Neurobiology of Learning and Memory

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.

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.

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.

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.

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.

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.

Wakeful rest after learning has been proposed to facilitate memory consolidation compared to engaging in a distraction task, with prior EEG studies linking slow oscillation power during rest to better memory performance. However, replication attempts have yielded mixed results. We investigated whether 10 minutes of wakeful rest would enhance associative memory performance relative to 10 minutes of a hippocampus-dependent auditory short-term memory distraction task, using a within-participant design with continuous EEG recording. We employed both a replication-inspired analytical approach, closely modeled on prior work, and a data-specific approach adapted to our dataset. Contrary to our hypotheses, we found no advantage of rest over distraction on associative memory performance. We did, however, observe an order effect: performance was better for the second learning than the first, and this improvement was more pronounced when rest was performed second compared to first. At the neurophysiological level, neither slow oscillation nor alpha power during the post-learning period correlated with memory performance, regardless of analytical pipeline, although cross-over analyses revealed that the choice of EEG reference influenced the direction of some correlations. At the phenomenological level, self-reported mental activity during rest and distraction, as well as trait daydreaming frequency, were not related to memory outcomes, despite the two conditions inducing distinct subjective cognitive states. Together, these findings do not support a robust benefit of post-learning wakeful rest over a hippocampus-dependent distraction task for associative memory, nor do they replicate prior EEG correlates of consolidation. We discuss methodological factors, including task-learning effects in within-participant designs, the coarseness of averaged spectral power measures, and variability in EEG preprocessing pipelines, that may contribute to inconsistencies across the literature, and we call for greater standardization and transparency in future studies.

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.

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.

Chronic partial and acute total sleep loss have a distinct impact on sleep architecture. Namely, acute sleep deprivation primarily leads to a strong rebound of slow wave sleep, while chronic sleep restriction results in an increased propensity of REM sleep. The aim of this work was to examine whether these different effects would translate into quantifiable changes in sleep state boundaries and dynamics using a model-based method. Besides conventional sleep stage scoring, we applied an EEG model (state space approach) for dynamic analysis of nocturnal EEG recordings in 14 healthy subjects under experimental chronic sleep restriction (last of 7 nights with 5 hours of time in bed) and after acute sleep deprivation (sleep following 40 hours of wakefulness), in comparison to baseline sleep. Subjects under chronic sleep restriction revealed increased similarities in the frequency composition of REM sleep and wakefulness and thus, a decreased differentiation of state boundaries between the two behavioral states. Contrarily, acute sleep deprivation affected the spectral composition of NREM sleep. Only acute sleep deprivation resulted in more stable slow wave sleep. Our explorative study confirmed that the distinct effects of increased REM sleep and slow wave sleep propensity following acute total and chronic partial sleep loss are reflected in differential changes of behavioral state boundaries and sleep dynamics. This suggests that these sleep structure characteristics are state dependent, which may allow using such measures in the future to track treatment effects in clinical populations characterized by sleep behavioral state dysregulation.

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.

Adaptive decision-making under ambiguity requires constant integration of reward- and loss-related information to guide behaviour. In humans and rodents, not all individuals maximise gains in decision-making tasks, such as the Iowa Gambling task or its rodent version, the Rat Gambling task (rGT). While the prefrontal and insular cortices have each been shown independently to support optimal probabilistic decision-making, how they interact functionally to shape individual differences in performance remains unclear. Here, we investigated the consequences of bilateral baclofen/muscimol-mediated inactivation of the prelimbic cortex (PLC) or the anterior insular cortex (AIC) vs. their functional disconnection on the performance of Sprague Dawley rats identified as safe (SDMs) or risky decision makers (RDMs) in the RGT. AIC inhibition decreased advantageous choice in SDMs, whereas it increased win-stay responding in RDMs. In contrast, PLC inhibition primarily affected lose-shift behaviour, reducing sensitivity to losses in SDMs while enhancing adaptive switching in RDMs. Functionally disconnecting the PLC from the AIC, which had no effect on the performance of SDMs, improved decision-making in RDMs by increasing loss-guided behavioural adaptation. Together, these findings identify parallel versus serial AIC-PLC processing as a potential neural mechanism underlying the tendency some individuals have to make suboptimal decisions.

