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There is an ongoing debate on the evolutionary origin of the episodic memory function of the hippocampus. A widely accepted hypothesis claims that the hippocampus first evolved as a dedicated system for spatial navigation in ancestral vertebrates, being transformed later in phylogeny to support a broader role in episodic memory with the emergence of mammals. On the contrary, an alternative hypothesis holds that the hippocampus of ancestral vertebrates originally encoded both the spatial and temporal dimensions of relational memories since its evolutionary appearance, thus suggesting that the episodic-like memory function of the hippocampus could be the primitive condition in vertebrate forebrain evolution. The present experiment was aimed at scrutinizing these opposing hypotheses by investigating whether the hippocampal pallium of teleost fish, a vertebrate group that shares with mammals a common ancestor that lived about 400 Mya, is, like the hippocampus of mammals, essential to associate time-discontiguous events. Thus, goldfish with lesions in the ventral part of the dorsolateral pallium (Dlv), a telencephalic region considered homologous to the hippocampal pallium of land vertebrates, were trained in trace versus delay eyeblink-like classical conditioning, two learning procedures that differ only in the temporal relationships between the stimuli to be associated in memory. The results showed that hippocampal pallium lesion in goldfish severely impairs trace conditioning, but spares delay conditioning. This finding challenges the idea that navigation preceded relational memory in evolutionary appearance and suggests the possibility that a relational memory function that associates the experienced events in both the spatial and temporal dimensions could be a primitive feature of the hippocampus that pre-existed in the common ancestor of vertebrates.

The cerebellum and the prefrontal cortex are assumed to play a role in the pathophysiology of essential tremor (ET). Trace eyeblink conditioning with a long interstimulus interval relies on an intact function of the hippocampus, prefrontal cortex (PFC), and, although marginally, of the cerebellum. The aim of the present study was to evaluate whether long trace eyeblink conditioning is impaired in patients with ET. In 18 patients with ET and 18 controls, a long trace conditioning paradigm was applied. Following 100 paired conditioned response-unconditioned response trials, 30 conditioned response alone trials were given as extinction trials. The degree of tremor and the presence of accompanying cerebellar signs were determined based on clinical scales. The acquisition of conditioned eyeblink responses was not impaired in the group of all patients compared to controls (mean total incidences of conditioned responses in patients 23.3 ± 14.5%, in controls 24.1 ± 13.9%; P = 0.88). In the subgroup of six patients with cerebellar signs, incidences of conditioned responses were numerically but not significantly lower (16.4 ± 9.9%) compared to patients without cerebellar signs (26.8 ± 15.5%; P = 0.16). Trace eyeblink conditioning with a long interstimulus interval was not impaired in subjects with ET. Patients with clinical cerebellar signs presented slightly reduced conditioning. Areas of the PFC contributing to trace eyeblink conditioning appear less affected in ET. Future studies also using a shorter trace interval should include a larger group of subjects in all stages of ET.

Recent success in training artificial agents and robots derives from a combination of direct learning of behavioural policies and indirect learning through value functions 1 – 3 . Policy learning and value learning use distinct algorithms that optimize behavioural performance and reward prediction, respectively. In animals, behavioural learning and the role of mesolimbic dopamine signalling have been extensively evaluated with respect to reward prediction 4 ; however, so far there has been little consideration of how direct policy learning might inform our understanding 5 . Here we used a comprehensive dataset of orofacial and body movements to understand how behavioural policies evolved as naive, head-restrained mice learned a trace conditioning paradigm. Individual differences in initial dopaminergic reward responses correlated with the emergence of learned behavioural policy, but not the emergence of putative value encoding for a predictive cue. Likewise, physiologically calibrated manipulations of mesolimbic dopamine produced several effects inconsistent with value learning but predicted by a neural-network-based model that used dopamine signals to set an adaptive rate, not an error signal, for behavioural policy learning. This work provides strong evidence that phasic dopamine activity can regulate direct learning of behavioural policies, expanding the explanatory power of reinforcement learning models for animal learning 6 . Analysis of data collected from mice learning a trace conditioning paradigm shows that phasic dopamine activity in the brain can regulate direct learning of behavioural policies, and dopamine sets an adaptive learning rate rather than an error-like teaching signal.

