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.

Neural activity ramps in frontal cortex signal extended motivation during learning.

Learning requires the ability to link actions to outcomes. How motivation facilitates learning is not well understood. We designed a behavioral task in which mice self-initiate trials to learn cue-reward contingencies and found that the anterior cingulate region of the prefrontal cortex (ACC) contains motivation-related signals to maximize rewards. In particular, we found that ACC neural activity was consistently tied to trial initiations where mice seek to leave unrewarded cues to reach reward-associated cues. Notably, this neural signal persisted over consecutive unrewarded cues until reward-associated cues were reached, and was required for learning. To determine how ACC inherits this motivational signal we performed projection-specific photometry recordings from several inputs to ACC during learning. In doing so, we identified a ramp in bulk neural activity in orbitofrontal cortex (OFC)-to-ACC projections as mice received unrewarded cues, which continued ramping across consecutive unrewarded cues, and finally peaked upon reaching a reward-associated cue, thus maintaining an extended motivational state. Cellular resolution imaging of OFC confirmed these neural correlates of motivation, and further delineated separate ensembles of neurons that sequentially tiled the ramp. Together, these results identify a mechanism by which OFC maps out task structure to convey an extended motivational state to ACC to facilitate goal-directed learning.

Achieving goals takes motivation. An individual may have to complete a task many times for a future reward. For example, an animal may have to forage repeatedly to find food, or a person may have to study to get a good grade on a test. How these complex behaviors are encoded in the brain's wiring is not fully understood. Patients with injuries to the frontal cortex of the brain display a lack of motivation to pursue goals. This discovery suggests the frontal cortex plays a vital role in motivation and goal-directed behavior. Animal studies show that part of their brain's frontal cortex, the anterior cingulate cortex (ACC), helps them stay motivated and put extra effort into achieving goals. Yet, scientists wonder how particular actions are associated with specific goals and suspect the orbital frontal cortex (OFC) contains the blueprint to support this association. Regalado et al. show that the OFC and ACC work together during goal-seeking behavior in mice. In the experiments, mice learned to complete a task to achieve a sugar water reward. As the mice were learning, Regalado et al. recorded activity in the ACC and found that the ACC is active during goal-seeking behavior. They also discovered that the activity of neurons in the OFC increased the longer mice went without receiving a reward, up until the reward was achieved, signaling a motivational state. Animals not motivated enough to maximize their rewards did not have an increased OFC activity. The experiments also showed that the motivational signals in the OFC were conveyed to ACC to support goal-directed learning, especially linking actions to positive future outcomes. The experiments help explain how an increase in neuronal activity in the OFC helps to increase motivation and goal-seeking behavior supported by the ACC. More studies will help scientists learn more about these processes and develop drugs or other therapies that can help people who have learning difficulties or struggle with motivation because of an injury or mental illness.

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.

Neural activity ramps in frontal cortex signal extended motivation during learning.

Learning requires the ability to link actions to outcomes. How motivation facilitates learning is not well understood. We designed a behavioral task in which mice self-initiate trials to learn cue-reward contingencies and found that the anterior cingulate region of the prefrontal cortex (ACC) contains motivation-related signals to maximize rewards. In particular, we found that ACC neural activity was consistently tied to trial initiations where mice seek to leave unrewarded cues to reach reward-associated cues. Notably, this neural signal persisted over consecutive unrewarded cues until reward associated cues were reached, and was required for learning. To determine how ACC inherits this motivational signal we performed projection specific photometry recordings from several inputs to ACC during learning. In doing so, we identified a ramp in bulk neural activity in orbitofrontal cortex (OFC) -to-ACC projections as mice received unrewarded cues, which continued ramping across consecutive unrewarded cues, and finally peaked upon reaching a reward associated cue, thus maintaining an extended motivational state. Cellular resolution imaging of OFC confirmed these neural correlates of motivation, and further delineated separate ensembles of neurons that sequentially tiled the ramp. Together, these results identify a mechanism by which OFC maps out task structure to convey an extended motivational state to ACC to facilitate goal-directed learning.

Increased food intake after starvation enhances sleep in Drosophila melanogaster.

Feeding and sleep are highly conserved, interconnected behaviors essential for survival. Starvation has been shown to potently suppress sleep across species; however, whether satiety promotes sleep is still unclear. Here we use the fruit fly, Drosophila melanogaster, as a model organism to address the interaction between feeding and sleep. We first monitored the sleep of flies that had been starved for 24 h and found that sleep amount increased in the first 4 h after flies were given food. Increased sleep after starvation was due to an increase in sleep bout number and average sleep bout length. Mutants of translin or adipokinetic hormone, which fail to suppress sleep during starvation, still exhibited a sleep increase after starvation, suggesting that sleep increase after starvation is not a consequence of sleep loss during starvation. We also found that feeding activity and food consumption were higher in the first 10-30 min after starvation. Restricting food consumption in starved flies to 30 min was sufficient to increase sleep for 1 h. Although flies ingested a comparable amount of food at differing sucrose concentrations, sleep increase after starvation on a lower sucrose concentration was undetectable. Taken together, our results suggest that increased food intake after starvation enhances sleep and reveals a novel relationship between feeding and sleep.

Enhanced Sleep Is an Evolutionarily Adaptive Response to Starvation Stress in Drosophila.

Animals maximize fitness by modulating sleep and foraging strategies in response to changes in nutrient availability. Wild populations of the fruit fly, Drosophila melanogaster, display highly variable levels of starvation and desiccation resistance that differ in accordance with geographic location, nutrient availability, and evolutionary history. Further, flies potently modulate sleep in response to changes in food availability, and selection for starvation resistance enhances sleep, revealing strong genetic relationships between sleep and nutrient availability. To determine the genetic and evolutionary relationship between sleep and nutrient deprivation, we assessed sleep in flies selected for desiccation or starvation resistance. While starvation resistant flies have higher levels of triglycerides, desiccation resistant flies have enhanced glycogen stores, indicative of distinct physiological adaptations to food or water scarcity. Strikingly, selection for starvation resistance, but not desiccation resistance, leads to increased sleep, indicating that enhanced sleep is not a generalized consequence of higher energy stores. Thermotolerance is not altered in starvation or desiccation resistant flies, providing further evidence for context-specific adaptation to environmental stressors. F2 hybrid flies were generated by crossing starvation selected flies with desiccation selected flies, and the relationship between nutrient deprivation and sleep was examined. Hybrids exhibit a positive correlation between starvation resistance and sleep, while no interaction was detected between desiccation resistance and sleep, revealing that prolonged sleep provides an adaptive response to starvation stress. Therefore, these findings demonstrate context-specific evolution of enhanced sleep in response to chronic food deprivation, and provide a model for understanding the evolutionary relationship between sleep and nutrient availability.