Modality-specific Subpopulations of Place Fields Coexist in the Hippocampus.

Hippocampal place cells integrate signals from multiple sensory modalities. However, it is unclear how these different inputs are combined to generate place fields. We investigated how visual spatial cues and an animal's locomotion are integrated by CA3 place cells of Mongolian gerbils. While the animals moved on a virtual linear track, we adapted the gain between the visually projected environment and the treadmill movement. Place cells responded differently to this manipulation. In a subset, place fields were kept in accord with salient visual cues in the virtual environment or reward location, whereas in another subset, place fields were strongly influenced by locomotion. Theta phase precession was present and indistinguishable between the place field types. Theta compression remained intact under gain changes and extended over both types of place field. Hippocampal place cells thus retain strong influence from distinct input streams suggesting a role of the hippocampus CA3 as a multimodal associator on the theta time scale.

The hippocampal code for space in Mongolian gerbils.

Large parts of our knowledge about the physiology of the hippocampus in the intact brain are derived from studies in rats and mice. While many of those findings fit well to the limited data available from humans and primates, there are also marked differences, for example, in hippocampal oscillation frequencies and in the persistence of theta oscillations. To test whether the distinct sensory specializations of the visual and auditory system of primates play a key role in explaining these differences, we recorded basic hippocampal physiological properties in Mongolian gerbils, a rodent species with high visual acuity, and good low-frequency hearing, similar to humans. We found that gerbils show only minor differences to rats regarding hippocampal place field activity, theta properties (frequency, persistence, phase precession, theta compression), and sharp wave ripple events. The only major difference between rats and gerbils was a considerably higher degree of head direction selectivity of gerbil place fields, which may be explained by their visual system being able to better resolve distant cues. Thus, differences in sensory specializations between rodent species only affect hippocampal circuit dynamics to a minor extent, which implies that differences to other mammalian lineages, such as bats and primates, cannot be solely explained by specialization in the auditory or visual system.

Spatial cognition in a virtual reality home-cage extension for freely moving rodents.

Virtual reality (VR) environments are a powerful tool to investigate brain mechanisms involved in the behavior of animals. With this technique, animals are usually head fixed or secured in a harness, and training for cognitively more complex VR paradigms is time consuming. A VR apparatus allowing free animal movement and the constant operator-independent training of tasks would enable many new applications. Key prospective usages include brain imaging of animal behavior when carrying a miniaturized mobile device such as a fluorescence microscope or an optetrode. Here, we introduce the Servoball, a spherical VR treadmill based on the closed-loop tracking of a freely moving animal and feedback counterrotation of the ball. Furthermore, we present the complete integration of this experimental system with the animals' group home cage, from which single individuals can voluntarily enter through a tunnel with radio-frequency identification (RFID)-automated access control and commence experiments. This automated animal sorter functions as a mechanical replacement of the experimenter. We automatically trained rats using visual or acoustic cues to solve spatial cognitive tasks and recorded spatially modulated entorhinal cells. When electrophysiological extracellular recordings from awake behaving rats were performed, head fixation can dramatically alter results, so that any complex behavior that requires head movement is impossible to achieve. We circumvented this problem with the use of the Servoball in open-field scenarios, as it allows the combination of open-field behavior with the recording of nerve cells, along with all the flexibility that a virtual environment brings. This integrated home cage with a VR arena experimental system permits highly efficient experimentation for complex cognitive experiments.NEW & NOTEWORTHY Virtual reality (VR) environments are a powerful tool for the investigation of brain mechanisms. We introduce the Servoball, a VR treadmill for freely moving rodents. The Servoball is integrated with the animals' group home cage. Single individuals voluntarily enter using automated access control. Training is highly time-efficient, even for cognitively complex VR paradigms.

Contextual processing of brightness and color in Mongolian gerbils.

Brightness and color cues are essential for visually guided behavior. However, for rodents, little is known about how well they do use these cues. We used a virtual reality setup that offers a controlled environment for sensory testing to quantitatively investigate visually guided behavior for achromatic and chromatic stimuli in Mongolian gerbils (Meriones unguiculatus). In two-alternative forced choice tasks, animals had to select target stimuli based on relative intensity or color with respect to a contextual reference. Behavioral performance was characterized using psychometric analysis and probabilistic choice modeling. The analyses revealed that the gerbils learned to make decisions that required judging stimuli in relation to their visual context. Stimuli were successfully recognized down to Weber contrasts as low as 0.1. These results suggest that Mongolian gerbils have the perceptual capacity for brightness and color constancy.