Two forms of associative learning—delay conditioning and trace conditioning—have been widely investigated in humans and higher-order mammals 1 . In delay conditioning, an unconditioned stimulus (for example, an electric shock) is introduced in the final moments of a conditioned stimulus (for example, a tone), with both ending at the same time. In trace conditioning, a ‘trace’ interval separates the conditioned stimulus and the unconditioned stimulus. Trace conditioning therefore relies on maintaining a neural representation of the conditioned stimulus after its termination (hence making distraction possible 2 ), to learn the conditioned stimulus–unconditioned stimulus contingency 3 ; this makes it more cognitively demanding than delay conditioning 4 . Here, by combining virtual-reality behaviour with neurogenetic manipulations and in vivo two-photon brain imaging, we show that visual trace conditioning and delay conditioning in Drosophila mobilize R2 and R4m ring neurons in the ellipsoid body. In trace conditioning, calcium transients during the trace interval show increased oscillations and slower declines over repeated training, and both of these effects are sensitive to distractions. Dopaminergic activity accompanies signal persistence in ring neurons, and this is decreased by distractions solely during trace conditioning. Finally, dopamine D1-like and D2-like receptor signalling in ring neurons have different roles in delay and trace conditioning; dopamine D1-like receptor 1 mediates both forms of conditioning, whereas the dopamine D2-like receptor is involved exclusively in sustaining ring neuron activity during the trace interval of trace conditioning. These observations are similar to those previously reported in mammals during arousal 5 , prefrontal activation 6 and high-level cognitive learning 7 , 8 . Trace and delay conditioning experiments in Drosophila reveal the different neurons and signalling mechanisms that underlie this behaviour and highlight similarities with observations of learning experiences in mammals.

Fear conditioning and extinction are basic forms of associative learning that have gained considerable clinical relevance in enhancing our understanding of anxiety disorders and facilitating their treatment. Modern neuroimaging techniques have significantly aided the identification of anatomical structures and networks involved in fear conditioning. On closer inspection, there is considerable variation in methodology and results between studies. This systematic review provides an overview of the current neuroimaging literature on fear conditioning and extinction on healthy subjects, taking into account methodological issues such as the conditioning paradigm. A Pubmed search, as of December 2008, was performed and supplemented by manual searches of bibliographies of key articles. Two independent reviewers made the final study selection and data extraction. A total of 46 studies on cued fear conditioning and/or extinction on healthy volunteers using positron emission tomography or functional magnetic resonance imaging were reviewed. The influence of specific experimental factors, such as contingency and timing parameters, assessment of conditioned responses, and characteristics of conditioned and unconditioned stimuli, on cerebral activation patterns was examined. Results were summarized descriptively. A network consisting of fear-related brain areas, such as amygdala, insula, and anterior cingulate cortex, is activated independently of design parameters. However, some neuroimaging studies do not report these findings in the presence of methodological heterogeneities. Furthermore, other brain areas are differentially activated, depending on specific design parameters. These include stronger hippocampal activation in trace conditioning and tactile stimulation. Furthermore, tactile unconditioned stimuli enhance activation of pain related, motor, and somatosensory areas. Differences concerning experimental factors may partly explain the variance between neuroimaging investigations on human fear conditioning and extinction and should, therefore, be taken into serious consideration in the planning and the interpretation of research projects.

Drugs that modulate serotonin (5-HT) synaptic concentrations impact neurogenesis and hippocampal (HPC)-dependent learning. The primary objective is to determine the extent to which psilocybin (PSOP) modulates neurogenesis and thereby affects acquisition and extinction of HPC-dependent trace fear conditioning. PSOP, the 5-HT 2A agonist 25I-NBMeO and the 5-HT 2A/C antagonist ketanserin were administered via an acute intraperitoneal injection to mice. Trace fear conditioning was measured as the amount of time spent immobile in the presence of the conditioned stimulus (CS, auditory tone), trace (silent interval) and post-trace interval over 10 trials. Extinction was determined by the number of trials required to resume mobility during CS, trace and post-trace when the shock was not delivered. Neurogenesis was determined by unbiased counts of cells in the dentate gyrus of the HPC birth-dated with BrdU co-expressing a neuronal marker. Mice treated with a range of doses of PSOP acquired a robust conditioned fear response. Mice injected with low doses of PSOP extinguished cued fear conditioning significantly more rapidly than high-dose PSOP or saline-treated mice. Injection of PSOP, 25I-NBMeO or ketanserin resulted in significant dose-dependent decreases in number of newborn neurons in hippocampus. At the low doses of PSOP that enhanced extinction, neurogenesis was not decreased, but rather tended toward an increase. Extinction of “fear conditioning” may be mediated by actions of the drugs at sites other than hippocampus such as the amygdala, which is known to mediate the perception of fear. Another caveat is that PSOP is not purely selective for 5-HT 2A receptors. PSOP facilitates extinction of the classically conditioned fear response, and this, and similar agents, should be explored as potential treatments for post-traumatic stress disorder and related conditions.

