Michael E. Ragozzino - US grants

There is accumulating evidence that the prefrontal cortex is involved in working memory in several mammalian species. Prefrontal cortex damage leads to a variety of working memory deficits in humans, as well as rodents. These results suggest that the prefrontal cortex may be involved in working memory for different attributes, i.e. space, affect, motor responses. Recent evidence suggest that the type of working memory deficit that results following prefrontal cortex damaged may be related to the lesion site. Understanding whether specific prefrontal cortex subregions mediate different types of information within a working memory context, will lend important insight into the biology of memory. To build a more comprehensive view of the neural processes that underlie memory within prefrontal cortex subregions, also calls for an examination of the neurotransmitter systems that may play a critical role. The present proposal examines the neural processes in the prefrontal cortex important for working memory of different attributes. The first set of experiments investigates whether there are dissociations between the anterior cingulate, prelimbic/infralimbic and agranular insular in mediating working memory for spatial locations, visual objects, affect and motor responses. Based on previous studies and preliminary data, it is predicted that the anterior cingulate mediates working memory for motor responses, the prelimbic/infralimbic mediates working memory for space and objects and the agranular insular mediates working memory for affect. The second set of experiments assesses whether acetylcholine within prefrontal cortex subregions modulates working memory for different attributes. The hypothesis is that the cholinergic system is important in all prefrontal subregions for processing working memory for specific attributes. Overall, these experiments will provide a better understanding of the mnemonic functions mediated by prefrontal cortex subregions and the neurochemical modulation of these functions. Thus, the studies may increase our knowledge about the neurobiology of memory and may ultimately lead to effective treatments for cognitive dysfunctions.

The thriving and survival of humans, as well as other species fundamentally depends on the ability to rapidly adapt to changing environmental contingencies. The long-term objective is to understand the brain circuitry that facilitates the learning of new rules with exposure to changing conditions. Huntington's and Parkinson's disease are marked by cellular alterations in the striatum and patients with these diseases exhibit deficits in cognitive flexibility. These findings suggest that the striatum is one brain area that may play a central role in cognitive flexibility. However, the striatum is made up of different subregions possibly subserving different cognitive and behavioral functions. Understanding whether particular striatal subregions facilitate the learning and flexible use of behavior-guiding rules, e.g. switiching strategies, will lend important insight into the neurobiology of learning and behavior flexibility. Ultimately, information obtained on the neurocircuitry underlying behavioral flexibility may enable the development of effective treatments for alleviating the cognitive symptomology observed in patients with Huntington's and Parkinson's disease. The present proposal examines whether the dorsomedial striatum in rats is involved in different forms of behavioral flexibility. In a related group of experiments, the effect of dorsomedial striatal inactivation on the learning and reversal of visual cue and turn discrimination rules are evaluated. Specific to behavioral flexibility, these experiments will examine whether dorsomedial striatal inactivation impairs learning when rats have to shift within a dimension (intra-dimensional shift), e.g. shift from a left turn rule to a right turn rule, or between a dimension (extra-dimension shift), e.g. shift from a visual cue rule to a turn rule. Overall, the findings from the proposed studies can increase the present knowledge about the brain circuitry underlying learning and behavioral flexibility.

