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Biomedical subjects

J R West

Publications and source records attributed to J R West.

At least 73 records · Page 4Linked to original sources
PubMed1993

Use of pup in a cup model to study brain development.

The pup in a cup artificial rearing procedure allows for experimental manipulation of brain development during the early postnatal brain growth spurt in the rat that coincides with that of the human third trimester. The technique has been used to demonstrate temporal windows of vulnerability to alcohol; the brain appears to be vulnerable to alcohol after most of the neuronal populations have been generated and are starting to differentiate. Alcohol exposure via gastrostomy feeding tubes during the third trimester equivalent results in alterations in neuronal circuitry and deficits in neuronal populations. Some of the alterations are permanent. Importantly, studies incorporating artificial rearing of rat pups have demonstrated that the pattern of alcohol exposure is a critical factor for inducing alcohol-related brain damage; brain damage is increased with peak blood alcohol concentrations.

Animals↗
PubMed1993

The effects of the timing of ethanol exposure during the brain growth spurt on the number of cerebellar Purkinje and granule cell nuclear profiles.

Ethanol exposure during development is particularly deleterious to cerebellar Purkinje cells and granule cells, but the mechanism(s) underlying this sensitivity and the variables which affect it remain unknown. One important variable that has not been fully investigated, is the timing of the ethanol exposure. Ethanol exposure during the brain growth spurt causes a differential loss of Purkinje cells across the 10 lobules of the vermal cerebellum. However, whether or not changing the timing of the ethanol exposure during the brain growth spurt alters the extent and location of the loss of Purkinje cells within the cerebellar vermis has not been investigated. Moreover, the loss of cerebellar granule cells has been shown to parallel the loss of Purkinje cells, leading to the conclusion that the loss of granule cells occurred as a function of the loss of their targets, the Purkinje cells. The purpose of this study was to address both issues. Male rat pups were exposed to ethanol, via an artificial-rearing method, during one of the following 2-day time periods: postnatal days (PD) 4-5, 5-6, 6-7, 7-8, 8-9, 9-10, or 12-13. Gastrostomy control (GC) and suckle control (SC) groups also were included. All pups were sacrificed on PD21. The number of Purkinje cell nuclear profiles from three vermal sections were counted in all groups, while the number of granule cell nuclear profiles in the ten lobules was estimated from pups in selected groups. No loss of Purkinje cells was observed in pups exposed to ethanol on PD7-8 or at any of the later exposure times. Additionally, among the three exposure groups in which significant Purkinje cell loss was observed (PD4-5, PD5-6 and PD6-7), seven lobules exhibited significant differences particularly between the PD4-5 and PD6-7 groups. The group with the greatest loss of Purkinje cells (PD4-5) also was the group with the greatest loss of granule cells. A significant loss of granule cells did not occur without a corresponding loss of Purkinje cells. The loss of both the Purkinje and granule cells was affected by the timing of the ethanol exposure, and that the extent and the location of Purkinje cell loss were extremely sensitive to the effects of the timing of the ethanol exposure.

Animals↗
PubMed1993

Vulnerability of cerebellar granule cells to alcohol-induced cell death diminishes with time in culture.

This study examined the effects of alcohol exposure on the viability of cerebellar granule cells in culture. Continuous alcohol exposure, starting 1 day after the cultures were established, significantly reduced granule cell numbers, even with a single day of exposure to an alcohol concentration as low as 100 mg/dl. The depletion of cerebellar granule cells by alcohol was concentration-dependent (greater loss of cells at higher alcohol concentrations) and duration-dependent (greater loss of cells at longer exposure durations). The loss of granule cells also depended on the number of days the granule cells were in culture before alcohol exposure. Alcohol was significantly more effective in reducing the cell numbers of newly established granule cell cultures (1 day in vitro) compared with older cultures (4 or 7 days in vitro). Cell cycle analysis established that the cerebellar granule cells did not proliferate in culture, indicating that alcohol exposure did not reduce cell numbers by interfering with cell proliferation in this system. Instead, alcohol-induced killing of the granule cells was the most likely mechanism to account for the depletion of granule cells in vitro. Granule cell cultures are a useful in vitro model system to study the cellular and molecular aspects of neuronal cell depletion associated with fetal alcohol exposure. The potential role of the N-methyl-D-aspartate receptor in this alcohol-induced neuronal cell death is discussed.

