Pavlovian or associative sensitization and its biological significance.

Pavlovian conditioning is typically distinguished from sensitization but a Pavlovian conditional stimulus (CS) also results in sensitization. A Pavlovian CS can sensitize responding to a probe stimulus that is related to the unconditional stimulus (US) or to the US itself. Pavlovian sensitization has been studied in the defensive, sexual, and feeding systems. In Pavlovian sensitization, the focus is not on a conditional response (CR) directly elicited by the CS but on the response mode that is activated by the CS. Activation of a response mode increases the probability of particular responses and also increases reactivity to various stimuli. Pavlovian sensitization reflects this increased stimulus reactivity. Pavlovian sensitization helps uncover successful learning in situations where a conventional CR does not occur. Pavlovian sensitization also encourages broadening our conceptions of Pavlovian conditioning to include changes in afferent processes. Implications for biological fitness and for basic and translational research are discussed.

Transient enhancement of stimulus-evoked activity in neocortex during sensory learning.

Synaptic potentiation has been linked to learning in sensory cortex, but the connection between this potentiation and increased sensory-evoked neural activity is not clear. Here, we used longitudinal in vivo Ca2+ imaging in the barrel cortex of awake mice to test the hypothesis that increased excitatory synaptic strength during the learning of a whisker-dependent sensory-association task would be correlated with enhanced stimulus-evoked firing. To isolate stimulus-evoked responses from dynamic, task-related activity, imaging was performed outside of the training context. Although prior studies indicate that multiwhisker stimuli drive robust subthreshold activity, we observed sparse activation of L2/3 pyramidal (Pyr) neurons in both control and trained mice. Despite evidence for excitatory synaptic strengthening at thalamocortical and intracortical synapses in this brain area at the onset of learning-indeed, under our imaging conditions thalamocortical axons were robustly activated-we observed that L2/3 Pyr neurons in somatosensory (barrel) cortex displayed only modest increases in stimulus-evoked activity that were concentrated at the onset of training. Activity renormalized over longer training periods. In contrast, when stimuli and rewards were uncoupled in a pseudotraining paradigm, stimulus-evoked activity in L2/3 Pyr neurons was significantly suppressed. These findings indicate that sensory-association training but not sensory stimulation without coupled rewards may briefly enhance sensory-evoked activity, a phenomenon that might help link sensory input to behavioral outcomes at the onset of learning.

Jingfeng Zhou.

Interview with Jingfeng Zhou, who studies how environmental factors impact associative learning and decision-making at the Chinese Institute for Brain Research, Beijing.

The Granular Retrosplenial Cortex Is Necessary in Male Rats for Object-Location Associative Learning and Memory, But Not Spatial Working Memory or Visual Discrimination and Reversal, in the Touchscreen Operant Chamber.

The retrosplenial cortex (RSC) is a hub of diverse afferent and efferent projections thought to be involved in associative learning. RSC shows early pathology in mild cognitive impairment and Alzheimer's disease (AD), which impairs associative learning. To understand and develop therapies for diseases such as AD, animal models are essential. Given the importance of human RSC in object-location associative learning and the success of object-location associative paradigms in human studies and in the clinic, it would be of considerable value to establish a translational model of object-location learning for the rodent. For this reason, we sought to test the role of RSC in object-location learning in male rats using the object-location paired-associates learning (PAL) touchscreen task. First, increased cFos immunoreactivity was observed in granular RSC following PAL training when compared with extended pretraining controls. Following this, RSC lesions following PAL acquisition were used to explore the necessity of the RSC in object-location associative learning and memory and two tasks involving only one modality: trial-unique nonmatching-to-location for spatial working memory and pairwise visual discrimination/reversal. RSC lesions impaired both memory for learned paired-associates and learning of new object-location associations but did not affect performance in either the spatial or visual single-modality tasks. These findings provide evidence that RSC is necessary for object-location learning and less so for learning and memory involving the individual modalities therein.

Learning performance and GABAergic pathway link to deformed wing virus in the mushroom bodies of naturally infected honey bees.

