Neurobiology of Learning and Memory

Interval timing (IT) is the ability to time events in the range from seconds to a few minutes, allowing animals to organize behavior in time at short durations. IT relies on two cognitive functions: 1) Measuring the passage of time; 2) Storing and retrieving temporal memories in a context appropriate manner. The hippocampus (HC) and medial prefrontal cortex (mPFC) have been shown critical to the accuracy and precision of time-contingent instrumental responses in IT. The anatomy supporting mPFC-HC interactions, required for memory encoding and retrieval, include projections from HC to mPFC, and indirect bidirectional connections through the ventral midline thalamus (VMT), most notably reuniens. Here, we explored VMTs role in retrieving fixed-interval (FI) temporal memories. Rats were trained on a 5s FI signaled by an auditory cue and demonstrated temporal memory by poking predominantly at the time of the expected reward. Timing responses on individual trials were classified into on-time, early, and random response. Across sessions, random response trials decreased following training. Next, we switched training to longer intervals (20s or 80s; daily sessions for weeks). To probe the role of the VMT in temporal memory retrieval, we infused the GABAA-agonist muscimol, or saline, before training sessions. Results show that VMT muscimol infusions decreased timing precision. Also, at both intervals, the number of on-time response trials decreased, and the number of random response trials significantly increased. The number of early response trials had no significant change at 20s, and significantly decreased at 80s. Overall, our results suggest that the VMT is critical for precise retrieval of temporal memories. We also describe per-trial response patterns with characteristics consistent across all trained intervals, suggesting multiple behavioral strategies at play during interval timing.

Sleep is thought to promote memory consolidation through the offline reactivation and reorganization of newly acquired information. However, most studies assess memory shortly after sleep, leaving unresolved whether an initial post-learning sleep episode produces enduring modifications that influence how memories respond to later reactivation. Importantly, the absence of behavioral differences after prolonged retention intervals does not necessarily imply that sleep failed to modify the original memory. Instead, sleep-dependent changes may persist in latent forms that are not readily captured by conventional memory assessments. Here, we investigated whether post-learning sleep produces lasting changes in declarative memories that influence their subsequent response to reactivation. In Study 1, participants learned a declarative memory task and were assigned to either a short nap, a wake condition, or an exploratory long-nap condition that included both NREM and REM sleep. Memory was assessed one week later. Despite substantial forgetting across the retention interval, no significant differences in memory performance were observed between groups. In Study 2, participants learned the same task and subsequently underwent either a short nap or wakefulness. Memory was reactivated six days after learning using an incomplete reminder previously shown to induce memory updating in human declarative memory, and memory was tested one day later. Under these conditions, participants who slept after learning showed better memory performance than wake controls. Moreover, sleep physiological measures predicted the magnitude of the post-reactivation memory benefit. These findings suggest that post-learning sleep induces enduring modifications in declarative memories that are not readily detectable through delayed memory testing alone. Instead, these sleep-dependent changes become evident when memories are challenged through subsequent reactivation. Our results indicate that sleep-dependent consolidation influences the future expression of memory, shaping how memories respond to later reactivation experiences and providing new insight into the relationship between consolidation and reconsolidation.

Memory impairment is a common and sometimes overlooked feature of major depressive disorder, and cognitive deficits may precede the onset of depressive symptoms in some cases. However, the cognitive benefits of first-line treatments such as SSRIs are mixed. Tianeptine is an atypical antidepressant and cognitive enhancer that neither interacts with monoamine receptors nor inhibits the reuptake of their neurotransmitters. Its antidepressant efficacy in animal models requires activation of the mu-opioid receptor (mu-OR) and phosphorylation of the AMPA receptor. However, the receptors that mediate its memory enhancing actions have never been investigated. We therefore tested the ability of tianeptine to improve spatial memory in a cross-maze task in wild-type (WT) mice compared to its effects in mice with global knockout of either the mu-OR or delta-OR. In parallel, we assessed the effects of tianeptine on hippocampal oscillatory activity and spontaneous locomotion in the same genotypes. Adult male and female WT, mu -/-, and delta -/- mice on a C57BL/6J background were implanted with hippocampal electrodes for the recording of local field potential (LFP) oscillations. Consistent with our previous observations in anaesthetised rats, injection of tianeptine (10 mg/kg and 30 mg/kg SC) caused a dose-dependent increase in beta-frequency power in WT mice that was maximal at circa 25 Hz. The same effect was observed in delta -/- mice, but the increase in beta was completely absent in mu -/- animals. As others have reported previously, tianeptine also caused a mu-OR-dependent increase in spontaneous locomotor activity, but with a time-course that was distinct from the increase in beta power. Separate groups of WT, mu -/-, and delta -/- mice were tested for their ability to learn a food-rewarded spatial memory task in a cross-maze. Over a 20-day training period, sub-groups of each genotype received either tianeptine (10 mg/kg SC) or vehicle injection 30 min before testing. Tianeptine increased the percentage of correct trials and the number of allocentric (place) responses in WT mice, but did not enhance memory in either mu -/- or delta -/- mice, even though both genotypes were able to learn the task. These results indicate that the ability of tianeptine to drive hippocampal beta oscillations is dependent on the mu-OR, whereas its memory-enhancing actions require the presence of both mu- and delta-ORs. The latter result is consistent with the actions of tianeptine on postsynaptic AMPA receptors, and we are currently exploring the signalling pathways involved in this process.

