Cells regulate function by synthesizing and degrading proteins. This turnover ranges from minutes to weeks, as it varies across proteins, cellular compartments, cell types, and tissues. Current methods for tracking protein turnover lack the spatial and temporal resolution needed to investigate these processes, especially in the intact brain, which presents unique challenges. We describe a pulse-chase method (DELTA) for measuring protein turnover with high spatial and temporal resolution throughout the body, including the brain. DELTA relies on rapid covalent capture by HaloTag of fluorophores that were optimized for bioavailability in vivo. The nuclear protein MeCP2 showed brain region- and cell type-specific turnover. The synaptic protein PSD95 was destabilized in specific brain regions by behavioral enrichment. A novel variant of expansion microscopy further facilitated turnover measurements at individual synapses. DELTA enables studies of adaptive and maladaptive plasticity in brain-wide neural circuits.

To successfully perform goal-directed navigation, animals must know where they are and what they are doing-e.g., looking for water, bringing food back to the nest, or escaping from a predator. Hippocampal neurons code for these critical variables conjunctively, but little is known about how this "where/what" code is formed or flexibly routed to other brain regions. To address these questions, we performed intracellular whole-cell recordings in mouse CA1 during a cued, two-choice virtual navigation task. We demonstrate that plateau potentials in CA1 pyramidal neurons rapidly strengthen synaptic inputs carrying conjunctive information about position and choice. Plasticity-induced response fields were modulated by cues only in animals previously trained to collect rewards based on available cues. Thus, we reveal that gradual learning is required for the formation of a conjunctive population code, upstream of CA1, while plateau-potential-induced synaptic plasticity in CA1 enables flexible routing of the code to downstream brain regions.

Neural circuits within the frontal cortex support the flexible selection of goal-directed behaviors by integrating input from brain regions associated with sensory, emotional, episodic, and semantic memory functions. From a connectomics perspective, determining how these disparate afferent inputs target their synapses to specific cell types in the frontal cortex may prove crucial in understanding circuit-level information processing. Here, we used monosynaptic retrograde rabies mapping to examine the distribution of afferent neurons targeting four distinct classes of local inhibitory interneurons and four distinct classes of excitatory projection neurons in mouse infralimbic cortex. Interneurons expressing parvalbumin, somatostatin, or vasoactive intestinal peptide received a large proportion of inputs from hippocampal regions, while interneurons expressing neuron-derived neurotrophic factor received a large proportion of inputs from thalamic regions. A more moderate hippocampal-thalamic dichotomy was found among the inputs targeting excitatory neurons that project to the basolateral amygdala, lateral entorhinal cortex, nucleus reuniens of the thalamus, and the periaqueductal gray. Together, these results show a prominent bias among hippocampal and thalamic afferent systems in their targeting to genetically or anatomically defined sets of frontal cortical neurons. Moreover, they suggest the presence of two distinct local microcircuits that control how different inputs govern frontal cortical information processing.

Our ability to remember the past is essential for guiding our future behavior. Psychological and neurobiological features of declarative memories are known to transform over time in a process known as systems consolidation. While many theories have sought to explain the time-varying role of hippocampal and neocortical brain areas, the computational principles that govern these transformations remain unclear. Here we propose a theory of systems consolidation in which hippocampal-cortical interactions serve to optimize generalizations that guide future adaptive behavior. We use mathematical analysis of neural network models to characterize fundamental performance tradeoffs in systems consolidation, revealing that memory components should be organized according to their predictability. The theory shows that multiple interacting memory systems can outperform just one, normatively unifying diverse experimental observations and making novel experimental predictions. Our results suggest that the psychological taxonomy and neurobiological organization of declarative memories reflect a system optimized for behaving well in an uncertain future.

To successfully perform goal-directed navigation, animals must know where they are and what they are doing—e.g., looking for water, bringing food back to the nest, or escaping from a predator. Hippocampal neurons code for these critical variables conjunctively, but little is known about how this where/what code is formed or flexibly routed to other brain regions. To address these questions, we performed intracellular whole-cell recordings in mouse CA1 during a cued, two-choice virtual navigation task. We demonstrate that plateau potentials in CA1 pyramidal neurons rapidly strengthen synaptic inputs carrying conjunctive information about position and choice. Plasticity-induced response fields were modulated by cues only in animals previously trained to collect rewards based on these cues. Thus, we reveal that gradual learning is required for the formation of a conjunctive population code, upstream of CA1, while plateau-potential-induced synaptic plasticity in CA1 enables flexible routing of the code to downstream brain regions.

To study how the brain drives cognition and behavior we need to understand its cellular composition. Advances in single-cell transcriptomics have revolutionized our ability to characterize neuronal diversity. To arrive at meaningful descriptions of cell types, however, gene expression must be linked to structural and functional properties. Axonal projection patterns are an appropriate measure, as they are diverse, change only gradually over time, and they influence and constrain circuit function. Here, we consider how efforts to map transcriptional and morphological diversity in the mouse brain could be linked to generate a modern taxonomy of the mouse brain.

To study how the brain drives cognition and behavior we need to understand its cellular composition. Advances in single-cell transcriptomics have revolutionized our ability to characterize neuronal diversity. To arrive at meaningful descriptions of cell types, however, gene expression must be linked to structural and functional properties. Axonal projection patterns are an appropriate measure, as they are diverse, change only gradually over time, and they influence and constrain circuit function. Here, we consider how efforts to map transcriptional and morphological diversity in the mouse brain could be linked to generate a modern taxonomy of the mouse brain.

As animals navigate, they must identify features within context. In the mammalian brain, the hippocampus has the ability to separately encode different environmental contexts, even when they share some prominent features. To do so, neurons respond to sensory features in a context-dependent manner; however, it is not known how this encoding emerges. To examine this, we performed electrical recordings in the hippocampus as mice navigated in two distinct virtual environments. In CA1, both synaptic input to single neurons and population activity strongly tracked visual cues in one environment, whereas responses were almost completely absent when the same cue was presented in a second environment. A very similar, highly context-dependent pattern of cue-driven spiking was also observed in CA3. These results indicate that CA1 inherits a complex spatial code from upstream regions, including CA3, that have already computed a context-dependent representation of environmental features.

Animals can store information about experiences by activating specific neuronal populations, and subsequent reactivation of these neural ensembles can lead to recall of salient experiences. In the hippocampus, granule cells of the dentate gyrus participate in such memory engrams; however, whether there is an underlying logic to granule cell participation has not been examined. Here, we find that a range of novel experiences preferentially activates granule cells of the suprapyramidal blade relative to the infrapyramidal blade. Motivated by this, we identify a suprapyramidal-blade-enriched population of granule cells with distinct spatial, morphological, physiological, and developmental properties. Via transcriptomics, we map these traits onto a sparse and discrete granule cell subtype that is recruited at a 10-fold greater frequency than expected by subtype prevalence, constituting the majority of all recruited granule cells. Thus, in behaviors known to involve hippocampal-dependent memory formation, a rare and spatially localized subtype dominates overall granule cell recruitment.