Barbara Strupp - US grants

The long term objective of this research is to characterize the role of vasopressin in cognitive functioning. There is a growing body of literature which demonstrates that vasopressin administration does affect performance on cognitive tasks in humans and animals. However, problems in both areas of research have limited the conclusions which may be drawn concerning this putative role. In the animal studies, the reliance on aversively motivated tasks, combined with the use of ambiguous measures of memory (e.g. extinction rate) have made it difficult to determine the generality or the nature of the observed behavioral effects. In the human research, the relative lack of studies using unimpaired subjects as well as the often arbitrary choice of cognitive measures here too prevent a more detailed description of vasopressin's cognitive effect. The research proposed here is designed to assess vasopressin's effect on the acquisition, storage, and retrieval of information in studies involving human and animal subjects. Cognitive tests were chosen for the human study that measure component processes that have been shown to be particularly sensitive to pharmacological and neuropathological insult. The animal tests were selected, in part, to provide parallel measures of these processes. In addition the animal paradigms were designed to clarify the generality of vasopressin's effect on learning and memory; for this reason tasks were chosen that involve either appetitive reinforcement or no overt reinforcement. Both studies include measures of (1) automatic and effortful processing, (2) incidental and intentional learning, and (3) working and reference memory. An integration of the animal and human data concerning the influence of these neuropeptides on learning and memory is important for a thorough understanding of the psychobiology of cognition as well as for the development of pharmacological treatments for cognitive dysfunction.

The clear link between neonatal hyperphenylalaninemia and severe, irreversible cognitive impairment offers a unique opportunity to study the role(s) played by several biochemical processes in the development of brain structure and ultimate cognitive functioning. The proposed research is designed the examine the lasting cognitive effects of three biochemical disturbances that result from HP: (1) brain protein synthesis inhibition, (2) inhibition of brain catecholamine synthesis, and (3) suppression of brain serotonin synthesis. Since each of these disrupted metabolic processes seems to play a critical role(s) in neural ontogeny, their disruption during early development may permanently affect brain function. Two approaches will be used to provide converging information on the effects of each, (1) these three metabolic abnormalities will each be pharmacologically induced during the suckling period; and (2) each of these disturbances will be independently prevented in HP rat pups. Biochemical, behavioral, and neuroanatomical measurements will all be taken, thus providing the optimal circumstances for integrating these different domains. In addition to its implications for basic science, the results of this research should have significant applied value. First, a knowledge of the functional consequences of developmental monoamine deficiencies is critical for determining the fetal risk that is incurred when pregnant and/or lactating women take drugs that have such effects. Second, determining the pathogenesis of HP-induced cognitive dysfunction is critical for improving the treatment of phenylketonuria, a genetic disease that produces both HP and permanent mental retardation.

The goals of this project are to determine if maternal cocaine use produces enduring cognitive dysfunction in the offspring and, should impairment be observed, to determine the specificity of the dysfunction. Expt. 1 examines the effects of gestational exposure, using doses that model relatively heavy human cocaine use but do not produce growth retardation or terata. Positive control groups are included so that conclusions can be drawn even if cocaine-related dysfunction is not observed. If cognitive alterations are observed, the second experiment will examine the effects of lower doses during this same period of development. If cognitive effects of combined gestational and neonatal cocaine exposure to include the period of development corresponding to the third trimester in humans. Both prenatal and neonatal cocaine exposure in the rat, at the doses and routes of administration proposed here, produce enduring changes in neuronal systems implicated in learning and memory processes. The proposed research is designed to elucidate the resulting cognitive effects. The cognitive measures are designed to tap specific areas of dysfunction that result from developmental disturbances in humans. Indices of learning transfer and attentional functioning are included, as dysfunction in these areas is considered paramount in mental retardation and attention deficit hyperactivity disorder, respectively. The fact that specific cognitive functions will be assessed offers several benefits, including: (1) an enhanced ability to select sensitive cognitive tests when assessing cocaine-exposed children; and (2) a facilitation of efforts to relate any observed dysfunction to underlying neurological damage. Two aspects of the present proposal are designed to provide a first step toward attainment of this latter goal. First, the idazoxan challenge included in the test of distractibility will provide a test of underlying differences in central noradrenergic systems as well as assess a possible therapeutic strategy. Second, if enduring cognitive dysfunction is detected in these studies, a subset of the animals will be examined for functional alterations in several central neuronal systems, using the quantified deoxyglucose autoradiographic method. These analyses would permit correlation of enduring changes in particular neuronal systems with specific types of lasting cognitive dysfunction.

