage, G.R. Chalmers, K.L. Eagle, M.H. Tuszynski, M.D. Kawaja, Functional Recovery Following Damage to the Adult Rat Septohippocampal System. M.L. Woodruff, R.H. Baisden, Variables Influencing Behavior After Transplants of Fetal Hippocampus. G.M.J. Ramakers, I.J.A. Urban, P.N.E. de Graan, W.H. Gispen, Hebbian Plasticity in the Hippocampus: Involvement of Protein Phosphorylation and Protein Kinase C. J.E. Springer, F.M. Sessler, B.J. Gwag, Neuronal Activity Regulates Nerve Growth Factor mRNA Expression in the Adult Rat Hippocampal Formation. B. Bohus, G.A. Cottrell, C. Nyakas, H.J.A. Beldhuis, P.G.M. Luiten, Stress, Stress Hormones, Kindling, and Neural Plasticity. Part III: Neural and Chemical Determinants of Normal and Abnormal Behavior. J.H. Hannigan, Behavioral Plasticity After Teratogenic Alcohol Exposure as Recovery of Function. S.A. McDougall, C.A. Crawford, A.J. Nonneman, Age-Related Differences in Dopamine-Mediated Behaviors: Effects of Irreversible Antagonism. C. Van Hartesveldt, Development of Dopamine Systems and Behavior. R.W. Doty, Brainstem Influences on Forebrain Processes, Including Memory. D. de Wied, ACTH Neuropeptides, Learning and Creativity. K.H. Pribram, The Enigma of Reinforcement. J.P. Ryan, Wandering in Alzheimer's Disease: Clinical and Neurobiological Perspectives. K.F. Jensen, Evaluating the Structural Integrity of the Nervous System for Risk Assessment.

Two experiments using male rats evaluated the effects of a range of doses of the neurosteroid, pregnenolone sulfate (PS), or of the synthetic neurosteroid, ethylestrenol (E), on the retention of a passive avoidance task. The steroids either were given immediately after the training trial or 1 h before the first retention test. Retention tests were given both 24 h and 48 h after acquisition. In both experiments, separate groups of animals were trained under low or moderate footshock conditions. At all doses tested both PS and E improved retention under the low footshock conditions. In groups trained with the higher footshock, the steroid-treated groups performed no better than the vehicle controls. Indeed, there were suggestions that some doses impaired retention. These results seem best understood as an induction of bimodality or 'turbulence' in behavior as used in Chaos theory rather than a shift in an inverted U-shaped retention function. In the second experiment in which the steroids were given before retention testing, they were generally without effect.

Ethylestrenol, a synthetic anabolic steroid, was administered to adult male Long-Evans rats to investigate its role in acquisition and retention of a spatial food-search task. The animals were injected i.p. every other day either with 100 µg of ethylestrenol or with the vehicle alone. Injections began 1 week prior to testing and continued throughout the study. A modified hole-board task was used. After modest food deprivation, the animals were required to find a food reward placed in a given hole. Acquisition of the task was measured by the time required to reach the food hole. Eight trials were given per day. Following a 10-day period without deprivation (but with 2 injections on separate days), eight retention trials were given. Following this, the rats were trained to find the reward at a new location for 2 subsequent days. There were small differences between the groups in performance during acquisition in the original 5-day period but not in the final 2-day “new-hole” training period. During the retention test, however, the ethylestrenol-treated rats reached the food reward significantly faster than did the vehicle-treated rats. These results indicate that retention was substantially enhanced by the synthetic hormone-like agent under conditions in which there was only limited enhancement of acquisition.

