Rodents monitor their error in self-generated duration on a single trial basis.

A fundamental question in neuroscience is what type of internal representation leads to complex, adaptive behavior. When faced with a deadline, individuals' behavior suggests that they represent the mean and the uncertainty of an internal timer to make near-optimal, time-dependent decisions. Whether this ability relies on simple trial-and-error adjustments or whether it involves richer representations is unknown. Richer representations suggest a possibility of error monitoring, that is, the ability for an individual to assess its internal representation of the world and estimate discrepancy in the absence of external feedback. While rodents show timing behavior, whether they can represent and report temporal errors in their own produced duration on a single-trial basis is unknown. We designed a paradigm requiring rats to produce a target time interval and, subsequently, evaluate its error. Rats received a reward in a given location depending on the magnitude of their timing errors. During the test trials, rats had to choose a port corresponding to the error magnitude of their just-produced duration to receive a reward. High-choice accuracy demonstrates that rats kept track of the values of the timing variables on which they based their decision. Additionally, the rats kept a representation of the mapping between those timing values and the target value, as well as the history of the reinforcements. These findings demonstrate error-monitoring abilities in evaluating self-generated timing in rodents. Together, these findings suggest an explicit representation of produced duration and the possibility to evaluate its relation to the desired target duration.

Disruption of amygdala Tsc2 in adolescence leads to changed prelimbic cellular activity and generalized fear responses at adulthood in rats.

Adolescence constitutes a period of vulnerability in the emergence of fear-related disorders (FRD), as a massive reorganization occurs in the amygdala-prefrontal cortex network, critical to regulate fear behavior. Genetic and environmental factors during development may predispose to the emergence of FRD at the adult age, but the underlying mechanisms are poorly understood. In the present study, we tested whether a partial knock-down of tuberous sclerosis complex 2 (Tsc2, Tuberin), a risk gene for neurodevelopmental disorders, in the basolateral amygdala (BLA) from adolescence could alter fear-network functionality and create a vulnerability ground to FRD appearance at adulthood. Using bilateral injection of a lentiviral vector expressing a miRNA against Tsc2 in the BLA of early (PN25) or late adolescent (PN50) rats, we show that alteration induced specifically from PN25 resulted in an increased c-Fos activity at adulthood in specific layers of the prelimbic cortex, a resistance to fear extinction and an overgeneralization of fear to a safe, novel stimulus. A developmental dysfunction of the amygdala could thus play a role in the vulnerability to FRD emergence at adulthood. We propose our methodology as an alternative to model the developmental vulnerability to FRD, especially in its comorbidity with TSC2-related autism syndrome.

Asymmetry in updating long-term memory for time.

The present study evaluates the updating of long-term memory for duration. After learning a temporal discrimination associating one lever with a standard duration (4 sec) and another lever with both a shorter (1-sec) and a longer (16-sec) duration, rats underwent a single session for learning a new standard duration. The temporal generalization gradient obtained 24 h later showed a modification in long-term memory for durations longer than the standard but only when the new duration was longer than the one initially learned. The effect was confirmed for another set of durations (0.5-2-8 sec). Our study demonstrates asymmetry in updating long-term memory for time.

Dorsal striatum and the temporal expectancy of an aversive event in Pavlovian odor fear learning.

Interval timing, the ability to encode and retrieve the memory of intervals from seconds to minutes, guides fundamental animal behaviors across the phylogenetic tree. In Pavlovian fear conditioning, an initially neutral stimulus (conditioned stimulus, CS) predicts the arrival of an aversive unconditioned stimulus (US, generally a mild foot-shock) at a fixed time interval. Although some studies showed that temporal relations between CS and US events are learned from the outset of conditioning, the question of the memory of time and its underlying neural network in fear conditioning is still poorly understood. The aim of the present study was to investigate the role of the dorsal striatum in timing intervals in odor fear conditioning in male rats. To assess the animal's interval timing ability in this paradigm, we used the respiratory frequency. This enabled us to detect the emergence of temporal patterns related to the odor-shock time interval from the early stage of learning, confirming that rats are able to encode the odor-shock time interval after few training trials. We carried out reversible inactivation of the dorsal striatum before the acquisition session and before a shift in the learned time interval, and measured the effects of this treatment on the temporal pattern of the respiratory rate. In addition, using intracerebral microdialysis, we monitored extracellular dopamine level in the dorsal striatum throughout odor-shock conditioning and in response to a shift of the odor-shock time interval. Contrary to our initial predictions based on the existing literature on interval timing, we found evidence suggesting that transient inactivation of the dorsal striatum may favor a more precocious buildup of the respiratory frequency's temporal pattern during the odor-shock interval in a manner that reflected the duration of the interval. Our data further suggest that the conditioning and the learning of a novel time interval were associated with a decrease in dopamine level in the dorsal striatum, but not in the nucleus accumbens. These findings prompt a reassessment of the role of the striatum and striatal dopamine in interval timing, at least when considering Pavlovian aversive conditioning.