Viral infections can be detrimental to the foraging ability of the western honey bee, Apis mellifera. The deformed wing virus (DWV) is the most common honey bee virus and has been proposed as a possible cause of learning and memory impairment. However, evidence for this phenomenon so far has come from artificially infected bees, while less is known about the implications of natural infections with the virus. Using the proboscis extension reflex (PER), we uncovered no significant association between a simple associative learning task and natural DWV load. However, when assessed through a reversal associative learning assay, bees with higher DWV load performed better in the reversal learning phase. DWV is able to replicate in the honey bee mushroom bodies, where the GABAergic signalling pathway has an antagonistic effect on associative learning but is crucial for reversal learning. Hence, we assessed the pattern of expression of several GABA-related genes in bees with different learning responses. Intriguingly, mushroom body expression of selected genes was positively correlated with DWV load, but only for bees with good reversal learning performance. We hypothesise that DWV might improve olfactory learning performance by enhancing the GABAergic inhibition of responses to unrewarded stimuli, which is consistent with the behavioural patterns that we observed. However, at higher disease burdens, which might be induced by an artificial infection or by a severe, natural Varroa infestation, this DWV-associated increase in GABA signalling could impair associative learning as previously reported by other studies.

Parvalbumin-expressing basal forebrain neurons mediate learning from negative experience.

Parvalbumin (PV)-expressing GABAergic neurons of the basal forebrain (BFPVNs) were proposed to serve as a rapid and transient arousal system, yet their exact role in awake behaviors remains unclear. We performed bulk calcium measurements and electrophysiology with optogenetic tagging from the horizontal limb of the diagonal band of Broca (HDB) while male mice were performing an associative learning task. BFPVNs responded with a distinctive, phasic activation to punishment, but showed slower and delayed responses to reward and outcome-predicting stimuli. Optogenetic inhibition during punishment impaired the formation of cue-outcome associations, suggesting a causal role of BFPVNs in associative learning. BFPVNs received strong inputs from the hypothalamus, the septal complex and the median raphe region, while they synapsed on diverse cell types in key limbic structures, where they broadcasted information about aversive stimuli. We propose that the arousing effect of BFPVNs is recruited by aversive stimuli to serve crucial associative learning functions.

Prediction, perception, and psychosis: Application of associative learning theories to schizophrenia research.

In recent years, there have been significant advances in our understanding of the positive symptoms of schizophrenia, such as hallucinations and delusions. This progress has been significantly aided by the use of associative learning-based approaches in human subjects and preclinical animal models. Here, we first review experimental research focusing on the abnormal processing of absent stimuli using three different conditioning phenomena: conditioned hallucinations, mediated conditioning, and trace conditioning. We then review studies investigating the ability to reduce focal processing of physically present but informationally redundant stimuli using habituation, latent inhibition, and blocking. The results of these different lines of research are then summarized within the framework of Wagner's (1981) standard operating procedures model, an associative learning model with explicit reference to the internal representations of both present and absent stimuli. Within this framework, the central deficit associated with positive symptoms can be described as a failure to suppress the focal processing of both absent stimuli and present but irrelevant stimuli. This can explain the wide range of results obtained in different experimental settings. Finally, we briefly discuss the role of the hippocampus and its interaction with dopaminergic transmission in the emergence of such abnormal stimulus representations and learning. Overall, we hope that the theoretical framework and empirical findings offered by the associative learning approach will continue to facilitate and integrate analyses of schizophrenia conducted at the psychological and behavioral levels on the one hand, and at the neural and molecular levels on the other, by serving as a useful interface between them. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Beyond prediction error: 25 years of modeling the associations formed in the insect mushroom body.

The insect mushroom body has gained increasing attention as a system in which the computational basis of neural learning circuits can be unraveled. We now understand in detail the key locations in this circuit where synaptic associations are formed between sensory patterns and values leading to actions. However, the actual learning rule (or rules) implemented by neural activity and leading to synaptic change is still an open question. Here, I survey the diversity of answers that have been offered in computational models of this system over the past decades, including the recurring assumption-in line with top-down theories of associative learning-that the core function is to reduce prediction error. However, I will argue, a more bottom-up approach may ultimately reveal a richer algorithmic capacity in this still enigmatic brain neuropil.

Cognitive limits of larval Drosophila: testing for conditioned inhibition, sensory preconditioning, and second-order conditioning.

