The hippocampus contains diverse types of GABAergic inhibitory neurons. Previous work suggests that different subtypes of these inhibitory neurons have distinct functions, but the rules for their regulation of the hippocampal circuit remain to be determined. We hypothesize that functional differences between inhibitory neurons result from distinct circuit connections of different types of inhibitory neurons. The goal of the proposed studies is to map local and long-range direct synaptic connections to major inhibitory neuronal types in CA1 of the mouse hippocampus. We hypothesize that specific types of inhibitory neurons selectively receive local and distant excitatory synaptic inputs from different brain regions, and that each of these inputs to specific inhibitory neurons differentially contributes to their inhibitory regulation of hippocampal target neurons. Specifically, (1) we aim to identify local excitatory connections to specific types of inhibitory hippocampal neurons by laser scanning photostimulation (LSPS). We have combined LSPS with whole-cell recordings from inhibitory neurons in living brain slices to map intrahippocampal sources of excitatory input to the most numerous inhibitory cell types including parvalbumin-expressing (PV+) basket cells, cholecystokinin- expressing (CCK+) basket cells, axo-axonic cells, and somatostatin-expressing (SOM+) oriens-lacunosum moleculare (O-LM) cells. We will test the hypothesis that axo-axonic cells, PV+ and CCK+ basket cells receive differential strength of excitatory input from CA3 vs. CA1 to support their feedforward and feedback inhibition of CA1 network activity. We will also test the hypothesis that O-LM cells only receive excitation from excitatory pyramidal cells in CA1 and strictly perform local feedback inhibition. (2) We aim to identify long-range synaptic connections to selected groups of inhibitory hippocampal neurons with a novel rabies-based tracing system and optogenetic stimulation. We will use knock-in mouse lines that express Cre (Cre recombinase) in selected groups of inhibitory neurons (e.g., PV-Cre, SOM-Cre or CCK-Cre) to limit rabies infection and monosynaptic retrograde tracing to each selected cell group in the intact brain. The rabies tracing will be followed by channelrhodopsin-assisted circuit mapping to functionally characterize the specificity of distant connections to identified cell type within each targeted Cre-expressing cell group. We will test the hypotheses that PV+ inhibitory cells, but not SOM+ inhibitory cells, receive strong distant connections from entorhinal cortex and the medial septum, and that the CCK+ cell group has strong direct synaptic connections with the amygdala. These studies should establish the operational rules of the major classes of inhibitory neurons within the hippocampal circuit.

Public Health Relevance

The proposed studies should increase our mechanistic understanding of inhibitory neuronal circuit organization in the hippocampus. This will guide future studies to assess and treat circuits in the brains that are altered following disease or injury. The results of this research also will enable better therapeutic targeting of neuronal components disrupted by disease in hippocampal circuits that contribute to epilepsy and learning and memory disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS078434-02
Application #
8536407
Study Section
Neurobiology of Learning and Memory Study Section (LAM)
Program Officer
Babcock, Debra J
Project Start
2012-09-01
Project End
2017-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
2
Fiscal Year
2013
Total Cost
$318,518
Indirect Cost
$107,424
Name
University of California Irvine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Xu, Xiangmin; Ikrar, Taruna; Sun, Yanjun et al. (2016) High-resolution and cell-type-specific photostimulation mapping shows weak excitatory vs. strong inhibitory inputs in the bed nucleus of the stria terminalis. J Neurophysiol 115:3204-16
Zhou, Qun-Yong; Burton, Katherine J; Neal, Matthew L et al. (2016) Differential arousal regulation by prokineticin 2 signaling in the nocturnal mouse and the diurnal monkey. Mol Brain 9:78
Sun, Yanjun; Ikrar, Taruna; Davis, Melissa F et al. (2016) Neuregulin-1/ErbB4 Signaling Regulates Visual Cortical Plasticity. Neuron 92:160-173
Baohan, Amy; Ikrar, Taruna; Tring, Elaine et al. (2016) Pten and EphB4 regulate the establishment of perisomatic inhibition in mouse visual cortex. Nat Commun 7:12829
Xu, Xiangmin; Sun, Yanjun; Holmes, Todd C et al. (2016) Noncanonical connections between the subiculum and hippocampal CA1. J Comp Neurol 524:3666-3673
Nguyen, Amanda Q; Dela Cruz, Julie A D; Sun, Yanjun et al. (2016) Genetic cell targeting uncovers specific neuronal types and distinct subregions in the bed nucleus of the stria terminalis. J Comp Neurol 524:2379-99
Xu, Xiangmin; Olivas, Nicholas D; Ikrar, Taruna et al. (2016) Primary visual cortex shows laminar-specific and balanced circuit organization of excitatory and inhibitory synaptic connectivity. J Physiol 594:1891-910
Stephany, Céleste-Élise; Ikrar, Taruna; Nguyen, Collins et al. (2016) Nogo Receptor 1 Confines a Disinhibitory Microcircuit to the Critical Period in Visual Cortex. J Neurosci 36:11006-11012
Roberts, Logan; Leise, Tanya L; Noguchi, Takako et al. (2015) Light evokes rapid circadian network oscillator desynchrony followed by gradual phase retuning of synchrony. Curr Biol 25:858-67
Shi, Yulin; Veidenbaum, Alexander V; Nicolau, Alex et al. (2015) Large-scale neural circuit mapping data analysis accelerated with the graphical processing unit (GPU). J Neurosci Methods 239:1-10

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