The hippocampus as a sorter and reverberatory integrator of sensory inputs

In entorhinal-hippocampal networks, the trisynaptic pathway, including the CA3 recurrent circuit, processes episodes of context and space. Recurrent connectivity can generate reverberatory activity, an intrinsic activity pattern of neurons that occurs after sensory inputs have ceased. However, the role of reverberatory activity in memory encoding remains incompletely understood. Here we demonstrate that in mice, synchrony between conditioned stimulus (CS) and unconditioned stimulus (US)-responsible cells occurs during the reverberatory phase, lasting for approximately 15 s, but not during CS and US inputs, in the CA1 and the reverberation is crucial for the linking of CS and US in the encoding of delay-type cued-fear memory. Retrieval-responsive cells developed primarily during the reverberatory phase. Mutant mice lacking N-methyl-D-aspartate receptors (NRs) in CA3 showed a cued-fear memory impairment and a decrease in synchronized reverberatory activities between CS- and US-responsive CA1 cells. Optogenetic CA3 silencing at the reverberatory phase during learning impaired cued-fear memory. Our findings suggest that reverberation recruits future retrieval-responsive cells via synchrony between CS- and US-responsive cells. The hippocampus uses reverberatory activity to link CS and US inputs, and avoid crosstalk during sensory inputs.

Reactivation of hedonic but not sensory representations in human emotional learning

Learning which stimuli in our environment co-occur with painful or pleasurable events is critical for survival. Previous research has established the basic neural and behavioural mechanisms of aversive and appetitive conditioning; however, it is unclear what precisely is learned. Here we examined what aspects of the unconditioned stimulus (US), sensory and hedonic, are transferred to the conditioned stimulus (CS). To decode the content of brain activation patterns elicited during appetitive (soft touch) and aversive (painful touch) conditioning of faces, a novel variation of representational similarity analysis (RSA) based on theoretically driven representational patterns of interest (POIs) was applied to fMRI data. Once face associations were learned through conditioning, globally the CS reactivated US representational patterns showing conditioning dependent reactivation. More specifically, in higher order brain regions, the CS only reactivated hedonic but not sensory aspects of the US, suggesting that affective conditioning primarily carries forward the valence of the experience rather than its sensory origins.

Schizotypal personality traits and the social learning of fear

Schizotypy can be defined as a combination of traits qualitatively similar to those found in schizophrenia, but milder in their expression, that can be found in clinical and non-clinical populations. In this research, we explore, to our knowledge, for the first time, whether schizotypal personality traits may affect the acquisition of conditioned fear by social means only. Apart from being an essential capacity to ensure learning in safe environments, social fear learning shares important characteristics with direct fear acquisition, which also makes it a great candidate for developing successful extinction procedures. Undergraduate students (n = 72) performed a task of social fear learning. In this task, participants watched a video of a person that simulated to receive electric shocks (unconditioned stimulus; US) paired with a coloured square (conditioned stimulus plus; CS+), while another coloured square was never paired (conditioned stimulus minus; CS−) with the shock. After that, they were presented with a similar sequence of coloured screens. Their Skin Conductance Responses (SCRs) were registered during the whole process. Once they finished, they completed the Schizotypal Personality Questionnaire (SPQ). Our results revealed that participants with a low score in the Cognitive-Perceptual factor of the SPQ exhibited higher SCRs when they saw the US than when they saw the CS− (all ps < 0.01) during the learning phase. Nevertheless, those with higher scores did not present any difference in their SCRs toward both stimuli (all ps > 0.05), a pattern that has been similarly found in schizophrenia. During the final trials of the test phase, participants with the highest scores in the Disorganized factor were the only ones that maintained a higher SCR towards the CS+ than towards the CS− (p = 0.006), which could be associated with an impairment in their extinction processes.

Higher-Order Conditioning With Simultaneous and Backward Conditioned Stimulus: Implications for Models of Pavlovian Conditioning

In a new environment, humans and animals can detect and learn that cues predict meaningful outcomes, and use this information to adapt their responses. This process is termed Pavlovian conditioning. Pavlovian conditioning is also observed for stimuli that predict outcome-associated cues; a second type of conditioning is termed higher-order Pavlovian conditioning. In this review, we will focus on higher-order conditioning studies with simultaneous and backward conditioned stimuli. We will examine how the results from these experiments pose a challenge to models of Pavlovian conditioning like the Temporal Difference (TD) models, in which learning is mainly driven by reward prediction errors. Contrasting with this view, the results suggest that humans and animals can form complex representations of the (temporal) structure of the task, and use this information to guide behavior, which seems consistent with model-based reinforcement learning. Future investigations involving these procedures could result in important new insights on the mechanisms that underlie Pavlovian conditioning.