Drosophila larvae are an established model system for studying the mechanisms of innate and simple forms of learned behavior. They have about 10 times fewer neurons than adult flies, and it was the low total number of their neurons that allowed for an electron microscopic reconstruction of their brain at synaptic resolution. Regarding the mushroom body, a central brain structure for many forms of associative learning in insects, it turned out that more than half of the classes of synaptic connection had previously escaped attention. Understanding the function of these circuit motifs, subsequently confirmed in adult flies, is an important current research topic. In this context, we test larval Drosophila for their cognitive abilities in three tasks that are characteristically more complex than those previously studied. Our data provide evidence for (i) conditioned inhibition, as has previously been reported for adult flies and honeybees. Unlike what is described for adult flies and honeybees, however, our data do not provide evidence for (ii) sensory preconditioning or (iii) second-order conditioning in Drosophila larvae. We discuss the methodological features of our experiments as well as four specific aspects of the organization of the larval brain that may explain why these two forms of learning are observed in adult flies and honeybees, but not in larval Drosophila.

Future avenues in Drosophila mushroom body research.

How does the brain translate sensory information into complex behaviors? With relatively small neuronal numbers, readable behavioral outputs, and an unparalleled genetic toolkit, the Drosophila mushroom body (MB) offers an excellent model to address this question in the context of associative learning and memory. Recent technological breakthroughs, such as the freshly completed full-brain connectome, multiomics approaches, CRISPR-mediated gene editing, and machine learning techniques, led to major advancements in our understanding of the MB circuit at the molecular, structural, physiological, and functional levels. Despite significant progress in individual MB areas, the field still faces the fundamental challenge of resolving how these different levels combine and interact to ultimately control the behavior of an individual fly. In this review, we discuss various aspects of MB research, with a focus on the current knowledge gaps, and an outlook on the future methodological developments required to reach an overall view of the neurobiological basis of learning and memory.

The caloric value of food intake structurally adjusts a neuronal mushroom body circuit mediating olfactory learning in Drosophila.

Associative learning enables the adaptive adjustment of behavioral decisions based on acquired, predicted outcomes. The valence of what is learned is influenced not only by the learned stimuli and their temporal relations, but also by prior experiences and internal states. In this study, we used the fruit fly Drosophila melanogaster to demonstrate that neuronal circuits involved in associative olfactory learning undergo restructuring during extended periods of low-caloric food intake. Specifically, we observed a decrease in the connections between specific dopaminergic neurons (DANs) and Kenyon cells at distinct compartments of the mushroom body. This structural synaptic plasticity was contingent upon the presence of allatostatin A receptors in specific DANs and could be mimicked optogenetically by expressing a light-activated adenylate cyclase in exactly these DANs. Importantly, we found that this rearrangement in synaptic connections influenced aversive, punishment-induced olfactory learning but did not impact appetitive, reward-based learning. Whether induced by prolonged low-caloric conditions or optogenetic manipulation of cAMP levels, this synaptic rearrangement resulted in a reduction of aversive associative learning. Consequently, the balance between positive and negative reinforcing signals shifted, diminishing the ability to learn to avoid odor cues signaling negative outcomes. These results exemplify how a neuronal circuit required for learning and memory undergoes structural plasticity dependent on prior experiences of the nutritional value of food.

Skewing information flow through pre- and postsynaptic plasticity in the mushroom bodies of Drosophila.

Animal brains need to store information to construct a representation of their environment. Knowledge of what happened in the past allows both vertebrates and invertebrates to predict future outcomes by recalling previous experience. Although invertebrate and vertebrate brains share common principles at the molecular, cellular, and circuit-architectural levels, there are also obvious differences as exemplified by the use of acetylcholine versus glutamate as the considered main excitatory neurotransmitters in the respective central nervous systems. Nonetheless, across central nervous systems, synaptic plasticity is thought to be a main substrate for memory storage. Therefore, how brain circuits and synaptic contacts change following learning is of fundamental interest for understanding brain computations tied to behavior in any animal. Recent progress has been made in understanding such plastic changes following olfactory associative learning in the mushroom bodies (MBs) of Drosophila A current framework of memory-guided behavioral selection is based on the MB skew model, in which antagonistic synaptic pathways are selectively changed in strength. Here, we review insights into plasticity at dedicated Drosophila MB output pathways and update what is known about the plasticity of both pre- and postsynaptic compartments of Drosophila MB neurons.

