Population dynamics of head-direction neurons during drift and reorientation.

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.

Revisiting Antarctic ice loss due to marine ice-cliff instability.

Predictions for sea-level rise this century due to melt from Antarctica range from zero to more than one metre. The highest predictions are driven by the controversial marine ice-cliff instability (MICI) hypothesis, which assumes that coastal ice cliffs can rapidly collapse after ice shelves disintegrate, as a result of surface and sub-shelf melting caused by global warming. But MICI has not been observed in the modern era and it remains unclear whether it is required to reproduce sea-level variations in the geological past. Here we quantify ice-sheet modelling uncertainties for the original MICI study and show that the probability distributions are skewed towards lower values (under very high greenhouse gas concentrations, the most likely value is 45 centimetres). However, MICI is not required to reproduce sea-level changes due to Antarctic ice loss in the mid-Pliocene epoch, the last interglacial period or 1992-2017; without it we find that the projections agree with previous studies (all 95th percentiles are less than 43 centimetres). We conclude that previous interpretations of these MICI projections over-estimate sea-level rise this century; because the MICI hypothesis is not well constrained, confidence in projections with MICI would require a greater range of observationally constrained models of ice-shelf vulnerability and ice-cliff collapse.

Glaciation as a destructive and constructive control on mountain building.

Theoretical analysis predicts that enhanced erosion related to late Cenozoic global cooling can act as a first-order influence on the internal dynamics of mountain building, leading to a reduction in orogen width and height. The strongest response is predicted in orogens dominated by highly efficient alpine glacial erosion, producing a characteristic pattern of enhanced erosion on the windward flank of the orogen and maximum elevation controlled by glacier equilibrium line altitude, where long-term glacier mass gain equals mass loss. However, acquiring definitive field evidence of an active tectonic response to global climate cooling has been elusive. Here we present an extensive new low-temperature thermochronologic data set from the Patagonian Andes, a high-latitude active orogen with a well-documented late Cenozoic tectonic, climatic and glacial history. Data from 38° S to 49° S record a marked acceleration in erosion 7 to 5 Myr ago coeval with the onset of major Patagonian glaciation and retreat of deformation from the easternmost thrust front. The highest rates and magnitudes of erosion are restricted to the glacial equilibrium line altitude on the windward western flank of the orogen, as predicted in models of glaciated critical taper orogens where erosion rate is a function of ice sliding velocity. In contrast, towards higher latitudes (49° S to 56° S) a transition to older bedrock cooling ages signifies much reduced late Cenozoic erosion despite dominantly glacial conditions here since the latest Miocene. The increased height of the orogenic divide at these latitudes (well above the equilibrium line altitude) leads us to conclude that the southernmost Patagonian Andes represent the first recognized example of regional glacial protection of an active orogen from erosion, leading to constructive growth in orogen height and width.

Time and experience are independent determinants of representational drift in CA1.

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.

Grid cell disruption in a mouse model of early Alzheimer's disease reflects reduced integration of self-motion cues.

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 (Aß) 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.

Optogenetic Silencing of Medial Septal GABAergic Neurons Disrupts Grid Cell Spatial and Temporal Coding in the Medial Entorhinal Cortex.

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 its GABAergic neurons, are essential for theta rhythm oscillations in the entorhinal-hippocampal network, however, it is unknown if this subpopulation is also essential for grid cell function. To investigate this, we used optogenetics to inhibit MS-GABAergic neurons during grid cell recordings. We found that MS-GABAergic inhibition disrupted grid cell spatial periodicity both during optogenetic inhibition and during short 30-second recovery periods. Longer recovery periods of 60 seconds between the optogenetic inhibition periods allowed for the recovery of grid cell spatial firing. Grid cell temporal coding was also disrupted, as observed by a significant attenuation of theta phase precession. Together, these results demonstrate that MS-GABAergic neurons are critical for grid cell spatial and temporal coding in the MEC.

Sustained year-round oceanographic measurements from Rothera Research Station, Antarctica, 1997-2017.

