Learning & Memory

RationaleAppetitive Pavlovian cues can drive maladaptive reward seeking via stimulus-reward memories. Disrupting memory reconsolidation offers a potential strategy to reduce their influence, but evidence for {beta}-adrenergic blockade with propranolol is inconsistent across behavioural paradigms, particularly relative to NMDA receptor antagonism. ObjectivesWe tested whether propranolol disrupts reconsolidation of appetitive sucrose memories in a discriminative goal-tracking paradigm, and compared its effects with those of the most commonly used NMDA receptor antagonist, MK-801. MethodsAdult Lister hooded rats underwent discriminative Pavlovian conditioning. Thirty minutes before a brief memory reminder (non-reinforced or reinforced), rats received systemic drug treatment or saline control. In study 1, MK-801 (0.1 mg/kg) was administered to male rats. In study 2, propranolol (10 mg/kg) was administered to equal numbers of male and female rats. Goal-tracking was tested drug-free at 1 and 8 days. ResultsIn study 1, MK-801 impaired subsequent discriminated responding at test. These effects were observed not only when reminder was non-reinforced as in previous successful demonstrations, but also with reinforced reminder. In study 2, Propranolol also impaired subsequent goal-tracking, regardless of reminder type, and the effects were consistent across sexes. ConclusionsPropranolol can disrupt reconsolidation of appetitive goal-tracking memories to a similar extent as MK-801 under conditions that promote memory destabilisation. These findings demonstrate that {beta}-adrenergic blockade can impair appetitive memory reconsolidation in a goal-tracking paradigm, challenging prior null findings and revitalising the potential for propranolol-based interventions in maladaptive reward-seeking behaviours.

Children often outperform adults in probabilistic statistical learning tasks, yet the mechanisms underlying this developmental advantage remain poorly understood. Here, we used eye-tracking measures of belief updating to examine how children and adults acquire and update predictions in a probabilistic sequence-learning task. Using the standard (oculomotor) reaction time measure, children showed stronger statistical learning than adults, replicating previous behavioral findings while revealing a more detailed profile of developmental differences in statistical learning. Critically, children updated their predictions more frequently: they were less likely to repeat previous predictions and more likely to shift their expectations in response to new input. Adults, in contrast, showed greater persistence, tending to maintain prior predictions even when those predictions were inconsistent with the underlying statistical structure. Despite these pronounced differences in updating behavior, the processing and use of prediction errors were remarkably similar across age groups. These findings indicate that developmental differences in statistical learning do not primarily arise from how prediction errors are computed, but rather from how prior beliefs and incoming information are weighted during belief updating. Children's enhanced learning may therefore reflect reduced reliance on stable priors and greater sensitivity to current sensory evidence, supporting a more exploratory learning strategy. Adults, by contrast, appear to favor an exploitative strategy that stabilizes existing predictions but reduces flexibility in probabilistic environments. More broadly, the results suggest that developmental changes in statistical learning may reflect age-related differences in how readily learners revise their predictions in response to incoming evidence. By integrating sensitive oculomotor measures with analyses that probe the mechanisms underlying belief updating, the present study provides a more fine-grained account of how predictive learning changes across development and offers a framework for reconciling previously inconsistent developmental findings in statistical learning.

Humans exhibit structured patterns of memory recall, including a tendency to recall more recent information and to recall events in the same order they were experienced. Classic computational models explain these patterns by positing that memories incorporate the ongoing ''temporal context'', formed by smoothly integrating the stimulus history. However, it is unclear whether a single mechanism can account for the full repertoire of human memory strategies, as the optimal approach may be task-dependent. For example, human memory experts widely apply the ''memory palace'' strategy, which is empirically better but not captured by temporal context models. Here we show that neural networks optimized for free recall develop diverse retrieval strategies, with only some of them resembling temporal context models.The best-performing models discovered a stimulus-invariant index code that emphasizes the studied position of each list item, instead of its temporal context. This creates a stable scaffold for forward recall akin to the memory palace technique. This index code was more likely to emerge when networks were i) encouraged to recall all studied items rather than prioritizing a few items, and ii) prevented from relying on recency, resonating with human data. Our findings demonstrate that human-like recall patterns can arise from multiple distinct computational mechanisms, and that sequential retrieval using item index is an optimal strategy that explains expert-level recall performance.

