Anticipating future outcomes is a fundamental task of the brain1-3. This process requires learning the states of the world as well as the transitional relationships between those states. In rodents, the hippocampal spatial cognitive map is thought to be one such internal model4. However, evidence for predictive coding5,6 and reward sensitivity7-10 in the hippocampal neuronal representation suggests that its role extends beyond purely spatial representation. How this reward representation evolves over extended experience remains unclear. Here we track the evolution of the hippocampal reward representation over weeks as mice learn to solve a cognitively demanding reward-based task. We find several lines of evidence, both at the population and the single-cell level, indicating that the hippocampal representation becomes predictive of reward as the mouse learns the task over several weeks. Both the population-level encoding of reward and the proportion of reward-tuned neurons decrease with experience. At the same time, the representation of features that precede the reward increases with experience. By tracking reward-tuned neurons over time, we find that their activity gradually shifts from encoding the reward itself to representing preceding task features, indicating that experience drives a backward-shifted reorganization of neural activity to anticipate reward. We show that a temporal difference model of place fields11 recapitulates these results. Our findings underscore the dynamic nature of hippocampal representations, and highlight their role in learning through the prediction of future outcomes.

Social valence is the directional emotional significance affiliated with social experiences. Maladaptive social information processing has been linked to mood disorder susceptibility, which is more prevalent in women. To determine whether there are sex differences in social valence processing, we employed behavioral tasks that associated conspecific identity recognition with either positive or negative valence, as well as tasks in which valence information originated from social targets. Male mice demonstrated identity recognition regardless of social valence. While male and female mice performed similarly in the positive social valence task, female mice did not show identity recognition following the negative social valence task. In vivo calcium imaging of the dorsal CA1 further revealed sex differences in negative social valence processing with reduced hippocampal representation of social information in female mice. Finally, enhancing dorsal CA1 neuronal activity by ampakine rescued identity recognition in female mice. These results suggest that sex differences in social valence processing may contribute to the heightened vulnerability to social stress-related mood disorders in women.

Decades of theoretical and empirical work have suggested the hippocampus instantiates some form of a cognitive map. Yet, tests of competing theories have been limited in scope and largely qualitative in nature. Here, we develop a novel framework to benchmark model predictions against observed neuronal population dynamics as animals navigate a series of geometrically distinct environments. In this task space, we show a representational structure in the dynamics of hippocampal remapping that generalizes across brains, discriminates between competing theoretical models, and effectively constrains biologically viable model parameters. With this approach, we find that accurate models capture the correspondence in spatial coding of a changing environment. The present dataset and framework thus serve to empirically evaluate and advance theories of cognitive mapping in the brain.

Vasoactive intestinal peptide (VIP) cells have emerged as a crucial component of the inhibitory network, facilitating interregional communication, particularly in the context of associative memory. To expand our current understanding of the role of this population, we combine anatomical and functional approaches to question the influence of VIP cells in the medial entorhinal cortex (MEC), a region key for navigation and spatial memory. From our anatomical tracing study, our findings reveal that neurons located in the anterodorsal thalamic nucleus (ADN) specifically project onto MEC interneurons, with a strong preference for MEC VIP cells. Additionally, MEC VIP cells receive input from the hippocampus, the subicular complex, and the retrosplenial cortex, suggesting a specialized role for MEC VIP cells in spatial memory. Indeed, we find that MEC VIP cells exhibit increased c-Fos expression in a spatial memory task and show that chemogenetic inhibition of these neurons impairs task performance. Together, these data reveal a specific projection of head-direction (HD) information onto MEC interneurons and confirm that MEC VIP-expressing cells play a critical role in spatial memory.

A deep understanding of how the brain controls behaviour requires mapping neural circuits down to the muscles that they control. Here, we apply automated tools to segment neurons and identify synapses in an electron microscopy dataset of an adult female Drosophila melanogaster ventral nerve cord (VNC)1, which functions like the vertebrate spinal cord to sense and control the body. We find that the fly VNC contains roughly 45 million synapses and 14,600 neuronal cell bodies. To interpret the output of the connectome, we mapped the muscle targets of leg and wing motor neurons using genetic driver lines2 and X-ray holographic nanotomography3. With this motor neuron atlas, we identified neural circuits that coordinate leg and wing movements during take-off. We provide the reconstruction of VNC circuits, the motor neuron atlas and tools for programmatic and interactive access as resources to support experimental and theoretical studies of how the nervous system controls behaviour.