Oceanographic changes adjacent to Antarctica have global climatic and ecological impacts. However, this is the most challenging place in the world to obtain marine data due to its remoteness and inhospitable nature, especially in winter. Here, we present more than 2000 Conductivity-Temperature-Depth (CTD) profiles and associated water sample data collected with (almost uniquely) full year-round coverage from the British Antarctic Survey Rothera Research Station at the west Antarctic Peninsula. Sampling is conducted from a small boat or a sled, depending on the sea ice conditions. When conditions allow, sampling is twice weekly in summer and weekly in winter, with profiling to nominally 500 m and with discrete water samples taken at 15 m water depth. Daily observations are made of the sea ice conditions in the area. This paper presents the first 20 years of data collection, 1997-2017. This time series represents a unique and valuable resource for investigations of the high-latitude ocean's role in climate change, ocean/ice interactions, and marine biogeochemistry and carbon drawdown.

Metabolic modulation of mitochondrial mass during CD4+ T cell activation.

Mitochondrial biogenesis initiates within hours of T cell receptor (TCR) engagement and is critical for T cell activation, function, and survival; yet, how metabolic programs support mitochondrial biogenesis during TCR signaling is not fully understood. Here, we performed a multiplexed metabolic chemical screen in CD4+ T lymphocytes to identify modulators of metabolism that impact mitochondrial mass during early T cell activation. Treatment of T cells with pyrvinium pamoate early during their activation blocks an increase in mitochondrial mass and results in reduced proliferation, skewed CD4+ T cell differentiation, and reduced cytokine production. Furthermore, administration of pyrvinium pamoate at the time of induction of experimental autoimmune encephalomyelitis, an experimental model of multiple sclerosis in mice, prevented the onset of clinical disease. Thus, modulation of mitochondrial biogenesis may provide a therapeutic strategy for modulating T cell immune responses.

Head direction cells in the postsubiculum do not show replay of prior waking sequences during sleep.

During slow-wave sleep (SWS) and rapid eye movement (REM) sleep, hippocampal place cells in the rat show replay of sequences previously observed during waking. We tested the hypothesis from computational modeling that the temporal structure of REM sleep replay could arise from an interplay of place cells with head direction cells in the postsubiculum. Physiological single-unit recording was performed simultaneously from five or more head direction or place by head direction cells in the postsubiculum during running on a circular track allowing sampling of a full range of head directions, and during sleep periods before and after running on the circular track. Data analysis compared the spiking activity during individual REM periods with waking as in previous analysis procedures for REM sleep. We also used a new procedure comparing groups of similar runs during waking with REM sleep periods. There was no consistent evidence for a statistically significant correlation of the temporal structure of spiking during REM sleep with spiking during waking running periods. Thus, the spiking activity of head direction cells during REM sleep does not show replay of head direction cell activity occurring during a previous waking period of running on the task. In addition, we compared the spiking of postsubiculum neurons during hippocampal sharp wave ripple events. We show that head direction cells are not activated during sharp wave ripples, whereas neurons responsive to place in the postsubiculum show reliable spiking at ripple events.

The representation of context in mouse hippocampus is preserved despite neural drift.

The hippocampus is thought to mediate episodic memory through the instantiation and reinstatement of context-specific cognitive maps. However, recent longitudinal experiments have challenged this view, reporting that most hippocampal cells change their tuning properties over days even in the same environment. Often referred to as neural or representational drift, these dynamics raise questions about the capacity and content of the hippocampal code. One such question is whether and how these long-term dynamics impact the hippocampal code for context. To address this, we image large CA1 populations over more than a month of daily experience as freely behaving mice participate in an extended geometric morph paradigm. We find that long-timescale changes in population activity occur orthogonally to the representation of context in network space, allowing for consistent readout of contextual information across weeks. This population-level structure is supported by heterogeneous patterns of activity at the level of individual cells, where we observe evidence of a positive relationship between interpretable contextual coding and long-term stability. Together, these results demonstrate that long-timescale changes to the CA1 spatial code preserve the relative structure of contextual representation.

Path integration in normal aging and Alzheimer's disease.