Animals balance staying in a favorable environment with exploring new ones. In C. elegans chemotaxis, the process by which worms migrate toward an attractant has been extensively studied. However, what happens after they reach it remains largely unexplored, partly because conventional assays immobilize worms at the point of arrival. Here, we quantitatively analyzed chemotactic behavior upon reaching an attractive odor source using an immobilization-free chemotaxis assay. We observed that 62% animals left the isoamyl alcohol region after initially approaching it, a behavior we termed "leaving behavior." Quantitative analysis revealed that leaving behavior represents a distinct locomotor state compared with free-moving, high-concentration odor avoidance, and approach behavior. To test whether leaving behavior is related to olfactory adaptation, we analyzed mutants in adaptation-related genes. The proportion of leaving behavior was significantly increased in egl-4 loss-of-function mutants compared with wild-type animals, whereas arr-1 mutants showed no significant difference. These results suggest that egl-4 negatively regulates leaving behavior, suggesting a role for this kinase in stabilizing post-arrival behavioral states beyond its known function in olfactory adaptation. Our findings indicate that chemotaxis involves dynamic behavioral transitions even after reaching an attractant, consistent with an exploration-exploitation trade-off framework.

The medial prefrontal cortex (mPFC) plays a significant role in modulating the threat response, particularly in ambiguous circumstances. The mPFC performs this role through its connectivity with multiple brain regions, including the amygdala, long regarded as the central hub for threat responses. However, the roles of specific prefrontal projections to the amygdala in contextual threat discrimination are not yet fully understood, particularly regarding more complex learning tasks and when disentangling the functionally distinct prelimbic (PL) subunit of the mPFC. Here, we challenged mice with a contextual differential threat conditioning (DTC) learning task in which subjects were repeatedly exposed to one context predictive of a foot shock (CS+) and to a similar yet distinct context that was not (CS-). While control mice showed a similar threat response in both contexts immediately after threat conditioning, within a few days of contextual exposures, controls acquire threat discrimination and freeze less to CS- than to CS+ during late DTC. However, we found that inducing localized hypofunction of neuroplasticity in PL neurons projecting to the basolateral amygdala (BLA) impairs performance on DTC. This finding identifies the specific population of neurons in PL cortices as a critical site for learning to discriminate threat.

Temporal Order Memory (TOM), the ability to discriminate between events according to when they occurred, is a key component of episodic-like memory. Understanding the molecular mechanisms that support temporal memory requires behavioral approaches capable of capturing the continuous dynamics of natural exploration. Despite extensive evidence implicating the prefrontal cortex (PFC) in temporal memory, the intracellular signaling mechanisms supporting temporal order discrimination remain poorly understood. Here, we combined high-resolution automated behavioral phenotyping with molecular analyses to characterize the behavioral and signaling dynamics underlying TOM in mice. Mice were trained in a spontaneous object-recognition TOM task and tested after short-term (3 h) or long-term (24 h) retention intervals. Exploration was quantified using an artificial intelligence-based behavioral analysis pipeline that enables continuous and unbiased assessment of object exploration. Phosphorylation of extracellular signal-regulated kinase 2 (ERK2) and expression of the ERK phosphatase MKP3/DUSP6 were analyzed in the PFC and hippocampus (HIP) following habituation, a single training session, or two sequential training sessions. Additionally, a Temporal Novel Object Recognition (TeNOR) protocol was used to evaluate the integrity of memory traces. Mice displayed robust TOM performance across sexes and retention intervals. Molecular analyses revealed no significant changes in hippocampal ERK signaling, whereas the cytosolic fraction of the PFC exhibited dynamic, experience-dependent modulation of ERK2 phosphorylation. A single 15-minute training session induced a transient increase in ERK2 activation, while a second session 45 minutes later actively suppressed this peak. This rapid molecular reset was accompanied by increased MKP3 expression, suggesting the targeted recruitment of an active regulatory feedback mechanism. Continuous behavioral tracking further revealed temporal features of memory expression that were not captured by conventional summary measures; it identified an early, rapid decay of discrimination for older object memories in the TeNOR task, suggesting that TOM performance relies on resolving competitive retrieval between co-existing memory traces. Together, these findings identify dynamic ERK2-MKP3 signaling in the PFC as the molecular substrate upon which temporal discrimination can take place, and demonstrate how high-resolution phenotyping in naturalistic behavioral paradigms can reveal mechanistic links between intracellular signaling and the temporal organization of experience.

