Cognitive deficits associated with neuronal dysfunction and aging constitute a serious health problem. Dopaminergic systems contribute to a number of cognitive disorders, such as schizophrenia, Alzheimer's dementia, and Parkinson's disease, which cost > $200 billion a year in the USA alone. Successful therapeutic approaches to alleviate cognitive problems should target appropriate neural circuits in the brain. Basic neuroscience research provides that information necessary to identify the networks, neurotransmitters, and mechanisms that underlie proper brain function and are the targets for potential therapies. Proper dopaminergic signaling is essential for cognitive processes such as attention, executive function, learning, and memory. The complex nature of these processes and the paucity of synaptic and cellular data linked to the systems-level behaviors have spurred the proposed studies. Our earlier work showed that induction of in vivo synaptic plasticity associated with a learning task requires local disinhibition of excitatory circuits coupled with an afferent dopamine signal. Recent results from our lab support the view that dopamine signaling in the hippocampus lowers the threshold for synaptic plasticity that underlies learning. Our preliminary results show that local dopaminergic activity is required for in vivo hippocampal long-term synaptic potentiation associated with diverse learning paradigms, such as aversive memory retention and novel object recognition. Presently however, there is a controversy regarding the source, density, and significance of hippocampal dopaminergic innervation and about dopaminergic regulation of synaptic plasticity and memory. In the proposed studies, we will identify the sources of dopaminergic neurotransmission in the hippocampus using multiple independent viral labeling methods. Then, we will examine dopaminergic influences over distinct hippocampal circuits during specific memory tasks. Our working hypothesis is that dopamine acts within critical time windows and controls the magnitude of synaptic plasticity within specific circuits that regulate different types of learning. Dopamine normally contributes to the efficient learning of appropriate behavioral responses motivated by environmental cues. The working hypothesis, however, also helps to explain the cognitive dysfunctions that arise during dopamine signaling imbalances found in diseases where inappropriate sensory gating, attention, and learning produce maladaptive behavior. A multidisciplinary approach that crosses neural levels of integration will be applied to understand the synaptic mechanisms underlying aversive memory retention and novelty detection. We will use an array of anatomical tracing and analytical techniques to determine the origin of dopamine signals that act upon hippocampal circuits. During the performance of behavioral tasks, these endogenous dopaminergic signals will be temporally controlled using optogenetic approaches, and in vivo synaptic plasticity will be measured in real-time. The delineated mechanisms within these critical neural circuits will provide targets for developing future therapeutic strategies that diminish cognitive impairments.

Public Health Relevance

Dopaminergic systems underlie a number of cognitive disorders, but the sources of dopamine signals that act upon hippocampal circuits to influence learning and memory remain controversial. Our multidisciplinary approach will determine the sources of dopamine innervation and will control dopamine signaling in the hippocampus in freely-moving mice during tasks that assess memory performance. The results will assess the roles and importance of dopamine signaling within the hippocampus to understand the normal mechanisms for learning and memory and to understand the potential for dysfunction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS021229-36
Application #
9963382
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Churn, Severn Borden
Project Start
1987-09-01
Project End
2022-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
36
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Neurosciences
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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