In this review we discuss converging evidence from human and rodent research demonstrating how path integration (PI) is impaired in healthy aging and Alzheimer's disease (AD), and point to the neural mechanisms that underlie these deficits. Importantly, we highlight that (i) the grid cell network in the entorhinal cortex is crucial for PI in both humans and rodents, (ii) PI deficits are present in healthy aging and are significantly more pronounced in patients with early-stage AD, (iii) compromised entorhinal grid cell computations in healthy older adults and in young adults at risk of AD are linked to PI deficits, and (iv) PI and grid cell deficits may serve as sensitive markers for pathological decline in early AD.

Disruption of the grid cell network in a mouse model of early Alzheimer's disease.

Early-onset familial Alzheimer's disease (AD) is marked by an aggressive buildup of amyloid beta (Aß) proteins, yet the neural circuit operations impacted during the initial stages of Aß 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 Aß 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 Aß fibril deposition and coincided with impaired spatial memory performance in a path integration task. These results demonstrate that widespread Aß-mediated damage to the entorhinal-hippocampal circuit results in an early impairment of the entorhinal grid cell network.

Skipping ahead: A circuit for representing the past, present, and future.

Envisioning the future is intuitively linked to our ability to remember the past. Within the memory system, substantial work has demonstrated the involvement of the prefrontal cortex and the hippocampus in representing the past and present. Recent data shows that both the prefrontal cortex and the hippocampus encode future trajectories, which are segregated in time by alternating cycles of the theta rhythm. Here, we discuss how information is temporally organized by these brain regions supported by the medial septum, nucleus reuniens, and parahippocampal regions. Finally, we highlight a brain circuit that we predict is essential for the temporal segregation of future scenarios.

A Characterization of the Electrophysiological and Morphological Properties of Vasoactive Intestinal Peptide (VIP) Interneurons in the Medial Entorhinal Cortex (MEC).

Circuit interactions within the medial entorhinal cortex (MEC) translate movement into a coherent code for spatial location. Entorhinal principal cells are subject to strong lateral inhibition, suggesting that a disinhibitory mechanism may drive their activation. Cortical Vasoactive Intestinal Peptide (VIP) expressing inhibitory neurons are known to contact other interneurons and excitatory cells and are thus capable of providing a local disinhibitory mechanism, yet little is known about this cell type in the MEC. To investigate the electrophysiological and morphological properties of VIP cells in the MEC, we use in vitro whole-cell patch-clamp recordings in VIPcre/tdTom mice. We report several gradients in electrophysiological properties of VIP cells that differ across laminae and along the dorsal-ventral MEC axis. We additionally show that VIP cells have distinct morphological features across laminae. Together, these results characterize the cellular and morphological properties of VIP cells in the MEC.

The McGill-Mouse-Miniscope platform: A standardized approach for high-throughput imaging of neuronal dynamics during behavior.

Understanding the rules that govern neuronal dynamics throughout the brain to subserve behavior and cognition remains one of the biggest challenges in neuroscience research. Recent technical advances enable the recording of increasingly larger neuronal populations to produce increasingly more sophisticated datasets. Despite bold and important open-science and data-sharing policies, these datasets tend to include unique data acquisition methods, behaviors, and file structures. Discrepancies between experimental protocols present key challenges in comparing data between laboratories and across different brain regions and species. Here, we discuss our recent efforts to create a standardized and high-throughput research platform to address these issues. The McGill-Mouse-Miniscope (M3) platform is an initiative to combine miniscope calcium imaging with standardized touchscreen-based animal behavioral testing. The goal is to curate an open-source and standardized framework for acquiring, analyzing, and accessing high-quality data of the neuronal dynamics that underly cognition throughout the brain in mice, marmosets, and models of disease. We end with a discussion of future developments and a call for users to adopt this standardized approach.

DG-CA3 circuitry mediates hippocampal representations of latent information.

Survival in complex environments necessitates a flexible navigation system that incorporates memory of recent behavior and associations. Yet, how the hippocampal spatial circuit represents latent information independent of sensory inputs and future goals has not been determined. To address this, we image the activity of large ensembles in subregion CA1 via wide-field fluorescent microscopy during a novel behavioral paradigm. Our results demonstrate that latent information is represented through reliable firing rate changes during unconstrained navigation. We then hypothesize that the representation of latent information in CA1 is mediated by pattern separation/completion processes instantiated upstream within the dentate gyrus (DG) and CA3 subregions. Indeed, CA3 ensemble recordings reveal an analogous code for latent information. Moreover, selective chemogenetic inactivation of DG-CA3 circuitry completely and reversibly abolishes the CA1 representation of latent information. These results reveal a causal and specific role of DG-CA3 circuitry in the maintenance of latent information within the hippocampus.