In most complex nervous systems there is a clear anatomical separation between the nerve cord, which contains most of the final motor outputs necessary for behaviour, and the brain. In insects, the neck connective is both a physical and information bottleneck connecting the brain and the ventral nerve cord (VNC, spinal cord analogue) and comprises diverse populations of descending (DN), ascending (AN) and sensory ascending neurons, which are crucial for sensorimotor signalling and control. Integrating three separate EM datasets, we now provide a complete connectomic description of the ascending and descending neurons of the female nervous system of Drosophila and compare them with neurons of the male nerve cord. Proofread neuronal reconstructions have been matched across hemispheres, datasets and sexes. Crucially, we have also matched 51% of DN cell types to light level data defining specific driver lines as well as classifying all ascending populations. We use these results to reveal the general architecture, tracts, neuropil innervation and connectivity of neck connective neurons. We observe connected chains of descending and ascending neurons spanning the neck, which may subserve motor sequences. We provide a complete description of sexually dimorphic DN and AN populations, with detailed analysis of circuits implicated in sex-related behaviours, including female ovipositor extrusion (DNp13), male courtship (DNa12/aSP22) and song production (AN hemilineage 08B). Our work represents the first EM-level circuit analyses spanning the entire central nervous system of an adult animal.

Animal movement is controlled by motor neurons (MNs), which project out of the central nervous system to activate muscles1. MN activity is coordinated by complex premotor networks that facilitate the contribution of individual muscles to many different behaviours2-6. Here we use connectomics7 to analyse the wiring logic of premotor circuits controlling the Drosophila leg and wing. We find that both premotor networks cluster into modules that link MNs innervating muscles with related functions. Within most leg motor modules, the synaptic weights of each premotor neuron are proportional to the size of their target MNs, establishing a circuit basis for hierarchical MN recruitment. By contrast, wing premotor networks lack proportional synaptic connectivity, which may enable more flexible recruitment of wing steering muscles. Through comparison of the architecture of distinct motor control systems within the same animal, we identify common principles of premotor network organization and specializations that reflect the unique biomechanical constraints and evolutionary origins of leg and wing motor control.

Head-direction (HD) cells are found across several regions in the brain, including the anterodorsal thalamic nucleus (ADN), the subicular complex, and the medial entorhinal cortex (MEC). A fundamental role of head direction cells is to provide input to MEC grid cells, which are thought to translate information about head direction into a metric code for spatial location. However, classic anatomical studies indicate that most thalamic HD projections pass indirectly to the MEC via the post- and para-subiculum, with only a small subset of ADN fibers terminating in the MEC. To further investigate the smaller and direct projection to the MEC, we use rabies-mediated retrograde tracing in mice to determine if this projection explicitly targets a subset of MEC neurons. Our findings reveal that ADN neurons specifically project onto MEC interneurons, with a preference for MEC VIP-expressing cells. Additionally, MEC VIP cells receive input from the hippocampus, the subicular complex, and the retrosplenial cortex - key centers for spatial memory - suggesting a specialized role for MEC VIP cells in spatial memory. Indeed, we find that MEC VIP cells exhibit increased c-Fos expression in a spatial memory task and show that chemogenetic inhibition of these neurons impairs task performance. Together, these data uncover a specific projection of head direction information onto MEC interneurons and confirm that MEC VIP-expressing cells are critical for spatial memory. ### Competing Interest Statement The authors have declared no competing interest.

The hippocampus and medial entorhinal cortex (MEC) form a cognitive map that facilitates spatial navigation. As part of this map, MEC grid cells fire in a repeating hexagonal pattern across an environment. This grid pattern relies on inputs from the medial septum (MS). The MS, and specifically GABAergic neurons, are essential for theta rhythm oscillations in the entorhinal-hippocampal network; however, the role of this population in grid cell function is unclear. To investigate this, we use optogenetics to inhibit MS-GABAergic neurons and observe that MS-GABAergic inhibition disrupts grid cell spatial periodicity. Grid cell spatial periodicity is disrupted during both optogenetic inhibition periods and short inter-stimulus intervals. In contrast, longer inter-stimulus intervals allow for the recovery of grid cell spatial firing. In addition, grid cell phase precession is also disrupted. These findings highlight the critical role of MS-GABAergic neurons in maintaining grid cell spatial and temporal coding in the MEC.