This study examined the behavioral effects of chronic ingestion of various monofluoroaluminum complexes (AlF3) in drinking water. Forty young adult male Long-Evans rats were divided into four groups of 10 rats each. The groups received different concentrations of AlF3 in the drinking water from three sample solutions having a total Al concentration of 0.5, 5.0, and 50 ppm, respectively, or double-distilled deionized water on an ad lib. basis for 45 weeks. General decline of bodily appearance was observed in the lowest concentration AlF3 group, and animals in this group succumbed in greater numbers during the course of the study than those in any other group. Examinations of performance in an open field, an analysis of walking patterns, and a balance beam test did not find any difficulties indicative of motor disorder. Indeed, on the initial trial on the balance beam, the AlF3-treated animals exhibited superior performance. No group differences were found in behavior assessed by spontaneous alternation or by a modified Morris water maze test. When retested in the Morris maze after a low dose of scopolamine (0.4 mg/kg), the control animals took longer to reach the platform while the AlF3-treated rats were not affected. In an olfactory preference test, the AlF3-treated animals failed to show preferences exhibited by the controls, indicating a possible olfactory impairment. The level of Al in the brains of the AlF3-exposed rats, as determined by direct current plasma analysis, was almost double that of the control animals. There was a similar trend for the Al content found in the kidneys.

In rats, sectioning the fimbria-fornix leads to a decrease in cells reactive for acetylcholinesterase and choline acetyltransferase, as well as other types of cells, in the medial septal area that project to the hippocampus. In this study cells in the medial septal area were stained for acetylcholinesterase reaction product or by a Nissl method two weeks after unilateral section of the fimbria-fornix. Counts were made of cells on each side of the midline by independent observers. The counts of the cells on the two sides of the brain were compared in rats that had been given nimodipine (70 μg/kg) just after the lesion and for 7 additional days and in rats that had been given only the vehicle for an equivalent amount of time. The number of cells reactive for acetylcholinesterase was reduced in the medial septal area on the side of the brain in which the forebrain fornix was sectioned, but this occurred to a significantly less extent in the nimodipine-treated rats. No differences were noted in the number of cells on the two sides of the medial septal area when counted in Nissl-stained sections.

The possible role of extracellular calcium ([Ca+2]e) in cryopreservation-induced cytotoxicity was tested using Madin-Darby canine kidney (MDCK) cells and a fluorescent multiple endpoint assay. MDCK cells maintained in 2 mM [Ca+2]e and treated with the calcium ionophore, ionomycin, increased their intracellular calcium ([Ca+2]i) as revealed by the calcium indicator dye, Fluo3 and the bottom-reading spectrofluorometer, CytoFluor 2300. The addition of 10 mM [ethylene bis (oxyethylenenitrilo)]-tetraacetic acid (EGTA) to the extracellular medium before treatment with ionomycin blocked this ionomycin-dependent increase in [Ca+2]i. A number of site and activity-specific fluorescent probes were surveyed to determine which indicator dye might best reveal the ionomycin-induced cytotoxic events during this increase in [Ca+2]i. Although most dyes changed their emission profiles in response to calcium, neutral red was found to best reflect the loss of [Ca+2]i homeostasis. The NR50 for a 15-min exposure to ionomycin in the presence of 2 mM [Ca+2]e was approximately 2 microM ionomycin, but ionomycin had little apparent effect on neutral red retention when 10 mM EGTA was added to the extracellular medium. Thus it was clear that an increase in [Ca+2]i could be cytotoxic to MDCK cells and that neutral red could monitor this cytotoxic episode. To test if [Ca+2]e was similarly cytotoxic during cryopreservation, MDCK cells were subjected to cryopreservation in the presence of dimethylsulfoxide (DMSO). In contrast to previous studies, plasma membrane integrity, not lysosomal function, seemed to best correlate with cell survival subsequent to cryopreservation. In addition, decreasing [Ca+2]e had no discernable effect on the retention of plasma membrane indicator dyes, neutral red, or cell survival. It is concluded that a) plasma membrane indicator dyes, not neutral red, might be better indicators of cytotoxicity occurring during cryopreservation; b) DMSO might be toxic to lysosomes during cryopreservation of cultured cells; and c) although [Ca+2]e can contribute to cytotoxicity, the presence of [Ca+2]e might not influence cryopreservation-induced cytotoxicity.

