Anteromedial thalamus gates the selection and stabilization of long-term memories.

Memories initially formed in hippocampus gradually stabilize to cortex over weeks-to-months for long-term storage. The mechanistic details of this brain re-organization remain poorly understood. We recorded bulk neural activity in circuits that link hippocampus and cortex as mice performed a memory-guided virtual-reality task over weeks. We identified a prominent and sustained neural correlate of memory in anterior thalamus, whose inhibition substantially disrupted memory consolidation. More strikingly, gain amplification enhanced consolidation of otherwise unconsolidated memories. To gain mechanistic insights, we developed a technology for simultaneous cellular-resolution imaging of hippocampus, thalamus, and cortex throughout consolidation. We found that whereas hippocampus equally encodes multiple memories, the anteromedial thalamus preferentially encodes salient memories, and gradually increases correlations with cortex to facilitate tuning and synchronization of cortical ensembles. We thus identify a thalamo-cortical circuit that gates memory consolidation and propose a mechanism suitable for the selection and stabilization of hippocampal memories into longer-term cortical storage.

A Thalamic Orphan Receptor Drives Variability in Short-Term Memory.

Working memory is a form of short-term memory that involves maintaining and updating task-relevant information toward goal-directed pursuits. Classical models posit persistent activity in prefrontal cortex (PFC) as a primary neural correlate, but emerging views suggest additional mechanisms may exist. We screened ∼200 genetically diverse mice on a working memory task and identified a genetic locus on chromosome 5 that contributes to a substantial proportion (17%) of the phenotypic variance. Within the locus, we identified a gene encoding an orphan G-protein-coupled receptor, Gpr12, which is sufficient to drive substantial and bidirectional changes in working memory. Molecular, cellular, and imaging studies revealed that Gpr12 enables high thalamus-PFC synchrony to support memory maintenance and choice accuracy. These findings identify an orphan receptor as a potent modifier of short-term memory and supplement classical PFC-based models with an emerging thalamus-centric framework for the mechanistic understanding of working memory.

Prefrontal feature representations drive memory recall.

Memory formation involves binding of contextual features into a unitary representation1-4, whereas memory recall can occur using partial combinations of these contextual features. The neural basis underlying the relationship between a contextual memory and its constituent features is not well understood; in particular, where features are represented in the brain and how they drive recall. Here, to gain insight into this question, we developed a behavioural task in which mice use features to recall an associated contextual memory. We performed longitudinal imaging in hippocampus as mice performed this task and identified robust representations of global context but not of individual features. To identify putative brain regions that provide feature inputs to hippocampus, we inhibited cortical afferents while imaging hippocampus during behaviour. We found that whereas inhibition of entorhinal cortex led to broad silencing of hippocampus, inhibition of prefrontal anterior cingulate led to a highly specific silencing of context neurons and deficits in feature-based recall. We next developed a preparation for simultaneous imaging of anterior cingulate and hippocampus during behaviour, which revealed robust population-level representation of features in anterior cingulate, that lag hippocampus context representations during training but dynamically reorganize to lead and target recruitment of context ensembles in hippocampus during recall. Together, we provide the first mechanistic insights into where contextual features are represented in the brain, how they emerge, and how they access long-range episodic representations to drive memory recall.

The Drosophila blood-brain barrier regulates sleep via Moody G protein-coupled receptor signaling.

Sleep is vital for most animals, yet its mechanism and function remain unclear. We found that permeability of the BBB (blood-brain barrier)-the organ required for the maintenance of homeostatic levels of nutrients, ions, and other molecules in the brain-is modulated by sleep deprivation (SD) and can cell-autonomously effect sleep changes. We observed increased BBB permeability in known sleep mutants as well as in acutely sleep-deprived animals. In addition to molecular tracers, SD-induced BBB changes also increased the penetration of drugs used in the treatment of brain pathologies. After chronic/genetic or acute SD, rebound sleep or administration of the sleeping aid gaboxadol normalized BBB permeability, showing that SD effects on the BBB are reversible. Along with BBB permeability, RNA levels of the BBB master regulator moody are modulated by sleep. Conversely, altering BBB permeability alone through glia-specific modulation of moody, gαo, loco, lachesin, or neuroglian-each a well-studied regulator of BBB function-was sufficient to induce robust sleep phenotypes. These studies demonstrate a tight link between BBB permeability and sleep and indicate a unique role for the BBB in the regulation of sleep.

