Optogenetics has revolutionized the experimental interrogation of neural circuits and holds promise for the treatment of neurological disorders. It is limited, however, because visible light cannot penetrate deep inside brain tissue. Upconversion nanoparticles (UCNPs) absorb tissue-penetrating near-infrared (NIR) light and emit wavelength-specific visible light. Here, we demonstrate that molecularly tailored UCNPs can serve as optogenetic actuators of transcranial NIR light to stimulate deep brain neurons. Transcranial NIR UCNP-mediated optogenetics evoked dopamine release from genetically tagged neurons in the ventral tegmental area, induced brain oscillations through activation of inhibitory neurons in the medial septum, silenced seizure by inhibition of hippocampal excitatory cells, and triggered memory recall. UCNP technology will enable less-invasive optical neuronal activity manipulation with the potential for remote therapy.

The ability to recognize information incongruous with previous experience is critical for survival, thus novelty signals in the mammalian brain have evolved to enhance attention, perception and memory 1-3 . Although the importance of regions such as the ventral tegmental area 4-6 and locus coeruleus 6,7 in broadly signaling novelty has been well established, these diffuse monoaminergic transmitters have yet to be shown to convey specific information regarding the type of stimuli that drive them 6 . Whether distinct types of novelty, such as contextual and social novelty, are differently processed and routed in the brain remain unclear. Here we identify a novelty hub in the hypothalamus -the supramammillary nucleus (SuM) 8 . Unique about this region is that it not only responds broadly to novel stimuli, but segregates and selectively routes different types of information to discrete cortical targets, the dentate gyrus (DG) and CA2 fields of the hippocampus, for the modulation of mnemonic processing. Taking advantage of a novel SuM-Cre transgenic mouse, we found that DG-projecting SuM neurons are activated by contextual novelty while the SuM-CA2 circuit is preferentially activated by novel social encounters. Circuitbased manipulation demonstrated that divergent novelty channeling in these projections significantly modifies hippocampal-based contextual or social memory. This content-

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