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      Interneuron Functional Diversity in the Mouse Accessory Olfactory Bulb

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          Abstract

          In the mouse accessory olfactory bulb (AOB), inhibitory interneurons play an essential role in gating behaviors elicited by sensory exposure to social odors. Several morphological classes have been described, but the full complement of interneurons remains incomplete. In order to develop a more comprehensive view of interneuron function in the AOB, we performed targeted patch clamp recordings from partially overlapping subsets of genetically labeled and morphologically defined interneuron types. Gad2 (GAD65), Calb2 (calretinin), and Cort (cortistatin)-cre mouse lines were used to drive selective expression of tdTomato in AOB interneurons. Gad2 and Calb2-labeled interneurons were found in the internal, external, and glomerular (GL) layers, whereas Cort-labeled interneurons were enriched within the lateral olfactory tract (LOT) and external cellular layer (ECL). We found that external granule cells (EGCs) from all genetically labeled subpopulations possessed intrinsic functional differences that allowed them to be readily distinguished from internal granule cells (IGCs). EGCs showed stronger voltage-gated Na + and non-inactivating voltage-gated K + currents, decreased I H currents, and robust excitatory synaptic input. These specific intrinsic properties did not correspond to any genetically labeled type, suggesting that transcriptional heterogeneity among EGCs and IGCs is not correlated with expression of these particular marker genes. Intrinsic heterogeneity was also seen among AOB juxtaglomerular cells (JGCs), with a major subset of Calb2-labeled JGCs exhibiting spontaneous and depolarization-evoked plateau potentials. These data identify specific physiological features of AOB interneurons types that will assist in future studies of AOB function.

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          A resource of Cre driver lines for genetic targeting of GABAergic neurons in cerebral cortex.

          A key obstacle to understanding neural circuits in the cerebral cortex is that of unraveling the diversity of GABAergic interneurons. This diversity poses general questions for neural circuit analysis: how are these interneuron cell types generated and assembled into stereotyped local circuits and how do they differentially contribute to circuit operations that underlie cortical functions ranging from perception to cognition? Using genetic engineering in mice, we have generated and characterized approximately 20 Cre and inducible CreER knockin driver lines that reliably target major classes and lineages of GABAergic neurons. More select populations are captured by intersection of Cre and Flp drivers. Genetic targeting allows reliable identification, monitoring, and manipulation of cortical GABAergic neurons, thereby enabling a systematic and comprehensive analysis from cell fate specification, migration, and connectivity, to their functions in network dynamics and behavior. As such, this approach will accelerate the study of GABAergic circuits throughout the mammalian brain. Copyright © 2011 Elsevier Inc. All rights reserved.
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            Interneurons of the hippocampus.

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              Defined types of cortical interneurone structure space and spike timing in the hippocampus.

              The cerebral cortex encodes, stores and combines information about the internal and external environment in rhythmic activity of multiple frequency ranges. Neurones of the cortex can be defined, recognized and compared on the comprehensive application of the following measures: (i) brain area- and cell domain-specific distribution of input and output synapses, (ii) expression of molecules involved in cell signalling, (iii) membrane and synaptic properties reflecting the expression of membrane proteins, (iv) temporal structure of firing in vivo, resulting from (i)-(iii). Spatial and temporal measures of neurones in the network reflect an indivisible unity of evolutionary design, i.e. neurones do not have separate structure or function. The blueprint of this design is most easily accessible in the CA1 area of the hippocampus, where a relatively uniform population of pyramidal cells and their inputs follow an instantly recognizable laminated pattern and act within stereotyped network activity patterns. Reviewing the cell types and their spatio-temporal interactions, we suggest that CA1 pyramidal cells are supported by at least 16 distinct types of GABAergic neurone. During a given behaviour-contingent network oscillation, interneurones of a given type exhibit similar firing patterns. During different network oscillations representing two distinct brain states, interneurones of the same class show different firing patterns modulating their postsynaptic target-domain in a brain-state-dependent manner. These results suggest roles for specific interneurone types in structuring the activity of pyramidal cells via their respective target domains, and accurately timing and synchronizing pyramidal cell discharge, rather than providing generalized inhibition. Finally, interneurones belonging to different classes may fire preferentially at distinct time points during a given oscillation. As different interneurones innervate distinct domains of the pyramidal cells, the different compartments will receive GABAergic input differentiated in time. Such a dynamic, spatio-temporal, GABAergic control, which evolves distinct patterns during different brain states, is ideally suited to regulating the input integration of individual pyramidal cells contributing to the formation of cell assemblies and representations in the hippocampus and, probably, throughout the cerebral cortex.
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                Author and article information

                Journal
                eNeuro
                eNeuro
                eneuro
                eneuro
                eNeuro
                eNeuro
                Society for Neuroscience
                2373-2822
                29 July 2019
                13 August 2019
                Jul-Aug 2019
                : 6
                : 4
                : ENEURO.0058-19.2019
                Affiliations
                [1 ]Department of Neuroscience, University of Texas Southwestern Medical Center , Dallas, TX 75390
                [2 ]Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center , Dallas, TX 75390
                Author notes

                The authors declare no competing financial interests.

                Author contributions: M.A.M., H.L.C., J.M.T., and J.P.M. performed research; M.A.M., H.L.C., K.E.Z., D.J.R., and J.P.M. analyzed data; J.P.M. designed research; J.P.M. wrote the paper.

                This work was supported by National Institutes of Health Grants R00DC11780, R01DC015784, R01DC017985, T32DA007290, and R21NS10482601. Partial support was provided by the Welch Foundation Grant I-1934-20170325 and the National Science Foundation Award IOS-1451034.

                Correspondence should be addressed to Julian P. Meeks at julian.meeks@ 123456utsouthwestern.edu .
                Author information
                http://orcid.org/0000-0001-8267-0515
                http://orcid.org/0000-0002-7537-4491
                Article
                eN-NWR-0058-19
                10.1523/ENEURO.0058-19.2019
                6712203
                31358509
                c962e9f7-c427-42f3-950c-d6da557dd4f2
                Copyright © 2019 Maksimova 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.

                History
                : 15 February 2019
                : 18 July 2019
                : 19 July 2019
                Page count
                Figures: 7, Tables: 1, Equations: 3, References: 77, Pages: 17, Words: 11958
                Funding
                Funded by: http://doi.org/10.13039/100000055HHS | NIH | National Institute on Deafness and Other Communication Disorders (NIDCD)
                Award ID: R00DC11780
                Award ID: R01DC015784
                Award ID: R01DC017985
                Funded by: http://doi.org/10.13039/100000026HHS | NIH | National Institute on Drug Abuse (NIDA)
                Award ID: T32DA007290
                Funded by: http://doi.org/10.13039/100000065HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)
                Award ID: R21NS10482601
                Funded by: http://doi.org/10.13039/100000001National Science Foundation (NSF)
                Award ID: IOS-1451034
                Funded by: http://doi.org/10.13039/100000928Welch Foundation
                Award ID: I-1934-20170325
                Categories
                8
                8.1
                New Research
                Sensory and Motor Systems
                Custom metadata
                July/August 2019

                accessory olfactory bulb,cell types,excitability,interneuron

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