Multicellular organisms have co-evolved with complex consortia of viruses, bacteria, fungi and parasites, collectively referred to as the microbiota. In mammals, changes in the composition of the microbiota can influence a wide range of physiologic processes (including development, metabolism, and immune cell function) and are associated with susceptibility to multiple diseases. Alterations in the microbiota can also modulate host behaviors such as social activity, stress, and anxiety-related responses that are linked to diverse neuropsychiatric disorders. However, the mechanisms through which the microbiota influence neuronal activity and host behavior remain poorly defined. Here we demonstrate that manipulation of the microbiota in either antibiotictreated or germ-free adult mice results in significant deficits in fear extinction learning. Single nucleus RNA-sequencing of the medial prefrontal cortex of the brain revealed significant alterations in gene expression in multiple cell types including excitatory neurons and glial cells. Transcranial two-photon imaging following deliberate manipulation of the microbiota demonstrated that extinction learning deficits were associated with defective learning-related remodeling of postsynaptic dendritic spines and reduced activity in cue-encoding neurons in the medial prefrontal cortex. In addition to effects of manipulating the microbiota on behavior in adult mice, selective re-establishment of the microbiota revealed a limited neonatal developmental window in which microbiota-derived signals can restore normal extinction learning in adulthood. Lastly, unbiased metabolomic analysis identified four metabolites that were significantly downregulated in germ-free mice and were previous reported to be related to human and mouse models of neuropsychiatric disorders, suggesting that microbiota-derived compounds may directly affect brain function and behavior. Together, these data indicate that fear extinction learning requires microbiota-derived signals during both early postnatal neurodevelopment and in adult mice, with implications for our understanding of how diet, infection, and lifestyle influence brain health and subsequent susceptibility to neuropsychiatric disorders.

Why is ketamine an antidepressant? A better understanding of the mechanisms underlying the action of antidepressants is urgently needed. Moda-Sava et al. explored a possible mode of action for the drug ketamine, which has recently been shown to help patients recover from depression (see the Perspective by Beyeler). Ketamine rescued behavior in mice that was associated with depression-like phenotypes by selectively reversing stress-induced spine loss and restoring coordinated multicellular ensemble activity in prefrontal microcircuits. The initial induction of ketamine's antidepressant effect on mouse behavior occurred independently of effects on spine formation. Instead, synaptogenesis in the prefrontal region played a critical role in nourishing these effects over time. Interventions aimed at enhancing the survival of restored synapses may thus be useful for sustaining the behavioral effects of fast-acting antidepressants. Science , this issue p. eaat8078 ; see also p. 129

We report an intensiometric, near-infrared (NIR) fluorescent, genetically encoded calcium ion (Ca 2+ ) indicator (GECI) with excitation and emission maxima at 678 nm and 704 nm, respectively. This GECI, designated NIR-GECO1, enables imaging of Ca 2+ transients in cultured mammalian cells and brain tissue with sensitivity comparable to currently available visible-wavelength GECIs. We demonstrate that NIR-GECO1 opens up new vistas for multicolor Ca 2+ imaging in combination with other optogenetic indicators and actuators.

Fear can be highly adaptive in promoting survival, yet it can also be detrimental when it persists long after a threat has passed. Flexibility of the fear response may be most advantageous during adolescence when animals are prone to explore novel, potentially threatening environments. Two opposing adolescent fear-related behaviours—diminished extinction of cued fear and suppressed expression of contextual fear—may serve this purpose, but the neural basis underlying these changes is unknown. Using microprisms to image prefrontal cortical spine maturation across development, we identify dynamic BLA-hippocampal-mPFC circuit reorganization associated with these behavioural shifts. Exploiting this sensitive period of neural development, we modified existing behavioural interventions in an age-specific manner to attenuate adolescent fear memories persistently into adulthood. These findings identify novel strategies that leverage dynamic neurodevelopmental changes during adolescence with the potential to extinguish pathological fears implicated in anxiety and stress-related disorders.