The immortalized septal cell line, SN56 B5 G4, generated by the fusion of mouse septal area cells and neuroblastoma cells, was used to determine if nimodipine, an antagonist of voltage sensitive calcium 'L' channels, might act in a neuroprotective fashion when intracellular calcium levels were raised by incubation in ouabain and monensin. Fluorescent indicator dyes and the automated spectrofluorometer, the CytoFluor 2300, were used to analyze specific cellular targets and functions affected by ouabain and monensin and possible protection by prior incubation with nimodipine. Ouabain and monensin were used together to create a time- and dose-dependent toxic episode. Increases in the emission intensity of Fluo3-AM demonstrated that the concentration of intracellular calcium was monotonically increased by increasing levels of ouabain-monensin. The calcein-AM fluorescent probe indicated that there were no changes in plasma membrane permeability during the toxic episode. Lysosomal integrity decreased as indicated by decreases in neutral red retention. The concentration of free radicals increased as shown by the increase in emission intensity of 2',7'-dichlorfluorescein. Nimodipine pretreatment of the cells incubated with ouabain and monensin resulted in apparent protection of lysosomes and a reduction in the level of free radicals. While nimodipine, by itself, produced a small decrease in intracellular calcium, it actually augmented the ouabain-monensin induced increase in intracellular calcium. The data suggest that in immortalized septal cells, (a) nimodipine offers protection to certain of the responses induced by ouabain-monensin, (b) the protection offered by nimodipine may be independent of antagonism of voltage sensitive calcium channels, and (c) that the protective changes can occur at the same time that intracellular calcium is increasing. These latter observations question the hypothesis that the protection against cell death and dysfunction offered by nimodipine is due solely to maintaining calcium homeostasis.

Our objective was to analyze the influence of ethanol ingestion on the in vitro inotropic effects of dihydropyridines alone, or in combination with ethanol, on atrial muscle from rats offered a liquid diet with ethanol ("ethanol rats," ER) or without ethanol ("normal rats," NR). Left atria from NR or ER were superfused with Tyrode's solution (36 degrees C) and driven at 1.5 Hz while recording tension. Bay K 8644 (BAYK) increased, while nimodipine or ethanol decreased, the tension developed and the velocity of development of tension. The preparations recovered rapidly from the effects of ethanol, but not from those of the dihydropyridines. The effects of ethanol and dihydropyridines in combination were the result of the additive or counteractive actions of the drugs. The effects of ethanol and nimodipine on ER preparations were not different from those observed in NR. The action of BAYK was significantly smaller in ER than in NR. In other words, chronic ingestion of ethanol reduced the positive inotropic effect of BAYK, but it did not modify the negative inotropic action of nimodipine or ethanol.

Male Wistar rats subjected to unilateral fimbria-fornix transection by mechanical knife cut or to sham operations were tested in a water maze and in an open field. Half the animals in each group were treated with either 0.06 mg/kg nimodipine or vehicle, administered i.p. for 7 days, beginning the day of surgery. Animals were sacrificed and brains were processed for acetylcholine esterase (AChE) histochemistry. In the water maze, lesioned rats showed a significant impairment relative to the sham-operated animals. Nimodipine treatment did not improve performance. There were no differences among the groups in the observed frequencies of the open field behaviors of locomotion, hole-poke, rearing and grooming. A significant reduction of AChE-positive cell bodies was found in the medial septal region on the side of the lesion. There were no differences in water maze performance among groups of rats treated with 0.0, 0.5, 1.0, or 5.0 mg/kg nimodipine for 7 days, beginning the day of fimbria-fornix transection, in an attempt to determine any dose-dependent effect of the drug.