Animals↗
PubMed1993

Acute and long-term changes in the cerebellum following developmental exposure to ethanol.

Ethanol exposure during development can lead to structural damage to the cerebellum with associated behavioral dysfunction. Deficits in cerebellar weight and Purkinje cell number in the cerebellum of the rat are a function of the timing of the exposure and the peak blood alcohol concentration (BAC). Purkinje cell loss is greater following exposure during the third trimester equivalent than during the second trimester equivalent. Interestingly, Purkinje cells switch rapidly from being highly vulnerable on postnatal days 4 and 5 to being much more resistant after postnatal day 7. Furthermore, the higher the peak BAC, the more severe the deficits. Both in vivo and in vitro studies indicate that alcohol can kill postmitotic cells in a dose-dependent manner. Ethanol exposure that produces neuronal deficits also produces associated behavioral dysfunction, including deficits in balance. The mechanisms responsible for these changes are unknown, but the likelihood of ethanol-induced structural and functional damage during development is associated with both regional and temporal vulnerability and to the peak BAC.

Animals↗
PubMed1992

Early postnatal alcohol exposure acutely and permanently reduces the number of granule cells and mitral cells in the rat olfactory bulb: a stereological study.

This study demonstrates that exposure to alcohol during a period of rapid brain growth can lead to severe and permanent deficits in the number of granule cells and mitral cells in the main olfactory bulb. Sprague-Dawley rat pups were reared artificially and were administered alcohol over postnatal days (PD) 4 through 9, a period of brain development comparable to part of the human third trimester. The daily alcohol dose of 6.6 g/kg was concentrated into two of the twelve daily feedings, producing high peak blood alcohol concentrations followed by near total clearance. Pups were either sacrificed on PD10 or were allowed to grow to adulthood and sacrificed on PD115. The total number of granule cells and mitral cells in the main olfactory bulb were estimated with the aid of unbiased stereological principles and systematic sampling techniques. Exposure to alcohol resulted in significant reductions in the number of both granule cells and mitral cells on PD10. Significant deficits in both neuronal populations remained on PD115. The results support the hypothesis that alcohol exposure can kill developing neurons and lead to permanent neuronal deficits. Substantial developmental changes also occurred in the total number of mitral cells and granule cells between PD10 and PD115 in the control groups. In untreated rats, the number of granule cells increased from 2.20 x 10(6) on PD10 to 5.06 x 10(6) on PD115, while the number of mitral cells decreased from 5.30 x 10(4) to 4.33 x 10(4) over the same time period. These results demonstrate that there is a natural loss of mitral cells during postnatal development at the same time that granule cell number is increasing.

Animals↗
PubMed1992

Dissociation of spatial navigation and visual guidance performance in Purkinje cell degeneration (pcd) mutant mice.

Spatial learning in rodents requires normal functioning of hippocampal and cortical structures. Recent data suggest that the cerebellum may also be essential. Neurological mutant mice with dysgenesis of the cerebellum provide useful models to examine the effects of abnormal cerebellar function. Mice with one such mutation, Purkinje cell degeneration (pcd), in which Purkinje cells degenerate between the third and fourth postnatal weeks, were evaluated for performance of spatial navigation learning and visual guidance learning in the Morris maze swim-escape task. Unaffected littermates and C57BL/6J mice served as controls. Separate groups of pcd and control mice were tested at 30, 50 and 110 days of age. At all ages, pcd mice had severe deficits in distal-cue (spatial) navigation, failing to decrease path lengths over training and failing to express appropriate spatial biases on probe trials. On the proximal-cue (visual guidance) task, whenever performance differences between groups did occur, they were limited to the initial trials. The ability of the pcd mice to perform the proximal-cue but not the distal-cue task indicates that the massive spatial navigation deficit was not due simply to motor dysfunction. Histological evaluations confirmed that the pcd mutation resulted in Purkinje cell loss without significant depletion of cells in the hippocampal formation. These data provide further evidence that the cerebellum is vital for the expression of behavior directed by spatial cognitive processes.

Age Factors↗
PubMed1991

Permanent neuronal deficits in rats exposed to alcohol during the brain growth spurt.

