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.

Flexible coding of time or distance in hippocampal cells.

Analysis of neuronal activity in the hippocampus of behaving animals has revealed cells acting as 'Time Cells', which exhibit selective spiking patterns at specific time intervals since a triggering event, and 'Distance Cells', which encode the traversal of specific distances. Other neurons exhibit a combination of these features, alongside place selectivity. This study aims to investigate how the task performed by animals during recording sessions influences the formation of these representations. We analyzed data from a treadmill running study conducted by Kraus et al., 2013, in which rats were trained to run at different velocities. The rats were recorded in two trial contexts: a 'fixed time' condition, where the animal ran on the treadmill for a predetermined duration before proceeding, and a 'fixed distance' condition, where the animal ran a specific distance on the treadmill. Our findings indicate that the type of experimental condition significantly influenced the encoding of hippocampal cells. Specifically, distance-encoding cells dominated in fixed-distance experiments, whereas time-encoding cells dominated in fixed-time experiments. These results underscore the flexible coding capabilities of the hippocampus, which are shaped by over-representation of salient variables associated with reward conditions.

Predictive learning by a burst-dependent learning rule.

Humans and other animals are able to quickly generalize latent dynamics of spatiotemporal sequences, often from a minimal number of previous experiences. Additionally, internal representations of external stimuli must remain stable, even in the presence of sensory noise, in order to be useful for informing behavior. In contrast, typical machine learning approaches require many thousands of samples, and generalize poorly to unexperienced examples, or fail completely to predict at long timescales. Here, we propose a novel neural network module which incorporates hierarchy and recurrent feedback terms, constituting a simplified model of neocortical microcircuits. This microcircuit predicts spatiotemporal trajectories at the input layer using a temporal error minimization algorithm. We show that this module is able to predict with higher accuracy into the future compared to traditional models. Investigating this model we find that successive predictive models learn representations which are increasingly removed from the raw sensory space, namely as successive temporal derivatives of the positional information. Next, we introduce a spiking neural network model which implements the rate-model through the use of a recently proposed biological learning rule utilizing dual-compartment neurons. We show that this network performs well on the same tasks as the mean-field models, by developing intrinsic dynamics that follow the dynamics of the external stimulus, while coordinating transmission of higher-order dynamics. Taken as a whole, these findings suggest that hierarchical temporal abstraction of sequences, rather than feed-forward reconstruction, may be responsible for the ability of neural systems to quickly adapt to novel situations.

Theta and gamma rhythmic coding through two spike output modes in the hippocampus during spatial navigation.

Hippocampal CA1 neurons generate single spikes and stereotyped bursts of spikes. However, it is unclear how individual neurons dynamically switch between these output modes and whether these two spiking outputs relay distinct information. We performed extracellular recordings in spatially navigating rats and cellular voltage imaging and optogenetics in awake mice. We found that spike bursts are preferentially linked to cellular and network theta rhythms (3-12 Hz) and encode an animal's position via theta phase precession, particularly as animals are entering a place field. In contrast, single spikes exhibit additional coupling to gamma rhythms (30-100 Hz), particularly as animals leave a place field. Biophysical modeling suggests that intracellular properties alone are sufficient to explain the observed input frequency-dependent spike coding. Thus, hippocampal neurons regulate the generation of bursts and single spikes according to frequency-specific network and intracellular dynamics, suggesting that these spiking modes perform distinct computations to support spatial behavior.

Septo-hippocampal dynamics and the encoding of space and time.

Encoding an event in memory requires neural activity to represent multiple dimensions of behavioral experience in space and time. Recent experiments have explored the influence of neural dynamics regulated by the medial septum on the functional encoding of space and time by neurons in the hippocampus and associated structures. This review addresses these dynamics, focusing on the role of theta rhythm, the differential effects of septal inactivation and activation on the functional coding of space and time by individual neurons, and the influence on phase coding that appears as phase precession. We also discuss data indicating that theta rhythm plays a role in timing the internal dynamics of memory encoding and retrieval, as well as the behavioral influences of these neuronal manipulations with regard to memory function.

Learning the Vector Coding of Egocentric Boundary Cells from Visual Data.