Phase precession of grid cells in a network model without external pacemaker.

Rodent brains encode space in both the firing rate and the spike timing of neurons in the medial entorhinal cortex. The rate code is realized by grid fields, that is, the neurons fire at multiple places that are arranged on a hexagonal lattice. Such activity is accompanied by theta oscillations of the local field potential. The phase of spikes thereby encodes space as well, since it decreases with the distance traveled in the field-a phenomenon called phase precession. A likely candidate for grid cells are entorhinal cortex stellate cells, which are type II oscillators and have been suggested to act as pacemakers. It is unclear how spiking of such putative pacemaker neurons would be able to precess in phase relative to a self-generated oscillation. This article presents a computational model of how this paradox can be resolved although the periodicity of the grid fields interferes with the periodic firing of the neurons. Our simulations show that the connections between stellate cells synchronize small cell groups, which allows a population oscillation during grid field activity that is accompanied by theta phase precession. Direct excitatory coupling between the stellate cells, indirect inhibitory coupling via a gamma-oscillating network of interneurons, or both could mediate this phase coordination. Our model further suggests modulation of h-currents to be a feasible mechanism to adjust phase precession to running-speed. The coexistence of rate and timing code for space hence follows as a natural consequence of the self-organization in a recurrent network.

Naturalistic neuroscience and virtual reality.

Virtual reality (VR) is one of the techniques that became particularly popular in neuroscience over the past few decades. VR experiments feature a closed-loop between sensory stimulation and behavior. Participants interact with the stimuli and not just passively perceive them. Several senses can be stimulated at once, large-scale environments can be simulated as well as social interactions. All of this makes VR experiences more natural than those in traditional lab paradigms. Compared to the situation in field research, a VR simulation is highly controllable and reproducible, as required of a laboratory technique used in the search for neural correlates of perception and behavior. VR is therefore considered a middle ground between ecological validity and experimental control. In this review, I explore the potential of VR in eliciting naturalistic perception and behavior in humans and non-human animals. In this context, I give an overview of recent virtual reality approaches used in neuroscientific research.

A virtual reality time reproduction task for rodents.

Estimates of the duration of time intervals and other magnitudes exhibit characteristic biases that likely result from error minimization strategies. To investigate such phenomena, magnitude reproduction tasks are used with humans and other primates. However, such behavioral tasks do not exist for rodents, one of the most important animal orders for neuroscience. We, therefore, developed a time reproduction task that can be used with rodents. It involves an animal reproducing the duration of a timed visual stimulus by walking along a corridor. The task was implemented in virtual reality, which allowed us to ensure that the animals were actually estimating time. The hallway did not contain prominent spatial cues and movement could be de-correlated from optic flow, such that the animals could not learn a mapping between stimulus duration and covered distance. We tested the reproduction of durations of several seconds in three different stimulus ranges. The gerbils reproduced the durations with a precision similar to experiments on humans. Their time reproductions also exhibited the characteristic biases of magnitude estimation experiments. These results demonstrate that our behavioral paradigm provides a means to study time reproduction in rodents.

Temporal compression mediated by short-term synaptic plasticity.

Time scales of cortical neuronal dynamics range from few milliseconds to hundreds of milliseconds. In contrast, behavior occurs on the time scale of seconds or longer. How can behavioral time then be neuronally represented in cortical networks? Here, using electrophysiology and modeling, we offer a hypothesis on how to bridge the gap between behavioral and cellular time scales. The core idea is to use a long time constant of decay of synaptic facilitation to translate slow behaviorally induced temporal correlations into a distribution of synaptic response amplitudes. These amplitudes can then be transferred to a sequence of action potentials in a population of neurons. These sequences provide temporal correlations on a millisecond time scale that are able to induce persistent synaptic changes. As a proof of concept, we provide simulations of a neuron that learns to discriminate temporal patterns on a time scale of seconds by synaptic learning rules with a millisecond memory buffer. We find that the conversion from synaptic amplitudes to millisecond correlations can be strongly facilitated by subthreshold oscillations both in terms of information transmission and success of learning.

Place cells create landmarks.

Hippocampal place cells are known to process path integration signals and sensory information about landmarks. In this issue of Neuron, Fischler-Ruiz et al., 2021 show how localized olfactory cues interact with path integration to drive place cells, turning the cues into landmarks.

Distributed coding of duration in rodent prefrontal cortex during time reproduction.