In this issue of Neuron, Khatib et al.(1) and Geva et al.(2) present complementary and breakthrough discoveries demonstrating that elapsed time and active experience independently affect unique aspects of representational drift in the hippocampus.

Summary The dorsal and ventral regions of the hippocampus (dCA1 and vCA1) are critical for contextual fear conditioning tasks, yet the dynamics of hippocampal neuronal representations during memory acquisition, retrieval, and extinction processes have yet to be fully elucidated. The canonical theory is that the hippocampus generates and retrieves spatial maps of contexts during memory acquisition and retrieval. It is hypothesized the hippocampus prevents memory interference by generating context representations that are dissimilar and the prediction follows that representation dissimilarity facilitates discrimination between contexts. Here, we developed a context fear memory retrieval task and combined it with 1-photon neuronal imaging in dCA1 and vCA1 of freely behaving mice to test this prediction. We identified several phenomena specific to vCA1. First, fear conditioning induced an immediate and strong representational change that was predictive of freezing behavior. During context discrimination, vCA1 representations of the threatening and neutral contexts became more similar. Third, during threatening context memory retrieval, vCA1 expressed rapid and strong context representations. These unexpected results suggest that representational similarity in vCA1 facilitates faster and more efficient network state transitions. In further support of this view, both phenomena of representational similarity and rapid context recall were no longer observed in vCA1 once fear behavior was extinguished. Together, these results reveal that vCA1 unexpectedly generates similar population codes, promoting faster transitions between network states essential for contextual fear memory retrieval. Highlights We established a novel context teleportation task that allows population level hippocampal recordings during key moments of threat memory acquisition, retrieval, and extinction. The ventral region of CA1 (vCA1) exhibited the greatest change in neural representation during fear memory acquisition, compared to dorsal CA1 (dCA1). After fear conditioning, representations for threatening and neutral contexts were more similar in vCA1 compared to dCA1, yet representational similarity in vCA1 supported rapid context memory retrieval. Context fear memory extinction reversed the context representation in vCA1 to patterns observed prior to fear conditioning. Graphical Abstract

The head direction (HD) system functions as the brain's internal compass1,2, classically formalized as a one-dimensional ring attractor network3,4. In contrast to a globally consistent magnetic compass, the HD system does not have a universal reference frame. Instead, it anchors to local cues, maintaining a stable offset when cues rotate5-8 and drifting in the absence of referents5,8-10. However, questions about the mechanisms that underlie anchoring and drift remain unresolved and are best addressed at the population level. For example, the extent to which the one-dimensional description of population activity holds under conditions of reorientation and drift is unclear. Here we performed population recordings of thalamic HD cells using calcium imaging during controlled rotations of a visual landmark. Across experiments, population activity varied along a second dimension, which we refer to as network gain, especially under circumstances of cue conflict and ambiguity. Activity along this dimension predicted realignment and drift dynamics, including the speed of network realignment. In the dark, network gain maintained a 'memory trace' of the previously displayed landmark. Further experiments demonstrated that the HD network returned to its baseline orientation after brief, but not longer, exposures to a rotated cue. This experience dependence suggests that memory of previous associations between HD neurons and allocentric cues is maintained and influences the internal HD representation. Building on these results, we show that continuous rotation of a visual landmark induced rotation of the HD representation that persisted in darkness, demonstrating experience-dependent recalibration of the HD system. Finally, we propose a computational model to formalize how the neural compass flexibly adapts to changing environmental cues to maintain a reliable representation of HD. These results challenge classical one-dimensional interpretations of the HD system and provide insights into the interactions between this system and the cues to which it anchors.