There is increasing evidence that low-level lead (Pb) exposure is associated with significant neurobehavioral deficits. Of particular concern is the recent finding that even slight elevations in blood lead (BPb) level in early childhood are associated with enduring cognitive deficits. This evidence creates a pressing need to both reduce exposure to Pb and develop more effective means of treating children with even slightly elevated BPb levels. One promising new therapy is the chelating agent, dimercaptosuccinic acid (DMSA). This drug is highly effective in acutely reducing BPb and tissue Pb levels. Moreover, it can be administered orally, on an outpatient basis, and does not cause the many side effects (e.g. zinc diuresis, painful administration) associated with currently available chelators. To data, no studies have examined either the efficacy of this compound in alleviating the neurobehavioral toxicity of Pb, or the possible behavioral teratogenicity of DMSA itself. Such studies are essential before the drug can be approved for widespread use. The major purpose of the proposed studies is to determine if chelation with DMSA lessens the neurobehavioral deficits associated with Pb exposure in rodent models of both childhood and adult Pb exposure. Separate groups of analyzed will be euthanized before and after the three DMSA regimens so that changes in the neurobehavioral measures can be correlated with changes in Pb level in both brain and blood. The proposed study of developmental Pb exposure is designed to parallel two studies recently funded by NIEHS to examine the efficacy of DMSA in alleviating the neurobehavioral toxicity of Pb: a multicenter pediatric trial (REP NIH-ES 92-93) and a similar study using a non-human primate model. The proposed project will provide important information about the efficacy of DMSA in alleviating Pb-induced cognitive dysfunction that will not be provided by either of these ongoing studies and that should aid in interpreting their results. Briefly, the novel contributions of this project, relative to these two recently funded studies, include (1) dose response information about DMSA in alleviating Pb-induced cognitive dysfunction; (2) examination of DMSA efficacy as a function of BPb level under conditions in which pb and DMSA treatment can be carefully controlled and monitored, and sociodemographic factors affecting cognition can be controlled; (3) the opportunity to relate changes in neurobehavioral function to changes in brain Pb; and (4) assessment of DMSA efficacy in alleviating neurobehavioral deficits in cases of adult Pb exposure.

DESCRIPTION (Adapted from applicant's abstract): Using a clinically relevant animal model, the applicants' studies have revealed that rats exposed to cocaine prenatally (IV) exhibit a selective impairment in two aspects of attentional function, whereas many other cognitive functions appear spared. The proposed studies are designed to test the hypothesis that: The type of attentional impairment seen following prenatal cocaine exposure results from alterations in catecholaminergic systems in prefrontal cortex (PFC) and/or anterior cingulate cortex (ACC), and that the targeting of these systems with potential therapeutic agents will ameliorate the attentional impairments. In the first set of studies, they will assess various attentional functions as well as the functional integrity of frontal dopaminergic (DA) and noradrenergic (NE) systems in the same animals. For the NE system, they will measure the density of alpha1 and alpha2 adrenoreceptors and NE transporter in PFC and ACC (and control regions). Similarly, the functional integrity of DA circuitry in ACC and PFC will be assessed by measures of D1, D2, and D3 receptor density, the DA transporter, and coupling of D1 and D2 receptors to their associated G proteins. In addition to providing new information about the effects of prenatal cocaine exposure on attentional function and on NE and DA systems in frontal cortex, these studies provide a unique opportunity to establish functional relationships between observed cognitive and neural changes. This is not possible with the more common approach of assessing behavioral and neural changes in separate groups of animals, often exposed to cocaine via different routes and doses, with very different handling and testing histories. In the second set of experiments, the efficacy of putative therapeutic agents will be examined. These studies will: (a) provide direct tests of putative links suggested by the first set of experiments and (b) identify drugs that are likely to be useful therapeutically. A final contribution of both sets of studies is to further elucidate the roles of the PFC and ACC and their catecholaminergic innervation in cognitive functioning. The use of tasks that specifically tap various attentional functions (including in-depth analyses of performance data), coupled with assessment of putative neural mechanisms in the same animals, should provide new information concerning the roles of these systems.

