Learning shifts the preferred theta phase of gamma oscillations in CA1.

Hippocampal neuronal oscillations reflect different cognitive processes and can therefore be used to dissect the role of hippocampal subfields in learning and memory. In particular, it has been suggested that encoding and retrieval is associated with slow gamma (25-55 Hz) and fast gamma (60-100 Hz) oscillations, respectively, which appear in a nested manner at specific phases of the ongoing theta oscillations (4-12 Hz). However, the relationship between memory demand and the theta phase of gamma oscillations remains unclear. Here, we assessed the theta phase preference of gamma oscillations in the CA1 region, at the starting and junction zones of a T-maze, while rats were learning an appetitive task. We found that the theta phase preference of slow gamma showed a ~180° phase shift when animals switched from novice to skilled performance during task acquisition. This phase-shift was not present at the junction zone, where animals chose a right or left turn within the T-maze, suggesting that a recall/decision process had already taken place at the starting zone. Our findings indicate that slow gamma oscillations support both encoding and retrieval, depending on the theta phase at which they occur. These properties are particularly evident prior to cognitive engagement in an acquired spatial task.

Emergence of complex dynamics of choice due to repeated exposures to extinction learning.

Extinction learning, the process of ceasing an acquired behavior in response to altered reinforcement contingencies, is not only essential for survival in a changing environment, but also plays a fundamental role in the treatment of pathological behaviors. During therapy and other forms of training involving extinction, subjects are typically exposed to several sessions with a similar structure. The effects of this repeated exposure are not well understood. Here, we studied the behavior of pigeons across several sessions of a discrimination-learning task in context A, extinction in context B, and a return to context A to test the context-dependent return of the learned responses (ABA renewal). By focusing on individual learning curves across animals, we uncovered a session-dependent variability of behavior: (1) during extinction, pigeons preferred the unrewarded alternative choice in one-third of the sessions, predominantly during the first one. (2) In later sessions, abrupt transitions of behavior at the onset of context B emerged, and (3) the renewal effect decayed as sessions progressed. We show that the observed results can be parsimoniously accounted for by a computational model based only on associative learning between stimuli and actions. Our work thus demonstrates the critical importance of studying the trial-by-trial dynamics of learning in individual sessions, and the power of "simple" associative learning processes.

Hippocampal Ripple Oscillations and Inhibition-First Network Models: Frequency Dynamics and Response to GABA Modulators.

Hippocampal ripples are involved in memory consolidation, but the mechanisms underlying their generation remain unclear. Models relying on interneuron networks in the CA1 region disagree on the predominant source of excitation to interneurons: either "direct," via the Schaffer collaterals that provide feedforward input from CA3 to CA1, or "indirect," via the local pyramidal cells in CA1, which are embedded in a recurrent excitatory-inhibitory network. Here, we used physiologically constrained computational models of basket-cell networks to investigate how they respond to different conditions of transient, noisy excitation. We found that direct excitation of interneurons could evoke ripples (140-220 Hz) that exhibited intraripple frequency accommodation and were frequency-insensitive to GABA modulators, as previously shown in in vitro experiments. In addition, the indirect excitation of the basket-cell network enabled the expression of intraripple frequency accommodation in the fast-gamma range (90-140 Hz), as in vivo In our model, intraripple frequency accommodation results from a hysteresis phenomenon in which the frequency responds differentially to the rising and descending phases of the transient excitation. Such a phenomenon predicts a maximum oscillation frequency occurring several milliseconds before the peak of excitation. We confirmed this prediction for ripples in brain slices from male mice. These results suggest that ripple and fast-gamma episodes are produced by the same interneuron network that is recruited via different excitatory input pathways, which could be supported by the previously reported intralaminar connectivity bias between basket cells and functionally distinct subpopulations of pyramidal cells in CA1. Together, our findings unify competing inhibition-first models of rhythm generation in the hippocampus.SIGNIFICANCE STATEMENT The hippocampus is a part of the brain of humans and other mammals that is critical for the acquisition and consolidation of memories. During deep sleep and resting periods, the hippocampus generates high-frequency (∼200 Hz) oscillations called ripples, which are important for memory consolidation. The mechanisms underlying ripple generation are not well understood. A prominent hypothesis holds that the ripples are generated by local recurrent networks of inhibitory neurons. Using computational models and experiments in brain slices from rodents, we show that the dynamics of interneuron networks clarify several previously unexplained characteristics of ripple oscillations, which advances our understanding of hippocampus-dependent memory consolidation.