The use of spatial maps to navigate through the world requires a complex ongoing transformation of egocentric views of the environment into position within the allocentric map. Recent research has discovered neurons in retrosplenial cortex and other structures that could mediate the transformation from egocentric views to allocentric views. These egocentric boundary cells respond to the egocentric direction and distance of barriers relative to an animal's point of view. This egocentric coding based on the visual features of barriers would seem to require complex dynamics of cortical interactions. However, computational models presented here show that egocentric boundary cells can be generated with a remarkably simple synaptic learning rule that forms a sparse representation of visual input as an animal explores the environment. Simulation of this simple sparse synaptic modification generates a population of egocentric boundary cells with distributions of direction and distance coding that strikingly resemble those observed within the retrosplenial cortex. Furthermore, some egocentric boundary cells learnt by the model can still function in new environments without retraining. This provides a framework for understanding the properties of neuronal populations in the retrosplenial cortex that may be essential for interfacing egocentric sensory information with allocentric spatial maps of the world formed by neurons in downstream areas, including the grid cells in entorhinal cortex and place cells in the hippocampus.SIGNIFICANCE STATEMENT The computational model presented here demonstrates that the recently discovered egocentric boundary cells in retrosplenial cortex can be generated with a remarkably simple synaptic learning rule that forms a sparse representation of visual input as an animal explores the environment. Additionally, our model generates a population of egocentric boundary cells with distributions of direction and distance coding that strikingly resemble those observed within the retrosplenial cortex. This transformation between sensory input and egocentric representation in the navigational system could have implications for the way in which egocentric and allocentric representations interface in other brain areas.

Gated transformations from egocentric to allocentric reference frames involving retrosplenial cortex, entorhinal cortex, and hippocampus.

This paper reviews the recent experimental finding that neurons in behaving rodents show egocentric coding of the environment in a number of structures associated with the hippocampus. Many animals generating behavior on the basis of sensory input must deal with the transformation of coordinates from the egocentric position of sensory input relative to the animal, into an allocentric framework concerning the position of multiple goals and objects relative to each other in the environment. Neurons in retrosplenial cortex show egocentric coding of the position of boundaries in relation to an animal. These neuronal responses are discussed in relation to existing models of the transformation from egocentric to allocentric coordinates using gain fields and a new model proposing transformations of phase coding that differ from current models. The same type of transformations could allow hierarchical representations of complex scenes. The responses in rodents are also discussed in comparison to work on coordinate transformations in humans and non-human primates.

Route-dependent spatial engram tagging in mouse dentate gyrus.

The dentate gyrus (DG) of hippocampus is hypothesized to act as a pattern separator that distinguishes between similar input patterns during memory formation and retrieval. Sparse ensembles of DG cells associated with learning and memory, i.e. engrams, have been labeled and manipulated to recall novel context memories. Functional studies of DG cell activity have demonstrated the spatial specificity and stability of DG cells during navigation. To reconcile how the DG contributes to separating global context as well as individual navigational routes, we trained mice to perform a delayed-non-match-to-position (DNMP) T-maze task and labeled DG neurons during performance of this task on a novel T-maze. The following day, mice navigated a second environment: the same T-maze, the same T-maze with one route permanently blocked but still visible, or a novel open field. We found that the degree of engram reactivation across days differed based on the traversal of maze routes, such that mice traversing only one arm had higher ensemble overlap than chance but less overlap than mice running the full two-route task. Mice experiencing the open field had similar ensemble sizes to the other groups but only chance-level ensemble reactivation. Ensemble overlap differences could not be explained by behavioral variability across groups, nor did behavioral metrics correlate to degree of ensemble reactivation. Together, these results support the hypothesis that DG contributes to spatial navigation memory and that partially non-overlapping ensembles encode different routes within the context of an environment.

Internally generated time in the rodent hippocampus is logarithmically compressed.

The Weber-Fechner law proposes that our perceived sensory input increases with physical input on a logarithmic scale. Hippocampal 'time cells' carry a record of recent experience by firing sequentially during a circumscribed period of time after a triggering stimulus. Different cells have 'time fields' at different delays up to at least tens of seconds. Past studies suggest that time cells represent a compressed timeline by demonstrating that fewer time cells fire late in the delay and their time fields are wider. This paper asks whether the compression of time cells obeys the Weber-Fechner Law. Time cells were studied with a hierarchical Bayesian model that simultaneously accounts for the firing pattern at the trial level, cell level, and population level. This procedure allows separate estimates of the within-trial receptive field width and the across-trial variability. After isolating across-trial variability, time field width increased linearly with delay. Further, the time cell population was distributed evenly along a logarithmic time axis. These findings provide strong quantitative evidence that the neural temporal representation in rodent hippocampus is logarithmically compressed and obeys a neural Weber-Fechner Law.

Mechanisms for maintaining information in working memory.

The review by Slotnick is valuable for raising the important question of how much the hippocampal activity induced by novel stimuli is due to mechanisms for encoding into long-term memory, and how much is due to working memory. Slotnick's paper implicitly defines working memory as being equivalent to sustained activation during the late delay period. In this commentary, we suggest that cognitive neuroscientists should consider a broader range of cellular and synaptic mechanisms for maintaining information in working memory.

Temporal dynamics of cholinergic activity in the septo-hippocampal system.