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.

The Strength of Alpha-Beta Oscillatory Coupling Predicts Motor Timing Precision.

Precise timing makes the difference between harmony and cacophony, but how the brain achieves precision during timing is unknown. In this study, human participants (7 females, 5 males) generated a time interval while being recorded with magnetoencephalography. Building on the proposal that the coupling of neural oscillations provides a temporal code for information processing in the brain, we tested whether the strength of oscillatory coupling was sensitive to self-generated temporal precision. On a per individual basis, we show the presence of alpha-beta phase-amplitude coupling whose strength was associated with the temporal precision of self-generated time intervals, not with their absolute duration. Our results provide evidence that active oscillatory coupling engages α oscillations in maintaining the precision of an endogenous temporal motor goal encoded in ß power; the when of self-timed actions. We propose that oscillatory coupling indexes the variance of neuronal computations, which translates into the precision of an individual's behavioral performance.SIGNIFICANCE STATEMENT Which neural mechanisms enable precise volitional timing in the brain is unknown, yet accurate and precise timing is essential in every realm of life. In this study, we build on the hypothesis that neural oscillations, and their coupling across time scales, are essential for the coding and for the transmission of information in the brain. We show the presence of alpha-beta phase-amplitude coupling (α-ß PAC) whose strength was associated with the temporal precision of self-generated time intervals, not with their absolute duration. α-ß PAC indexes the temporal precision with which information is represented in an individual's brain. Our results link large-scale neuronal variability on the one hand, and individuals' timing precision, on the other.

Duration-specific effects of outcome devaluation in temporal control are differentially sensitive to amount of training.

This study demonstrates that overtraining in temporal discrimination modifies temporal stimulus control in a bisection task and produces habitual responding, as evidenced through insensitivity to food devaluation. Rats were trained or overtrained in a 2- versus 8-sec temporal discrimination task, with each duration associated with a lever (left or right) and food (grain or sucrose). Overtraining produced a leftward shift in the bisection point. Devaluation treatment induced a differential loss of responding depending on stimulus duration (short versus long) and the level of training (training versus overtraining). The relationships between timing behavior and habitual behavior are discussed.

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.

The amygdalo-nigrostriatal network is critical for an optimal temporal performance.

The amygdalo-nigrostriatal (ANS) network plays an essential role in enhanced attention to significant events. Interval timing requires attention to temporal cues. We assessed rats having a disconnected ANS network, due to contralateral lesions of the medial central nucleus of the amygdala (CEm) and dopaminergic afferents to the lateral striatum, as compared to controls (sham and ipsilateral lesions of CEm and dopaminergic afferents to LS) in a temporal bisection task. ANS disconnection induced poorer temporal precision and increased response latencies to a short duration. The present results reveal a role of the ANS network in temporal processing.

Reduced impact of emotion on choice behavior in presymptomatic BACHD rats, a transgenic rodent model for Huntington Disease.

Executive dysfunction and psychiatric symptoms are hallmarks of Huntington disease (HD), a neurodegenerative disorder genetically characterized by expanded CAG repeats in the HTT gene. Using the BACHD rat model of HD (97 CAG-CAA repeats), the present research seeks to characterize the progressive emergence of decision-making impairments in a rat version of the Iowa Gambling Task (RGT) and the impact of emotional modulation, whether positive or negative, on choice behavior. The choice efficiency shown both by WT rats (independent of their age) and the youngest BACHD rats (2 and 8months old) evidenced that they are able to integrate outcomes of past decisions to determine expected reward values for each option. However, 18months old BACHD rats made fewer choices during the RGT session and were less efficient in choosing advantageous options than younger animals. Presenting either chocolate pellets or electrical footshocks half-way through a second RGT session reduced exploratory activity (inefficient nose-poking) and choices with a weaker effect on BACHD animals than on WT. Choice efficiency was left intact in transgenic rats. Our results bring new knowledge on executive impairments and impact of emotional state on decision-making at different stages of the disease, increasing the face-validity of the BACHD rat model.

