We propose a collaborative effort to characterize the cellular and systems mechanisms of persistent cortical activity and its contributions to working memory in the rat. The project will leverage the advantages of trace eyelid conditioning (TEC) and combine the systems-neuroscience expertise of the Mauk lab with the cellular- neuroscience expertise of the Johnston lab. We will utilize several novel approaches designed to establish links between the cellular mechanisms of persistent activity in prefrontal cortex (PFC) and the systems mechanisms of working memory. The Mauk lab has demonstrated that TEC requires persistent activity of an interconnected pathway from medial (m) PFC to lateral pons (and then to cerebellum) that is required for TEC. The Johnston lab has injected vital retrograde tracers (Lumafluor beads) in vivo to identify in vitro a subpopulation of L5 pyramidal neurons in mPFC with unique electrophysiological properties that projects to the lateral pons. Finally, in vitro recordings from these mPFC neurons from behaviorally trained animals have been made to investigate the cellular mechanisms associated with the behavioral task. These and other findings establish TEC as an especially tractable means to study the systems and cellular mechanisms of a working- memory-related behavior. We propose 1) to use local injections of pharmacological agents and multiunit stimulation and recordings to provide a systems-level analysis of persistent firing, TEC, and working memory in the behaving rat;2) to use local injections in vivo of vital ortho- and retrograde tracers to determine the pathways required for TEC. A 3D anatomical map of these pathways will be constructed from the data;and 3) to investigate the cellular and neuromodulatory properties of labeled neurons in these pathways that participate in the behavior. The latter experiments will be accomplished using whole-cell and cell-attached patch recordings and Ca2+ imaging from PFC neurons in brain slices. This project should permit an unprecedented analysis of persistent cortical activity and significantly enhance the prospects for treating disease-related deficits in working memory.

Public Health Relevance

Working memory processes contribute to a wide variety of cognitive processes, and working memory deficits are associated with a host of age- and disease-related cognitive dysfunction. These include Alzheimer's disease, attentional disorders such as ADHD, autism, and schizophrenia, as well as a variety of other learning disabilities.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH094839-03
Application #
8464279
Study Section
Neurobiology of Learning and Memory Study Section (LAM)
Program Officer
Osborn, Bettina D
Project Start
2011-07-20
Project End
2016-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
3
Fiscal Year
2013
Total Cost
$370,400
Indirect Cost
$130,400
Name
University of Texas Austin
Department
Neurosciences
Type
Schools of Arts and Sciences
DUNS #
170230239
City
Austin
State
TX
Country
United States
Zip Code
78712
Kalmbach, Brian E; Johnston, Daniel; Brager, Darrin H (2015) Cell-Type Specific Channelopathies in the Prefrontal Cortex of the fmr1-/y Mouse Model of Fragile X Syndrome. eNeuro 2:
Kim, Chung Sub; Johnston, Daniel (2015) A1 adenosine receptor-mediated GIRK channels contribute to the resting conductance of CA1 neurons in the dorsal hippocampus. J Neurophysiol 113:2511-23
Ashhad, Sufyan; Johnston, Daniel; Narayanan, Rishikesh (2015) Activation of InsP₃ receptors is sufficient for inducing graded intrinsic plasticity in rat hippocampal pyramidal neurons. J Neurophysiol 113:2002-13
Desai, Niraj S; Siegel, Jennifer J; Taylor, William et al. (2015) MATLAB-based automated patch-clamp system for awake behaving mice. J Neurophysiol 114:1331-45
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
Brager, Darrin H; Johnston, Daniel (2014) Channelopathies and dendritic dysfunction in fragile X syndrome. Brain Res Bull 103:11-7
Siegel, Jennifer J (2014) Modification of persistent responses in medial prefrontal cortex during learning in trace eyeblink conditioning. J Neurophysiol 112:2123-37
Clemens, Ann M; Johnston, Daniel (2014) Age- and location-dependent differences in store depletion-induced h-channel plasticity in hippocampal pyramidal neurons. J Neurophysiol 111:1369-82
Edwards, John; Daniel, Eric; Kinney, Justin et al. (2014) VolRoverN: enhancing surface and volumetric reconstruction for realistic dynamical simulation of cellular and subcellular function. Neuroinformatics 12:277-89
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

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