Cholinergic projection neurons in the medial septum and diagonal band of Broca are the major source of cholinergic modulation of hippocampal circuit functions that support neural coding of location and running speed. Changes in cholinergic modulation are known to correlate with changes in brain states, cognitive functions, and behavior. However, whether cholinergic modulation can change fast enough to serve as a potential speed signal in hippocampal and parahippocampal cortices and whether the temporal dynamics in such a signal depend on the presence of visual cues remain unknown. In this study, we use a fiber-photometric approach to quantify the temporal dynamics of cholinergic activity in freely moving mice as a function of the animal's movement speed and visual cues. We show that the population activity of cholinergic neurons in the medial septum and diagonal band of Broca changes fast enough to be aligned well with changes in the animal's running speed and is strongly and linearly correlated to the logarithm of the animal's running speed. Intriguingly, the cholinergic modulation remains strongly and linearly correlated to the speed of the animal's neck movements during periods of stationary activity. Furthermore, we show that cholinergic modulation is unaltered during darkness. Lastly, we identify rearing, a stereotypic behavior where the mouse stands on its hindlimbs to scan the environment from an elevated perspective, is associated with higher cholinergic activity than expected from neck movements on the horizontal plane alone. Taken together, these data show that temporal dynamics in the cholinergic modulation of hippocampal circuits are fast enough to provide a potential running speed signal in real-time. Moreover, the data show that cholinergic modulation is primarily a function of the logarithm of the animal's movement speed, both during locomotion and during stationary activity, with no significant interaction with visual inputs. These data advance our understanding of temporal dynamics in cholinergic modulation of hippocampal circuits and their functions in the context of neural coding of location and running speed.

Complementary representations of time in the prefrontal cortex and hippocampus.

Episodic memory binds the spatial and temporal relationships between the elements of experience. The hippocampus encodes space through place cells that fire at specific spatial locations. Similarly, time cells fire sequentially at specific time points within a temporally organized experience. Recent studies in rodents, monkeys, and humans have identified time cells with discrete firing fields and cells with monotonically changing activity in supporting the temporal organization of events across multiple timescales. Using in vivo electrophysiological tetrode recordings, we simultaneously recorded neurons from the prefrontal cortex and dorsal CA1 of the hippocampus while rats performed a delayed match to sample task. During the treadmill mnemonic delay, hippocampal time cells exhibited sparser firing fields with decreasing resolution over time, consistent with previous results. In comparison, temporally modulated cells in the prefrontal cortex showed more monotonically changing firing rates, ramping up or decaying with the passage of time, and exhibited greater temporal precision for Bayesian decoding of time at long time lags. These time cells show exquisite temporal resolution both in their firing fields and in the fine timing of spikes relative to the phase of theta oscillations. Here, we report evidence of theta phase precession in both the prefrontal cortex and hippocampus during the temporal delay, however, hippocampal cells exhibited steeper phase precession slopes and more punctate time fields. To disentangle whether time cell activity reflects elapsed time or distance traveled, we varied the treadmill running speed on each trial. While many neurons contained multiplexed representations of time and distance, both regions were more strongly influenced by time than distance. Overall, these results demonstrate the flexible integration of spatiotemporal dimensions and reveal complementary representations of time in the prefrontal cortex and hippocampus in supporting memory-guided behavior.

Impact of optogenetic pulse design on CA3 learning and replay: A neural model.

Optogenetic manipulation of hippocampal circuitry is an important tool for investigating learning in vivo. Numerous approaches to pulse design have been employed to elicit desirable circuit and behavioral outcomes. Here, we systematically test the outcome of different single-pulse waveforms in a rate-based model of hippocampal memory function at the level of mnemonic replay extension and de novo synaptic weight formation in CA3 and CA1. Lower-power waveforms with long forward or forward and backward ramps yield more natural sequence replay dynamics and induce synaptic plasticity that allows for more natural memory replay timing, in contrast to square or backward ramps. These differences between waveform shape and amplitude are preserved with the addition of noise in membrane potential, light scattering, and protein expression, improving the potential validity of predictions for in vivo work. These results inform future optogenetic experimental design choices in the field of learning and memory.

Adaptive integration of self-motion and goals in posterior parietal cortex.

Rats readily switch between foraging and more complex navigational behaviors such as pursuit of other rats or prey. These tasks require vastly different tracking of multiple behaviorally significant variables including self-motion state. To explore whether navigational context modulates self-motion tracking, we examined self-motion tuning in posterior parietal cortex neurons during foraging versus visual target pursuit. Animals performing the pursuit task demonstrate predictive processing of target trajectories by anticipating and intercepting them. Relative to foraging, pursuit yields multiplicative gain modulation of self-motion tuning and enhances self-motion state decoding. Self-motion sensitivity in parietal cortex neurons is, on average, history dependent regardless of behavioral context, but the temporal window of self-motion integration extends during target pursuit. Finally, many self-motion-sensitive neurons conjunctively track the visual target position relative to the animal. Thus, posterior parietal cortex functions to integrate the location of navigationally relevant target stimuli into an ongoing representation of past, present, and future locomotor trajectories.