To quantify animals perceptual capabilities, studies typically assess behavioral accuracy, the proportion of correct choices accumulated over trials on a given task. However, recent works on humans and rodents have shown that task decisions exhibit dynamic shifts from trial to trial, thus casting doubt on the reliability of behavioral accuracy as a true measure of capabilities. Here, these decision-making dynamics were tested on archerfish, an animal lacking a fully developed cortex, whose behavioral decisions are easy to read out. We conducted a series of experiments involving a two-alternative choice task where a target and a non-target shape were randomly placed in two possible positions. Fitting dynamic generalized linear models to each fishs binary choice data revealed that target position strongly affected accuracy and that this effect fluctuated over a timescale of [~]100 trials. The archerfish often repeated their choices regardless of the reward: they frequently selected one target or non-target shape on numerous consecutive trials, which is suggestive of high object recognition capacity. Importantly, the findings indicated that similar latent decision variables underlying mammalian decision-making, such as choice history, were also operational in the archerfish. Then, to investigate behavioral accuracy in more detail, we introduced unrewarded probe trials. Unlike the findings reported in rodents, archerfish performance remained stable during these unrewarded trials. Finally, a decision-making paradigm with stimuli at multiple locations yielded results that were consistent with the simpler task variant. More generally, these findings suggest that an animals decision-making dynamics can mask its true perceptual capabilities when performing an object recognition task, with broad implications for the ways in which behavioral assays are designed and animal performance is interpreted across taxa.

Studying chess experts helps researchers understand how intensive practice shapes thinking skills. Cognitive flexibility is the ability to adjust thoughts when rules or tasks change. Working memory is the ability to hold and use information over short periods. This study compared cognitive flexibility and working memory precision between adolescent chess players and non-players. Twenty-four professional chess players and twenty-five controls completed two novel behavioral tasks. Chess players showed better accuracy in both tasks than controls. They adapted more efficiently when rules changed during a continuous learning task. They also remembered facial expressions more precisely in a working memory task. Learning rates in the flexibility task did not differ between groups. These results indicate that chess expertise may improve rule-guided flexibility and visual working memory precision in adolescents.

Neural activity in frontal-striatal circuits underlies reinforcement learning. Traditional theories suggest that reinforcement signals, which drive learning, strengthen connections within the basal ganglia. This strengthening is believed to shift information processing from cortical regions to subcortical regions as learning becomes established over time. To examine this hypothesis, we trained macaques to associate multiple sets of images with their values. Selecting different images led to either an increase (+2, +1) or a decrease (-1, -2) in the number of tokens, which subsequently determined the amount of juice reward the macaques received. We simultaneously recorded neuronal activity from orbitofrontal cortex, ventral striatum, amygdala, and dorsomedial thalamic nucleus, analyzing the dynamic changes in these brain regions during both the initial learning and overlearned stages. The results indicated that as learning progressed from the initial stage to the overlearned stage, information processing shifted from the ventral striatum to the orbitofrontal cortex, corresponding to the abstraction from stimulus value to state value. This finding challenges traditional theories and provides a new perspective on the neural circuit mechanisms of learning.