Hippocampal and orbitofrontal neurons contribute to complementary aspects of associative structure.

The ability to establish associations between environmental stimuli is fundamental for higher-order brain functions like state inference and generalization. Both the hippocampus and orbitofrontal cortex (OFC) play pivotal roles in this, demonstrating complex neural activity changes after associative learning. However, how precisely they contribute to representing learned associations remains unclear. Here, we train head-restrained mice to learn four 'odor-outcome' sequence pairs composed of several task variables-the past and current odor cues, sequence structure of 'cue-outcome' arrangement, and the expected outcome; and perform calcium imaging from these mice throughout learning. Sequence-splitting signals that distinguish between paired sequences are detected in both brain regions, reflecting associative memory formation. Critically, we uncover differential contents in represented associations by examining, in each area, how these task variables affect splitting signal generalization between sequence pairs. Specifically, the hippocampal splitting signals are influenced by the combination of past and current cues that define a particular sensory experience. In contrast, the OFC splitting signals are similar between sequence pairs that share the same sequence structure and expected outcome. These findings suggest that the hippocampus and OFC uniquely and complementarily organize the acquired associative structure.

Behaviorally Conditioned Immune Responses: "To Learn New Things, Read Old Books and Papers".

BACKGROUND: More than a century ago, experimental work and clinical observations revealed the functional communication between the brain and the peripheral immune system. This is documented on the one hand by studies first demonstrating the effects of catecholamines on the circulation of leukocytes in experimental animals and humans, and on the other hand via the work of Russian physiologist Ivan Petrovic Pavlov and his coworkers, reporting observations that associative learning can modify peripheral immune functions. This work later fell into oblivion since little was known about the endocrine and immune system's function and even less about the underlying mechanisms of how learning, a central nervous system activity, could affect peripheral immune responses. SUMMARY: In this article, we embark on a fascinating exploration of the historical trajectory of behaviorally conditioned immune responses. KEY MESSAGE: We will pay homage to the visionary scientists who laid the groundwork for this field of research, tracing its evolution from early theories of how associative learning can affect immunity to the modern-day insights that behavioral conditioning of pharmacological responses can be exploited to improve the efficacy of medical interventions for patients.

Neural correlates of retrospective memory confidence during face-name associative learning.

The ability to accurately assess one's own memory performance during learning is essential for adaptive behavior, but the brain mechanisms underlying this metamemory function are not well understood. We investigated the neural correlates of memory accuracy and retrospective memory confidence in a face-name associative learning task using magnetoencephalography in healthy young adults (n = 32). We found that high retrospective confidence was associated with stronger occipital event-related fields during encoding and widespread event-related fields during retrieval compared to low confidence. On the other hand, memory accuracy was linked to medial temporal activities during both encoding and retrieval, but only in low-confidence trials. A decrease in oscillatory power at alpha/beta bands in the parietal regions during retrieval was associated with higher memory confidence. In addition, representational similarity analysis at the single-trial level revealed distributed but differentiable neural activities associated with memory accuracy and confidence during both encoding and retrieval. In summary, our study unveiled distinct neural activity patterns related to memory confidence and accuracy during associative learning and underscored the crucial role of parietal regions in metamemory.

Interactions between physical exercise, associative memory, and genetic risk for Alzheimer's disease.

The ε4 allele of the APOE gene heightens the risk of late onset Alzheimer's disease. ε4 carriers, may exhibit cognitive and neural changes early on. Given the known memory-enhancing effects of physical exercise, particularly through hippocampal plasticity via endocannabinoid signaling, here we aimed to test whether a single session of physical exercise may benefit memory and underlying neurophysiological processes in young ε3 carriers (ε3/ε4 heterozygotes, risk group) compared with a matched control group (homozygotes for ε3). Participants underwent fMRI while learning picture sequences, followed by cycling or rest before a memory test. Blood samples measured endocannabinoid levels. At the behavioral level, the risk group exhibited poorer associative memory performance, regardless of the exercising condition. At the brain level, the risk group showed increased medial temporal lobe activity during memory retrieval irrespective of exercise (suggesting neural compensatory effects even at baseline), whereas, in the control group, such increase was only detectable after physical exercise. Critically, an exercise-related endocannabinoid increase correlated with task-related hippocampal activation in the control group only. In conclusion, healthy young individuals carrying the ε4 allele may present suboptimal associative memory performance (when compared with homozygote ε3 carriers), together with reduced plasticity (and functional over-compensation) within medial temporal structures.