Temporal contiguity between conditioned (CS) and unconditioned stimuli (US) is a crucial factor in Pavlovian learning, yet little is known about its role in appetitive conditioning and extinction. In a within-subject design, 60 participants underwent both a delay (DC) and trace conditioning (TC) session with partial reinforcement (75%) by monetary rewards (US) and varying interval between CS offset and US onset (DC: 0s; TC: 4s). In addition to self-report indices (reward expectancy, arousal, valence), psychophysiological markers (pupil dilation, heart-period and startle reflex modulation) were recorded during acquisition and extinction training. For most measures, significant differential conditioned responses emerged, irrespective of temporal contiguity, with no major differences observed between TC and DC during acquisition (except for potentially diminished startle attenuation in TC). Despite overall similar patterns in conditioned responding (with small to moderate effects on physiological measures), there was no intraindividual concordance between sessions, yet evidence for differential TC effects on extinction learning. Specifically, smaller reductions in differential reward expectancy, heart-period deceleration and startle modulation after extinction in TC suggested relatively diminished extinction learning. Conditioned pupil dilation (0–2 s after CS onset) remained comparatively stable. Taken together, our findings extend evidence of differences in underlying learning mechanisms between TC and DC to the context of reward learning.

Learning which stimuli (classical conditioning) or which actions (operant conditioning) predict rewards or punishments can improve chances of survival. However, the circuit mechanisms that underlie distinct types of associative learning are still not fully understood. Automated, high-throughput paradigms for studying different types of associative learning, combined with manipulation of specific neurons in freely behaving animals, can help advance this field. The Drosophila melanogaster larva is a tractable model system for studying the circuit basis of behaviour, but many forms of associative learning have not yet been demonstrated in this animal. Here, we developed a high-throughput (i.e. multi-larva) training system that combines real-time behaviour detection of freely moving larvae with targeted opto- and thermogenetic stimulation of tracked animals. Both stimuli are controlled in either open- or closed-loop, and delivered with high temporal and spatial precision. Using this tracker, we show for the first time that Drosophila larvae can perform classical conditioning with no overlap between sensory stimuli (i.e. trace conditioning). We also demonstrate that larvae are capable of operant conditioning by inducing a bend direction preference through optogenetic activation of reward-encoding serotonergic neurons. Our results extend the known associative learning capacities of Drosophila larvae. Our automated training rig will facilitate the study of many different forms of associative learning and the identification of the neural circuits that underpin them.

Trace conditioning involves the pairing of a neutral conditioned stimulus (CS), followed by a short interval with a motivationally significant unconditioned stimulus (UCS). Recently, trace conditioning has been proposed as a test for animal consciousness due to its correlation in humans with subjective report of the CS–UCS connection. We argue that the distractor task in the Clark and Squire (1998) study on trace conditioning has been overlooked. Attentional inhibition played a crucial role in disrupting trace conditioning and awareness of the CS–UCS contingency in the human participants of that study. These results may be understood within the framework of the Temporal Representation Theory that asserts consciousness serves the function of selecting information into a representation of the present moment. While neither sufficient nor necessary, attentional processes are the primary means to select stimuli for consciousness. Consciousness and attention are both needed by an animal capable of flexible behavioral response. Consciousness keeps track of the current situation; attention amplifies task-relevant stimuli and inhibits irrelevant stimuli. In light of these joint functions, we hypothesize that the failure to trace condition under distraction in an organism known to successfully trace condition otherwise can be one of several tests that indicates animal consciousness. Successful trace conditioning is widespread and by itself does not indicate consciousness.

The eyelid motor system has been used for years as an experimental model for studying the neuronal mechanisms underlying motor and cognitive learning, mainly with classical conditioning procedures. Nonetheless, it is not known yet which brain structures, or neuronal mechanisms, are responsible for the acquisition, storage, and expression of these motor responses. Here, we studied the temporal correlation between unitary activities of identified eyelid and vibrissae motor cortex neurons and the electromyographic activity of the orbicularis oculi and vibrissae muscles and magnetically recorded eyelid positions during classical conditioning of eyelid and vibrissae responses, using both delay and trace conditioning paradigms in behaving mice. We also studied the involvement of motor cortex neurons in reflexively evoked eyelid responses and the kinematics and oscillatory properties of eyelid movements evoked by motor cortex microstimulation. Results show the involvement of the motor cortex in the performance of conditioned responses elicited during the classical conditioning task. However, a timing correlation analysis showed that both electromyographic activities preceded the firing of motor cortex neurons, which must therefore be related more with the reinforcement and/or proper performance of the conditioned responses than with their acquisition and storage.