Aaron A. Wilber - US grants

DESCRIPTION (provided by applicant): Many studies have documented the relationship between adverse early experience and the development of psychiatric disorders such as depression, post-traumatic stress disorder, and schizophrenia. Neonatal maternal separation in the rat is a good model system for assessing the effects of adverse early experience, and eyeblink conditioning learning and memory is a good model system for studying the relationship between neonatal stress and adult behavior. This research will support the scientific integration of brain and behavior, to provide a foundation for understanding mental disorders, and will also define environmental risk for mental disorders. Previously, I showed that neonatal maternal separation increases adult glucocorticoid receptor expression in the interpositus nucleus of the cerebellum and impairs eyeblink conditioning. I have subsequently found that maternal separation during the first two postnatal weeks prevents a decrease in glucocorticoid receptor expression in the interpositus nucleus that occurs with normal development during the third postnatal week. The objective of the proposed research is to characterize the role of glucocorticoids in the impairment of learning I observed, and to explore alterations in neuronal morphology as a potential consequence of glucocorticoid alterations and mechanism of impaired eyeblink conditioning. In addition, perinatal corticosterone exposure influences development of several brain structures, including the cerebellum, and the effects we observed may be mediated by neonatal increases in corticosterone. Therefore, in two different experiments, I will assess a) the effect of glucocorticoid receptor blockade during maternal separation on adult eyeblink conditioning, neuronal morphology, and glucocorticoid receptor expression;and b) the effect of neonatal corticosterone administration on adult eyeblink conditioning and glucocorticoid receptor expression. If the increased glucocorticoid receptor expression in the interpositus nucleus is responsible for the adult eyeblink conditioning deficits we observed, then blocking these receptors during conditioning in adult rats that were separated neonatally should improve eyeblink conditioning. To test this hypothesis, I will assess the effects of infusion of a glucocorticoid receptor antagonist into the interpositus nucleus during eyeblink conditioning in neonatally separated rats. The findings of this research are relevant for public health. One in four U. S. citizens are affected by mental disorders every year. Understanding the mental health consequences of intentional (e.g., abuse and neglect) and unintentional (e.g., NICU) perinatal stressors is crucial to preventative treatment.

DESCRIPTION (provided by applicant): Learning sequences is part of our daily lives, from getting dressed to remembering the event sequence of our day. Humans and other animals who develop mental disorders both have problems with many types of sequence learning. The objective of the proposed research is to understand how spatial sequences are learned and encoded by brain circuits so future experiments can measure deficits in brain coding of sequences that may underlie mental disorders. Currently, an animal model of how the normal brain accomplishes sequence learning does not exist and is necessary for understanding what goes wrong to produce deficits. Our laboratory has made progress towards developing a model of sequence learning by recording simultaneously from many neurons in the brain while rats learn to navigate to a series of spatial locations arranged around a circular arena. This task has allowed us to begin to understand how part of the brain, the hippocampus, encodes where the animal is in this spatial sequence; however, we do not yet know how the brain translates this information about position in the sequence into a motor response to navigate to the next reward location. Previous research suggests that the parietal cortex may translate an appropriate motor response for the current position in the sequence. Therefore, I will investigate the brain mechanism for translating information about position in a sequence to an appropriate motor response. In three different experiments, I will assess: a) the frames of reference (person centered vs world centered) that are used when spatial cues are encoded in the parietal cortex; b) activity patterns in the parietal cortex during sequence learning; c) contributions of the parietal cortex to encoding learned sequences (specifically, what happens when the parietal cortex is inhibited during particular portions of spatial sequence learning and memory). These initial experiments will provide a foundation for the neural basis of sequence learning so that we can assess deficits in brain coding of sequences that may underlie psychiatric disorders.

? DESCRIPTION (provided by applicant): Alzheimer's disease is devastating for both individuals and society. Impaired spatial navigation and memory is one of its major symptoms. Similarly, rodent models of Alzheimer's disease also exhibit impairments in spatial navigation. Emerging evidence suggests abnormal communication between the posterior parietal cortex (PPC) and hippocampus in humans with Alzheimer's. The objective of the proposed research is to explore the functionality of the hippocampal-PPC network in an animal model of amyloidosis, in order to develop a model for assessing potential contributions of altered cortico-hippocampal function to Alzheimer's disease. To do this, I will utilize a triple transgenic mouse model of Alzheimer's where three major genes associated with familial Alzheimer's disease are expressed. This mouse model mimics both plaque and tangle pathological hallmarks of the disease with a distribution pattern similar to human patients, including synaptic changes in the limbic system. Specifically, in three different experiments I will: a) assess hippocampal population activity and behavior to measure the ability of triple transgenic mice to utilize an external (room based) reference frame when their internal position reference frame is disrupted; b) assess both rest related memory replay and functional synaptic connectivity within and across the hippocampus and posterior parietal cortex in the triple transgenic mouse; c) utilize a novel pharmacogenetic approach to test the theory that temporary and specific hippocampal inactivation will produce impairments in memory replay that mimic those seen in animal models. Finally, findings in the triple transgenic model will be confirmed in a newer model of Alzheimer's that is more similar to sporadic Alzheimer's in humans. Therefore, this project will provide insight into the normal function of a circuit that is dysfunctional in Alzheimer's disease and allo me to probe this circuit in a mouse model of Alzheimer's, so that we can begin to understand changes in this network that may underlie impairments observed in individuals with Alzheimer's disease.

PROJECT SUMMARY/ABSTRACT Alzheimer?s disease is devastating for individuals and society. Impaired learning and memory, particularly in the context of spatial navigation, is one of its early and major symptoms. Similarly, rodents recapitulating aspects of Alzheimer?s disease also exhibit early impairments in spatial navigation. A preponderance of evidence suggests abnormal cortical-hippocampal communication in humans with Alzheimer?s disease. Hippocampal-cortical interactions during sleep are thought to be critical for consolidation of newly acquired memories. However, no studies have assessed these brain dynamics during sleep in rodents modeling Tau and amyloid beta (A?) aggregation aspects of Alzheimer?s disease. Thus, the proposed research will explore the functionality of brain dynamics during sleep in the hippocampal-PC network in animal models of Tau and A? aggregation (TA?A). To do this, we will use a triple transgenic mouse where three major genes associated with familial Alzheimer?s disease are expressed leading to TA?A. This mouse model mimics plaque and tangle pathological hallmarks of the disease, with a distribution pattern similar to human patients, including synaptic changes in the limbic system. In addition, all findings will be confirmed in a transgenic rat with A? accumulation, plaque formation, tau accumulation, cell loss, and spatial memory impairments. Specifically, we will: 1) assess the relationship between spatial learning and memory, as well as brain dynamics during sleep, both within and across the hippocampus and cortex; 2) use a novel targeted optogenetic approach to functionally dissect the relative contributions of TA?A in the hippocampus to impaired hippocampal-cortical coupling during sleep and impaired spatial learning. 3) test the efficacy of a non-invasive visual stimulation approach, known for clearing cortical TA?A, to relieve impaired hippocampal-cortical coupling during sleep and impaired spatial learning. This project will provide insight into the normal function of a circuit that is dysfunctional in Alzheimer?s disease and allow us to probe dysfunction in this circuit that emerges in very early stages of disease progression in rodents modeling TA?A aspects of Alzheimer?s disease. This research will allow us to begin understanding changes in this network which may underlie the emergence of cognitive impairments observed in Alzheimer?s disease and begin testing the efficacy of a non-invasive treatment for reversing the functional brain abnormalities and impaired cognition.