Recruitment of oriens-lacunosum-moleculare interneurons during hippocampal ripples.

Sharp wave-associated ∼200-Hz ripple oscillations in the hippocampus have been implicated in the consolidation of memories. However, knowledge on mechanisms underlying ripples is still scarce, in particular with respect to synaptic involvement of specific cell types. Here, we used cell-attached and whole-cell recordings in vitro to study activity of pyramidal cells and oriens-lacunosum-moleculare (O-LM) interneurons during ripples. O-LM cells received ripple-associated synaptic input that arrived delayed (3.3 ± 0.3 ms) with respect to the maximum amplitude of field ripples and was locked to the ascending phase of field oscillations (mean phase: 209 ± 6°). In line, O-LM cells episodically discharged late during ripples (∼6.5 ms after the ripple maximum), and firing was phase-locked to field oscillations (mean phase: 219 ± 9°). Our data unveil recruitment of O-LM neurons during ripples, suggesting a previously uncharacterized role of this cell type during sharp wave-associated activity.

Trial-by-trial dynamics of reward prediction error-associated signals during extinction learning and renewal.

Reward prediction errors (RPEs) have been suggested to drive associative learning processes, but their precise temporal dynamics at the single-neuron level remain elusive. Here, we studied the neural correlates of RPEs, focusing on their trial-by-trial dynamics during an operant extinction learning paradigm. Within a single behavioral session, pigeons went through acquisition, extinction and renewal - the context-dependent response recovery after extinction. We recorded single units from the avian prefrontal cortex analogue, the nidopallium caudolaterale (NCL) and found that the omission of reward during extinction led to a peak of population activity that moved backwards in time as trials progressed. The chronological order of these signal changes during the progress of learning was indicative of temporal shifts of RPE signals that started during reward omission and then moved backwards to the presentation of the conditioned stimulus. Switches from operant choices to avoidance behavior (and vice versa) coincided with changes in population activity during the animals' decision-making. On the single unit level, we found more diverse patterns where some neurons' activity correlated with RPE signals whereas others correlated with the absolute value during the outcome period. Finally, we demonstrated that mere sensory contextual changes during the renewal test were sufficient to elicit signals likely associated with RPEs. Thus, RPEs are truly expectancy-driven since they can be elicited by changes in reward expectation, without an actual change in the quality or quantity of reward.

Subiculum as a generator of sharp wave-ripples in the rodent hippocampus.

Sharp wave-ripples (SWRs) represent synchronous discharges of hippocampal neurons and are believed to play a major role in memory consolidation. A large body of evidence suggests that SWRs are exclusively generated in the CA3-CA2 network. In contrast, here, we provide several lines of evidence showing that the subiculum can function as a secondary SWRs generator. SWRs with subicular origin propagate forward into the entorhinal cortex as well as backward into the hippocampus proper. Our findings suggest that the output structures of the hippocampus are not only passively facilitating the transfer of SWRs to the cortex, but they also can actively contribute to the genesis of SWRs. We hypothesize that SWRs with a subicular origin may be important for the consolidation of information conveyed to the hippocampus via the temporoammonic pathway.

Context-dependent extinction learning emerging from raw sensory inputs: a reinforcement learning approach.

The context-dependence of extinction learning has been well studied and requires the hippocampus. However, the underlying neural mechanisms are still poorly understood. Using memory-driven reinforcement learning and deep neural networks, we developed a model that learns to navigate autonomously in biologically realistic virtual reality environments based on raw camera inputs alone. Neither is context represented explicitly in our model, nor is context change signaled. We find that memory-intact agents learn distinct context representations, and develop ABA renewal, whereas memory-impaired agents do not. These findings reproduce the behavior of control and hippocampal animals, respectively. We therefore propose that the role of the hippocampus in the context-dependence of extinction learning might stem from its function in episodic-like memory and not in context-representation per se. We conclude that context-dependence can emerge from raw visual inputs.

A critical experimental study of the classical tactile threshold theory.