The platform-mediated active avoidance (PMA) task has been used as a rodent model of decision-based active avoidance in which rat learn to avoid a tone-signaled shock. Prior studies utilizing the PMA task have primarily investigated avoidance, freezing, and food-seeking behaviors, but few studies have thoroughly assessed darting behavior, a more recently identified measure of fear that has been largely explored in conditional fear paradigms. Here, we investigated the properties of darting that occur during the PMA task, in which rats either acquired the PMA task alone or with a social partner. We found that rats undergoing solitary PMA produced significantly more darting bouts, whereas rats undergoing social partner PMA produced darts that were faster and shorter in duration. We also found that darting in solitary PMA was predominantly concentrated at the platform, whereas darting in social partner PMA occurred more often outside of the platform and lever zones. Analysis of darting trajectories, which included movements surrounding each darting bout, revealed that darting was embedded in a broader movement strategy between the platform and lever zones, especially during solitary PMA, and this pattern increased across training days. These findings suggest that darting during the PMA task serves as a learned strategy to navigate between reward and safety and is modulated by social context, which is distinct from escape-like darting observed in auditory fear conditioning.

Post-encoding sleep plays an essential role in episodic memory consolidation. Much of the existing literature on sleep and memory relies on deprivation paradigms or laboratory-controlled sleep. Relatively few studies have examined how naturalistic post-encoding sleep relates to memory retrieval and its supporting neural activity, or whether age-related impairments in this sleep are linked to those in episodic memory. In the present study, we used actigraphy and electroencephalography to examine how post-encoding sleep quality relates to context memory performance and retrieval-related ERPs supporting performance in younger and older adults. Participants encoded object-scene pairs and were tested on matching and mismatching pairs after a 96-hour sleep-filled delay. We found that greater post-encoding sleep continuity predicted better delayed context memory performance for mismatching pairs across age groups. Post-encoding sleep continuity was also associated with larger ERP differences between context hits and misses for context-matching pairs, for ERP effects associated with post-retrieval monitoring operations across age groups. Together, these findings suggest that more continuous, naturalistic post-encoding sleep facilitates episodic memory performance and neural mechanisms supporting episodic memory retrieval across adult age.

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.

Relapse-prevention strategies aimed at reducing relapse following abstinence, primarily focus on reducing cravings that lead to drug-seeking triggered by stress, drug-related cues, or re-exposure to the drug. Because addictive drugs form persistent associative contextual memories, we investigated how reactivation of cocaine-related hippocampal memories influences subsequent drug-seeking. Here, we tagged dorsal dentate gyrus (dDG) memory ensembles involved in encoding either a first or fourth cocaine exposure (15mg/kg, i.p) in male and female c57BL/6 mice using a TetTag approach. Mice underwent cocaine conditioned place preference (CPP), extinction, and reinstatement. We assessed whether optical reactivation of tagged cocaine-related ensembles could substitute for a cocaine priming injection to reinstate CPP, whether reactivation altered cocaine-induced reinstatement, and if these effects differed depending on stage of drug exposure. We also compared these effects to reactivation of saline-associated ensembles. Cocaine produced robust locomotor activation during conditioning, and sensitization developed across repeated drug exposures. Reactivation of a cocaine-related engram alone did not reinstate CPP. However, reactivation of the first cocaine exposure engram attenuated cocaine-induced reinstatement. In contrast, reactivation of the fourth exposure engram did not confer this protective effect. Interestingly, reactivation of saline-associated ensembles also reduced cocaine-induced reinstatement specifically in females, suggesting dDG ensemble reactivation may modulate relapse-related behavior through interference or neuromodulatory disruption of cocaine-associated representations, consistent with our prior work. These findings raise the possibility that early contextual experiences form competing or destabilizing representations that interfere with later cocaine-seeking when reactivated. Females also displayed greater sensitivity to locomotor-inducing effects of cocaine memory reactivation, although this was dissociated from CPP. Together, these findings show that cocaine memories are distinct across drug experience and selective reactivation of dDG engrams can differentially influence drug-seeking.