As we interact with the external world, we judge magnitudes from sensory information. The estimation of magnitudes has been characterized in primates, yet it is largely unexplored in nonprimate species. Here, we use time interval reproduction to study rodent behavior and its neural correlates in the context of magnitude estimation. We show that gerbils display primate-like magnitude estimation characteristics in time reproduction. Most prominently their behavioral responses show a systematic overestimation of small stimuli and an underestimation of large stimuli, often referred to as regression effect. We investigated the underlying neural mechanisms by recording from medial prefrontal cortex and show that the majority of neurons respond either during the measurement or the reproduction of a time interval. Cells that are active during both phases display distinct response patterns. We categorize the neural responses into multiple types and demonstrate that only populations with mixed responses can encode the bias of the regression effect. These results help unveil the organizing neural principles of time reproduction and perhaps magnitude estimation in general.

GABAB receptor-dependent modulation of network activity in the rat prefrontal cortex in vitro.

GABA (gamma-aminobutyric acid) can mediate inhibition via pre- and post/extrasynaptic GABA receptors. In this paper we demonstrate potentially post/extrasynaptic GABA(B) receptor-dependent tonic inhibition in L2/3 pyramidal cells of rat medial prefrontal cortex (mPFC) in vitro. First, we show via voltage-clamp experiments the presence of a tonic GABA(B) receptor-dependent outward current in these neurons. This GABA(B)ergic current could be induced by ambient GABA when present at sufficient concentrations. To increase ambient GABA levels in the usually silent slice preparation, we amplified network activity and hence synaptic GABA release with a modified artificial cerebrospinal fluid. The amplitude of tonic GABA(B) current was similar at different temperatures. In addition to the tonic GABA(B) current, we found presynaptic GABA(B) effects, GABA(B)-mediated inhibitory postsynaptic currents and tonic GABA(A) currents. Second, we performed current-clamp experiments to evaluate the functional impact of GABA(B) receptor-mediated inhibition in the mPFC. Activating or inactivating GABA(B) receptors led to rightward (reduction of excitability) or leftward (increase of excitability) shifts, respectively, of the input-output function of mPFC L2/3 pyramidal cells without effects on the slope. Finally, we showed in electrophysiological recordings and epifluorescence Ca(2+)-imaging that GABA(B) receptor-mediated tonic inhibition is capable of regulating network activity. Blocking GABA(B) receptors increased the frequency of excitatory postsynaptic currents impinging on a neuron and prolonged network upstates. These results show that ambient GABA via GABA(B) receptors is powerful enough to modulate neuronal excitability and the activity of neural networks.

Time and distance estimation in children using an egocentric navigation task.

Navigation crucially depends on the capability to estimate time elapsed and distance covered during movement. From adults it is known that magnitude estimation is subject to characteristic biases. Most intriguing is the regression effect (central tendency), whose strength depends on the stimulus distribution (i.e. stimulus range), a second characteristic of magnitude estimation known as range effect. We examined regression and range effects for time and distance estimation in eleven-year-olds and young adults, using an egocentric virtual navigation task. Regression effects were stronger for distance compared to time and depended on stimulus range. These effects were more pronounced in children compared to adults due to a more heterogeneous performance among the children. Few children showed veridical estimations similar to adults; most children, however, performed less accurate displaying stronger regression effects. Our findings suggest that children use magnitude processing strategies similar to adults, but it seems that these are not yet fully developed in all eleven-year-olds and are further refined throughout adolescence.

Virtual reality systems for rodents.

Over the last decade virtual reality (VR) setups for rodents have been developed and utilized to investigate the neural foundations of behavior. Such VR systems became very popular since they allow the use of state-of-the-art techniques to measure neural activity in behaving rodents that cannot be easily used with classical behavior setups. Here, we provide an overview of rodent VR technologies and review recent results from related research. We discuss commonalities and differences as well as merits and issues of different approaches. A special focus is given to experimental (behavioral) paradigms in use. Finally we comment on possible use cases that may further exploit the potential of VR in rodent research and hence inspire future studies.

Magnitude Estimation with Noisy Integrators Linked by an Adaptive Reference.