Consistent population activity on the scale of minutes in the mouse hippocampus.

Neurons in the hippocampus fire in consistent sequence over the timescale of seconds during the delay period of some memory experiments. For longer timescales, the firing of hippocampal neurons also changes slowly over minutes within experimental sessions. It was thought that these slow dynamics are caused by stochastic drift or a continuous change in the representation of the episode, rather than consistent sequences unfolding over minutes. This paper studies the consistency of contextual drift in three chronic calcium imaging recordings from the hippocampus CA1 region in mice. Computational measures of consistency show reliable sequences within experimental trials at the scale of seconds as one would expect from time cells or place cells during the trial, as well as across experimental trials on the scale of minutes within a recording session. Consistent sequences in the hippocampus are observed over a wide range of time scales, from seconds to minutes. The hippocampal activity could reflect a scale-invariant spatiotemporal context as suggested by theories of memory from cognitive psychology.

Neural responses in retrosplenial cortex associated with environmental alterations.

The retrosplenial cortex (RSC) is an area interconnected with regions of the brain that display spatial correlates. Neurons in connected regions may encode an animal's position in the environment and location or proximity to objects or boundaries. RSC has also been shown to be important for spatial memory, such as tracking distance from and between landmarks, contextual information, and orientation within an environment. For these reasons, it is important to determine how neurons in RSC represent cues such as objects or boundaries and their relationship to the environment. In the current work, we performed electrophysiological recordings in RSC, whereas rats foraged in arenas that could contain an object or in which the environment was altered. We report RSC neurons display changes in mean firing rate responding to alterations of the environment. These alterations include the arena rotating, changing size or shape, or an object being introduced into the arena.

Neural circuits and symbolic processing.

The ability to use symbols is a defining feature of human intelligence. However, neuroscience has yet to explain the fundamental neural circuit mechanisms for flexibly representing and manipulating abstract concepts. This article will review the research on neural models for symbolic processing. The review first focuses on the question of how symbols could possibly be represented in neural circuits. The review then addresses how neural symbolic representations could be flexibly combined to meet a wide range of reasoning demands. Finally, the review assesses the research on program synthesis and proposes that the most flexible neural representation of symbolic processing would involve the capacity to rapidly synthesize neural operations analogous to lambda calculus to solve complex cognitive tasks.

The Unexplored Territory of Neural Models: Potential Guides for Exploring the Function of Metabotropic Neuromodulation.

The space of possible neural models is enormous and under-explored. Single cell computational neuroscience models account for a range of dynamical properties of membrane potential, but typically do not address network function. In contrast, most models focused on network function address the dimensions of excitatory weight matrices and firing thresholds without addressing the complexities of metabotropic receptor effects on intrinsic properties. There are many under-explored dimensions of neural parameter space, and the field needs a framework for representing what has been explored and what has not. Possible frameworks include maps of parameter spaces, or efforts to categorize the fundamental elements and molecules of neural circuit function. Here we review dimensions that are under-explored in network models that include the metabotropic modulation of synaptic plasticity and presynaptic inhibition, spike frequency adaptation due to calcium-dependent potassium currents, and afterdepolarization due to calcium-sensitive non-specific cation currents and hyperpolarization activated cation currents. Neuroscience research should more effectively explore possible functional models incorporating under-explored dimensions of neural function.

Hippocampal spatial memory representations in mice are heterogeneously stable.

The population of hippocampal neurons actively coding space continually changes across days as mice repeatedly perform tasks. Many hippocampal place cells become inactive while other previously silent neurons become active, challenging the idea that stable behaviors and memory representations are supported by stable patterns of neural activity. Active cell replacement may disambiguate unique episodes that contain overlapping memory cues, and could contribute to reorganization of memory representations. How active cell replacement affects the evolution of representations of different behaviors within a single task is unknown. We trained mice to perform a delayed nonmatching to place task over multiple weeks, and performed calcium imaging in area CA1 of the dorsal hippocampus using head-mounted miniature microscopes. Cells active on the central stem of the maze "split" their calcium activity according to the animal's upcoming turn direction (left or right), the current task phase (study or test), or both task dimensions, even while spatial cues remained unchanged. We found that, among reliably active cells, different splitter neuron populations were replaced at unequal rates, resulting in an increasing number of cells modulated by turn direction and a decreasing number of cells with combined modulation by both turn direction and task phase. Despite continual reorganization, the ensemble code stably segregated these task dimensions. These results show that hippocampal memories can heterogeneously reorganize even while behavior is unchanging.