The selectivity of aversive memory reconsolidation and extinction processes depends on the initial encoding of the Pavlovian association.

In reconsolidation studies, memories are typically retrieved by an exposure to a single conditioned stimulus (CS). We have previously demonstrated that reconsolidation processes are CS-selective, suggesting that memories retrieved by the CS exposure are discrete and reconsolidate separately. Here, using a compound stimulus in which two distinct CSs are concomitantly paired with the same aversive unconditioned stimulus (US), we show in rats that reexposure to one of the components of the compound CS triggers extinction or reconsolidation of the other component. This suggests that the original training conditions play a critical role in memory retrieval and reconsolidation.

Distinct neural adaptations to time demand in the striatum and the hippocampus.

How do neural codes adjust to track time across a range of resolutions, from milliseconds to multi-seconds, as a function of the temporal frequency at which events occur? To address this question, we studied time-modulated cells in the striatum and the hippocampus, while macaques categorized three nested intervals within the sub-second or the supra-second range (up to 1, 2, 4, or 8 s), thereby modifying the temporal resolution needed to solve the task. Time-modulated cells carried more information for intervals with explicit timing demand, than for any other interval. The striatum, particularly the caudate, supported the most accurate temporal prediction throughout all time ranges. Strikingly, its temporal readout adjusted non-linearly to the time range, suggesting that the striatal resolution shifted from a precise millisecond to a coarse multi-second range as a function of demand. This is in line with monkey's behavioral latencies, which indicated that they tracked time until 2 s but employed a coarse categorization strategy for durations beyond. By contrast, the hippocampus discriminated only the beginning from the end of intervals, regardless of the range. We propose that the hippocampus may provide an overall poor signal marking an event's beginning, whereas the striatum optimizes neural resources to process time throughout an interval adapting to the ongoing timing necessity.

NCAM function in the adult brain: lessons from mimetic peptides and therapeutic potential.

Neural cell adhesion molecules (NCAMs) are complexes of transmembranal proteins critical for cell-cell interactions. Initially recognized as key players in the orchestration of developmental processes involving cell migration, cell survival, axon guidance, and synaptic targeting, they have been shown to retain these functions in the mature adult brain, in relation to plastic processes and cognitive abilities. NCAMs are able to interact among themselves (homophilic binding) as well as with other molecules (heterophilic binding). Furthermore, they are the sole molecule of the central nervous system undergoing polysialylation. Most interestingly polysialylated and non-polysialylated NCAMs display opposite properties. The precise contributions each of these characteristics brings in the regulations of synaptic and cellular plasticity in relation to cognitive processes in the adult brain are not yet fully understood. With the aim of deciphering the specific involvement of each interaction, recent developments led to the generation of NCAM mimetic peptides that recapitulate identified binding properties of NCAM. The present review focuses on the information such advances have provided in the understanding of NCAM contribution to cognitive function.

Temporal order processing in rats depends on the training protocol.

The perception of temporal order can help infer the causal structure of the world. By investigating the perceptual signatures of audiovisual temporal order in rats, we demonstrate the importance of the protocol design for reliable order processing. Rats trained with both reinforced audiovisual trials and non-reinforced unisensory trials (two consecutive tones or flashes) learned the task surprisingly faster than rats trained with reinforced multisensory trials only. They also displayed signatures of temporal order perception, such as individual biases and sequential effects that are well described in humans, and impaired in clinical populations. We conclude that an experimental protocol requiring individuals to process all stimuli in a sequence is compulsory to ensure temporal order processing. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Sensory-specific associations stored in the lateral amygdala allow for selective alteration of fear memories.

Consolidated long-term fear memories become labile and can be disrupted after being reactivated by the presentation of the unconditioned stimulus (US). Whether this is due to an alteration of the conditioned stimulus (CS) representation in the lateral amygdala (LA) is not known. Here, we show in rats that fear memory reactivation through presentation of the aversive US, like CS presentation, triggers a process which, when disrupted, results in a selective depotentiation of CS-evoked neural responses in the LA in correlation with a selective suppression of CS-elicited fear memory. Thus, an aversive US triggers the reconsolidation of its associated predictor representation in LA. This new finding suggests that sensory-specific associations are stored in the lateral amygdala, allowing for their selective alteration by either element of the association.

Behavioral and in vivo electrophysiological evidence for presymptomatic alteration of prefrontostriatal processing in the transgenic rat model for huntington disease.