Many forms of memory are thought to rely on visual imagery, but individuals who report lacking visual imagery (aphantasia) can still perform various memory tasks. There is, however, evidence that aphantasia may lead to less detailed autobiographical memories, suggesting there may be deficits in the underlying cognitive processes that support personal memories. One such process is associative memory, which requires binding of different types of information. Here, we tested whether associative visual memory is intact in aphantasia. We assessed 72 self-identified individuals with aphantasia and 77 controls who reported having visual imagery. Participants completed an associative memory task which involved memorising displays where a unique object in a specific location was associated with a particular colour fixation point. Individuals with aphantasia performed equivalently to controls for object locations and outperformed controls on the associated object-identity. In addition, whereas controls were significantly worse at remembering associated object-identity than object-location, individuals with aphantasia showed no such difference. Both groups showed good metacognitive performance evidenced by a positive correlation between confidence and accuracy; there were no significant differences in confidence between the groups. Reported strategies varied between groups: a large proportion of control participants reported using visual imagery and self-reported use of imagery positively correlated with performance. Conversely, individuals with aphantasia mostly reported using nonvisual strategies to remember the associations. Overall, the findings suggest that individuals with aphantasia can form associative memories using nonvisual strategies. Thus, difficulties with autobiographical memory in aphantasia seem unlikely to be due to fundamental issues with associative memory.

Past sensory experience shapes our perceptual decision-making in the now. Popular models frame perceptual decisions as either attracted towards or repelled away from recent sensory information, but it is unclear when and why these distinct effects emerge. We here ask whether effects turn from attractive to repulsive depending on the level of surprise elicited by the precision-weighted discrepancy between past and present sensory states. This model is based upon the idea that attraction is adaptive for optimizing efficiency and accuracy when discrepancies are small, because they likely reflect sensory noise rather than real change in the environment. In contrast, repulsion may reflect the upweighting of counterfactual evidence when discrepancies are large because they more likely signal the need for model updating. We test this model on a large amount of recently-collated trial-by-trial serial dependence data and consistently find support for it across the dataset, participant, and trial-by-trial level. Specifically, serial dependence effects are attractive at low discrepancies between past and current sensory states but turn repulsive when discrepancies are larger. Higher sensory precision is found to accelerate this flip by reducing the modal discrepancy threshold required to trigger repulsion effects. We discuss how these findings necessitate extending existing theories of serial dependence, and how they may resolve conflicts in the broader predictive processing, learning and perception literatures.

Background: Dopamine (DA) is a neurotransmitter critically involved in food-related reinforcement learning. While mesolimbic DA reward-associated signaling in the nucleus accumbens has been widely investigated, far less is known about DA function in the hippocampus (HPC), a brain region traditionally known for its role in episodic and spatial memory processes that has recently been associated with appetite and food intake control. Methods: Here we investigated dorsal HPC DA signaling dynamics in rats using fiber photometry to detect changes in DA binding (via GRAB-DA sensors) before, during, and after a meal consumption in food-restricted rats. Pharmacological studies targeting HPC dopamine 2 receptors (D2R) assessed the functional role of HPC DA signaling in food intake and meal-related memory processes. Results: HPC DA binding was significantly elevated in the post-meal relative to the pre-meal state following standard chow consumption. This effect was replicated after consuming a high fat diet or liquid sucrose, but not a low-calorie sweetener. These post-meal DA signaling elevations are dependent on nutrient consumption, as HPC DA binding levels were unaffected by intraperitoneal administration of glucose or the satiation hormone, cholecystokinin, in otherwise fasted rats. Direct HPC D2R agonists administration reduced food intake, whereas HPC D2R blockade after a meal reduced the latency to the next meal and impaired spatial memory for meal location without affecting spatial memory for object location. Conclusions: Collective results identify HPC DA-D2R signaling as a candidate neurobiological mechanism through which nutrient consumption promotes meal-related episodic memory formation, and by extension, reduces subsequent food intake.