The purpose of this study was to determine whether developmental alcohol exposure could induce permanent neuronal deficits, whether the peak blood alcohol concentration (BAC) influences the severity of the effects, and whether the effects are gender related. Rat pups were reared artificially over postnatal days (PD) 4 through 11 (a period of rapid brain growth, comparable to part of the human third trimester). Alcohol treatments were administered on PD 4 through 9. Patterns of alcohol exposure that produce different peak BACs have been shown to affect differentially the amount of brain weight deficits and neuron loss shortly after the exposure period, so this study investigated whether the pattern of alcohol exposure was also effective in producing permanent deficits. Two groups received a daily alcohol dose of 4.5 g/kg, condensed into either four or two feedings. A third group received a higher daily alcohol dose of 6.6 g/kg administered in 12 uniformly spaced daily feedings. Pups were fostered back to dams on PD 11 and perfused on PD 90. Brain weights were measured, and Purkinje cells and granule cells were counted in each of the 10 lobules of the cerebellar vermis. In the hippocampal formation, cell counts were made of the pyramidal cells of fields CA1 and CA2/3, the multiple cell types of CA4 and the granule cells of the dentate gyrus. The groups receiving the lower daily dose (4.5 g/kg) condensed into either four or two feedings were exposed to higher peak BACs and suffered significant permanent brain weight deficits and neuronal losses, relative to controls. The group receiving the higher daily dose (6.6 g/kg) in continuous fractions had no significant brain weight reductions or neuronal loss. Vulnerability to alcohol-induced neuronal loss varied among regions and cell populations and as a function of peak BAC. In the hippocampus, only the CA1 pyramidal cells were significantly reduced in number and only in group receiving the most condensed alcohol treatment. In the cerebellum, the severity of Purkinje cell and granule cell losses varied among lobules, and Purkinje cell vulnerability appeared to depend on the maturational state of the neuron at the time of the alcohol exposure, with the more mature Purkinje cells being the more vulnerable.

Animals↗
PubMed1991

Indices of stress in rats: effects of sex, perinatal alcohol and artificial rearing.

Three groups of rats were normally reared by dams, artificially reared but not exposed to alcohol or artificially reared and exposed to 6.6 g/kg/day of ethanol condensed into 8 h of each 24-h period. Alcohol exposure was given from postnatal day 4 through 9 and artificial rearing was conducted from postnatal day 4 to 12. In adulthood, approximately half of the rats were fitted with a chronic jugular catheter and were exposed to swim stress for 1 min in 21 degrees C water. Alcohol exposure augmented the corticosteroid stress response to the swim stress in female rats but not in male rats. The other half of the animals were tested for acquisition and extinction of a conditioned emotional response (CER). While alcohol exposure had no effects on the CER, extinction of CER was greatly accelerated by artificial rearing alone in female rats but not in male rats. Taken together, these findings suggest that some aspects of the stress response in female rats are more vulnerable to insults during the early postnatal period than those in male rats and that the insult-induced alterations can affect hormonal and behavioral measures differentially.

Adrenal Cortex Hormones↗
PubMed1991

Forebrain ischemia induces selective behavioral impairments associated with hippocampal injury in rats.

Two groups of rats were tested on a variety of motor and cognitive tasks after either 10 minutes of two-vessel occlusion forebrain ischemia (n = 8) or sham operative procedures (n = 6). Histological injury was absent in the sham-operated group. In the ischemic group, hippocampal injury was restricted to field CA1, while damage in the neocortex and caudoputamen was sparse. Motor tests performed on postoperative days 18 and 28 revealed no significant differences between the ischemic and sham-operated groups. Retention performance of a radial maze discrimination task was impaired, with a significant but transient increase in both working and reference memory errors. Passive avoidance acquisition and retention were not significantly affected, although conclusions concerning the utility of this task must be reserved because of variability in the behavior of the sham-operated rats. Morris maze spatial navigation (place learning) and open-field activity were insensitive to treatment group. These functional results are consistent with the observed histological injury and what is known about hippocampal injury and behavior, and they provide further guidance for the development of neurological assays appropriate for discriminating outcome from forebrain ischemia in rats.

Animals↗
PubMed1990

Regional differences in the timing of dendritic outgrowth of Purkinje cells in the vermal cerebellum demonstrated by MAP2 immunocytochemistry.