Stress during critical developmental periods causes lasting neurobiological alterations. Rodent models like neonatal maternal separation (NMS) induce cognitive alterations, particularly spatial memory deficits. Oxytocin (OT) system has been suggested to underlie these consequences, as it is critical for neurodevelopment. This neuropeptide also promotes maternal nurturing, prevents neuroinflammation and displays anxiolytic properties. This study hypothesized that early postnatal OT administration could prevent NMS-induced memory alterations in adult rats. Sprague-Dawley rat pups (both sexes, n=8-12/group) underwent NMS with concomitant intraperitoneal OT injections. At adulthood, novel object recognition and object location tasks were performed. Further investigation was conducted through ex vivo electrophysiological recordings of functional plasticity at Schaffer collateral-CA1 synapses (male, n=7-12/group), alongside RT-qPCR of synaptic, GABAergic, neuro-inflammatory, and oxytocin receptor markers in dorsal CA1 (male, n=4-6/group). NMS induced male-specific spatial memory impairment without affecting recognition memory. Early OT completely prevented spatial memory deficits in NMS males. Electrophysiological recordings revealed that NMS suppressed CA1 long-term potentiation (LTP), and neonatal OT restored it. NMS induced transcript overexpression of neuro-inflammatory markers, GABAergic markers, and synaptic proteins in dorsal CA1. OT treatment normalized or reduced these mRNA expressions, consistent with restoration of CA1 synaptic function. Early postnatal OT prevents NMS-induced spatial memory deficits and hippocampal LTP impairments in male rats, which is associated with normalized or reduced neuro-inflammatory and GABAergic transcript expressions. These findings establish exogenous oxytocin administration during a critical neonatal window as sufficient to prevent male-specific hippocampal dysfunction and cognitive deficits induced by early-life stress, identifying the oxytocinergic system as a promising target for early neuroprotective interventions.

Cognitive flexibility is an executive function that allows individuals to adjust behaviour in response to changing environmental demands. We assessed volitional switching under uncertainty, without rule-based learning, in the Change Your Mind task. Nineteen patients with obsessive-compulsive disorder (OCD), 19 patients with attention-deficit hyperactivity disorder (ADHD) and matched control participants (20 per group) completed the task whilst undergoing a functional MRI scan. The task was a two-alternative forced choice paradigm where each stimulus was presented twice successively, with spurious feedback following the first presentation. This allowed participants the opportunity to repeat or change their response. Participants with ADHD changed their response more frequently than controls following a previously correct response, associated with reduced accuracy on the second trial. This was accompanied with smaller differences between change and repeat trials in the superior frontal gyrus, paracingulate gyrus and frontal pole compared to controls. Participants with OCD did not differ from healthy controls in their performance but exhibited greater activity on both change and repeat trials in the pre- and postcentral gyri than controls. These results point to distinct neurobehavioural differences in patients with ADHD and OCD underlying what is often termed more broadly inflexible behaviour.

Although female rats are typically less aggressive than male rats, lactating females will vigorously defend their nests and pups against an intruder. Much attention has been directed at the consequences of this aggression on the intruder and less on the consequences for the mother and her subsequent interactions with her pups. Here, we exposed resident Sprague-Dawley dams to the resident-intruder paradigm twice daily for five consecutive days, beginning when the dam's (RES) pups were 7 days old, to assess social stress effects on maternal behavior and neurobiology. Controls were dams that had time-matched (TMC) separation from their pups but were not exposed to intruders, and naive moms which were never separated nor exposed to an intruder (CTL). We assessed the dam's subsequent behavior and interactions with her pups on Day 1 and Day 5, and Fos expression after Day 5 in select regions of the prefrontal cortex, amygdala, hypothalamus and periaqueductal gray of the midbrain. In separate cohorts, after pups were weaned, the dams underwent restraint stress and plasma corticosterone assayed. PCA analysis of the dam's behaviors identified three components: normal self-focused behaviors; nurturing behaviors and rough non-nurturing behaviors. Relative to CTL, RES dams exhibited more disrupted behaviors towards their pups, including, rough transport, stepping on pups, and flinging/tossing pups around the cage. In contrast, TMC Dams showed some, but fewer changes relative to CTL, suggesting that separation from pups alone does not account for all disrupted behavior in RES dams. The bulk of these behavioral effects occurred in the first 5-10 min after reunion with the pups and were seen on both the first and fifth day of testing. Of the brain regions examined, the prefrontal cortex was activated by both the defeat/intruder stress (RES) and separation stress (TMC), whereas the dorsal PAG was activated specifically by the defeat/intruder stress. The medial and basolateral amygdala exhibited differential neuronal activity between the RES defeat/intruder-exposed dams and the other two groups. The RES moms exhibited an insufficient adrenocortical response to acute restraint stress. The results suggest that amygdala-dPAG activity is important for dissociating disrupted maternal care in RES (due to defense of the nest against an intruder) from simple pup separation, both of which activate the mPFC. The experience of repeatedly defending the nest may induce subsequent disruptions in HPA responses. The amygdala-dPAG pathway may regulate aspects of stress and emotional regulation exhibited by mothers who defend their offspring against intruders.