Verbal fluency (VF) tasks are widely used to differentiate patients with cognitive impairment from healthy controls, but total word count produced during these tasks becomes unreliable when patients and controls exhibit comparable proficiency. This study examined, in detail, whether item-level and sequential properties of words produced during a VF task could reliably differentiate high-proficiency patients indistinguishable from controls by word count alone. Seventy-seven native Mandarin Chinese speakers (38 controls and 39 patients with mild cognitive impairment or mild dementia) completed a semantic VF task. Participants were subdivided by proficiency into four groups: high-proficiency controls (HC), low-proficiency controls (LC), high-proficiency patients (HP), and low-proficiency patients (LP). The LC and HP subgroups were matched on semantic fluency scores and thus provided a key focus for the investigation. We examined item-level properties (word frequency, contextual diversity, semantic diversity, surprisal) and sequential properties (positional frequency variation) of the words produced. Significant group differences emerged across item-level psycholinguistic properties, though these were primarily driven by the LP group, with no reliable differentiation between LC and HP. Crucially, positional frequency variation distinguished LC from HP. LC participants began their lists with high-frequency words followed by a systematic decline, whereas HP patients produced words within a consistently narrow frequency band throughout. These findings indicate that item-level psycholinguistic properties alone are insufficient to differentiate HP from LC, whereas sequential word frequency variation provides a potential index of cognitive impairment, reflecting underlying differences in semantic retrieval and memory organisation. Future work with larger samples is needed to validate generalisability.

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.

Sleep supports episodic memory consolidation, yet it remains unclear how naturalistic post-encoding sleep quality relates to the neural reinstatement of episodic representations across adulthood. The present study examined whether sleep discontinuity during the retention interval predicted delayed context memory and encoding-retrieval similarity (ERS) of EEG in younger and older adults. Participants completed an object-scene context memory task with immediate and delayed retrieval, while EEG was recorded during encoding and retrieval. Actigraphy was used to measure sleep across the post-encoding retention period, and principal component analysis identified sleep discontinuity and sleep time components. Behavioral results showed that greater post-encoding sleep discontinuity, but not sleep time, was associated with poorer delayed memory accuracy for mismatching object-context pairs across age. ERS analyses further showed that greater sleep discontinuity was associated with reduced ERS for correctly rejected mismatching pairs across frontal and posterior spatiotemporal clusters. Age moderated sleep-ERS associations: greater sleep discontinuity was generally related to lower ERS in younger adults, whereas some spatiotemporal clusters showed positive associations in older adults, potentially reflecting compensatory or effortful retrieval-related processing in poorer sleepers. Together, these findings suggest that sleep continuity during the post-encoding retention interval is important for preserving high-fidelity episodic representations needed for later context discrimination. More broadly, the results demonstrate that naturalistic sleep fragmentation is linked to both behavioral memory outcomes and neural reinstatement across adults.

Linking environmental contexts with stressful experiences is critical for engaging adaptive responses necessary to avoid future threats. Yet, active context-dependent avoidance remains poorly understood. Here, we establish a restraint-induced conditioned place aversion (CPA) paradigm to examine how an acute physiological stressor acquires negative motivational value through contextual association. We found that mice repeatedly exposed to physical restraint in a contextually distinguishable chamber later avoid that location, demonstrating that restraint stress can drive learned aversion in the absence of continued exposure. To identify potential neuronal correlates underlying this learned association, we quantified c-Fos expression in several areas implicated in aversive motivation, emotional salience, and contextual encoding. We found that restraint within the context of the CPA paradigm was associated with increased c-Fos in the nucleus accumbens (NAc) and basolateral amygdala (BLA) while c-Fos expression increased in the ventral hippocampus in response to exposure to the contextual cues alone. These findings reveal region-specific engagement in processing aversive contextual memories induced by restraint stress. This work bridges classical stress models with associative learning frameworks, providing a platform to further dissect the neural mechanisms underlying stress-related negative affect and avoidance behaviors.

