We propose to use trace eyelid conditioning to study the neural mechanisms operating in prefrontal cortex to mediate working memory. We have demonstrated that trace eyelid conditioning in rabbit is a working memory task that involves the persistent activity of the so called """"""""delay cells"""""""" of prefrontal cortex. There are many fundamental questions about delay cells and the mechanisms of working memory that have remained unanswered largely owing to limitations of studies in primates: the traditional system for working memory studies. Specifically, working with trace conditioning in rabbits makes it feasible to study the origins of delay cell activity in PFC: what roles are played by learning? what are the inputs to PFC that are necessary for delay cells? Because recordings are feasible in rabbits completely na?ve to the task, which is not feasible with primates, such questions become feasible and affordable to answer. We will use recordings from PFC neurons to determine how delay cell activity arises and to characterize the rules that govern changes in delay cell responding as task demands are changed. Rabbit studies also make feasible analysis of the pathways projecting to prefrontal cortex that are involved in trace conditioning and delay cell activity. The completion of these studies will therefore yield fundamental new insights into the mechanisms responsible for the formation of working memories and their modulation by changes in environmental demands. Such knowledge will greatly facilitate our ability to develop strategies for the prevention or treatment of a host of neurological disorders that appear to relate to working memory deficits, including attention disorders and age-related dementias.

Public Health Relevance

These studies investigate the mechanisms in prefrontal cortex of working memory. Working memory deficits are known to be associated with attention disorders such as ADD and ADHD, and with forms of age-related senility including Alzheimer's disease. As such, understanding the normal operation of working memory mechanisms is as fundamental to the treatment and prevention of these disorders as understanding how a car works is to being a car mechanic.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Neurobiology of Learning and Memory Study Section (LAM)
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Osborn, Bettina D
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University of Texas Austin
Schools of Arts and Sciences
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Khilkevich, Andrei; Halverson, Hunter E; Canton-Josh, Jose Ernesto et al. (2016) Links Between Single-Trial Changes and Learning Rate in Eyelid Conditioning. Cerebellum 15:112-21
Halverson, Hunter E; Khilkevich, Andrei; Mauk, Michael D (2015) Relating cerebellar purkinje cell activity to the timing and amplitude of conditioned eyelid responses. J Neurosci 35:7813-32
Moya, Maria V; Siegel, Jennifer J; McCord, Eedann D et al. (2014) Species-specific differences in the medial prefrontal projections to the pons between rat and rabbit. J Comp Neurol 522:3052-74
Siegel, Jennifer J (2014) Modification of persistent responses in medial prefrontal cortex during learning in trace eyeblink conditioning. J Neurophysiol 112:2123-37
Li, Wen-Ke; Hausknecht, Matthew J; Stone, Peter et al. (2013) Using a million cell simulation of the cerebellum: network scaling and task generality. Neural Netw 47:95-102
Siegel, Jennifer J; Mauk, Michael D (2013) Persistent activity in prefrontal cortex during trace eyelid conditioning: dissociating responses that reflect cerebellar output from those that do not. J Neurosci 33:15272-84
Kalmbach, Brian E; Mauk, Michael D (2012) Multiple sites of extinction for a single learned response. J Neurophysiol 107:226-38
Siegel, Jennifer J; Kalmbach, Brian; Chitwood, Raymond A et al. (2012) Persistent activity in a cortical-to-subcortical circuit: bridging the temporal gap in trace eyelid conditioning. J Neurophysiol 107:50-64
Kalmbach, Brian E; Voicu, Horatiu; Ohyama, Tatsuya et al. (2011) A subtraction mechanism of temporal coding in cerebellar cortex. J Neurosci 31:2025-34
Kalmbach, Brian E; Ohyama, Tatsuya; Mauk, Michael D (2010) Temporal patterns of inputs to cerebellum necessary and sufficient for trace eyelid conditioning. J Neurophysiol 104:627-40

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