Ambiguity represents a form of uncertainty in which outcome probabilities cannot be explicitly learned, making decisions dependent on emotional states and cognitive biases. Early-life stress (ELS) increases the risk of adverse mental and physical health outcomes and alters affective processing and learning. ELS may thus affect how ambiguous information is processed, which may depend on interactions with adulthood stress (AS) and mechanistically on bioenergetic mechanisms mediated by top-down cognitive control systems within the prefrontal cortex (PFC). The present study investigated the effects of AS in rats exposed to early maternal separation (MS), a rodent model of ELS, on a task assessing cognitive bias, together with putatively accompanying alterations in PFC mitochondrial function. Cognitive bias was assessed using an ambiguous cue task (ACT) in MS and non-separated control rats tested at baseline and following repeated unpredictable mild stress during adulthood. MS did not affect baseline cognitive bias but increased response latencies. Following AS, control animals showed a significant negative shift in cognitive bias, whereas MS animals were resistant to this shift. MS was also associated with greater PFC mitochondrial respiratory capacity and uncoupling of oxidative phosphorylation following AS. These findings suggest that ELS is associated with a recalibrated phenotype that buffers against the affective consequences of later stress. Enhanced PFC mitochondrial bioenergetics may underlie this resilience, highlighting the importance of developmental context in shaping affective-cognitive responses to stress.

Adolescence is a sensitive period during which unhealthy diets may shape metabolic health and cognition. Diets high in fat and sugar have been linked to obesity, impaired glucose regulation and hippocampus-dependent deficits, but the exposure duration required to affect cognition remains unclear. This study examined whether adolescent-onset exposure to a high-fat high-sucrose (HFHS) diet induces metabolic dysfunction and impairs object-based memory, spatial working memory and spatial pattern separation in male Long Evans rats. Rats were assigned to a control or HFHS diet at four weeks of age and remained on this diet into adulthood. Basal blood glucose was assessed monthly and home-cage behaviour using 48-hour LABORAS recordings. Cognitive testing started after 10 weeks of diet exposure, when basal glucose was elevated in HFHS-fed rats. Object displacement and novel object recognition were used in short open-field test settings, whereas touchscreen-based trial-unique nonmatching-to-location testing (TUNL) assessed spatial working memory and pattern separation across repeated operant sessions. Finally, glucose (in)tolerance and tissue weights were measured. HFHS diet exposure produced a metabolic phenotype, including increased body weight, elevated basal glucose, impaired glucose tolerance and increased liver and gonadal white adipose tissue weights. The diet also altered the general behavioural repertoire, with increased immobility and grooming and reduced rearing. HFHS-fed rats did not differ from controls in object displacement or novel object recognition performance. In the touchscreen task, both groups acquired the task at a comparable rate. Long-delay and spatial separation challenges reduced performance as expected, confirming task sensitivity, but did not reveal diet-related impairments. These findings show that adolescent-onset HFHS diet exposure induces metabolic dysfunction but does not necessarily produce detectable cognitive impairment when behavioural testing starts after 10 weeks of exposure. Longer exposure or advanced diet-induced inflammatory or neurobiological alterations may be required to reveal cognitive consequences.