Gap in the conditioned stimulus: Differential impacts on temporal expectancy in appetitive and aversive conditions in rats.

We analyzed, through a Pavlovian conditioning procedure in rats, the temporal pattern of behavior in appetitive and aversive conditions within subjects, and the difference in inferred temporal working memory functioning with the Gap paradigm. For both conditions, we paired a 60-s conditioned stimulus (CS: tone1 or tone2) with an unconditioned stimulus (US: shock or chocolate pellet) delivered 20s after CS onset. The analyses of mean response rate and individual-trial data were performed during Probe trials, consisting of CS alone, and trials in which gaps of different position or duration were inserted, to assess the effect of the temporal manipulation on behavior. The results showed: (1) An anticipatory peak time in the aversive condition but better accuracy in the appetitive condition, (2) constancy in the Weber fraction suggesting that the difference in peak time was under clock control, (3) a graded effect of gap parameters only in the aversive condition and (4) different gap effects between conditions when a gap was inserted early in the CS. These results highlight behavioral differences between aversive and appetitive conditions and suggest that the temporal working memory mechanism was not engaged in the same manner in each condition.

Beyond Freezing: Temporal Expectancy of an Aversive Event Engages the Amygdalo-Prefronto-Dorsostriatal Network.

During Pavlovian aversive conditioning, a neutral conditioned stimulus (CS) becomes predictive of the time of arrival of an aversive unconditioned stimulus (US). Using a paradigm where animals had to discriminate between a CS+ (associated with a footshock) and a CS- (never associated with a footshock), we show that, early in training, dynamics of neuronal oscillations in an amygdalo-prefronto-striatal network are modified during the CS+ in a manner related to the CS-US time interval (30 or 10 s). This is the case despite a generalized high level of freezing to both CS+ and CS-. The local field potential oscillatory power was decreased between 12 and 30 Hz in the dorsomedial striatum (DMS) and increased between 55 and 95 Hz in the prelimbic cortex (PL), while the coherence between DMS, PL, and the basolateral amygdala was increased in the 3-6 Hz frequency range up to the expected time of US arrival only for the CS+ and not for the CS-. Changing the CS-US interval from 30 to 10 s shifted these changes in activity toward the newly learned duration. The results suggest a functional role of the amygdalo-prefronto-dorsostriatal network in encoding temporal information of Pavlovian associations independently of the behavioral output.

Neural encoding of time in the animal brain.

The processing of temporal intervals is essential to create causal maps and to predict future events so as to best adapt one's behavior. In this review, we explore the different brain activity patterns associated with processing durations and expressing temporally-adapted behavior in animals. We begin by describing succinctly some of the current models of the internal clock that can orient us in what to look for in brain activity. We then outline how durations can be decoded by single cell activity and which activity patterns could be associated with interval timing. We further point to similar patterns that have been observed at a more global level within brain areas (e.g. local field potentials) or, even, between these areas, that could represent another way of encoding duration or could constitute a necessary part for more complex temporal processing. Finally, we discuss to what extent neural data fit with internal clock models, and highlight improvements for experiments to obtain a more in-depth understanding of the brain's temporal encoding and processing.

Impaired cerebellar Purkinje cell potentiation generates unstable spatial map orientation and inaccurate navigation.

Cerebellar activity supported by PKC-dependent long-term depression in Purkinje cells (PCs) is involved in the stabilization of self-motion based hippocampal representation, but the existence of cerebellar processes underlying integration of allocentric cues remains unclear. Using mutant-mice lacking PP2B in PCs (L7-PP2B mice) we here assess the role of PP2B-dependent PC potentiation in hippocampal representation and spatial navigation. L7-PP2B mice display higher susceptibility to spatial map instability relative to the allocentric cue and impaired allocentric as well as self-motion goal-directed navigation. These results indicate that PP2B-dependent potentiation in PCs contributes to maintain a stable hippocampal representation of a familiar environment in an allocentric reference frame as well as to support optimal trajectory toward a goal during navigation.

Non-linear auto-regressive models for cross-frequency coupling in neural time series.

We address the issue of reliably detecting and quantifying cross-frequency coupling (CFC) in neural time series. Based on non-linear auto-regressive models, the proposed method provides a generative and parametric model of the time-varying spectral content of the signals. As this method models the entire spectrum simultaneously, it avoids the pitfalls related to incorrect filtering or the use of the Hilbert transform on wide-band signals. As the model is probabilistic, it also provides a score of the model "goodness of fit" via the likelihood, enabling easy and legitimate model selection and parameter comparison; this data-driven feature is unique to our model-based approach. Using three datasets obtained with invasive neurophysiological recordings in humans and rodents, we demonstrate that these models are able to replicate previous results obtained with other metrics, but also reveal new insights such as the influence of the amplitude of the slow oscillation. Using simulations, we demonstrate that our parametric method can reveal neural couplings with shorter signals than non-parametric methods. We also show how the likelihood can be used to find optimal filtering parameters, suggesting new properties on the spectrum of the driving signal, but also to estimate the optimal delay between the coupled signals, enabling a directionality estimation in the coupling.

Updating of aversive memories after temporal error detection is differentially modulated by mTOR across development.