[unreadable] DESCRIPTION (provided by applicant): The main objective of this proposal is to build a greater understanding of how the striatal cholinergic system contributes to behavioral flexibility. There is accumulating evidence that neurological and psychiatric disorders that lead to striatal neuropathology, i.e. Parkinson's disease, Huntington's disease and schizophrenia, produce severe deficits in cognitive flexibility. In addition to the common cognitive symptomology, Parkinson's and Huntington's disease patients both exhibit decreases in cholinergic markers in the anterior regions of the caudate and putamen. At present, unknown is what striatal circuitry or neurochemical mechanisms underlie cognitive flexibility. Advances in elucidating the etiology of these disorders and development of effective treatments for the cognitive deficits relies, in part, on identifying the basic neurochemical mechanisms within the striatum that underlie the cognitive functions impaired in Parkinson's and Huntington's disease. The first goal of the proposal is to understand the dynamic changes in acetylcholine output in the dorsomedial and dorsolateral striatum during acquisition and reversal learning of a visual cue discrimination, using in vivo microdialysis with high pressure liquid chromatography. Recent timings in Parkinson's disease patients suggest that anti-cholinergic treatments lead to cognitive flexibility deficits. The second goal of the proposal is to determine whether specific muscarinic receptor subtypes in the dorsomedial striatum contribute to behavioral flexibility. Previous studies found that dopamine activity in the striatum also influences cognitive flexibility. Furthermore, extant research indicates an interaction between the dopaminergic and cholinergic systems in the basal ganglia related to motor behavior. The third goal of the proposal is to determine whether dopamine D1 and/or D2 receptors modulate acetylcholine efflux in the dorsomedial striatum to influence behavioral flexibility. Overall, this approach takes a unique approach in examining the dynamic changes in striatal acetylcholine release during the actual learning and shifting of strategies. The proposed studies will also provide complimentary information on the specific muscarinic receptors that may facilitate behavioral flexibility in the dorsomedial striatum. Moreover, the proposed studies can help unravel the complex interaction of neurotransmitters in specific striatal circuitry as it relates to behavioral flexibility. The findings from these experiments may enable the development of selective and targeted pharmacological interventions to alleviate the cognitive symptomology in Parkinson's and Huntington's disease without producing unwanted motoric side effects. [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): Normal aging and Alzheimer's disease are characterized by severe deficits in the ability to learn new information while inhibiting the use of previously relevant information. There is accumulating evidence that the neurotransmitter, serotonin (5-HT) may enable learning when conditions require a shift in strategies. More recent findings suggest that activation of 5-HT4 receptors, in particular, may improve cognition, as well as produce neuroprotection. The long-term objective of this proposal is to determine whether treatment with a selective, 5-HT4 agonist improves learning when conditions demand a shift in response patterns in young adult and aged rats. Previous attempts to alleviate cognitive deficits in aging and Alzheimer's disease have focused on directly altering the brain cholinergic system. This approach has had limited success. There is recent evidence that 5-HT4 agonist treatment may improve memory, however, unknown is whether activation of 5-HT4 receptors enhances learning when conditions require a shift in strategies. One study will examine whether administration of the selective 5-HT4 agonist, RS 67333, in young adult and aged rats affects reversal learning in a two-choice place discrimination. Aged individuals and those with Alzheimer's disease sometimes only manifest cognitive deficits under conditions that have an increased level of difficulty. A second experiment will determine whether administration of RS 67333 in young adult and aged rats affects reversal learning in a four-choice place discrimination. Because two of the choices in this task act as distracter choices this study will be able to determine whether increases in interference may contribute to possible age-related impairments and whether activation of 5-HT4 receptors may reduce this deficit. Activation of brain 5-HT4 receptors is known to affect acetylcholine release. A third experiment will determine whether RS 67333 concomitantly enhances striatal acetylcholine output and reversal learning. These initial experiments will be essential in developing a broader research program to understand what neurochemical mechanisms in specific brain circuitry is altered that leads to cognitive flexiblity deficits in aging. Overall, the findings from the proposed studies will provide new and significant information on the processes underlying possible age-related deficits in cognitive flexibility and whether activation of 5-HT4 receptors may be effective in alleviating cognitive flexibility impairments. Normal aging and Alzheimer's disease is characterized by deficits in learning and the ability to switch strategies. The major goal of this project is to determine whether activating serotonin 4 receptors may alleviate learning deficits in aging. These studies have the potential of developing a novel treatment for the learning and memory deficits observed in aging and Alzheimer's disease. [unreadable] [unreadable] [unreadable]

NSF MRI Proposal (R. L. Magin, P. I.)

Acquisition of a High Field Magnetic Resonance Imaging System for Science and Engineering Research

Abstract

Technical Description The applications of magnetic resonance imaging (MRI) and spectroscopy (MRS) are rapidly expanding beyond the traditional domains of chemistry and medicine. Engineers, biologists, and even artists are seeing their problems in new ways through the use of non-contact, radiation free and fully three dimensional MR imaging. The flow of fluids, the efficiency of catalysts, the strength of polymers, and the hidden structure of developing plants can all be viewed with micron scale resolution and in time periods as short as a fraction of a second. Neuroscientists can probe models of memory and cognition, while chemical engineers can study processes from the molecular to the industrial scale. This is all achieved using special MRI techniques that encode system structure, function, and dynamics.

Significance & Impact The overall goal of this proposal is to bring the imaging and analytical power of MRI (Bruker 9.4 T imaging spectrometer) to a larger community of engineers and scientists at the University of Illinois at Chicago (UIC) and the Illinois Institute of Technology (IIT). We plan to operate the system under the jurisdiction of the UIC Research Resources Center in a dedicated campus research space. The new MRI will also be the principal imaging system for undergraduate and graduate laboratory courses in magnetic resonance imaging and a key asset for REU, RET and K-12 outreach programs at UIC. In this manner we will increase the shared access of these campus communities to state of the art magnetic resonance imaging.