This study investigated the effects of fetal rat umbilical cord compression on anatomical, biochemical, and behavioral parameters of development. Further, the study examined the ability of the calcium channel antagonist nimodipine to afford protection from this insult. Near the day of birth (E21), the umbilical cord of individual fetuses was not clamped or clamped for 2, 6, or 12 min. Before clamping, mothers were given 70 μg/kg (i.p.) nimodipine in a polyethylene glycol (PEG) vehicle or the vehicle alone. Selected animals were sacrificed for cytochrome oxidase histochemistry. The remainder of the pups were given to foster mothers and allowed to develop through adulthood. At the end of testing all animals were sacrificed and the brains weighed and measured. Histochemical analysis revealed that clamping resulted in a decrease in cytochrome oxidase reaction product in the hippocampus. The reduction in this marker of oxidative metabolism was not as pronounced in animals from drug-treated mothers. Alterations in behavior produced by clamping were detectable as early as the third day after birth (P3). At this age, pups subjected to cord clamping exhibited impaired righting and diminished avoidance of a 'cliff' on which they had been placed. On P67-P75, clamped animals exhibited hyperactivity in an open field, low rates of spontaneous alternation in a T-maze, and impaired learning and memory in a Pavlovian conditioned aversion-to-brightness test. The calcium channel blocker afforded protection from the effects of cord clamping, since the nimodipine-treated animals were less impaired in these behavioral tests. Animals that had been subjected to cord clamping showed reduced brain volumes and dimensions on P80. Nimodipine treatment normalized these parameters of brain development relative to non-clamped controls. Taken together, these results indicate that brief periods of umbilical cord occlusion near the time of birth can have both immediate and long-term effects on different parameters of development. In addition, the calcium channel blocker nimodipine affords partial protection from damage induced by compression of the fetal umbilical cord.

The effects of ethanol and dihydropyridines on atrial membrane potentials (MP) were studied. Rat atrial strips superfused with Tyrode's solution (36 degrees C) were driven at 5 Hz while recording MP with intracellular microelectrodes. Bay K 8644 7 X 10(-7) M (BAYK) increased the amplitude of the action potential (AAP) without affecting the resting membrane potential (RMP) or the Vmax of phase 0 (Vmax 0). The velocity of change in voltage decreased at the beginning of the repolarization, causing an increase in the action potential duration (APD), but it was not modified at negative voltages. Nimodipine 4.2 X 10(-6) M reduced the AAP without affecting RMP or Vmax 0. The velocity of change in voltage increased at the beginning of the repolarization, causing a decrease in the APD, but was not modified at negative voltages. Ethanol 5.3 X 10(-2) M exerted actions similar to those of nimodipine. Simultaneous exposure to ethanol and nimodipine resulted in changes not different from those obtained with each of the two compounds. The MP remained unchanged when the preparations were exposed to ethanol and BAYK simultaneously. In summary, ethanol and nimodipine exerted similar actions on the atrial MP while BAYK had opposite actions. The effects of ethanol and BAYK cancelled each other.

The data presented in this article are commensurate with the idea that in the not-too-distant future, pharmacologic interventions will be available to prevent many of the deleterious effects of brain damage due to hypoxia and other causes of global brain insult. It is also likely that even after highly localized brain damage, there will be specific interventions to reduce the usual mental and behavioral changes induced by the damage. While the specific experimental studies use adult animals, similar beneficial effects are being found in studies in which damage occurs in the perinatal period.

The effects of ethanol and/or dihydropyridines (DHPs) on force of contraction of atrial muscle were studied. Guinea pig atrial strips superfused with Tyrode's solution (36°C) were driven (1.5 Hz) while recording muscle tension. Bay K 8644 (BAYK) increased, while nimodipine or ethanol reduced, the peak tension developed and the maximum velocity of development of tension. The effects of ethanol were readily reversible, but those of the DHPs were not. The combined actions of ethanol and DHPs were the result of the synergism or antagonism of the drugs tested. The shorter duration of the action of ethanol resulted in the effect of DHPs being still evident well after the exposure to the drugs ended. In summary, ethanol and nimodipine exerted depressant actions on atrial contractile force, while BAYK had opposite effects. The different mechanisms of action may explain the different duration of the effects of ethanol (physical agent) and DHPs (receptor-binding chemicals).

The IBM 300 mm wafer manufacturing line provides a case study for the optimization of an automated macro defect inspection system to accurately flag global wafer color variation. The IBM inspection system was falsely flagging a large number of wafers primarily for global wafer color variation, leading to unacceptable amounts of production volume being placed on hold. A review of the macro inspection system identified several areas for improvement. An investigation into the installed hardware base found a panel behind the beam splitter was introducing noise through reflected light. This panel was replaced with a less reflective material. A review of the failed wafers found that maximum light levels were not achieved across all tools and an improved diffuser plate for the fiber optic output was designed to improve light transmittance. Global wafer color is determined by comparing the scanned wafer image to a "golden" data set, referred to as a "color baselist," which is composed of data from 30 wafers. A review of the recipe baselists revealed that some of the wafer samples did not accurately represent process conditions, and new wafer samples were collected. Finally, a tool-to-tool matching test revealed that the set of weightings given to each of the color parameters in the baselists was not optimized. After implementing the above changes, false global wafer color failures were virtually eliminated.