[unreadable] DESCRIPTION (provided by applicant): In addition to mental retardation, individuals with Down syndrome (DS) universally develop the neuropathological hallmarks of Alzheimer's Disease (AD) in early adulthood. A mouse model of DS and AD, the Ts65Dn mouse, exhibits key features of these disorders, including early degeneration of cholinergic basal forebrain (CBF) neurons and impairments in the cognitive functions dependent on these neurons and their projection systems, namely, explicit memory and attentional function. We recently completed a study to test the hypothesis that supplementation of the maternal diet with excess choline during pregnancy and lactation would lessen the attentional dysfunction seen in Ts65Dn mice. This study revealed a remarkable benefit of perinatal choline supplementation for the Ts65Dn mice: They performed significantly better than unsupplemented Ts65Dn mice on a series of visual attention tasks, and in fact, on some tasks, did not differ from the disomic (2N) controls. For one task, the 2N mice also benefited from the increased maternal choline intake. The studies proposed herein are designed to elaborate upon these observations with three Specific Aims: (1) To test the hypothesis that the benefit of perinatal choline supplementation in Ts65Dn and 2N mice extends to functions dependent on the cholinergic septo-hippocampal system; (2) To test the hypothesis that the cognitive benefit produced by early choline supplementation in Ts65Dn and 2N mice is mediated by increased number, size, and/or phenotypic expression of cholinergic neurons in specific basal forebrain nuclei (medial septal nucleus and nucleus basalis) and/or their projection systems, using unbiased stereologic cell counting techniques. Quantitative morphometry will be correlated with measures of memory and attention from these same animals to assess the functional significance of any observed changes; (3) To test the hypothesis that improved cognitive functioning in Ts65Dn and 2N mice is mediated by alterations in the nerve growth factor (NGF) family of neurotrophins and its cognate receptors in CBF target regions (frontal cortex and hippocampus). Levels of these neurotrophins and receptors will be measured using immunoblotting and correlated with measures of memory and attention from these same subjects to establish structure-function relationships. The evidence for lifelong cognitive and neural benefits of perinatal choline supplementation in normal rodents and this mouse model of DS/AD raises the possibility that recommendations for choline intake, currently based on preventing liver damage, may need to be re-evaluated, and that higher levels may be needed for optimal brain function. These recent findings suggest that perinatal choline supplementation might significantly reduce the cognitive dysfunction seen in DS as well as reduce the risk of AD and age-related cognitive decline in the population at large. The proposed research is designed to increase our understanding of these effects and begin to elucidate the underlying neural mechanisms subserving these behavioral changes, information that is needed to inform these potential changes in recommendations for choline intake during pregnancy, lactation, and early development. Project Narrative: Recent findings from our lab suggest that providing excess choline during early development might significantly reduce the cognitive dysfunction seen in Down syndrome and reduce the risk of AD and age-related cognitive decline in the population at large. The proposed research is designed to increase our understanding of these effects and begin to elucidate the underlying neural mechanisms. This information is needed to inform potential changes in the recommended dietary intake of choline during pregnancy, lactation and early postnatal development, which may in turn, lead to lifelong improvements in cognitive functioning for individuals with DS and the population at large. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): In addition to mental retardation, individuals with Down syndrome (DS) universally develop the neuropathological hallmarks of Alzheimer's Disease (AD) in early adulthood. A mouse model of DS and AD, the Ts65Dn mouse, exhibits key features of these disorders, including early degeneration of cholinergic basal forebrain (CBF) neurons and impairments in the cognitive functions dependent on these neurons and their projection systems, namely, explicit memory and attentional function. We recently completed a study to test the hypothesis that supplementation of the maternal diet with excess choline during pregnancy and lactation would lessen the attentional dysfunction seen in Ts65Dn mice. This study revealed a remarkable benefit of perinatal choline supplementation for the Ts65Dn mice: They performed significantly better than unsupplemented Ts65Dn mice on a series of visual attention tasks, and in fact, on some tasks, did not differ from the disomic (2N) controls. For one task, the 2N mice also benefited from the increased maternal choline intake. The studies proposed herein are designed to elaborate upon these observations with three Specific Aims: (1) To test the hypothesis that the benefit of perinatal choline supplementation in Ts65Dn and 2N mice extends to functions dependent on the cholinergic septo-hippocampal system; (2) To test the hypothesis that the cognitive benefit produced by early choline supplementation in Ts65Dn and 2N mice is mediated by increased number, size, and/or phenotypic expression of cholinergic neurons in specific basal forebrain nuclei (medial septal nucleus and nucleus basalis) and/or their projection systems, using unbiased stereologic cell counting techniques. Quantitative morphometry will be correlated with measures of memory and attention from these same animals to assess the functional significance of any observed changes; (3) To test the hypothesis that improved cognitive functioning in Ts65Dn and 2N mice is mediated by alterations in the nerve growth factor (NGF) family of neurotrophins and its cognate receptors in CBF target regions (frontal cortex and hippocampus). Levels of these neurotrophins and receptors will be measured using immunoblotting and correlated with measures of memory and attention from these same subjects to establish structure-function relationships. The evidence for lifelong cognitive and neural benefits of perinatal choline supplementation in normal rodents and this mouse model of DS/AD raises the possibility that recommendations for choline intake, currently based on preventing liver damage, may need to be re-evaluated, and that higher levels may be needed for optimal brain function. These recent findings suggest that perinatal choline supplementation might significantly reduce the cognitive dysfunction seen in DS as well as reduce the risk of AD and age-related cognitive decline in the population at large. The proposed research is designed to increase our understanding of these effects and begin to elucidate the underlying neural mechanisms subserving these behavioral changes, information that is needed to inform these potential changes in recommendations for choline intake during pregnancy, lactation, and early development.