John P. Bruno - US grants

There are three striking differences between the effects of 6-HDA-induced brain lesions in infant and adult rats. First, rats lesioned as infants are apparently spared from the profound behavioral deficits seen in rats lesioned as adults. Second, dopamine receptor antagonists, which in low doses produce profound akinesia and catalepsy in adult-lesioned animals, have little or no effect on animals lesioned as infants. Third, there is an apparent sprouting of serotonin-containing neurons in the striatum of infant-lesioned but not adult-lesioned rats. The proposed research further addresses the differences between these two groups of animals by focusing on the following specific aims. 1. Characterization of the Behavioral Effects of 6-HDA-Induced Lesions in Infant Rats. These experiments will extend our initial observations that infant-lesioned rats are apparently spared from the severe behavioral deficits produced in comparably lesioned adults by determining if there are any initial deficits soon after the lesion and any residual deficits once the lesioned rats have reached adulthood. 2. Determination of the Functional Significance of the Serotonin-Containing Neurons in the striatum of Infant-Lesioned Rats. We propose to use two approaches in assessing the function of these neurons. First, we will determine whether they permit increased synthesis and release of serotonin and if so, whether serotonin has a greater influence on cholinergic target cells in the striatum in these brain-damaged rats than in controls. Second, we will determine whether serotonin-containing neurons participate in the apparent sparing from behavioral deficits that is seen when rats are lesioned as infants.

The aims of this proposal are to characterize the neuronal mechanisms underlying age-dependent plasticity of mesotelencephalic dopamine (DA) systems in rats. The literature suggests that the neural and behavioral effects of mesotelencephalic DA depletions are highly dependent upon the animal's age at the time of damage. Animals depleted during development are spared from the severe deficits in self-stimulation and sensorimotor function seen in comparably depleted adults. Moreover, the specific neural mechanisms underlying this sparing phenomenon differ as a function of age at the time of damage. These various forms of plasticity involve age-related changes in the functional interactions between D1 and D2 DA receptor subtypes. This proposal will allow our laboratory to establish two new techniques in order to further reveal the mechanisms underlying this age-dependent plasticity. First, we will employ IN VIVO MICRODIALYSIS IN FREELY MOVING ANIMALS in order to determine whether the age-related changes in the contributions of Dl and D2 receptors to behavior are paralleled by similar changes in the D1 and D2 mediation of DA, ACh, and GABA release within the basal ganglia. Such studies may reveal critical synapses associated with the sparing from deficits in sensorimotor and self-stimulation behavior. Second, we will utilize QUANTITATIVE DA RECEPTOR AUTORADIOGRAPHY to determine whether there are age-related changes in the density and/or distribution of D1 and D2 receptors that parallel the age-dependent effects of D1 and D2 receptors on behavior. Mesotelencephalic DA systems are involved in a wide range of behaviors, including; reward functions, self-stimulation, attention, and sensorimotor integration. Dysfunctions within these DA systems are associated with a variety of disorders relevant to mental health, including; drug abuse, learning deficits, affective disorders, Parkinson's disease, and schizophrenia. The results obtained from this proposal will provide insights into the neurochemical and neuroanatomical bases for plasticity in sensorimotor and self-stimulation behavior and how age constrains the extent of this plasticity.

DESCRIPTION (Adapted from applicant's abstract): Dysfunctions of mesolimbic pathways have been postulated to underlie major neuropsychiatric disorders and drug abuse. While the role of NAC inputs in the regulation of DAergic transmission has received considerable attention, the role of DA receptor activity in modulating NAC efferent projection neurons has not been well studied. The determination of the DAergic regulation of NAC efferents and its role in cognition will provide critical insights into the behavioral consequences of abnormal mesolimbic functioning. The proposed research is designed to test the hypothesis that NAC DA inhibits the main NAC efferents - a GABAergic projection to ventral pallidal areas [specifically, to the substantia innominate (SI)]. As a result of this DA-mediated inhibition of GABA release in SI, DAergic transmission within NAC regulates the activity of basal forebrain AChergic system. This AChergic system innervates all cortical areas and thus, potently gates cortical information processing. The proposed research uses the technique of in vivo microdialysis to characterize the dynamic, trans-synaptic regulation of cortical ACh release. The pharmacological and behavioral determinants of DA (NAC), GABA (SI) and ACh (cortex) efflux will be determined in awake rats. The first series of experiments will test the hypothesis that increases in NAC DA receptor activity with local perfusions of amphetamine will decrease GABA efflux in SI and, as a result, increase ACh efflux in cortex. The second series of experiments will demonstrate that the ability of intra-NAC amphetamine to increase cortical ACh efflux can be potentiated and attenuated by drugs that increase and decrease, respectively, GABAergic transmission in SI. The final series of experiments will utilize microdialysis in task-performing animals in order to test the hypothesis that NAC DA-basal forebrain GABAergic modulation of cortical ACh selectively mediates attentional functions. These experiments will substantiate the role of mesolimbic-cortical circuits in fundamental aspects of cognitive processes, and thus will contribute to our understanding of the cognitive consequences of aberrations within these circuits.

