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Conducting memory formation

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Science  04 Oct 2019:
Vol. 366, Issue 6461, pp. 46
DOI: 10.1126/science.aaz3883

Listening to the harmonic performance of a symphonic orchestra is a peculiar experience indeed. The music changes dynamically: Sometimes the strenuous voice of the brasses dominates, sometimes only a faltering violin can be heard. The musicians, masters of their instruments, play together, but they form a perfect harmony only by following the instructions of the conductor to play loudly or softly, or to wait in silence.

The cofiring of subpopulations of pyramidal cells in the CA1 region of the hippocampus encodes the episodic memories of our life much like the voices of the instruments form a symphony. To fulfill this role, CA1 pyramidal cells receive multisensory information from the CA3 region and direct sensory-related information from the entorhinal cortex (1, 2). The information carried by these inputs is associated by CA1 pyramidal cells to encode episodic memories (3, 4).


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The number of CA1 pyramidal cells that encode a memory trace must be tightly regulated. The participation of too many may engender memory interference, whereas the activation of too few pyramidal cells will lead to unstable memories (5, 6). γ-Aminobutyric acid (GABA)–mediated inhibitory interneurons control how many CA1 neurons are recruited during this process (7).

Somatostatin (SOM)–positive dendrite-targeting interneurons play an essential role in the recruitment of memory-encoding CA1 pyramidal cells. SOM-positive interneurons restrict direct sensory-related information from reaching most of the pyramidal cells during memory formation and are activated by the excitatory glutamatergic and cholinergic cells of the medial septum (MS) (810).

But who is the conductor of this symphony? Which inputs help fine-tune the number of CA1 pyramidal cells that encode a given memory trace? Together with my mentor, Gábor Nyiri, in the laboratory of Tamás Freund, I hypothesized that the little-known nucleus incertus (NI) would be ideal to fulfill this role, as it strongly projects to the septo-hippocampal system (11).

Hippocampal Dendrite–Targeting Interneurons are Inhibited by the Nucleus Incertus

Using cell-type–specific anatomical tracing, electron microscopic analysis, and in vitro optogenetics, we discovered that the NI selectively targets SOM-positive dendrite-targeting interneurons in the CA1 and that it establishes GABAergic inhibitory synapses on these interneurons (12). The NI also inhibits glutamatergic and cholinergic neurons in the MS that send subcortical excitatory inputs onto SOM-positive hippocampal interneurons. NI neurons frequently project into the hippocampus and MS simultaneously, suggesting that they can inhibit hippocampal SOM-positive interneurons through both a direct and an indirect pathway at the same time.

The Nucleus Incertus is Rapidly Activated by Salient Sensory Stimuli

On the basis of our research, NI neurons should “know” if something needs to be memorized. We therefore tested whether the NI is activated by salient sensory inputs, which would allow them to regulate SOM-positive hippocampal interneurons at the right time.

We labeled NI cells with a fluorescent calcium indicator and performed two-photon imaging of the NI fibers in the CA1 region of head-fixed, awake mice. The mice ran on a treadmill while they received different sensory stimuli.

We found that NI fibers were activated by different sensory stimuli at a different rate. Aversive air-puffs and water rewards evoked a larger response in NI fibers than did light flashes or auditory tones, suggesting that the NI is fine-tuned by different sensory inputs on the basis of their relevance and/or modality.

Using rabies virus tracing, we also examined which brain areas modulate NI GABAergic neurons directly. We found that areas that process relevant environmental inputs, including the lateral habenula or prefrontal cortex, innervated NI GABAergic neurons monosynaptically for potentially rapid activation (12).

The Nucleus Incertus Bidirectionally Controls Contextual Memory Formation

To better understand how NI GABAergic cells orchestrate behavior, we placed virus-injected mice into an unfamiliar environment, where they received mild, aversive foot-shocks. NI GABAergic cells, or their fibers in the CA1 region, were activated optogenetically precisely during the foot-shocks. On the next day, mice had to face the same environment. Whereas control mice showed appropriate fear behavior, optogenetically stimulated mice showed no fear in the same environment. This effect was absent when optogenetic stimulation was not precisely aligned with foot-shock presentation.

In a separate experiment, mice received foot-shocks paired with auditory cues while we optogenetically inhibited the NI. Optogenetically inhibited mice formed enhanced hippocampus-dependent contextual memories compared to control mice, as indicated by higher levels of fear on the next day, in the environment where they received foot-shocks. By contrast, there was no difference between the non–hippocampus-dependent cued fear levels of the two mouse groups when we presented them with the auditory cue in a different environment. These experiments confirmed that NI GABAergic cells can regulate hippocampus-dependent episodic memory formation bidirectionally (12).

The Role of the Nucleus Incertus in Normal and Pathological Memory Formation

We have shown that the NI rapidly processes salient environmental stimuli. Our data suggest that the NI tightly controls contextual memory formation by the direct and indirect inhibition of SOM-positive dendrite-targeting interneurons in the CA1. This action fine-tunes the recruitment of memory-encoding pyramidal cells on the basis of the relevance and/or modality of the different sensory stimuli.

We have also shown that optogenetic stimulation of the NI at the moment when an aversive stimulus is presented prevents contextual memory formation. This suggests that the NI may play a role in filtering nonrelevant everyday experiences, the unnecessary encoding of which could lead to cognitive symptoms (13).

By contrast, because optogenetic inhibition of the NI causes pathologically strong fear memory formation, dysfunction of NI GABAergic neurons may contribute to generalized anxiety-like syndromes or to post-traumatic stress disorder.


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PHOTO: ZSOFIA BOCZAN

FINALIST András Szőnyi

András Szőnyi received undergraduate degrees in medicine and a Ph.D. in neurosciences from the Semmelweis University in Budapest, Hungary. He performed research in the Institute of Experimental Medicine of the Hungarian Academy of Sciences. Currently, Szőnyi is a postdoctoral fellow in the Friedrich Miescher Institute for Biomedical Research in Basel, Switzerland. He studies the cellular mechanisms of learning and memory formation in mice using in vivo imaging and optogenetics. www.sciencemag.org/content/366/6461/46.1

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