Study ObjectivesSleep spindles are implicated in memory consolidation. Yet direct evidence linking spindle dynamics to declarative memory outcomes remains limited. We thus tested whether targeted memory reactivation (TMR) time-locked to sleep spindles enhances declarative memory, and whether the temporal organization of stimulated spindles-trains versus isolated events-is selectively associated with distinct memory outcomes. MethodsTwenty-eight healthy young adults learned image locations from two categories (animals, clothing) in a grid, each paired with a distinct auditory cue. During overnight NREM sleep, one cue was replayed time-locked to spindles detected in real-time using a closed-loop system (TMR condition); the other served as the non-reactivated control (No-TMR condition). Category-cue assignment was counterbalanced. Post-sleep recall, recognition accuracy, and movement time were assessed. ResultsRecall accuracy was significantly higher in the TMR than the No-TMR condition (93.96% vs. 90.61%, p = .024), whereas recognition accuracy (p = .139) and movement time (p = .651) did not differ. Stimulation intensity within spindle trains correlated with the TMR effect on recall (Spearman {rho} = .531, p = .004), whereas the proportion of isolated spindle stimulations correlated with the TMR effect on recognition ({rho} = .563, p = .002). Cross-associations were not significant. ConclusionsSpindle-locked TMR enhances recall-based declarative memory retention. The selective association between spindle temporal clustering and memory outcomes suggests that train-embedded and isolated spindles support different aspects of memory consolidation, highlighting spindle temporal context as a functionally relevant dimension of sleep-dependent memory processing.

Spatial memory is crucial for navigation and adapting to changing environmental conditions. Known neurophysiological mechanisms of spatial memory center on the importance of hippocampal activity and its spatial tuning. Yet, the behavioral strategies that support adaptive spatial encoding remain poorly understood. We have shown that dorsal hippocampal activity during rearing is necessary for spatial working memory, highlighting a role of information seeking behaviors for spatial memory encoding. Similarly, spatial tuning by dorsal hippocampal neurons is substantially updated during another information seeking behavior: attentive head scanning. However, the functional relationship between these behaviors is unknown. Here, to assess the relevance of environmental context for the expression of these behaviors, we quantified rearing and head scanning in a radial-arm-maze spatial working memory task while manipulating the height of the maze walls. Our goal was to test whether the stereotyped patterns of rearing that rats generate with tall walls are replaced with attentive head scanning when the walls are short enough to reach the top without rearing. We found that rats reared significantly less often when the walls were shortened and, instead, exhibited frequent attentive head scanning. The head scanning was done when and where the rats had previously exhibited stereotyped rearing. These results support the hypothesis that rearing and head scanning are functionally related behaviors. Future work should test two key inferences: 1) Head scanning is a critical epoch of spatial memory encoding, and 2) Spatial tuning by hippocampal neurons is updated during rearing. Significance statementSpatial memory is a core cognitive function, essential for healthy independent living. Though the hippocampus is critical for spatial memory, it remains unclear when and how. Separate prior studies link rearing and lateral head scanning to key periods of hippocampal processing, suggesting both behaviors support sensory information gathering for updating cognitive maps. However, their relationship is unresolved. Here, we test whether these behaviors are functionally interchangeable, with environmental structure determining expression. In a radial-arm maze, rats reared frequently with 21 cm walls but showed reduced rearing when walls were shortened to 4.6 cm, instead increasing head scanning at similar locations. These findings suggest rearing and head scanning share underlying motivations and provide a basis for comparing hippocampal activity during exploration.

Relapse after treatment for various mental health disorders has been linked to tendency for reductions in responding to increase over time or following re-exposure to motivating stimuli. Here we show that, in rats, responding reduced through non-contingent outcome delivery does not recover in these ways, and that this learning depends on an intact lateral orbitofrontal cortex. These findings suggest that contingency degradation overwrites original learning which may support the development of relapse-resistant behavioural interventions.