Attentional control balances proactive suppression of predictable distractors with reactive suppression of unexpected ones. Yet, how internal states such as alertness shape this balance is unclear. Using pupillometry and eye tracking across two probability-cueing experiments (conducted in 2024) with varying distractor prevalence, we distinguished tonic (baseline pupil size across blocks) from trial-level pupil size fluctuations (trial-by-trial residual variability in pre-stimulus pupil size). With moderate prevalence, suppression of frequent-region distractors developed gradually, whereas high prevalence induced near-immediate suppression. Behavioral measures (e.g., reaction times) were closely linked to tonic and trial-level pupil size fluctuations. Critically, both alertness components jointly influenced control: during early learning, heightened trial-level pupil size increased distractor capture and reduced target fixations, whereas later on, suppression shifted to a proactive mode resilient to trial-level fluctuations. Under high prevalence, this shift occurred faster. Notably, higher trial-level pupil size generally accelerated first target selection. These findings show that tonic alertness and trial-level alertness fluctuations dynamically regulate reactive and proactive control during statistical learning. Impact StatementThis study shows that people become better at ignoring predictable distractions over time, but that this improvement depends not only on what they have learned about the task environment, but also on their current level of alertness. By combining eye tracking and pupil measures, we found that temporary increases in alertness can sometimes help people orient more quickly to relevant information, yet during earlier stages of learning they can also make attention more vulnerable to distracting events. These findings suggest that successful focus in complex environments depends on a dynamic interplay between learned expectations and moment-to-moment fluctuations in mental state, with implications for understanding sustained attention in settings such as monitoring, driving, and other tasks that require people to stay engaged while resisting distraction.

Previous research on the brain correlates of working memory using functional magnetic resonance imaging (fMRI) and multivariate pattern analysis (MVPA) have shown that neural activity related to information currently needed to respond on a test is considered to be in the focus of attention (FoA). An ongoing controversy pertains to the neural representation of information in working memory that is not needed for the upcoming test but possibly for a subsequent one, which is considered to reside in an activated portion of long-term memory (aLTM). The key theoretical issue regarding aLTM is whether it corresponds solely to an activity-silent neural state. Here, by using a retrospective cuing task in which two arrays of stimuli from different categories were presented in succession on the same trial, and a pattern classifier trained on the first-presented category during the presentation of the second, we provide evidence that aLTM is associated with an active neural state. Specifically, the aLTM effect was demonstrated to be dissociable in direction from that related to the FoA, there was considerable overlap between brain regions representing information in a stronger form in the FoA and a weaker form in aLTM, and the two states appeared to be differentially subject to flexible cognitive control versus natural decay.

Serotonin (5-HT) 2A receptors (5-HT2AR) modulate corticolimbic circuits regulating fear extinction. Although activation of these receptors has been shown to facilitate fear extinction, the behavioral consequences of 5-HT2AR antagonism during extinction is not well defined. Here, we examined the systemic effects of two 5-HT2A receptor antagonists, the mixed 5-HT2A/2C antagonist MDL 11,939 (Glemanserin) and the selective 5-HT2A antagonist MDL 100,907 (Volinanserin) on fear extinction in adult C57BL/6J mice. Prior to drug administration, mice assigned to future treatment groups acquired comparable conditioned freezing responses during delay fear conditioning. Twenty-four hours later, acute administration of MDL 11,939 (1.0 mg/kg) or MDL 100,907 (0.01 mg/kg) increased freezing to the first conditioned stimulus (CS) presentation on Extinction Day 1, indicating enhanced expression of conditioned fear. However, acquisition of fear extinction differed between the respective cohorts of mice treated with the two 5-HT2AR antagonists. Repeated administration of MDL 11,939 significantly impaired extinction, as evidenced by increased freezing across extinction trials and an increased number of trials required to reach extinction criterion. In contrast, MDL 100,907 has reported affinity for did not significantly alter extinction under either acute or repeated dosing conditions. Because MDL 11,939 has reported affinity for 5-HT2C receptors, we tested potential contributions of 5-HT2C receptor antagonism in a separate cohort of mice using two doses of the selective 5-HT2C antagonist, SB 242084. Neither dose affected conditioned fear expression, extinction learning, or trials required to reach extinction criterion. Together, these findings demonstrate ligand-specific and dose-dependent effects of 5-HT2AR antagonism on fear extinction and suggest that distinct intracellular receptor signaling pathways may differentially regulate extinction-related behavior.