Genetic mapping identifies Homer1 as a developmental modifier of attention.

Attention is required for most higher-order cognitive functions. Prior studies have revealed functional roles for the prefrontal cortex and its extended circuits to enabling attention, but the underlying molecular processes and their impacts on cellular and circuit function remain poorly understood. To develop insights, we here took an unbiased forward genetics approach to identify single genes of large effect on attention. We studied 200 genetically diverse mice on measures of pre-attentive processing and through genetic mapping identified a small locus on chromosome 13 (95%CI: 92.22-94.09 Mb) driving substantial variation (19%) in this trait. Further characterization of the locus revealed a causative gene, Homer1, encoding a synaptic protein, where down-regulation of its short isoforms in prefrontal cortex (PFC) during early postnatal development led to improvements in multiple measures of attention in the adult. Subsequent mechanistic studies revealed that prefrontal Homer1 down-regulation is associated with GABAergic receptor up-regulation in those same cells. This enhanced inhibitory influence, together with dynamic neuromodulatory coupling, led to strikingly low PFC activity at baseline periods of the task but targeted elevations at cue onset, predicting short-latency correct choices. Notably high-Homer1, low-attentional performers, exhibited uniformly elevated PFC activity throughout the task. We thus identify a single gene of large effect on attention - Homer1 - and find that it improves prefrontal inhibitory tone and signal-to-noise (SNR) to enhance attentional performance. A therapeutic strategy focused on reducing prefrontal activity and increasing SNR, rather than uniformly elevating PFC activity, may complement the use of stimulants to improve attention.

Anteromedial Thalamus Gates the Selection & Stabilization of Long-Term Memories.

Memories initially formed in hippocampus gradually stabilize to cortex, over weeks-to-months, for long-term storage. The mechanistic details of this brain re-organization process remain poorly understood. In this study, we developed a virtual-reality based behavioral task and observed neural activity patterns associated with memory reorganization and stabilization over weeks-long timescales. Initial photometry recordings in circuits that link hippocampus and cortex revealed a unique and prominent neural correlate of memory in anterior thalamus that emerged in training and persisted for several weeks. Inhibition of the anteromedial thalamus-to-anterior cingulate cortex projections during training resulted in substantial memory consolidation deficits, and gain amplification more strikingly, was sufficient to enhance consolidation of otherwise unconsolidated memories. To provide mechanistic insights, we developed a new behavioral task where mice form two memories, of which only the more salient memory is consolidated, and also a technology for simultaneous and longitudinal cellular resolution imaging of hippocampus, thalamus, and cortex throughout the consolidation window. We found that whereas hippocampus equally encodes multiple memories, the anteromedial thalamus forms preferential tuning to salient memories, and establishes inter-regional correlations with cortex, that are critical for synchronizing and stabilizing cortical representations at remote time. Indeed, inhibition of this thalamo-cortical circuit while imaging in cortex reveals loss of contextual tuning and ensemble synchrony in anterior cingulate, together with behavioral deficits in remote memory retrieval. We thus identify a thalamo-cortical circuit that gates memory consolidation and propose a mechanism suitable for the selection and stabilization of hippocampal memories into longer term cortical storage.

FGF receptors are required for proper axonal branch targeting in Drosophila.

Proper axonal branch growth and targeting are essential for establishing a hard-wired neural circuit. Here, we examined the role of Fibroblast Growth Factor Receptors (FGFRs) in axonal arbor development using loss of function and overexpression genetic analyses within single neurons. We used the invariant synaptic connectivity patterns of Drosophila mechanosensory neurons with their innate cleaning reflex responses as readouts for errors in synaptic targeting and circuit function. FGFR loss of function resulted in a decrease in axonal branch number and lengths, and overexpression of FGFRs resulted in ectopic branches and increased lengths. FGFR mutants produced stereotyped axonal targeting errors. Both loss of function and overexpression of FGFRs within the mechanosensory neuron decreased the animal's frequency of response to mechanosensory stimulation. Our results indicate that FGFRs promote axonal branch growth and proper branch targeting. Disrupting FGFRs results in miswiring and impaired neural circuit function.