This paper discusses the controls benefit accomplished on both product wafers and process tools at IBM's 300mm wafer manufacturing line by using integrated auto-macro defect inspection in all the photolithography tool clusters for after-develop-inspection (ADI). Inspection is supported on all production wafers (with possibility to sample wafers if desired). To get to this level of control the overall 'ADI process' in the line had to be first rendered manufacturable. Therefore, significant effort had to be focused towards decreasing false fails and nuisance holds. As a result, over the last year inspection software related false fails were reduced 3X, hardware related PC communication fails were decreased 5X, and fab automation related nuisance wafer holds were reduced 12X. Fail rate has been sustainable at 6% (± 2%) for over two quarters. At this point only 20% of the fail rate is false and is mostly attributable to hardware related wafer alignment issues during inspection. By decreasing false fails and hold rates, sensitivity and effectiveness in the line towards correctly reacting to real fail signals significantly improved. Product wafers with real fails are now consistently reacted to real-time in the line leading to rework and elimination of photo sector generated macro defects. Contribution of this integrated metrology system to fab rework rate in eliminating yield impacting macro defects from product wafers, as well as examples of captured defects that have identified several process tool problems are also presented. Majority of rework contributors are defects generated from intermittent photo process tool issues that randomly occur and disappear (versus systematic process tool issues that typically end up being flagged within two consecutive failed lots). Typically 0.5 to 1% of the ADI inspected wafers get reworked for macro defectivity translating to a significant number of wafers - thus justifying ADI return-on- investment. Note that real fails as a result of defectivity propagation from prior photolevels - estimated at 15% of the fail rate, do not get reworked. Additionally, real fails determined to be non-reworkable as a result of defectivity from the current photolevel - estimated at 50% of the fail rate, also do not get reworked. Further, by analyzing real fails for intra/inter wafer signatures systematic process tool issues are being consistently flagged on the line. Overall, ADI at IBM's 300mm wafer fab has evolved into a real-time wafer level go/no-go control for both product and process tools.

Satellite spot defects are a class of defects widely observed in photoresist processing in 248 nm and 193 nm lithography. These defects become more and more significant as the feature sizes shrink and can potentially become “killer” defects, leading to bridging between lines and/or blocking vias. Traditional potential solutions (i.e., optimization of development rinse step) have yielded improvements in the past but did not eliminate the problem. The use of water-soluble topcoat layers was shown to eliminate these defects but it imposes limitations on throughput and cost and it is incompatible with 157 nm lithography and 193 nm immersion schemes. In this work, we report the use of aqueous surfactant solutions for the suppression of defects in 248 nm and 193 nm lithography, with emphasis on satellite spot defects. Suppression of total defects by up to ~99% and practically complete elimination of satellite spot defects were achieved by use of aqueous surfactant solutions for various resists. A handful of materials that can be incorporated into rinse solution for the successful elimination of blob defects in a variety of resists were identified. It was determined that the two most important factors that enable successful defect elimination are the surfactant concentration and the extent of surfactant adsorption to specific resist systems.

The brain depends on other organ systems of the body for oxygen, nutrients, and the elimination of metabolic byproducts. The primary route for such transfer of these essentials is the cerebrovasculature. The cerebrovasculature also participates in metabolizing or excluding xenobiotics, segregating components of the immune response, regulating pH and osmolarity of the cerebrospinal fluid, selectively distributing hormones, and impeding pathogenic invasion. Various aspects of these diverse functions are attributed to the complex structural and molecular properties of cerebral endothelial cells collectively referred to as the blood-brain barrier (1-7). The hallmark structural specialization of the blood-brain barrier is the tight junction between the endothelial cells, which prevents diffusion of plasma proteins and molecules of a similar size or larger (8-12). Other structural specializations include close apposition of astrocytic endfeet, sparsely distributed pericytes, and extensive association with microglia. Molecular specializations include endothelial expression of transporters and enzymes, such as those involved in xenobiotic metabolism (12-27).

