SUMMARY There is emerging evidence that circadian misalignment may alter energy expenditure, leading to obesity risk among those with irregular schedules[1–5]. It has been reported that energy expenditure is affected by the timing of sleep, exercise, and meals[6]. However, it is unclear whether the circadian system also modulates energy expenditure, independent of behavioral state and food intake. Here, we used a forced desynchrony protocol to examine whether fasted resting energy expenditure (REE) varies with circadian phase in 7 participants. This protocol allowed us to uncouple sleep-wake and activity-related effects from the endogenous circadian rhythm, demonstrating that REE varies by circadian phase. REE is lowest at circadian phase ~0°, corresponding to the endogenous core body temperature (CBT) nadir in the late biological night, and highest at circadian phase ~180° in the biological afternoon/evening. Furthermore, we found that respiratory quotient (RQ), reflecting macronutrient utilization, also varies by circadian phase. RQ is lowest at circadian phase ~240° and highest at circadian phase ~60°, which corresponds to biological morning. This is the first characterization of a circadian profile in fasted resting energy expenditure and fasted respiratory quotient (with rhythmic profiles in both carbohydrate and lipid oxidation), decoupled from effects of activity, sleep-wake cycle, and diet in humans. The rhythm in energy expenditure and macronutrient metabolism may contribute to greater weight gain in shift workers and others with irregular schedules.

Compared with the dorsal hippocampus, relatively few studies have characterized neuronal responses in the ventral hippocampus. In particular, it is unclear whether and how cells in the ventral region represent space and/or respond to contextual changes. We recorded from dorsal and ventral CA1 neurons in freely moving mice exposed to manipulations of visuospatial and olfactory contexts. We found that ventral cells respond to alterations of the visuospatial environment such as exposure to novel local cues, cue rotations, and contextual expansion in similar ways to dorsal cells, with the exception of cue rotations. Furthermore, we found that ventral cells responded to odors much more strongly than dorsal cells, particularly to odors of high valence. Similar to earlier studies recording from the ventral hippocampus in CA3, we also found increased scaling of place cell field size along the longitudinal hippocampal axis. Although the increase in place field size observed toward the ventral pole has previously been taken to suggest a decrease in spatial information coded by ventral place cells, we hypothesized that a change in spatial scaling could instead signal a shift in representational coding that preserves the resolution of spatial information. To explore this possibility, we examined population activity using principal component analysis (PCA) and neural location reconstruction techniques. Our results suggest that ventral populations encode a distributed representation of space, and that the resolution of spatial information at the population level is comparable to that of dorsal populations of similar size. Finally, through the use of neural network modeling, we suggest that the redundancy in spatial representation along the longitudinal hippocampal axis may allow the hippocampus to overcome the conflict between memory interference and generalization inherent in neural network memory. Our results indicate that ventral population activity is well suited for generalization across locations and contexts.

Fear is an emotional response to danger that is highly conserved throughout evolution because it is critical for survival. Accordingly, episodic memory for fearful locations is widely studied using contextual fear conditioning, a hippocampus-dependent task (Kim and Fanselow, 1992; Phillips and LeDoux, 1992). The hippocampus has been implicated in episodic emotional memory and is thought to integrate emotional stimuli within a spatial framework. Physiological evidence supporting the role of the hippocampus in contextual fear indicates that pyramidal cells in this region, which fire in specific locations as an animal moves through an environment, shift their preferred firing locations shortly after the presentation of an aversive stimulus (Moita et al., 2004). However, the long-term physiological mechanisms through which emotional memories are encoded by the hippocampus are unknown. Here we show that during and directly after a fearful experience, new hippocampal representations are established and persist in the long term. We recorded from the same place cells in mouse hippocampal area CA1 over several days during predator odor contextual fear conditioning and found that a subset of cells changed their preferred firing locations in response to the fearful stimulus. Furthermore, the newly formed representations of the fearful context stabilized in the long term. Our results demonstrate that place cells respond to the presence of an aversive stimulus, modify their firing patterns during emotional learning, and stabilize a long-term spatial representation in response to a fearful encounter. The persistent nature of these representations may contribute to the enduring quality of emotional memories.