Judgments of physical stimuli show characteristic biases; relatively small stimuli are overestimated whereas relatively large stimuli are underestimated (regression effect). Such biases likely result from a strategy that seeks to minimize errors given noisy estimates about stimuli that itself are drawn from a distribution, i.e., the statistics of the environment. While being conceptually well described, it is unclear how such a strategy could be implemented neurally. The present paper aims toward answering this question. A theoretical approach is introduced that describes magnitude estimation as two successive stages of noisy (neural) integration. Both stages are linked by a reference memory that is updated with every new stimulus. The model reproduces the behavioral characteristics of magnitude estimation and makes several experimentally testable predictions. Moreover, the model identifies the regression effect as a means of minimizing estimation errors and explains how this optimality strategy depends on the subject's discrimination abilities and on the stimulus statistics. The latter influence predicts another property of magnitude estimation, the so-called range effect. Beyond being successful in describing decision-making, the present work suggests that noisy integration may also be important in processing magnitudes.

Estimation of self-motion duration and distance in rodents.

Spatial orientation and navigation rely on information about landmarks and self-motion cues gained from multi-sensory sources. In this study, we focused on self-motion and examined the capability of rodents to extract and make use of information about own movement, i.e. path integration. Path integration has been investigated in depth in insects and humans. Demonstrations in rodents, however, mostly stem from experiments on heading direction; less is known about distance estimation. We introduce a novel behavioural paradigm that allows for probing temporal and spatial contributions to path integration. The paradigm is a bisection task comprising movement in a virtual reality environment in combination with either timing the duration ran or estimating the distance covered. We performed experiments with Mongolian gerbils and could show that the animals can keep track of time and distance during spatial navigation.

Mongolian gerbils learn to navigate in complex virtual spaces.

Virtual reality (VR) environments are increasingly used to study spatial navigation in rodents. So far behavioral paradigms in virtual realities have been limited to linear tracks or open fields. However, little is known whether rodents can learn to navigate in more complex virtual spaces. We used a VR setup with a spherical treadmill but no head-fixation, which permits animals not only to move in a virtual environment but also to freely rotate around their vertical body axis. We trained Mongolian gerbils to perform spatial tasks in virtual mazes of different complexity. Initially the animals learned to run back and forth between the two ends of a virtual linear track for food reward. Performance, measured as path length and running time between the virtual reward locations, improved to asymptotic performance within about five training sessions. When more complex mazes were presented after this training epoch, the animals generalized and explored the new environments already at their first exposure. In a final experiment, the animals also learned to perform a two-alternative forced choice task in a virtual Y-maze. Our data thus shows that gerbils can be trained to solve spatial tasks in virtual mazes and that this behavior can be used as a readout for psychophysical measurements.

Dopamine increases the gain of the input-output response of rat prefrontal pyramidal neurons.

Dopaminergic modulation of prefrontal cortical activity is known to affect cognitive functions like working memory. Little consensus on the role of dopamine modulation has been achieved, however, in part because quantities directly relating to the neuronal substrate of working memory are difficult to measure. Here we show that dopamine increases the gain of the frequency-current relationship of layer 5 pyramidal neurons in vitro in response to noisy input currents. The gain increase could be attributed to a reduction of the slow afterhyperpolarization by dopamine. Dopamine also increases neuronal excitability by shifting the input-output functions to lower inputs. The modulation of these response properties is mainly mediated by D1 receptors. Integrate-and-fire neurons were fitted to the experimentally recorded input-output functions and recurrently connected in a model network. The gain increase induced by dopamine application facilitated and stabilized persistent activity in this network. The results support the hypothesis that catecholamines increase the neuronal gain and suggest that dopamine improves working memory via gain modulation.

Phase precession through synaptic facilitation.

Phase precession is a relational code that is thought to be important for episodic-like memory, for instance, the learning of a sequence of places. In the hippocampus, places are encoded through bursting activity of so-called place cells. The spikes in such a burst exhibit a precession of their firing phases relative to field potential theta oscillations (4-12 Hz); the theta phase of action potentials in successive theta cycles progressively decreases toward earlier phases. The mechanisms underlying the generation of phase precession are, however, unknown. In this letter, we show through mathematical analysis and numerical simulations that synaptic facilitation in combination with membrane potential oscillations of a neuron gives rise to phase precession. This biologically plausible model reproduces experimentally observed features of phase precession, such as (1) the progressive decrease of spike phases, (2) the nonlinear and often also bimodal relation between spike phases and the animal's place, (3) the range of phase precession being smaller than one theta cycle, and (4) the dependence of phase jitter on the animal's location within the place field. The model suggests that the peculiar features of the hippocampal mossy fiber synapse, such as its large efficacy, long-lasting and strong facilitation, and its phase-locked activation, are essential for phase precession in the CA3 region of the hippocampus.