Cognitive decline precedes motor symptoms in Huntington disease (HD). A transgenic rat model for HD carrying only 51 CAG repeats recapitulates the late-onset HD phenotype. Here, we assessed prefrontostriatal function in this model through both behavioral and electrophysiological assays. Behavioral examination consisted in a temporal bisection task within a supra-second range (2 vs.8 s), which is thought to involve prefrontostriatal networks. In two independent experiments, the behavioral analysis revealed poorer temporal sensitivity as early as 4 months of age, well before detection of overt motor deficits. At a later symptomatic age, animals were impaired in their temporal discriminative behavior. In vivo recording of field potentials in the dorsomedial striatum evoked by stimulation of the prelimbic cortex were studied in 4- to 5-month-old rats. Input/output curves, paired-pulse function, and plasticity induced by theta-burst stimulation (TBS) were assessed. Results showed an altered plasticity, with higher paired-pulse facilitation, enhanced short-term depression, as well as stronger long-term potentiation after TBS in homozygous transgenic rats. Results from the heterozygous animals mostly fell between wild-type and homozygous transgenic rats. Our results suggest that normal plasticity in prefrontostriatal circuits may be necessary for reliable and precise timing behavior. Furthermore, the present study provides the first behavioral and electrophysiological evidence of a presymptomatic alteration of prefrontostriatal processing in an animal model for Huntington disease and suggests that supra-second timing may be the earliest cognitive dysfunction in HD.

The neural cell adhesion molecule-derived peptide FGL facilitates long-term plasticity in the dentate gyrus in vivo.

The neural cell adhesion molecule (NCAM) is known to play a role in developmental and structural processes but also in synaptic plasticity and memory of the adult animal. Recently, FGL, a NCAM mimetic peptide that binds to the Fibroblast Growth Factor Receptor 1 (FGFR-1), has been shown to have a beneficial impact on normal memory functioning, as well as to rescue some pathological cognitive impairments. Whether its facilitating impact may be mediated through promoting neuronal plasticity is not known. The present study was therefore designed to test whether FGL modulates the induction and maintenance of synaptic plasticity in the dentate gyrus (DG) in vivo. For this, we first assessed the effect of the FGL peptide on synaptic functions at perforant path-dentate gyrus synapses in the anesthetized rat. FGL, or its control inactive peptide, was injected locally 60 min before applying high-frequency stimulation (HFS) to the medial perforant path. The results suggest that although FGL did not alter basal synaptic transmission, it facilitated both the induction and maintenance of LTP. Interestingly, FGL also modified the heterosynaptic plasticity observed at the neighboring lateral perforant path synapses. The second series of experiments, using FGL intracerebroventricular infusion in the awake animal, confirmed its facilitating effect on LTP for up to 24 h. Our data also suggest that FGL could alter neurogenesis associated with LTP. In sum, these results show for the first time that enhancing NCAM functions by mimicking its heterophilic interaction with FGFR facilitates hippocampal synaptic plasticity in the awake, freely moving animal.

Temporal prediction error triggers amygdala-dependent memory updating in appetitive operant conditioning in rats.

Reinforcement learning theories postulate that prediction error, i.e., a discrepancy between the actual and expected outcomes, drives reconsolidation and new learning, inducing an updating of the initial memory. Pavlovian studies have shown that prediction error detection is a fundamental mechanism in triggering amygdala-dependent memory updating, where the temporal relationship between stimuli plays a critical role. However, in contrast to the well-established findings in aversive situations (e.g., fear conditioning), only few studies exist on prediction error in appetitive operant conditioning, and even less with regard to the role of temporal parameters. To explore if temporal prediction error in an appetitive operant paradigm could generate an updating and consequent reconsolidation and/or new learning of temporal association, we ran four experiments in adult male rats. Experiment 1 verified whether an unexpected delay in the time of reward's availability (i.e., a negative temporal prediction error) in a single session produces an updating in long-term memory of temporal expectancy in an appetitive operant conditioning. Experiment 2 showed that negative prediction errors, either due to the temporal change or through reward omission, increased in the basolateral amygdala nucleus (BLA) the activation of a protein that is critical for memory formation. Experiment 3 revealed that the presence of a protein synthesis inhibitor (anisomycin) in the BLA during the session when the reward was delayed (Error session) affected the temporal updating. Finally, Experiment 4 showed that anisomycin, when infused immediately after the Error session, interfered with the long-term memory of the temporal updating. Together, our study demonstrated an involvement of BLA after a change in temporal and reward contingencies, and in the resulting updating in long-term memory in appetitive operant conditioning.

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.