Memorizing a new phone number or address is hard at first, but becomes easier with repetition, as information shifts from working memory to long-term memory. Here we investigated how repetition affects the storage and transition of different aspects of mnemonic information by comparing univariate neural markers of active object storage with multivariate decoding of memory content. Thirty participants encoded lateralized stimuli from a continuous shape space into memory. Memory items were repeated six times in a row to induce learning. In line with earlier work, EEG recordings revealed that repetition led to a reduction in contralateral delay activity (CDA), a measure of active storage that has been taken to reflect a pointer-like representation of the individual object or its original source. In contrast, shape decoding during the retention and also after an impulse perturbation remained constant across repetitions. These results suggest that learning over repetitions reflects the abolishment of active and individuated object memory representations while passive, source-independent memory representations are retained.

Language production requires the coordination of multiple cognitive processes. The ability to anticipate and override a habitual response in favor of a contextually-appropriate response are key subprocesses of cognitive control which enable speakers to communicate effectively. Word retrieval involves the co-activation of semantically related alternatives from which the speaker must select the appropriate target representation. Although cognitive control mechanisms have been proposed to contribute to resolving semantic interference during language production, the nature of these control processes remain unclear. Studies investigating the temporal dynamics of cognitive control during decision making tasks have led to a distinction between two operating processes: proactive control, initiated prior to the occurrence of conflict, and reactive control recruited after conflict is detected. We investigated the roles of proactive and reactive control in resolving interference between competing linguistic representations during word retrieval. We analyzed congruency sequence effects combined with delta-plot distributional analyses to dissociate potential adjustments in proactive versus reactive cognitive control in a picture-naming task manipulating semantic context compared to a minimally-linguistic Stroop-like paradigm. Reaction time distributional properties following semantically related trials revealed the engagement of proactive control in semantic interference resolution during word retrieval in the PWI task. In contrast, reactive inhibitory control was engaged in resolving semantic interference following low conflict trials. This distinction was not present in the minimally-linguistic task, which did not appear to engage adaptive control to the same extent. These findings demonstrate that both proactive and reactive cognitive control mechanisms contribute to language production, and are engaged dynamically, adjusting trial-by-trial to resolve semantic interference during word retrieval. In addition, our study provides important insight into the comparison of language with other cognitive domains and positions linguistic paradigms as being instrumental in the study of cognitive control dynamics.

Rationale: Early life stress (ELS) is acknowledged to underlie cognitive and emotional abnormalities linked to stress-related mood disorders. ELS can lead to persistent biases in how uncertain feedback is processed to affect the flexibility of decision-making. Objectives: (1) To investigate the effects of ELS on the flexibility of rats trained on a serial probabilistic reversal learning (PRL) task involving spurious positive and negative feedback. (2) To elucidate the involvement of the stress hormone corticosterone and the noradrenergic and serotonergic systems in modulating how ELS affects PRL. Methods: Male and female rats were intermittently separated from maternal care on postnatal days five to nineteen, inclusively. As adults, the same rats were trained on a deterministic reversal learning task involving certain rewarded or non-rewarded outcomes followed by a PRL task where correct and incorrect responses were rewarded on 80% and 20% of trials, respectively. Dose-dependent effects of the beta-blocker, propranolol, selective serotonin reuptake inhibitor, citalopram and corticosterone were subsequently determined. Results: ELS resulted in an increased responsivity to feedback, specifically in males making more win-stay responses following a reward, that was associated with an increased punishment learning rate. In both control and MS rats, propranolol increased feedback sensitivity, but delayed updating following a rule switch. In contrast, neither citalopram nor corticosterone significantly affected reversal learning. Conclusions: ELS is sufficient to cause persistent changes in how feedback is processed by male rats on a reversal learning task. Activation of beta-adrenergic receptors may be necessary for updating learned associations during decision-making involving uncertain feedback.