Previously we reported delayed cell death, defined by clear-cut cell loss 60 days after a nitrite-induced hypoxic episode. The loss of cells was not apparent two weeks after the treatment, although some changes in cellular appearance were observed at that time. A similar delayed loss of neurons in the hippocampus after hypoxia induced by blood vessel occlusion has also been found. In addition, we reported that the amount of methemoglobinemia induced by the sodium nitrite can be reduced by the stress produced by handling and the injection of saline 2 or 24 h before the nitrite administration. The degree of methemoglobin formed is directly related to cell death in certain areas of the brain, including regions within the hippocampus. Considering the many effects that can be produced by chronic and acute stress of several kinds and the length of time during which these effects manifest themselves, we undertook to determine the histologic effects of the stresses of transport on the neuroanatomic effects of sodium nitrite administration 60 days post administration. Comparisons were made of the effects of two methods of transport from the laboratory in which the animals (male CD-1 mice) were injected with the sodium nitrite or saline (Tufts Medical School) to the laboratory in which the histologic evaluations were made (Binghamton University). The animals began their travel several hours after the injections. One transport method was by commuter airline and the other was by automobile. All animals had the same transport from the supplier to the Boston location (truck). Thus, the stress of experimental interest occurred after the nitrite administration. Upon arrival at Binghamton University, the animals were housed at the University in their own colony room for 60 days before sacrifice. After sacrifice, sections from their brains were subjected to a number of histologic staining procedures, including PTAH, the Bielschowsky silver method, GFAP, and the standard Nissl procedure. Although special attention was paid to hippocampal areas, changes in cells in the habenulae and the linings of ventricular areas were also prominent. Surprisingly, the nitrite treatment before transport to Binghamton offered partial protection against the very substantial and lasting effects of the injections, transport, and handling found in the control animals. Differential effects caused by the two methods of transport were also noted.

Until our knowledge of the etiology of Alzheimer's dementia, as well as related conditions involving mental impairments, is greatly extended, no line of investigation should be ignored. We believed that the possible contributions of aluminum exposure to neural impairments deserved further study. In coming to this opinion we were mindful of the work of Roberts on the neurotoxic effects of inhaled aluminum silicate' as well as the neuropathologic results reported by Per1 and his associates indicating an association of aluminum with disease-affected neurons in Alzheimer's patients.*.' The possibility that certain metals including aluminum, either alone or in combination, play a role in dementia remains a viable hypothesisP While the possibility of transport of A1 to the brain via the olfactory system, especially under conditions of a partially compromised immune system, remains a likely route of entry into the nervous system, it is not the only entry route for aluminum. A1 and other elements with toxic potential enter the nervous system through many pathways, including our food and water. Initially, we investigated the effects of low doses of aluminum given to rats through their drinking water. The entry of A1 into the circulation and the brain depends on the particular species of A1 available as well as the conditions in the stomach and the digestive tract. The bioavailability of A1 may be enhanced by its complexing with fluorine (F) to form various monomeric fluoaluminum species. Of these, AIF3 was of special interest due to its lipid solubility and ability to pass