Project Abstract The central goal is to determine whether glutamate signaling is disrupted in different striatal circuits that underlie repetitive behaviors in mouse models of autism. Biosensor technology will be employed concomitantly with behavioral testing to determine real-time glutamate changes in the striatum during learning, reversal learning and marble burying. Restricted and repetitive behaviors are common to autism spectrum disorders (ASD) but have considerable heterogeneity that can vary in severity and type. A varying severity of cognitive impairment may arise from the degree of heightened dependence on positive reinforcement and increased salience to unpredicted non-reinforcement. This can lead to either a learning deficit or inflexible behavior. Developing probabilistic learning tests for mouse models that match those used to test ASD individuals, we have captured some of the cognitive heterogeneity reported in ASD by testing SHANK3+/- and BTBR mice. SHANK3+/- mice exhibit a probabilistic learning deficit while BTBR mice exhibit a selective probabilistic reversal learning deficit. In a complementary way, we found that BTBR and SHANK3+/- mice exhibit elevated marble burying behavior, but BTBR mice have greater levels than SHANK3+/- mice. To date, there are significant gaps in our knowledge of what neural circuitry and neurochemical mechanisms are altered that underlie repetitive behaviors in ASD. Accumulating evidence indicates that abnormal striatal circuits may underlie certain repetitive behaviors. Further, a long-standing hypothesis to explain ASD features, including cognitive deficits, is an imbalance in the brain excitation/inhibition ratio. There are different lines of evidence that support this hypothesis, although at present, there have been no direct real-time glutamate measurements during behavioral expression of the symptoms. The proposed project will for the first time in two different mouse models of ASD directly examine dynamic changes in striatal glutamate signaling during cognitive tests and expression of a stereotyped behavior. Specific Aim 1 will determine whether real-time glutamate signaling in the dorsomedial striatum, dorsolateral striatum or nucleus accumbens of SHANK3+/- and BTBR mice is altered during spatial learning and reversal learning under conditions in which feedback is certain (100% accurate) and feedback is uncertain (80% accurate for correct choice). Specific Aim 2 will determine in SHANK3+/- and BTBR mice whether glutamate signaling differs in striatal subregions during marble burying behavior. Overall, examination of in vivo glutamate transmission during behavioral testing can provide a better mechanistic understanding of ASD pathophysiology and identify novel therapeutic targets in a disorder known to have heterogeneous symptomology.

Project Abstract The cognitive and behavioral features of autism spectrum disorders (ASD) are likely due to alterations in synaptic communication among forebrain neurons. Heterogeneity in ASD features, commonly observed in the disorder, may arise from a complex interaction of environmental and genetic risk factors that affect synaptic communication. Over the past decade the prevalence of ASD has increased from 1 in 150 to 1 in 68 making ASD the fastest growing neurodevelopmental disorder. Comparable to the prevalence of ASD, antidepressant use in pregnancy has more than tripled in recent years with selective serotonin reuptake inhibitors (SSRI) the most commonly used. To date, there is a gap in knowledge of whether prenatal SSRI exposure differentially interacts with syndromic (monogenic) or idiopathic (polygenic) risk factors for ASD. Related, unknown is whether prenatal SSRI exposure differentially affects male and female offspring. Fragile-X Syndrome, an intellectual disability syndrome caused by silencing of FMR1 gene, results in one-third of affected individuals exhibiting autistic features. A mouse model for Fragile-X exhibits some social and cognitive deficits reminiscent of ASD. The vast majority of ASD cases (~95%) are not attributed to a single gene mutation or polymorphism or to any identified environmental cause. A second model, the BTBR mouse, exhibits ASD-related behaviors and altered transcription of multiple genes that confer risk in ASD. The broad goal of this project is to use animal models to define the mechanisms by which prenatal factors contribute to cognitive and synaptic plasticity deficits related to ASD features. The proposal aims to test whether prenatal SSRI exposure in a syndromic (monogenic) mouse model and idiopathic (polygenic) mouse model of ASD exacerbates existing cognitive and synaptic plasticity phenotypes or produces new ASD-related cognitive impairments and synaptic alterations. Specific Aim 1 will determine whether prenatal SSRI exposure in Fragile-X and BTBR mice affects spatial learning and reversal learning under conditions in which feedback is certain (100% accurate) and under conditions in which feedback is uncertain (80% accurate for correct choice). Specific Aim 2 will determine in the same animals from Aim 1 whether prenatal SSRI exposure affects different aspects of hippocampal synaptic plasticity in adult Fragile-X and BTBR mice. The two aims will be integrated by determining whether there is a relationship between different learning phenomena (Aim 1) and various forms of hippocampal synaptic plasticity (Aim 2). Together, the findings from this project will advance understanding of how a prenatal risk factor interacts with genetic factors to alter synaptic and cognitive function related to ASD. Overall, this approach can provide promising new neurobehavioral endophenotypes for developing mechanistically-based neuropharmacological interventions.