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.

Beyond hippocampus: Thalamic and prefrontal contributions to an evolving memory.

The hippocampus has long been at the center of memory research, and rightfully so. However, with emerging technological capabilities, we can increasingly appreciate memory as a more dynamic and brain-wide process. In this perspective, our goal is to begin developing models to understand the gradual evolution, reorganization, and stabilization of memories across the brain after their initial formation in the hippocampus. By synthesizing studies across the rodent and human literature, we suggest that as memory representations initially form in hippocampus, parallel traces emerge in frontal cortex that cue memory recall, and as they mature, with sustained support initially from limbic then diencephalic then cortical circuits, they become progressively independent of hippocampus and dependent on a mature cortical representation. A key feature of this model is that, as time progresses, memory representations are passed on to distinct circuits with progressively longer time constants, providing the opportunity to filter, forget, update, or reorganize memories in the process of committing to long-term storage.

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.

Oral Feeding of Cow Milk Containing A1 Variant of ß Casein Induces Pulmonary Inflammation in Male Balb/c Mice.

Milk is globally consumed as a rich source of protein and calcium. A major protein component of milk is casein, with ß-casein having 2 major variants A1 and A2. Of these, A1 casein variant has been implicated as a potential etiological factor in several pathologies, but direct effect on lungs has not been studied. The objective of the present study was to evaluate the A1and A2 ß casein variants of cow milk as factors causing allergic airway disease in murine model. Mice fed with A1A1 milk exhibited increased airway hyperresponsiveness with increasing concentration of bronchoconstrictor (methacholine), which was not observed in mice fed with A2A2 milk. Significantly elevated levels of IL-4 and IL-5 were found in bronchoalveolar lavage and serum of A1A1 variant fed mice. Increased IgE and IgG levels along with increased infiltration of lymphocytes and eosinophils, leading to peribronchial inflammation was also observed in A1A1 variant fed mice, although, no goblet cell hyperplasia or airway remodeling was observed. In contrast, A2A2 milk fed mice presented phenotype matching the control group, while A1A2 milk fed group presented an intermediate phenotype. In summary, our results show that A1 form of cow milk has a proinflammatory effect on the lung resulting in phenotype closely matching with the typical allergic asthma phenotype.