Yoshihito Saito

SUMMARY: Prior experience allows selective learning by filtering out redundant cues, as exemplified by blocking, in which prior learning about one cue prevents a novel but redundant cue from being learned during subsequent compound conditioning. Top-down cortico-cortical pathways have been implicated in sensory filtering, but whether, how, and when they contribute to blocking remain unknown. Here we establish a head-fixed blocking paradigm in mice in which prior auditory cue-reward learning prevents a redundant somatosensory cue-reward association during subsequent compound conditioning. We found that a projection from anterior cingulate cortex (ACC) to primary somatosensory cortex (S1) facilitates blocking. Prior auditory learning establishes ACC-driven inhibitory control over S1 via parvalbumin neurons, before explicit somatosensory experience, thereby suppressing burst responses to the somatosensory cue, limiting network plasticity, and promoting blocking. These findings propose a proactive cortical filter that preconfigures inhibitory sensory bias to constrain future learning about redundant cues. Graphical

Light scattering in the skull limits optical access to the brain. Here we present SeeThrough, a skull-clearing technique that enables simple, high-resolution, and minimally-invasive brain imaging without skull removal. Through systematic screening of over 1600 chemicals, we rationally developed a refractive index-matching solution that combines water- and organic solvent-based components, achieving both high clearing efficiency and biocompatibility. The reagents exhibit minimal brain penetration, maintain tissue integrity, and avoid inflammatory responses. Notably, SeeThrough provides imaging sensitivity and contrast comparable to open-skull window imaging, while permitting minimally-invasive monitoring of brain border macrophages as well as blood and cerebrospinal fluid dynamics. Combined with two-photon imaging, SeeThrough enables spatially and temporally scalable imaging applications in the mouse brain, including ~400 µm deep imaging, one-month longitudinal imaging, and mesoscale, cellular-resolution monitoring of brain activity for network-level analysis. Thus, SeeThrough offers a broadly accessible platform for high-throughput, physiology-preserving imaging of the brain parenchyma and brain-skull interface.

The brain is an intricate neuronal network that orchestrates our thoughts, emotions and actions through dynamic interactions between neurons. If we could record the activity of all neurons simultaneously in detail, it could revolutionize our understanding of brain function and lead to breakthroughs in treating neurological diseases. Recent technological innovations, particularly in large field-of-view two-photon microscopes, have made it possible to record the activity of tens of thousands of neurons simultaneously. However, the size and complexity of the datasets present significant challenges in extracting interpretable information. Conventional analysis methods are often insufficient, necessitating the development of new theoretical frameworks and computational efficiencies. In this review, we describe the characteristics of the data obtained from advanced imaging techniques and discuss analytical methods to facilitate mutual understanding between experimentalists and theorists. This interdisciplinary approach is crucial for effectively managing and interpreting large-scale neural activity datasets, ultimately advancing our understanding of brain function.

Emotional arousal is thought to enhance the consolidation of associated memories by activating the basolateral amygdala (BLA) and its projections to memory-storing regions ^1–4 . Although the importance of both rapid eye movement (REM) and non-REM (NREM) sleep-state specific BLA activity for emotional memory processing has been proposed ^5–9 , how and when the BLA interacts with other brain regions to enhance memory consolidation remains unclear ¹⁰ . Here, by adding emotional information to a perceptual recognition task that relies on top-down inputs from frontal to sensory cortices, we demonstrated that the BLA not only associates emotional information with perceptual information, but also enhances the retention of associated perceptual memory through BLA-frontal projections. Electrophysiological recordings revealed that emotional association increases the reactivation of coordinated activity across the BLA-frontal-sensory region during NREM sleep, but not during REM sleep. Notably, this inter-regional coordinated reactivation during NREM sleep was entrained to the BLA high-frequency oscillations in the emotional condition, suggesting that the BLA triggers inter-regional interaction. Optogenetic silencing of BLA terminals in the frontal cortex during NREM sleep, but not REM sleep, disrupted the enhanced retention of the perceptual memory, but not the association itself or the emotional component of associative memory. Our results indicate that the inter-regional coordination through the BLA-cortical inputs during NREM sleep is causally required for memory enhancement by emotional arousal.