Transcriptional Correlates of Chronic Alcohol Neuroadaptation in Drosophila Larvae

When presented with the choice, Drosophila melanogaster females will often prefer to lay eggs on food containing a significant amount of alcohol. While, in some cases, this behavioral decision can provide a survival advantage to the developing larvae, it can also lead to developmental and cognitive problems. Alcohol consumption can affect executive functions, episodic memory, and other brain function capacities. However, in the fruit fly, the initial cognitive effects of alcohol consumption have been shown to reverse upon persistent exposure to alcohol. Using an olfactory conditioning assay where an odorant is implemented as a conditioned stimulus and paired with a heat shock as an unconditioned stimulus, a previous study has shown that when exposed to a short acute dose of alcohol, Drosophila larvae can no longer learn this association. Interestingly, upon prolonged chronic alcohol exposure, larvae seem to successfully avoid the conditioned stimulus just as well as control alcohol-naive larvae, suggestive of alcohol-induced neuroadaptations. However, the mechanisms by which Drosophila adapt to the presence of alcohol remains unknown. In this study, we explore the transcriptional correlates of neuroadaptation in Drosophila larvae exposed to chronic alcohol to understand the genetic and cellular components responsible for this adaptation. For this, we employed RNA sequencing technology to evaluate differences in gene expression in the brain of larvae chronically exposed to alcohol. Our results suggest that alcohol-induced neuroadaptations are modulated by a diverse array of synaptic genes within the larval brain through a series of epigenetic modulators.

Higher-Order Conditioning: What Is Learnt and How it Is Expressed

Pairing a neutral conditioned stimulus (CS) with a motivationally significant unconditioned stimulus (US) results in the CS coming to elicit conditioned responses (CRs). The widespread significance and translational value of Pavlovian conditioning are increased by the fact that pairing two neutral CSs (A and X) enables conditioning with X to affect behavior to A. There are two traditional informal accounts of such higher-order conditioning, which build on more formal associative analyses of Pavlovian conditioning. But, higher-order conditioning and Pavlovian conditioning have characteristics that are beyond these accounts: Notably, the two are influenced in different ways by the same experimental manipulations, and both generate conditioned responses that do not reflect the US per se. Here, we present a formal analysis that sought to address these characteristics.

Simulation-based learning shapes real-life attitudes

Humans can vividly simulate hypothetical experiences. This ability draws on our memories (e.g., of familiar people and locations) to construct imaginings that resemble real-life events (e.g., of meeting a person at a location). Here, we examine the hypothesis that we also learn from such simulated episodes much like from actual experiences. Specifically, we show that the mere simulation of meeting a familiar person (unconditioned stimulus; US) at a known location (conditioned stimulus; CS) changes how people value the location. We provide key evidence that this simulation-based learning strengthens pre-existing CS-US associations and that it leads to a transfer of valence from the US to the CS. The data thus highlight a mechanism by which we learn from simulated experiences.

Sleep and conditioning of the siphon withdrawal reflex in Aplysia

Sleep is essential for memory consolidation after learning as shown in mammals and invertebrates such as bees and flies. Aplysia californica displays sleep and sleep in this mollusk was also found to support memory for an operant conditioning task. Here, we investigated whether sleep in Aplysia is also required for memory consolidation in a simpler type of learning, i.e., the conditioning of the siphon withdrawal reflex. Two groups of animals (Wake, Sleep, each n=11) were conditioned on the siphon withdrawal reflex with the training following a classical conditioning procedure where an electrical tail shock served as unconditioned stimulus (US) and a tactile stimulus to the siphon as conditioned stimulus (CS). Responses to the CS were tested before (Pre-test), 24 and 48 hours after training. While Wake animals remained awake for 6 hours after training, Sleep animals had undisturbed sleep. The 24h-test in both groups was combined with extinction training, i.e., the extended presentation of the CS alone over two blocks. At the 24h-test, siphon withdrawal durations to the CS were distinctly enhanced in both Sleep and Wake groups with no significant difference between groups, consistent with the view that consolidation of a simple conditioned reflex response does not require post-training sleep. Surprisingly, extinction training did not reverse the enhancement of responses to the CS. On the contrary, at the 48h-test, withdrawal durations to the CS were even further enhanced across both groups. This suggests that processes of sensitization, an even simpler non-associative type of learning, contributed to the withdrawal responses. Our study provides evidence for the hypothesis that sleep preferentially benefits consolidation of more complex learning paradigms than conditioning of simple reflexes.

Differential conditioning produces merged long-term memory in Drosophila

Multiple spaced trials of aversive differential conditioning can produce two independent long-term memories (LTMs) of opposite valence. One is an aversive memory for avoiding the conditioned stimulus (CS+), and the other is a safety memory for approaching the non-conditioned stimulus (CS-). Here, we show that a single trial of aversive differential conditioning yields one merged LTM (mLTM) for avoiding both CS+ and CS-. Such mLTM can be detected after sequential exposures to the shock-paired CS+ and unpaired CS-, and be retrieved by either CS+ or CS-. The formation of mLTM relies on triggering aversive-reinforcing dopaminergic neurons and subsequent new protein synthesis. Expressing mLTM involves αβ Kenyon cells and corresponding approach-directing mushroom body output neurons (MBONs), in which similar-amplitude long-term depression of responses to CS+ and CS- seems to signal the mLTM. Our results suggest that animals can develop distinct strategies for occasional and repeated threatening experiences.