The monoethylcholine aziridinium ion, AF64A, (3 nmol in 1 microliter) or artificial CSF (1 microliter) was infused unilaterally into the right dorsal lateral ventricle of male adult rats. Treatment with the L-type calcium channel antagonist, nimodipine (70 micrograms/kg b.wt.) or its vehicle was administered beginning before and for seven days following surgery. The infusion of AF64A reduced spontaneous alternation rates in the T-maze when compared to CSF and sham infused animals. AF64A-treated animals also took longer to reach the goal area in a complex maze task on specific trials relative to CSF and sham-infused animals. Locomotion and habituation to the open field did not differ between surgery groups. Unilateral AF64A significantly depleted acetylcholinesterase (AChE) positive terminals in the ipsilateral hippocampus and cell bodies in the ipsilateral medial septal area (MSA). Receptors for nerve growth factor (NGF-R), often colocalized with cholinergic cell bodies and terminals, also were depleted in the ipsilateral MSA of AF64A infused animals. Treatment with nimodipine did not have a neuroprotective effect on AF64A animals in either behavioral or histological results. However, some degree of protection was found in the vehicle-treated rats. This effect was likely a consequence of the stress of the injection procedure rather than the content of the vehicle, largely polyethylene glycol 400. Nimodipine-treated animals, regardless of surgery group, exhibited fewer emotional responses and had lower spontaneous alternation rates than untreated animals. The behavioral alterations found in the nimodipine groups are most easily explained in terms of altered emotionality. Overall our findings indicate that AF64A is a potent cholinotoxin that can selectively eliminate the ipsilateral septohippocampal cholinergic system when unilaterally infused into the lateral ventricle. It is possible that the mechanism of action of AF64A, like other nitrogen mustard analogues, involves disruption of basic processes involved in protein synthesis and DNA activities. Because of this, the toxic effects of the aziridinium mustard are independent of extracellular calcium and thus may not be susceptible to protection by calcium channel antagonists.

Two experiments were undertaken in which the effects of semichronic administration of the precursor steroid, pregnenolone, were examined in a food search task. In both experiments male rats were required to find a food reward in a designated hole in an arena with 16 equally spaced holes. Hormone administration began 8 days before the onset of training. Training was given on an every-other-day schedule for five sessions. Animals were deprived of food for 18 h before training or testing. Retention testing occurred 10 days after acquisition and this was followed by 2 days of training using a different hole for the reward. The two experiments differed only in the method of hormone administration. In one experiment the rats received an implanted (sc) slow release pellet containing pregnenolone before training. In the second experiment the animals received ip injections of pregnenolone sulfate before and during initial training and then had the slow release pellet implanted between acquisition and retention. Significant enhancement of retention was found during the middle trials of the retention test when the treated and control groups from the two experiments were combined. No differences were found during acquisition training in either experiment. On the first day of training the animals to find the reward in a new location, the group injected with pregnenolone sulfate and later implanted with pregnenolone slow-release pellets exhibited performance superior to that of their matched control group.

The effects of a 4-day nimodipine treatment (70 μg/kg IP beginning on the day of surgery) given to rats with lesions directed at the medial septal area were monitored for 120 days. Body weight, water intake, open-field activity, rearing, hole-poking, and repetitive motor acts were periodically measured through 120 postsurgical days. Although no differences were found in water intake between any of the groups, the body weights of rats with any medial septal damage, whether treated with nimodipine or not, were lower than rats with control operations by postsurgery day 120. Rats with any medial septal damage, whether treated with nimodipine or not, had lower rearing frequencies, rearing durations, and holepoking frequencies than controls on all test days. However, rats with complete medial septal lesions treated with nimodipine exhibited movement in the open field and frequencies of stereotyped, species-typical acts similar to those of control rats by postsurgery day 60. This nimodipine effect was not observed in rats with partial lesions of the medial septal region. This study emphasizes that a brief administration of nimodipine shortly after brain damage can influence behavioral changes 40–60 days after surgery, but that this effect was not apparent in rats with only partial medial lesions.

The Vulnerable Brain and Environmental Risks , The Vulnerable Brain and Environmental Risks , کتابخانه مرکزی دانشگاه علوم پزشکی تهران

In order to test the possible effectiveness of peripheral interventions with the adrenergic system for the alleviation of certain disorders that typically follow bilateral hippocampal lesions, rats with bilateral lesions of the hippocampus, the overlying neocortex, or sham operations were tested at two postoperative times in the Morris water maze, a frequently used "spatial task." Half of the animals in all groups were exposed to the adrenergic manipulations, i.e., a chronic, 7-day, systemic bretylium regime (5 mg/kg) and, in addition, a peripheral injection of norepinephrine (4 micrograms/kg) 30 min before the start of each training day. The other half received saline chronically and a single saline injection before each training day. Five days of training were given at each of the two training periods. The first began 7 days after surgery while the second began 33 days after surgery. As expected, the hippocampally lesioned animals were severely impaired in the task. The adrenergic treatment produced enhanced performances in the rats with hippocampal lesions at both training sessions, although the improvement was greatest at the later period. Although the animals receiving the pharmacologic treatment located the general area of the hidden platform better than the saline-treated animals with hippocampal lesions, the treated animals were still impaired, swimming directly to the hidden platform on fewer trials than did animals in the other groups.