Subthreshold depression is associated with significant functional impairment and elevated risk of major depressive disorder. A negative self-concept may disrupt the implicit positive association evoked by ones own face, impairing incidental encoding of self-relevant information. Whether subthreshold depression involves a selective deficit in encoding self-face identity remains unclear. The attribute amnesia paradigm is well suited to address this question because it can dissociate attentional selection from working memory encoding. Using this paradigm, we examined the issue across two experiments. Experiment 1 employed nonsocial stimuli (animal drawings) and confirmed an intact attribute amnesia effect in subthreshold depression (n = 30) comparable to healthy controls (n = 30), ruling out a generalized encoding deficit. Experiment 2 replaced targets with faces (self or other) and revealed a selective enhancement of the attribute amnesia effect for self-face identity in subthreshold depression. Specifically, on the surprise trial, accuracy for self-face identity dropped to near-chance levels in the subthreshold depression group, whereas no such deficit emerged for other-faces or in controls. Encoding recovered rapidly once explicit memory expectations were introduced, indicating intact basic encoding capacity. These findings suggest that subthreshold depression is associated with a specific impairment in incidentally encoding self-face identity. This impairment likely stems from a negative self-concept that weakens self-face salience under incidental encoding conditions. By capturing this selective encoding failure, the present study reveals that the self-processing deficit in subthreshold depression can arise at the gating stage between attention and working memory consolidation.

Memory engrams emerge from dynamic, coordinated interactions among synchronized functional brain networks. Yet, how these networks are selectively reactivated upon cued recall and gradually (re)organized over time, especially through sleep, remains poorly understood. Using magnetoencephalography (MEG), sleep electroencephalography (EEG) and behavioral measures, we investigated the spatiotemporal neural dynamics of cued recall memory during immediate and post-sleep (i.e., 90-minute post-learning nap) recall sessions in school-aged children. Results showed that immediate recall engaged a temporally ordered sequence of theta-band phase synchronization across two transiently synchronized networks: an early (150-350 ms) network involving the ventral visual pathway and left medial temporal lobe (MTL), followed by a later (550-750 ms) network encompassing the bilateral MTL and widespread neocortical associative regions. Post-sleep recall was associated, relative to wakefulness, with strengthened theta-band phase synchronization between the left MTL and widespread bilateral neocortical regions in a similar late window (450-650 ms). Post-sleep theta-band synchronization and memory gains in performance positively correlated with slow oscillation-spindle coupling during the post-learning nap. Altogether, these findings highlight oscillatory and spatiotemporal dynamics of memory recall networks and suggest that sleep, possibly driven by slow-oscillation-spindle coupling mechanisms, supports the efficient reinstatement of memory traces in the developing brain.

Sleep consolidates episodic memory through a hippocampus-dependent process in adults. Whether and how sleep supports memory consolidation during early life, when hippocampal function is immature, remains unclear. Here, we examined effects of sleep on the consolidation of spatial context, a core component of episodic memory, in toddlers aged 2 -3 years. Toddlers were familiarized with two spatial contexts, followed by a [~]90-min nap or an equivalent wake period. Afterwards, with a hide-and-seek game we tested their ability to relocate toys within these contexts. Only after post-familiarization sleep, the toddlers showed significant context memory and formed stronger associations between toys and specific contexts compared to wakefulness. Contextual memory was positively correlated with spindle density and slow oscillation-spindle phase-amplitude coupling during non-rapid eye movement (NonREM) sleep. Despite hippocampal immaturity, the sleeping toddlers brain seems to engage consolidation processes similar to those in adults to form spatial context memory for the flexible use in novel situations.

