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      Noradrenergic Suppression of Persistent Firing in Hippocampal CA1 Pyramidal Cells through cAMP-PKA Pathway

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          Persistent firing is believed to be a cellular correlate of working memory. While the effects of noradrenaline (NA) on working memory have widely been described, its effect on the cellular mechanisms of persistent firing remains largely unknown. Using in vitro intracellular recordings, we demonstrate that persistent firing is supported by individual neurons in hippocampal CA1 pyramidal cells through cholinergic receptor activation, but is dramatically attenuated by NA. In contrast to the classical theory that recurrent synaptic excitation supports persistent firing, suppression of persistent firing by NA was independent of synaptic transmission, indicating that the mechanism is intrinsic to individual cells. In agreement with detrimental effects of cAMP on working memory, we demonstrate that the suppressive effect of NA was through cAMP-PKA pathway. In addition, activation of β1 and/or β3 adrenergic receptors, which increases cAMP levels, suppressed persistent firing. These results are in line with working memory decline observed during high levels of NA and cAMP, which are implicated in high stress, aging, and schizophrenia.

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          Most cited references 69

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          Cellular basis of working memory

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            Mnemonic coding of visual space in the monkey's dorsolateral prefrontal cortex.

            1. An oculomotor delayed-response task was used to examine the spatial memory functions of neurons in primate prefrontal cortex. Monkeys were trained to fixate a central spot during a brief presentation (0.5 s) of a peripheral cue and throughout a subsequent delay period (1-6 s), and then, upon the extinction of the fixation target, to make a saccadic eye movement to where the cue had been presented. Cues were usually presented in one of eight different locations separated by 45 degrees. This task thus requires monkeys to direct their gaze to the location of a remembered visual cue, controls the retinal coordinates of the visual cues, controls the monkey's oculomotor behavior during the delay period, and also allows precise measurement of the timing and direction of the relevant behavioral responses. 2. Recordings were obtained from 288 neurons in the prefrontal cortex within and surrounding the principal sulcus (PS) while monkeys performed this task. An additional 31 neurons in the frontal eye fields (FEF) region within and near the anterior bank of the arcuate sulcus were also studied. 3. Of the 288 PS neurons, 170 exhibited task-related activity during at least one phase of this task and, of these, 87 showed significant excitation or inhibition of activity during the delay period relative to activity during the intertrial interval. 4. Delay period activity was classified as directional for 79% of these 87 neurons in that significant responses only occurred following cues located over a certain range of visual field directions and were weak or absent for other cue directions. The remaining 21% were omnidirectional, i.e., showed comparable delay period activity for all visual field locations tested. Directional preferences, or lack thereof, were maintained across different delay intervals (1-6 s). 5. For 50 of the 87 PS neurons, activity during the delay period was significantly elevated above the neuron's spontaneous rate for at least one cue location; for the remaining 37 neurons only inhibitory delay period activity was seen. Nearly all (92%) neurons with excitatory delay period activity were directional and few (8%) were omnidirectional. Most (62%) neurons with purely inhibitory delay period activity were directional, but a substantial minority (38%) was omnidirectional. 6. Fifteen of the neurons with excitatory directional delay period activity also had significant inhibitory delay period activity for other cue directions. These inhibitory responses were usually strongest for, or centered about, cue directions roughly opposite those optimal for excitatory responses.(ABSTRACT TRUNCATED AT 400 WORDS)
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              Synaptic reverberation underlying mnemonic persistent activity.

              Stimulus-specific persistent neural activity is the neural process underlying active (working) memory. Since its discovery 30 years ago, mnemonic activity has been hypothesized to be sustained by synaptic reverberation in a recurrent circuit. Recently, experimental and modeling work has begun to test the reverberation hypothesis at the cellular level. Moreover, theory has been developed to describe memory storage of an analog stimulus (such as spatial location or eye position), in terms of continuous 'bump attractors' and 'line attractors'. This review summarizes new studies, and discusses insights and predictions from biophysically based models. The stability of a working memory network is recognized as a serious problem; stability can be achieved if reverberation is largely mediated by NMDA receptors at recurrent synapses.

                Author and article information

                Society for Neuroscience
                26 February 2021
                19 March 2021
                Mar-Apr 2021
                : 8
                : 2
                [1 ]Faculty of Psychology, Mercator Research Group-Structure of Memory, Ruhr-University Bochum , Bochum 44780, Germany
                [2 ]German Center for Neurodegenerative Diseases (DZNE), Magdeburg 39120, Germany
                [3 ]Leibniz Institute for Neurobiology (LIN), Magdeburg 39118, Germany
                [4 ]Otto von Guericke University, Functional Neuroplasticity, Medical Faculty, Magdeburg 39120, Germany
                [5 ]Center for Behavioral Brain Sciences (CBBS), 39106, Magdeburg, Germany
                Author notes

                The authors declare no competing financial interests.

                Author contributions: M.J.V.-A., A.R., M.S., and M.Y. designed research; M.J.V.-A., A.R., and A.A. performed research; M.J.V.-A., A.R., and A.A. analyzed data; M.J.V.-A., A.R., and M.Y. wrote the paper.

                This work was supported by the Mercator Stiftung and by German Research Foundation (DFG) Project Grants YO177/4-1 and YO177/7-1.


                M.J.V.-A. and A.R. contributed equally to this work.

                M. J. Valero-Aracama’s present address: Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, 91054, Germany.

                Correspondence should be addressed to Motoharu Yoshida at motoharu.yoshida@ 123456lin-magdeburg.de .
                Copyright © 2021 Valero-Aracama et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

                Page count
                Figures: 5, Tables: 2, Equations: 0, References: 69, Pages: 12, Words: 00
                Funded by: http://doi.org/10.13039/501100001659Deutsche Forschungsgemeinschaft (DFG)
                Award ID: YO177/4-1
                Award ID: YO177/7-1
                Funded by: Mercator Stiftung
                Research Article: New Research
                Neuronal Excitability
                Custom metadata
                March/April 2021


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