The updating of a memory is triggered whenever it is reactivated and a mismatch from what is expected (i.e., prediction error) is detected, a process that can be unraveled through the memory's sensitivity to protein synthesis inhibitors (i.e., reconsolidation). As noted in previous studies, in Pavlovian threat/aversive conditioning in adult rats, prediction error detection and its associated protein synthesis-dependent reconsolidation can be triggered by reactivating the memory with the conditioned stimulus (CS), but without the unconditioned stimulus (US), or by presenting a CS-US pairing with a different CS-US interval than during the initial learning. Whether similar mechanisms underlie memory updating in the young is not known. Using similar paradigms with rapamycin (an mTORC1 inhibitor), we show that preweaning rats (PN18-20) do form a long-term memory of the CS-US interval, and detect a 10-sec versus 30-sec temporal prediction error. However, the resulting updating/reconsolidation processes become adult-like after adolescence (PN30-40). Our results thus show that while temporal prediction error detection exists in preweaning rats, specific infant-type mechanisms are at play for associative learning and memory.

Updating temporal expectancy of an aversive event engages striatal plasticity under amygdala control.

Pavlovian aversive conditioning requires learning of the association between a conditioned stimulus (CS) and an unconditioned, aversive stimulus (US) but also involves encoding the time interval between the two stimuli. The neurobiological bases of this time interval learning are unknown. Here, we show that in rats, the dorsal striatum and basal amygdala belong to a common functional network underlying temporal expectancy and learning of a CS-US interval. Importantly, changes in coherence between striatum and amygdala local field potentials (LFPs) were found to couple these structures during interval estimation within the lower range of the theta rhythm (3-6 Hz). Strikingly, we also show that a change to the CS-US time interval results in long-term changes in cortico-striatal synaptic efficacy under the control of the amygdala. Collectively, this study reveals physiological correlates of plasticity mechanisms of interval timing that take place in the striatum and are regulated by the amygdala.

Impaired Decision Making and Loss of Inhibitory-Control in a Rat Model of Huntington Disease.

Cognitive deficits associated with Huntington disease (HD) are generally dominated by executive function disorders often associated with disinhibition and impulsivity/compulsivity. Few studies have directly examined symptoms and consequences of behavioral disinhibition in HD and its relation with decision-making. To assess the different forms of impulsivity in a transgenic model of HD (tgHD rats), two tasks assessing cognitive/choice impulsivity were used: risky decision-making with a rat gambling task (RGT) and intertemporal choices with a delay discounting task (DD). To assess waiting or action impulsivity the differential reinforcement of low rate of responding task (DRL) was used. In parallel, the volume as well as cellular activity of the amygdala was analyzed. In contrast to WT rats, 15 months old tgHD rats exhibited a poor efficiency in the RGT task with difficulties to choose advantageous options, a steep DD curve as delays increased in the DD task and a high rate of premature and bursts responses in the DRL task. tgHD rats also demonstrated a concomitant and correlated presence of both action and cognitive/choice impulsivity in contrast to wild type (WT) animals. Moreover, a reduced volume associated with an increased basal cellular activity of the central nucleus of amygdala indicated a dysfunctional amygdala in tgHD rats, which could underlie inhibitory dyscontrol. In conclusion, tgHD rats are a good model for impulsivity disorder that could be used more widely to identify potential pharmacotherapies to treat these invasive symptoms in HD.

Individual trial analysis evidences clock and non-clock based conditioned suppression behaviors in rats.

We analyzed the temporal pattern of conditioned suppression of lever-pressing for food in rats conditioned with tone-shock pairings using either a 10 or 15s conditioned stimulus (CS)-unconditioned stimulus (US) interval with a CS duration that was three times the CS-US interval. The analysis of average suppression and of individual trials was performed during Probe CS-alone trials and when a short gap was inserted during the CS. The pattern of suppression followed the classical temporal rules: (1) scalar property, (2) a shift in peak suppression due to a gap, compatible with a Stop rule, (3) a three-state pattern of lever-pressing in individual trials, with abrupt start and stop of suppression. The peak of the average suppression curve, but not the middle time, was anticipatory to the programmed US time. The pattern of lever-pressing in individual trials unraveled two types of start of suppression behavior: a clock-based biphasic responding, with a burst of lever-pressing before suppression, and a non-clock based monophasic reduction of lever-pressing close to the CS onset. The non-clock based type of behavior may be responsible for the anticipatory peak time, and the biphasic pattern of lever-pressing may reflect the decision stage described in clock models.

The amygdala: a potential player in timing CS-US intervals.

Pavlovian conditioning is the reference paradigm for the study of associative learning based on the programmed relation of two stimuli, the conditioned stimulus (CS) and the unconditioned stimulus (US). Some authors believe that learning the CS-US interval is a co-requisite of or a pre-requisite to learning the CS-US association. There is a substantial literature showing that the amygdala is a critical player in Pavlovian conditioning, with both aversive and appetitive USs. We review a sparse but growing body of literature suggesting that the amygdala may also participate in processing the timing of the CS-US interval. We discuss whether the amygdala, in particular its central, basal and lateral nuclei, in concert with the network it belongs to, may play a role in learning the CS-US interval. We also suggest new and dedicated strategies that would result in better knowledge of the neural mechanisms underlying the learning of the CS-US time interval in isolation from the CS-US association.