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Brainstem Nucleus Incertus Controls Contextual Memory Formation András Szonyi, Katalin E

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Brainstem Nucleus Incertus Controls Contextual Memory Formation András Szonyi, Katalin E RESEARCH ◥ and also indirectly through inhibition of excit- RESEARCH ARTICLE SUMMARY atory neurons in the MS (see the figure, panels A and B). We observed that NI GABAergic neu- rons receive direct inputs from several brain NEUROSCIENCE areasthatprocesssalientenvironmentalstimuli, including the prefrontal cortex and lateral ha- Brainstem nucleus incertus controls benula, and that these salient sensory stimuli (e.g., air puffs, water rewards) rapidly activated hippocampal fibers of NI GABAergic neurons contextual memory formation in vivo. Behavioral experiments revealed that ◥ optogenetic stimulation of András Szőnyi, Katalin E. Sos, Rita Nyilas, Dániel Schlingloff, Andor Domonkos, ON OUR WEBSITE NI GABAergic neurons or Virág T. Takács, Balázs Pósfai, Panna Hegedüs, James B. Priestley, Read the full article their fibers in hippocampus, Andrew L. Gundlach, Attila I. Gulyás, Viktor Varga, Attila Losonczy, at http://dx.doi. precisely at the moment Tamás F. Freund, Gábor Nyiri* org/10.1126/ of aversive stimuli (see the science.aaw0445 figure, panel C), prevented .................................................. the formation of fear mem- INTRODUCTION: Associative learning is es- interneurons should be inhibited precisely in ories, whereas this effect was absent if light sential for survival, and the mammalian hippo- time, on the basis of subcortical information; stimulation was not aligned with the stimuli. campal neurocircuitry has been shown to play otherwise, underrecruitment of pyramidal neu- However, optogenetic inhibition of NI GABAergic Downloaded from a central role in the formation of specific con- rons would lead to unstable memory formation. neurons during fear conditioning resulted in textual memories. Contrary to the slow, neuro- the formation of excessively enhanced con- modulatory role commonly associated with RATIONALE: g-aminobutyric acid (GABA)– textual memories. Optogenetic stimulation of brainstem systems, we discovered a highly spe- releasing inhibitory neurons of the brainstem NI GABAergic neurons also changed memory cific, spatiotemporally precise, inhibitory as- nucleus incertus (NI) seemed well suited to encoding–related hippocampal theta rhythms. cending brainstem pathway that effectively counterbalance the activation of SOM interneu- http://science.sciencemag.org/ controls hippocampal fear memory formation. rons, as they specifically project to the stratum CONCLUSION: AroleofNIGABAergicneu- Pyramidal neurons of the dorsal hippocampus oriens of the hippocampus, where most SOM rons may be fine-tuning of the selection of CA1 region pair multisensory contextual infor- cells arborize. Using cell type–specific neuronal memory-encoding pyramidal cells, on the basis mation (see the figure, panel A, CA3) with direct tract tracing, immunoelectron microscopy, and of the relevance and/or modality of environ- sensory-related inputs (see the figure, panel A, electrophysiological methods, we investigated mental inputs. They may also help filter non- EntCx). Each memory trace is encoded by a spe- the targets of NI in the mouse hippocampus, relevant everyday experiences (e.g., those to cific subset of pyramidal neurons. Remaining and in the MS, where excitation of SOM cells which animals have already accommodated), by pyramidal cells must be actively excluded from originates. We also used monosynaptic rabies regulating the sparsity of memory-encoding the given memory-encoding process by direct tracing to identify the inputs of GABAergic NI dorsal CA1 pyramidal neurons. NI GABAergic dendritic inhibition, which is executed by neurons. Two-photon calcium imaging was used neuron dysfunction may also contribute to somatostatin-positive (SOM) dendrite-targeting to analyze the response of GABAergic NI fibers dementia-like disorders or pathological mem- on December 1, 2019 interneurons. SOM interneurons are activated to sensory stimuli in vivo. Finally, we used ory formation in certain types of anxiety or by excitatory inputs from the medial septum (MS) in vivo optogenetics combined with behavioral stress disorders. Our data represent an unex- upon salient environmental stimuli. Previous experiments or electrophysiological recordings pectedly specific role of an ascending inhibitory models suggested that the subset of memory- to explore the role of the NI in contextual mem- pathwayfromabrainstemnucleusinmemory forming pyramidal cells escape this dendritic ory formation and hippocampal network activity. encoding.