DESCRIPTION (provided by applicant): This proposal requests funds to support the Tenth Annual Meeting of The International Behavioral Neuroscience Society's (IBNS) that will be held in Cancun, Quintana Roo, Mexico, April 25-29, 2001. The funds requested in this proposal are to support Young Investigator Travel Awards, reimburse expenses for invited symposium speakers, and defray some of the expenses associated with the publication of the meeting abstracts. The 2001 meeting format includes the Presidential Address (Jacqueline Crawley on galanin in learning and memory; using transgenic mice), two Keynote Addresses (Mark Geyer on sensorimotor-gating; Stephen Woods on metabolic signals and food intake), a Slide "Blitz" 5 min presentations by attendees of exciting new data, and five Special Symposia: (Transgenic and Knockout Mice: Powerful Tools for Behavioral Neuroscience; Feeding and Body Weight Regulation: Current Perspectives; Antisense Oligonucleotides in Behavioral Neuroscience; The Reductionistic Dopamine Hypothesis of ADHO: Hyper, Hypo, or Both? Animal Models of Age-Related Cognitive Dysfunctions). Scientific communications are Oral Presentations and Poster Presentations. Special Interest Sessions are designed by the student members (e.g., grant writing workshops; job opportunities in science-related areas, etc.). In addition to the formal scientific program, three additional programs help carry out the mission of the Society. First, a Young Investigator Travel Awards Program sponsors pre- and post-doctoral students to attend the meeting in an effort to educate and nurture developing young scientists in behavioral neuroscience. A second, recently instituted program is the "Public Lecture" series, where one of the members of the Society delivers a public lecture in the local language to the hosting community to help increase awareness of the importance of basic research and it's relevance. A third program is the Awards Banquet Program where, the Travel Awardees are honored and the recipient of the Myers Lifetime Achievement Award in Behavioral Neuroscience is announced. The IBNS was formed to encourage research and education in the field of behavioral neuroscience. Founded in 1992, the IBNS has approximately 600 members from 33 different countries and consists of scientists, clinicians, teachers and others with a background and interest in the relationship between the brain and behavior. The IBNS is governed by an elected president and officers, an elected council representing approximately 7 countries, including 2 student council members, and 13 standing committees. The Central Office of the IBNS is located in the United States.