The hippocampal CA3 subfield is central to associative learning and memory consolidation. The principal cells of the CA3, pyramidal neurons, execute these functions by generating hypersynchronous bursts that feed forward to the CA1. Extensive recurrent collateral connections within the CA3 neuron population are crucial for the generation of this burst activity. Double C2 domain-containing protein (Doc2) and synaptotagmin 7 (Syt7) are high-affinity calcium sensors implicated in asynchronous synaptic vesicle (SV) release and in the exocytosis of dense-core vesicles (DCVs). Additionally, Doc2 is a sensor for miniature neurotransmission, whereas Syt7 is involved in synaptic facilitation and SV replenishment. Both Doc2 and Syt7 are expressed in the hippocampus, but their potential roles in spontaneous excitatory network activity remain unanswered. Using whole-cell recordings in disinhibited acute hippocampal slices obtained from juvenile Doc2- and Syt7- knockout (KO) mice (P15-21), we report increased CA3 burst generation without changes in spontaneous excitatory postsynaptic current (sEPSC) frequency or amplitude. Moreover, the intrinsic properties of CA3 pyramidal neurons, such as the resting membrane potential, firing rate and input resistance, are unchanged. We propose that this novel burst phenotype in Doc2- and Syt7- KO mice is unrelated to changes in SV release but might be mediated by changes in neuropeptide release from DCVs. Regardless of the underlying mechanisms, this work reveals that both proteins act to regulate network activity. The hippocampal CA3 subfield is central to associative learning and memory consolidation. The principal cells of the CA3, pyramidal neurons, execute these functions by generating hypersynchronous bursts that feed forward to the CA1. Extensive recurrent collateral connections within the CA3 neuron population are crucial for the generation of this burst activity. Double C2 domain-containing protein (Doc2) and synaptotagmin 7 (Syt7) are high-affinity calcium sensors implicated in asynchronous synaptic vesicle (SV) release and in the exocytosis of dense-core vesicles (DCVs). Additionally, Doc2 is a sensor for miniature neurotransmission, whereas Syt7 is involved in synaptic facilitation and SV replenishment. Both Doc2 and Syt7 are expressed in the hippocampus, but their potential roles in spontaneous excitatory network activity remain unanswered. Using whole-cell recordings in disinhibited acute hippocampal slices obtained from juvenile Doc2- and Syt7- knockout (KO) mice (P15-21), we report increased CA3 burst generation without changes in spontaneous excitatory postsynaptic current (sEPSC) frequency or amplitude. Moreover, the intrinsic properties of CA3 pyramidal neurons, such as the resting membrane potential, firing rate and input resistance, are unchanged. We propose that this novel burst phenotype in Doc2- and Syt7- KO mice is unrelated to changes in SV release but might be mediated by changes in neuropeptide release from DCVs. Regardless of the underlying mechanisms, this work reveals that both proteins act to regulate network activity.

In animal learning research, learning is often represented by plotting a behavioral measure as a function of training trials. A particularly clear case is habituation, a basic form of learning in which repeated presentation of a stimulus produces a decrement in responding. Although retention tests provide the strongest basis for evaluating durable habituation once short-lived performance effects have dissipated, the pattern of response change across stimulus repetitions, or habituation curve, remains theoretically and empirically relevant because it is used to characterize determinants of habituation, individual and clinical profiles, and functional forms, including linear, curvilinear, asymptotic, and mixed incremental-decremental patterns of responding. However, group averaged curves may conceal substantial individual heterogeneity. Here, we analyzed archived human eyeblink habituation data from 157 participants to ask whether the curve shape selected for the group average reflects the curve shapes observed at the individual level. Five candidate functions were fitted separately to each participant and to the corresponding group average. No single function characterized most individuals. More importantly, the model selected for the group average differed from the most frequent individual model in all four groups. When data were pooled across groups, the average favored a dual-process form, a shape that matched the individual plurality in none of them. Simulation analyses showed that averaging heterogeneous individual trajectories can itself produce a group curve that favors a more complex model. Our findings show that group averaged habituation curves should not be treated as direct descriptions of the typical individual trajectory.