▪ inhibition only by a stochastic, self-regulatory The list of author affiliations is available in the full article online. process, in which some SOM interneurons be- RESULTS: We discovered that NI GABAergic *Corresponding author Email: [email protected] come inactive. However, we hypothesized that this neurons selectively inhibit hippocampal SOM Cite this article as A. Szőnyi et al., Science 364, eaaw0445 process must be regulated more actively, and SOM interneurons in the stratum oriens both directly (2019). DOI: 10.1126/science.aaw0445 Nucleus incertus (NI) activation A C Light impulses and foot CTRL NI GABAergic cells D Freezing time prevents memory formation. SOM shocks are applied are insensitive IN (memory test) NI GABAergic neurons regulate simultaneously to light contextual memory formation ** by inhibiting somatostatin PC + + + + interneurons (SOM IN) directly in % time n=10 A hippocampus (HIPP) ( )and MS 20 indirectly through inhibition NI of their excitatory inputs in the CA3 EntCx 15 medial septum (MS). Pairing ChR2 NI GABAergic cells are sensitive 10 optical stimulation (B)with Optic B fiber to light aversive stimuli (C)eliminates 25Hz light 5 n=9 impulses fear memory formation, whereas HIPP Foot 0 control mice display normal fear shocks (freezing) after exposure to the MS NI CTRL ChR2 same environment a day later (D). Inter-shock: 30 sec Szőnyi et al., Science 364, 752 (2019) 24 May 2019 1of1 RESEARCH ◥ Thepontinenucleusincertus(NI),character- RESEARCH ARTICLE ized by expression of the neuropeptide relaxin-3 (26–28), sends an ascending g-aminobutyric acid (GABA)–mediated pathway to the septo- NEUROSCIENCE hippocampal system. NI neurons display activity related to hippocampal theta rhythm and are thought to play an important role in stress and Brainstem nucleus incertus controls arousal (29–34). Here, using cell type–specific neuronal tract contextual memory formation tracing, immunogold receptor localization, and electrophysiological methods, we discovered that NI GABAergic neurons selectively inhibit hippo- András Szőnyi1,2, Katalin E. Sos1,2, Rita Nyilas3, Dániel Schlingloff 1,2, 1 1 1,2 1,2 campal SOM-positive neurons both monosynap- Andor Domonkos , Virág T. Takács , Balázs Pósfai , Panna Hegedüs , tically and also indirectly through inhibition of 3 4 1 1 James B. Priestley , Andrew L. Gundlach , Attila I. Gulyás , Viktor Varga , excitatory glutamatergic and cholinergic neurons 3 1 1 Attila Losonczy , Tamás F. Freund , Gábor Nyiri * in the MS. Using monosynaptic rabies tracing, we observed that NI receives direct inputs from Hippocampal pyramidal cells encode memory engrams, which guide adaptive behavior. several brain areas that process salient environ- Selection of engram-forming cells is regulated by somatostatin-positive dendrite-targeting mental stimuli, and indeed, using in vivo two- interneurons, which inhibit pyramidal cells that are not required for memory formation. photon calcium imaging in head-fixed awake – Downloaded from Here, we found that g-aminobutyric acid (GABA) releasing neurons of the mouse nucleus mice, we demonstrated that such stimuli rapidly incertus (NI) selectively inhibit somatostatin-positive interneurons in the hippocampus, activated hippocampal fibers of NI GABAergic both monosynaptically and indirectly through the inhibition of their subcortical excitatory neurons. Behavioral conditioned fear experi- inputs. We demonstrated that NI GABAergic neurons receive monosynaptic inputs from brain ments revealed that optogenetic stimulation of areas processing important environmental information, and their hippocampal projections are NI GABAergic cells or their fibers in the dorsal strongly activated by salient environmental inputs in vivo. Optogenetic manipulations of NI HIPP, precisely at the moment of US presenta- GABAergic neurons can shift hippocampal network state and bidirectionally modify the tion, prevented the formation of contextual fear http://science.sciencemag.org/ strength of contextual fear memory formation. Our results indicate that brainstem NI memories. In parallel, optogenetic stimulation of GABAergic cells are essential for controlling contextual memories. NI GABAergic neurons decreased the power and frequency of the encoding-related hippocampal ear memories, which allow mice to avoid hibited, (i.e., excluded from memory encoding at theta rhythm in vivo. By contrast, optogenetic future aversive events, are formed by asso- the moment of memory formation), because if the inhibition of NI GABAergic neurons during fear ciating aversive stimuli (unconditioned stim- US information reaches too many pyramidal cells, conditioning resulted in the formation of exces- ulus, US) with their environmental context. engrams may lack specificity, which may engen- sively enhanced contextual memories. These F 16 17 The dorsal hippocampus (HIPP) plays an der memory interference ( , ). Exclusion of US findings demonstrate the fundamental impor- essential role in contextual memory encoding information in hippocampal CA1 is achieved by tance of NI GABAergic neurons in
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