[unreadable] DESCRIPTION (provided by applicant): This proposal focuses on the effects of stimulant drugs on cortical cholinergic transmission. It is driven by the theory that changes in cortical cholinergic transmission mediate the hyper-attentional biases postulated to contribute to processes of craving and relapse in addiction. This monopolization of attentional resources bias the addict toward the processing of drug-related cues and reduces the likelihood of evaluating alternative behaviors and coping strategies. A more thorough understanding of the neurobiological mechanisms underlying these cognitive changes will aid in the development of more efficacious ways to treat this major public health problem. The proposed experiments utilize an innovative enzyme-selective microelectrode array to reveal the effects of psychostimulants (nicotine and amphetamine) on cortical neurochemistry. The studies are designed to validate the rapid, in situ detection of extracellular ACh using these microelectrodes as a sensitive measure of cholinergic transmission. ACh-derived signals will be determined at a temporal (i.e. second-by-second) and spatial (i.e. 10-20 mu m) resolution that far exceeds conventional techniques. We will first test this electrochemical method in anaesthetized rats (in order to optimize several electrochemical, neurobiological, and procedural variables). After optimizing the parameters of electrochemical recording, we will then validate the method in awake rats following the administration of psychostimulants and environmental stimuli - stimuli that have been shown to increase cortical ACh release following more conventional methods. But, this is only a starting point for a series of important experiments on the neurochemistry of attentional mechanisms in conditions of drug abuse. For the first time, we will be able to study cholinergic transmission within a time-frame that is consistent with the cognitive processes that have been linked to cortical cholinergic transmission and believed to underlie compulsive drug use. In much the same fashion that enhanced voltammetric techniques, and the focus on phasic DA release, have revealed new perspectives on the contributions of accumbens DA to drug-seeking behaviors the ACh- and choline-sensitive microelectrode arrays will allow us to measure cholinergic transmission in subsecond time periods and within discrete regions in order to address important issues in addiction. [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): The purpose of this project is to secure funds to help defray the costs associated with the Annual Meeting of the International Behavioral Neuroscience Society (IBNS). This project is a renewal of our existing R13 grant that has been instrumental in vaulting the IBNS into a position of the premiere behavioral neuroscience society in the world. The Annual Meeting represents a main component of the society's mission. The meeting is a 4 day event where attendees (~150-200) are housed at or within close walking distance to the meeting site - fostering a close community for scientific exchange. The locations of the meetings are predominantly in the US mainland but every 3-4 years the meeting occurs at some international site to acknowledge its international members. The meeting is comprised of a series of special symposia, keynote addresses, oral and poster presentations and workshops for professional skill development. Student Travel Award winners are featured prominently in this program with their own session that is attended by all registrants of the meeting. There are no concurrent sessions or programs, again, fostering a sense of communal scientific exchange. [unreadable] [unreadable] In this application, funds are requested for five years in order to support the following components of the Annual Meeting; Young Investigator Travel Awards, Registration Costs for invited Symposium Speakers, Speaker's Fee for Keynote Speakers, and money to help defray the costs of Publication of Abstracts of the Meeting on the IBNS website. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Schizophrenia (SZ) is a debilitating mental disorder with significant and complex pathophysiology in the prefrontal cortex (PFC). Several aspects of this cortical pathology have been linked to deficits in executive functions such as working memory, attention, and cognitive flexibility. A more thorough understanding of the neurochemical mechanisms contributing to these cognitive disorders is critical, as conventional antipsychotics are not particularly effective in alleviating these impairments, and since the severity of these deficits is predictive of the patient's ability to integrate into society. The activity of 17 nicotinic receptors (17nAChR) in the PFC has been positively linked to performance in a number of behavioral tasks that measure executive cognitive functions. Conversely, dysregulation of cortical 17nAChRs has been implicated in the etiology of SZ. Kynurenic acid (KYNA) is an astrocyte-derived neuromodulator that, at endogenous concentrations, inhibits 17nAChR activity in several brain regions, including the PFC. KYNA levels are elevated in the PFC of individuals with schizophrenia, and this increase is not secondary to antipsychotic medication. This project is designed to define the role of KYNA in the modulation of basal and stimulated glutamate and acetylcholine (ACh) levels in the PFC and in the mediation of a prefrontally- mediated cognitive behavior (perceptual set-shifting). Our preliminary data in rats demonstrate that fluctuations in the endogenous levels of KYNA modulate levels of glutamate and ACh in the PFC. The proposed experiments will use complementary biochemical, pharmacological and behavioral methods, and the synergistic expertise of two experienced PIs, to evaluate key chemical events and functional implications of this link between KYNA, ACh and glutamate in the rat PFC. Aim #1 will utilize in vivo microdialysis to test the hypothesis that fluctuations in endogenous KYNA levels within the PFC influence glutamate and ACh levels under conditions of basal levels of 17nAChR activity. We will also determine whether these effects, as hypothesized, can be traced to KYNA's ability to antagonize the 17nAChR and whether the KYNA-related modulation of ACh levels is mediated by local glutamate. Aim #2 will determine, as a prelude to subsequent aims in task-performing rats, the extent to which KYNA retains the ability to modulate prefrontal glutamate and ACh release under two conditions that activate the 17nAChR (a centrally-administered drug and a behavioral conditioning paradigm). Aim #3 extends these neurochemical studies to the realm of cognitive behavior and will test the hypothesis that elevations in cortical KYNA levels selectively impair the ability of rats to perform in a perceptual set-shifting task, which is dependent upon the integrity of neurotransmission in the PFC. We will also determine the relative roles of diminished cholinergic and glutamatergic function in this KYNA-induced behavioral deficit. This is especially relevant to the pathophysiology of SZ which is associated with excessive KYNA levels in the PFC, abnormal cortical glutamatergic and nicotinergic transmission, and pronounced impairments in set- shifting tasks. Finally, since prolonged elevations of cortical KYNA levels are seen in SZ, we will, in Aim #4, study the biochemical and functional consequences of persistent increases in brain KYNA levels. These chronic effects will be evaluated both in control animals and in rats treated with typical (haloperidol) or atypical (clozapine) neuroleptic drugs in combination with an adjunctive therapy targeting the 17nAChR with a clinically used cognition-enhancing drug (galantamine). Collectively, the proposed experiments will test the new hypothesis that fluctuations in astrocyte-derived KYNA levels potently modulate cortical neurotransmission and prefrontally-mediated cognitive behavior. We will use these findings to generate an experimental platform for testing the therapeutic efficacy of KYNA-based treatments in alleviating the cognitive deficits seen in SZ.