Cholinergic dysfunction in the dorsal striatum promotes habit formation and maladaptive eating.

Dysregulation of habit formation has been recently proposed as pivotal to eating disorders. Here, we report that a subset of patients suffering from restrictive anorexia nervosa have enhanced habit formation compared with healthy controls. Habit formation is modulated by striatal cholinergic interneurons. These interneurons express vesicular transporters for acetylcholine (VAChT) and glutamate (VGLUT3) and use acetylcholine/glutamate cotransmission to regulate striatal functions. Using mice with genetically silenced VAChT (VAChT conditional KO, VAChTcKO) or VGLUT3 (VGLUT3cKO), we investigated the roles that acetylcholine and glutamate released by cholinergic interneurons play in habit formation and maladaptive eating. Silencing glutamate favored goal-directed behaviors and had no impact on eating behavior. In contrast, VAChTcKO mice were more prone to habits and maladaptive eating. Specific deletion of VAChT in the dorsomedial striatum of adult mice was sufficient to phenocopy maladaptive eating behaviors of VAChTcKO mice. Interestingly, VAChTcKO mice had reduced dopamine release in the dorsomedial striatum but not in the dorsolateral striatum. The dysfunctional eating behavior of VAChTcKO mice was alleviated by donepezil and by l-DOPA, confirming an acetylcholine/dopamine deficit. Our study reveals that loss of acetylcholine leads to a dopamine imbalance in striatal compartments, thereby promoting habits and vulnerability to maladaptive eating in mice.

Linking cellular mechanisms to behavior: entorhinal persistent spiking and membrane potential oscillations may underlie path integration, grid cell firing, and episodic memory.

The entorhinal cortex plays an important role in spatial memory and episodic memory functions. These functions may result from cellular mechanisms for integration of the afferent input to entorhinal cortex. This article reviews physiological data on persistent spiking and membrane potential oscillations in entorhinal cortex then presents models showing how both these cellular mechanisms could contribute to properties observed during unit recording, including grid cell firing, and how they could underlie behavioural functions including path integration. The interaction of oscillations and persistent firing could contribute to encoding and retrieval of trajectories through space and time as a mechanism relevant to episodic memory.

Hippocampal Neural Circuits Respond to Optogenetic Pacing of Theta Frequencies by Generating Accelerated Oscillation Frequencies.

Biological oscillations can be controlled by a small population of rhythmic pacemaker cells, or in the brain, they also can emerge from complex cellular and circuit-level interactions. Whether and how these mechanisms are combined to give rise to oscillatory patterns that govern cognitive function are not well understood. For example, the activity of hippocampal networks is temporally coordinated by a 7- to 9-Hz local field potential (LFP) theta rhythm, yet many individual cells decouple from the LFP frequency to oscillate at frequencies ∼1 Hz higher. To better understand the network interactions that produce these complex oscillatory patterns, we asked whether the relative frequency difference between LFP and individual cells is retained when the LFP frequency is perturbed experimentally. We found that rhythmic optogenetic stimulation of medial septal GABAergic neurons controlled the hippocampal LFP frequency outside of the endogenous theta range, even during behavioral states when endogenous mechanisms would otherwise have generated 7- to 9-Hz theta oscillations. While the LFP frequency matched the optogenetically induced stimulation frequency, the oscillation frequency of individual hippocampal cells remained broadly distributed, and in a subset of cells including interneurons, it was accelerated beyond the new base LFP frequency. The inputs from septal GABAergic neurons to the hippocampus, therefore, do not appear to directly control the cellular oscillation frequency but rather engage cellular and circuit mechanisms that accelerate the rhythmicity of individual cells. Thus, theta oscillations are an example of cortical oscillations that combine inputs from a subcortical pacemaker with local computations to generate complex oscillatory patterns that support cognitive functions.