Detailed, within-subjects Golgi analyses of regional differences in cerebellar Purkinje cell dendritic development are impractical due to the capriciousness of that technique. Immunocytochemical labeling of microtubule-associated protein 2 (MAP2) was used to reveal the dendritic development of Purkinje cells, and indicated marked differences in the timing of initial outgrowth of Purkinje cell dendrites for different lobules in the developing rat cerebellar vermis. In particular, an early maturing region of Purkinje cell dendritic outgrowth (lobules I, II, IX and X and along the primary fissure), and a late maturing region (distal lobule VI, lobule VII and dorsal lobule VIII) were documented.

Aging↗
PubMed1990

Alcohol-induced neuronal loss in developing rats: increased brain damage with binge exposure.

A rat model of third trimester fetal alcohol exposure was used to determine whether a smaller daily dose of alcohol can induce more severe microencephaly and neuronal loss than a larger dose, if the small dose is consumed in such a way that it produces higher blood alcohol concentrations (BACs). The possibility of regional differences within the developing brain to alcohol-induced neuronal loss was also investigated. Sprague-Dawley rat pups were reared artificially over postnatal Days 4-10 (a period of rapid brain growth similar to that of the human third trimester). Two groups received a daily alcohol dose of 4.5 g/kg, administered either as a 5.1% solution in four of the 12 daily feedings or as a 10.2% solution in two of the 12 feedings. A third group received a higher daily dose (6.6 g/kg) administered as a 2.5% solution in every feeding. Gastrostomy and suckle controls were also reared. On postnatal Day 10, the animals were perfused, and brain weights were obtained. In the hippocampal formation, cell counts were made of the pyramidal cells of fields CA1 and CA2/3, the multiple cell types of CA4 and the granule cells of the dentate gyrus. In the cerebellum, Purkinje cells and granule cells were counted in each of the ten lobules of the vermis. The lower daily dose (4.5 g/kg) condensed into two or four feedings produced high maximum BACs (means of 361.6 and 190.7 mg/dl, respectively) and significant microencephaly and cell loss, relative to controls. The higher daily dose (6.6 g/kg), administered continuously, resulted in low BACs (mean of 39.2 mg/dl) and induced no microencephaly or cell loss. Regional differences in neuronal vulnerability to alcohol were evident. In the hippocampus, CA1 neuronal number was significantly reduced only by the most condensed alcohol treatment, while CA3, CA4, and the dentate gyrus populations were not reduced with any alcohol treatment. In the cerebellum, some lobules suffered significantly greater Purkinje cell loss and granule cell loss than did others. The regions in which Purkinje cells were most mature at the time of the alcohol exposure were the most vulnerable to Purkinje cell loss.

Animals↗
PubMed1990

New approaches to research on the long-term consequences of prenatal exposure to alcohol.

As the summary presentation of a symposium on prenatal alcohol-induced brain damage and long-term postnatal consequences, this paper proposes the establishment of two main research priorities--to begin to correlate long-term behavioral effects with alterations in underlying neural substrates, and to explore the mechanisms of neuroteratogenicity. To reach these goals, three objectives are described. First, animal and human research must become more interrelated. Second, experimental observations should be integrated into formal models that incorporate both neural structure and function. Third, researchers should choose well-defined dependent measures that are derived from models of brain function based on modern concepts of cognitive neuroscience. Examples of neuropsychological tests that may serve as the bases for structure/function relationships are presented. Incorporating these objectives into future research will facilitate understanding of the fundamental issues concerning prenatal alcohol exposure and will begin to provide the bases for rational intervention or treatment.

Alcohol Drinking↗
PubMed1990

Cell population depletion associated with fetal alcohol brain damage: mechanisms of BAC-dependent cell loss.