Diabetes mellitus is associated with disturbances of cognitive functioning. The aim of this study was to examine cognitive functioning in diabetic rats using the ‘Can test’, a novel spatial/object learning and memory task, without the use of aversive stimuli. Rats were trained to select a single rewarded can from seven cans. Mild water deprivation provided the motivation to obtain the reward (0.3 ml of water). After 5 days of baseline training, in which the rewarded can was marked by its surface and position in an open field, the animals were divided into two groups. Diabetes was induced in one group, by an intravenous injection of streptozotocin. Retention of baseline training was tested at 2-weekly intervals for 10 weeks. Next, two adapted versions of the task were used, with 4 days of training in each version. The rewarded can was a soft-drink can with coloured print. In a ‘simple visual task’ the soft-drink can was placed among six white cans, whereas in a ‘complex visual task’ it was placed among six soft-drink cans from different brands with distinct prints. In diabetic rats the number of correct responses was lower and number of reference and working memory errors higher than in controls in the various versions of the test. Switches between tasks and increases in task complexity accentuated the performance deficits, which may reflect an inability of diabetic rats to adapt behavioural strategies to the demands of the tasks.

Animals with anterior or posterior neocortical lesions as well as intact control animals were evaluated for changes in α-adrenergic sensitivity at five postoperative times. Colonic temperature decreases were measured in response to clonidine at each of the postoperative periods. The result indicated that a heightened heat-loss response was induced by clonidine that lasted 21 or more days after destruction of the posterior neocortex. This exaggerated response to the drug was not found in animals with anterior neocortical lesions.

Offspring from pregnant rats injected with 4mg/kg body weight colchicine on Embryonic Days 18, 19, and 20 were found to have isocortical and hippocampal structures greatly reduced in mass when examined at birth. Cells with pyknotic nuclei were found in Layers 5, 4, and 3 of the cerebral isocortex, the habenula, and anterior medial nuclei of the thalamus. Brains taken at Postnatal Days 22 and 132 were reduced in overall size, and had a 20-30% reduction of cells at the vertex of the neocortex with up to 50% reduction in the thickness of the corpus callosum. A decrease in activity, an increase in fearfulness and/or decreased tendency to explore, reduced error scores on the Hebb-Williams maze, poor performance on the Maier elevated maze, and a lessened sensitivity to sound-induced seizures were correlated with these anatomical changes.

In the first experiment, rats were placed in observation chambers in an isolated room for 60 min over 7 consecutive days. On the following day, the animals were injected with saline before testing and given a 1-min period of footshock halfway through the session. On the next day, testing was done after pretreatment with either saline or naloxone (1 mg/kg). The animals tested after saline exhibited excessive grooming in the first half of the observation period. Those tested with naloxone did not. In a second experiment, rats treated in a similar fashion to those of Experiment 1, but shocked outside the testing chambers, failed to demonstrate excessive grooming. These data suggest that a stress-related response, possibly involving ACTH release, can be associated with stimuli of the observation chambers in the first experiment and lead to excessive grooming on subsequent tests. As with other means of induction of excessive grooming, naloxone attenuates the response.

Adult mice (Binghamton Heterogeneous stock) received different doses of ethanol (0.5, 1.0, or 2.0 g/kg) administered alone or in combination with the voltage-sensitive calcium channel antagonist, nimodipine (Bay e 9736). Both 20 and 60 minutes later, sensitivity to ethanol was assessed in terms of rotorod activity and changes in rectal temperatures. Nimodipine (5 mg/kg) alone did not alter rectal temperature or motor coordination, but at both observation periods nimodipine potentiated the hypothermia induced by the highest dose of alcohol (2.0 g/kg) and exaggerated alcohol-induced motor incoordination at all doses. The present set of results indicates that the inhibition of voltage-dependent calcium channels can exaggerate ethanol-induced effects.