Summary The involvement of rapid-eye-movement sleep (REMs) in spatial memory formation was recently demonstrated, although how neural activity during REMs influences newly-formed place field stability remains unclear. Here, we combined large-scale single-unit recordings of mouse hippocampal CA1 with an established optogenetic approach enabling REMs-selective inhibition of medial septum GABAergic neurons (MSGABA), resulting in spatial memory deficits when applied post-learning. Although individual neural activity was unaffected by REMs-selective MSGABA inhibition during a post-learning rest session, both the synchrony of population-level activity bursts observed during REMs occurring in the rest session and place field stability measured during subsequent memory recall testing were reduced vs controls. However, the latter effect was limited to place cells participating in population activity during REMs, as stability of non-participant place cells was relatively weak and indifferent between groups. This suggests that synchronous CA1 population activity during REMs stabilizes spatial representations in a plastic subpopulation of participating CA1 neurons.

This dataset contains the data used in this research from each experiment. Data in each experiment is summarized in a Matlab structure array with the following variables: - Deconvolved_spikes: as obtained using the algorithm from Friedrich et al., 2017 (see references in the paper). - measured_HD: from the behavioral camera. - visual_cue_angle - event_start_all: Time stamp of the beginning of each event (i.e.: baseline, shifted-cue event, darkness, cue-rotation). - event_length_all: Duration, in frames, of each event. internal_HD: decoded head direction from neural activity using the algorithm from Wei et al., 2020 (see references in the paper). mouse_ID: Mouse ID RawTraces: Calcium traces obtained using the miniscope algorithm (miniscope.org (2018)) cue_rotation: Direction of cue rotation in the cue rotation experiment.IMPORTANT: The dataset should not be used for republication without prior consent from the authors.

Converging evidence from human and rodent studies suggests that disrupted grid cell coding in the medial entorhinal cortex (MEC) underlies path integration behavioral deficits during early Alzheimer's disease (AD). However, grid cell firing relies on both self-motion cues and environmental features, and it remains unclear whether disrupted grid coding can account for specific path integration deficits reported during early AD. Here, we report in the J20 transgenic amyloid beta (Aβ) mouse model of early AD that grid cells were spatially unstable toward the center of the arena, had qualitatively different spatial components that aligned parallel to the borders of the environment, and exhibited impaired integration of distance traveled via reduced theta phase precession. Our results suggest that disrupted early AD grid coding reflects reduced integration of self-motion cues but not environmental information via geometric boundaries, providing evidence that grid cell impairments underlie path integration deficits during early AD.

In a delayed alternation spatial working memory task, hippocampal time cells fire during specific moments of the delay period to form a stable, sequential representation of the entire delay interval. The causal relationship between these sequences and working memory remains unclear. Similarly, hippocampal theta oscillations are thought to support working memory, primarily through the generation of time cell sequences. To causally examine these relationships, we optogenetically silenced the medial septal GABAergic theta-generating circuit during the delay portion of a delayed spatial alternation task. Without hippocampal theta oscillations, many time cells exhibited remapping, new time cells were recruited, and time cell information was increased; collectively resulting in a new time cell sequence during the delay period. Despite this remapping of time cells on random selection of theta-reduced trials, behavioral performance was unimpaired, demonstrating that working memory is not dependent on a single or unique time cell sequence during the delay period. ### Competing Interest Statement The authors have declared no competing interest.

Early-onset familial Alzheimer's disease (AD) is marked by an aggressive buildup of amyloid beta (Aβ) proteins, yet the neural circuit operations impacted during the initial stages of Aβ pathogenesis remain elusive. Here, we report a coding impairment of the medial entorhinal cortex (MEC) grid cell network in the J20 transgenic mouse model of familial AD that over-expresses Aβ throughout the hippocampus and entorhinal cortex. Grid cells showed reduced spatial periodicity, spatial stability, and synchrony with interneurons and head-direction cells. In contrast, the spatial coding of non-grid cells within the MEC, and place cells within the hippocampus, remained intact. Grid cell deficits emerged at the earliest incidence of Aβ fibril deposition and coincided with impaired spatial memory performance in a path integration task. These results demonstrate that widespread Aβ-mediated damage to the entorhinal-hippocampal circuit results in an early impairment of the entorhinal grid cell network.