BACKGROUND: The tactile sense is being used in a variety of applications involving tactile human-machine interfaces. In a significant number of publications the classical threshold concept plays a central role in modelling and explaining psychophysical experimental results such as in stochastic resonance (SR) phenomena. In SR, noise enhances detection of sub-threshold stimuli and the phenomenon is explained stating that the required amplitude to exceed the sensory threshold barrier can be reached by adding noise to a sub-threshold stimulus. We designed an experiment to test the validity of the classical vibrotactile threshold. Using a second choice experiment, we show that individuals can order sensorial events below the level known as the classical threshold. If the observer's sensorial system is not activated by stimuli below the threshold, then a second choice could not be above the chance level. Nevertheless, our experimental results are above that chance level contradicting the definition of the classical tactile threshold. RESULTS: We performed a three alternative forced choice detection experiment on 6 subjects asking them first and second choices. In each trial, only one of the intervals contained a stimulus and the others contained only noise. According to the classical threshold assumptions, a correct second choice response corresponds to a guess attempt with a statistical frequency of 50%. Results show an average of 67.35% (STD = 1.41%) for the second choice response that is not explained by the classical threshold definition. Additionally, for low stimulus amplitudes, second choice correct detection is above chance level for any detectability level. CONCLUSIONS: Using a second choice experiment, we show that individuals can order sensorial events below the level known as a classical threshold. If the observer's sensorial system is not activated by stimuli below the threshold, then a second choice could not be above the chance level. Nevertheless, our experimental results are above that chance level. Therefore, if detection exists below the classical threshold level, then the model to explain the SR phenomenon or any other tactile perception phenomena based on the psychophysical classical threshold is not valid. We conclude that a more suitable model of the tactile sensory system is needed.

Coincidence-enhanced stochastic resonance: experimental evidence challenges the psychophysical theory behind stochastic resonance.

Stochastic resonance (SR) is the counterintuitive phenomenon in which noise enhances detection of sub-threshold stimuli. The SR psychophysical threshold theory establishes that the required amplitude to exceed the sensory threshold barrier can be reached by adding noise to a sub-threshold stimulus. The aim of this study was to test the SR theory by comparing detection results from two different randomly-presented stimulus conditions. In the first condition, optimal noise was present during the whole attention interval; in the second, the optimal noise was restricted to the same time interval as the stimulus. SR threshold theory predicts no difference between the two conditions because noise helps the sub-threshold stimulus to reach threshold in both cases. The psychophysical experimental method used a 300 ms rectangular force pulse as a stimulus within an attention interval of 1.5 s, applied to the index finger of six human subjects in the two distinct conditions. For all subjects we show that in the condition in which the noise was present only when synchronized with the stimulus, detection was better (p<0.05) than in the condition in which the noise was delivered throughout the attention interval. These results provide the first direct evidence that SR threshold theory is incomplete and that a new phenomenon has been identified, which we call Coincidence-Enhanced Stochastic Resonance (CESR). We propose that CESR might occur because subject uncertainty is reduced when noise points at the same temporal window as the stimulus.

Early Cortical Changes in Gamma Oscillations in Alzheimer's Disease.

The entorhinal cortices in the temporal lobe of the brain are key structures relaying memory related information between the neocortex and the hippocampus. The medial entorhinal cortex (MEC) routes spatial information, whereas the lateral entorhinal cortex (LEC) routes predominantly olfactory information to the hippocampus. Gamma oscillations are known to coordinate information transfer between brain regions by precisely timing population activity of neuronal ensembles. Here, we studied the organization of in vitro gamma oscillations in the MEC and LEC of the transgenic (tg) amyloid precursor protein (APP)-presenilin 1 (PS1) mouse model of Alzheimer's Disease (AD) at 4-5 months of age. In vitro gamma oscillations using the kainate model peaked between 30-50 Hz and therefore we analyzed the oscillatory properties in the 20-60 Hz range. Our results indicate that the LEC shows clear alterations in frequency and power of gamma oscillations at an early stage of AD as compared to the MEC. The gamma-frequency oscillation slows down in the LEC and also the gamma power in dorsal LEC is decreased as early as 4-5 months in the tg APP-PS1 mice. The results of this study suggest that the timing of olfactory inputs from LEC to the hippocampus might be affected at an early stage of AD, resulting in a possible erroneous integration of the information carried by the two input pathways to the hippocampal subfields.