Neuronal death is one of the most serious consequences of alcohol exposure during development. Studies described in this paper used a neonatal rat model to address factors affecting neuronal death following alcohol exposure during the period of rapid brain growth, and relate them to possible mechanisms of damage. The profile of blood alcohol concentrations (BACs) is an important variable influencing both brain growth deficits and neuronal death--a smaller daily dose of alcohol can be more damaging than a larger daily dose, if it is consumed in a binge-like pattern that produces relatively higher BACs. Alcohol exposure for a single day also can be damaging, producing both brain growth deficits and neuron loss, if high BACs are obtained. Various brain regions and different neuronal populations within a given brain area exhibit different degrees of vulnerability. Some neuronal loss clearly is a function of cell death due to direct effects of alcohol, while other deficits may be due to either primary or secondary effects of the alcohol insult. In the cerebellum, a maturational or metabolic factor also appears to be involved with alcohol-induced neuronal death. Immunocytochemical studies using a monoclonal antibody against microtubule-associated protein 2 (MAP2) indicated that cerebellar lobules containing Purkinje cells that are in the process of extending dendrites are ones that are more vulnerable to alcohol than lobules containing Purkinje cells that mature later. Alcohol exposure during brain development may be producing neuron attrition in multiple ways, including disruption of membrane integrity, inhibition of protein synthesis or other alterations such as lipid solubility, or by disruption of cytoskeletal elements.

Animals↗
PubMed1990

Teratogenic effects of alcohol on brain development.

There is convincing evidence that alcohol is teratogenic both in humans and animals and that its most devastating effects are on the developing brain. However, much information is still needed to determine the circumstances that increase the risk and severity of fetal alcohol-induced brain damage and to identify the mechanisms underlying such damage. Animal research has been used to address these issues because, for the most part, they are unapproachable experimentally in humans. In the past, the rather restricted focus of research into the teratology of alcohol has led to several theoretical biases. Recent findings conflict with these biases. Alcohol-induced damage to the developing brain encompasses a longer developmental time-frame, affects more cell populations, occurs at lower levels of exposure, produces greater numbers of permanent effects, and is modulated by more factors than was initially suggested by earlier teratological studies.

Abnormalities, Drug-Induced↗
PubMed1989

Alz-50 immunoreactivity in the neonatal rat: changes in development and co-distribution with MAP-2 immunoreactivity.

Alz-50 is a monoclonal antibody that recognizes pathological alterations in Alzheimer's disease. It has recently been noted also to mark some subplate neurons in human infants under the age of 2 years. We now report that Alz-50 recognizes many neurons in the normal neonatal rat in a pattern that changes with development. Immunoreactivity decreases substantially in intensity as the rat matures. This immunoreactivity co-distributes with microtubule-associated protein-2 (MAP-2) immunoreactivity in terms of topography, cellular localization and changes over the developmental time-course. This observation raises the possibility of exploring cytologic triggers that may lead to re-expression of Alz-50 immunoreactivity in aging and in pathological conditions.

Alzheimer Disease↗
PubMed1989

The development of laminar staining for neuron-specific enolase in the rat somatosensory cortex.

The expression of the enzyme neuron-specific enolase (NSE) in the central nervous system (CNS) has been used as a developmental marker based on observations that it is expressed shortly after the arrival of afferent inputs. The immunostaining pattern of NSE was examined in the laminae of the somatosensory cortex of the rat and the relationship of this staining pattern with previous data on the timing of afferent and efferent arrival was determined. Male rat pups were sacrificed on postnatal days 1 (24 h after birth), 3, 5, 8, 10, 12, 15 and 20, and as an adult (over 90 days of age). Sections were stained with an anti-NSE antibody using the avidin-biotin immunocytochemical method. Sections from day 1 animals revealed stained cells in the subplate layer and cortical plate, presumably in cells destined to form layers VI and V. By day 8 there was staining in layers II, III, V and VI, the same layers that exhibited staining in the adult rat. This appears consistent with the arrival of afferents and efferents which is completed by approximately postnatal day 7. On day 10, there was a change in the staining pattern: cell staining in layer VI was decreased and then increased gradually up to adult levels by day 20. A stable pattern of NSE staining was not observed previous to day 20. These results suggest that changes in NSE expression following the initial arrival of afferents may relate to maturation of the neurons.

Aging↗
PubMed1989

Long-term deficits in water maze spatial conditional alternation performance following retrohippocampal lesions in rats.

The effects of large bilateral retrohippocampal lesions on long-term performance of conditional spatial alternation, incorporating a strong working memory component, were examined using a T-maze task motivated by swim-escape. The lesions, which included entorhinal cortex, subiculum, pre- and parasubiculum and invaded the molecular layer of the dentate gyrus, completely eliminated the previously acquired conditional alternation learning, and performance failed to recover with 40 days of testing. These findings support the contention that retrohippocampal structures are an important and necessary component of the neural circuitry mediating working memory.

Animals↗