Merging meaningful classes and abstract equivalence classes by exclusion.

The current experiment assessed whether relating abstract stimuli with familiar pictures by exclusion would produce the formation of a meaningful equivalence class. Ten participants learned conditional discrimination relations with abstract stimuli and established equivalence classes (ABC classes). They then learned DA (D1A1, D2A2, and D3A3) conditional discriminations with written words as D stimuli; two words (D1 and D2) were meaningful stimuli in the participants verbal community ("Dentist" and "Baker"), whereas the third (D3) was a pseudoword ("Tabilu"). In testing trials, participants evidenced derived relations between pictures related preexperimentally to D1 and D2 with the experimental equivalence classes related to D1 and D2. For some participants, the decontextualized stimuli were a set of boat pictures (Condition 1), whereas for others they were a set of miscellaneous pictures (Condition 2). Participants in both conditions successfully matched decontextualized pictures (unrelated to dentist and baker contexts) to all abstract stimuli in the class related to D3 (exclusion responding). In Condition 1 the meaning reported to the word Tabilu was similar across participants, but in Condition 2 participants showed more variations to answer to the meaning of Tabilu. These results suggest that exclusion learning can occur under different stimulus control topographies.

Distinct Hippocampal Oscillation Dynamics in Trace Eyeblink Conditioning Task for Retrieval and Consolidation of Associations.

Trace eyeblink conditioning (TEBC) has been widely used to study associative learning in both animals and humans. In this paradigm, conditioned responses (CRs) to conditioned stimuli (CS) serve as a measure for retrieving learned associations between the CS and the unconditioned stimuli (US) within a trial. Memory consolidation, that is, learning over time, can be quantified as an increase in the proportion of CRs across training sessions. However, how hippocampal oscillations differentiate between successful memory retrieval within a session and consolidation across TEBC training sessions remains unknown. To address this question, we recorded local field potentials (LFPs) from the rat dorsal hippocampus during TEBC and investigated hippocampal oscillation dynamics associated with these two functions. We show that transient broadband responses to the CS were correlated with memory consolidation, as indexed by an increase in CRs across TEBC sessions. In contrast, induced alpha (8-10 Hz) and beta (16-20 Hz) band responses were correlated with the successful retrieval of the CS-US association within a session, as indexed by the difference in trials with and without CR.

Climbing fibers provide essential instructive signals for associative learning.

Supervised learning depends on instructive signals that shape the output of neural circuits to support learned changes in behavior. Climbing fiber (CF) inputs to the cerebellar cortex represent one of the strongest candidates in the vertebrate brain for conveying neural instructive signals. However, recent studies have shown that Purkinje cell stimulation can also drive cerebellar learning and the relative importance of these two neuron types in providing instructive signals for cerebellum-dependent behaviors remains unresolved. In the present study we used cell-type-specific perturbations of various cerebellar circuit elements to systematically evaluate their contributions to delay eyeblink conditioning in mice. Our findings reveal that, although optogenetic stimulation of either CFs or Purkinje cells can drive learning under some conditions, even subtle reductions in CF signaling completely block learning to natural stimuli. We conclude that CFs and corresponding Purkinje cell complex spike events provide essential instructive signals for associative cerebellar learning.

Distributional coding of associative learning in discrete populations of midbrain dopamine neurons.

Midbrain dopamine neurons are thought to play key roles in learning by conveying the difference between expected and actual outcomes. Recent evidence suggests diversity in dopamine signaling, yet it remains poorly understood how heterogeneous signals might be organized to facilitate the role of downstream circuits mediating distinct aspects of behavior. Here, we investigated the organizational logic of dopaminergic signaling by recording and labeling individual midbrain dopamine neurons during associative behavior. Our findings show that reward information and behavioral parameters are not only heterogeneously encoded but also differentially distributed across populations of dopamine neurons. Retrograde tracing and fiber photometry suggest that populations of dopamine neurons projecting to different striatal regions convey distinct signals. These data, supported by computational modeling, indicate that such distributional coding can maximize dynamic range and tailor dopamine signals to facilitate specialized roles of different striatal regions.