The slow oscillation (SO) of non-rapid eye movement (NREM) sleep has been implicated in the restorative properties of sleep. Slow oscillatory transcranial direct current stimulation (SO-tDCS), involving a positive oscillatory current applied to the scalp at a peak frequency of 0.75 Hz, has been used to enhance SO power during NREM sleep. We examined whether enhancing SO power with SO-tDCS during a restricted nighttime sleep opportunity would accelerate the restorative properties of sleep during an otherwise insufficient sleep period and help sustain performance during subsequent extended wakefulness. A total of twenty-six healthy young adults (ages 18-39, n=16 females) completed a 15-day study. After 7 baseline nights at home and 3 baseline nights in the laboratory, participants entered the laboratory for 5 consecutive days including a baseline day, a 2-hour nighttime sleep period with participants randomized to the SO-tDCS (n=11) or SHAM (n=15) condition, 46 hours of sleep deprivation, and two recovery nights. In the SO-tDCS condition, stimulation was administered for one hour starting exactly 60 minutes after sleep onset, with intervals of five minutes of continuous stimulation followed by one minute of no stimulation. Polysomnographic recordings were conducted during each sleep period. Performance was assessed using the Psychomotor Vigilance Test (PVT) approximately every 75 minutes across baseline, sleep deprivation, and recovery. Prior to the two-hour sleep opportunity, a Paired Words Associate Task was administered. Participants listened to 54-word pairs and were asked to recall 46 of the word pairs, with up to three attempts to successfully recall at least 60% of word pairs (T0). Recall was also assessed 20- (T20) and 120-minutes (T120) after awakening from the two-hour sleep period. Data were analyzed using mixed-effects ANOVA. PVT performance (defined as mean response time and number of response times greater than 1,000 ms) significantly declined across sleep deprivation with performance degradations peaking in the early morning hours. Participants in the STIM condition demonstrated significantly better performance during sleep deprivation relative to the SHAM condition. On the PWAT, participants in the SHAM condition recalled fewer word-pairs upon awakening relative to T0. In sharp contrast, performance of participants in the SO-tDCS condition did not deteriorate at T20 and was actually improved at T120 relative to T0. We conclude that SO-tDCS can robustly accelerate the restorative properties of sleep and can additionally enhance sleep related memory consolidation when sleep opportunity is restricted.

Summary paragraphA hallmark of learning is the need for sensory stimuli (Ginns, 2015; McGraw et al., 2009; Reinwein, 2012; Spence, 1950) so that learning is fundamentally based on sensory input signals affecting behaviour, physiology, and neurology. If behavioural measures of learning can be causally linked to physiological and neurological variables, a broader understanding of the mechanisms related to learning in schools, learning disabilities, and learning and health issues may emerge (McGraw et al., 2009). Despite decades of research on the physiological/neurological variable of sympathetic activation, learning, and achievement (Horvers et al., 2021), any causal relation remains unclear (Cowley et al., 2014; Mason et al., 2020; Pijeira-Diaz et al., 2016; Sung et al., 2023; Yu et al., 2024) and issues with instrument validation remain (Costantini et al., 2023; Hu et al., 2024; Milstein & Gordon, 2020; Van Der Mee et al., 2021). Here we investigate the effect of sensory input on sympathetic activation by using validated instruments for skin conductance measurement (Batista et al., 2019) and whether sympathetic activation is connected to learning in a cognitive laboratory context and an ecologically valid classroom context. In both contexts, we found a physiological variable which correlated with learning and that sensory input affected this variable while student movement did not. These sensory inputs varied depending on the different instructional activities the students participated in. Together, these findings bring us one step closer to a model linking sensory input to behavioural, physiological, and neurological variables.

Sleep spindles are rhythmic electroencephalographic signatures of non-rapid-eye-movement sleep. Their dysregulation has been implicated in several neuropsychiatric illnesses. Spindles have a characteristic waxing and waning shape, but the cellular and circuit mechanisms controlling their shape are not well understood. Recent but sparse research has implied that sleep spindle shape becomes abnormal in post-traumatic stress disorder (PTSD). PTSD patients have dysfunctional GABAA receptors in midline thalamic regions, areas involved in the orchestration of sleep spindles. We modelled this GABAA dysfunction within thalamocortical (TC) neurons using localized CRISPR-Cas9 technology to test the hypothesis that GABA dysfunction would dysregulate sleep spindle shape and cause symptoms of PTSD, in mouse model behavioral evaluations. We found sleep spindles were shorter and abnormally shaped, having lost their characteristic waxing and waning shape, in mice with GABAA receptor knock-down in TC neurons (TC-1KD). TC-1KD mice failed to recover from learned fearful reactions following an aversive stimulus. We tested this with a contextual fear conditioning paradigm using electric foot shocks. A control group with intact GABAA receptors successfully habituated to the fear conditioned location in subsequent visits to that context without foot shocks. In contrast, TC-1KD mice never habituated, suggesting abnormally extended fearful memories. The number of inhibitory post synaptic currents in TC neurons were significantly decreased in vitro, confirming an effective knock-down. Our results imply that abnormally shaped sleep spindles may serve as a biomarker of GABAA receptor dysfunction in TC neurons which may be involved in abnormal fear processing in PTSD. We postulate GABAA receptor dysfunction in TC neurons may be underlying pathophysiology of PTSD and our findings here may inspire the development of screens, diagnostics and objective characteristics of stress related disorders, including PTSD.