Arc and BDNF mediated effects of hippocampal astrocytic glutamate uptake blockade on spatial memory stages.

Glutamate is involved in fundamental functions, including neuronal plasticity and memory. Astrocytes are integral elements involved in synaptic function, and the GLT-1 transporter possesses a critical role in glutamate uptake. Here, we study the role of GLT-1, specifically located in astrocytes, in the consolidation, expression, reconsolidation and persistence of spatial object recognition memory in rats. Administration of dihydrokainic acid (DHK), a selective GLT-1 inhibitor, into the dorsal hippocampus around a weak training which only induces short-term memory, promotes long-term memory formation. This promotion is prevented by hippocampal administration of protein-synthesis translation inhibitor, blockade of Activity-regulated cytoskeleton-associated protein (Arc) translation or Brain-Derived Neurotrophic Factor (BDNF) action, which are plasticity related proteins necessary for memory consolidation. However, DHK around a strong training, which induces long-term memory, does not affect memory consolidation. Administration of DHK before the test session impairs the expression of long-term memory, and this effect is dependent of Arc translation. Furthermore, DHK impairs reconsolidation if applied before a reactivation session, and this effect is independent of Arc translation. These findings reveal specific consequences on spatial memory stages developed under hippocampal GLT-1 blockade, shedding light on the intricate molecular mechanisms, governed in part for the action of glia.

Retrieval of contextual memory can be predicted by CA3 remapping and is differentially influenced by NMDAR activity in rat hippocampus subregions.

Episodic memory is essential to navigate in a changing environment by recalling past events, creating new memories, and updating stored information from experience. Although the mechanisms for acquisition and consolidation have been profoundly studied, much less is known about memory retrieval. Hippocampal spatial representations are key for retrieval of contextually guided episodic memories. Indeed, hippocampal place cells exhibit stable location-specific activity which is thought to support contextual memory, but can also undergo remapping in response to environmental changes. It is unclear if remapping is directly related to the expression of different episodic memories. Here, using an incidental memory recognition task in rats, we showed that retrieval of a contextually guided memory is reflected by the levels of CA3 remapping, demonstrating a clear link between external cues, hippocampal remapping, and episodic memory retrieval that guides behavior. Furthermore, we describe NMDARs as key players in regulating the balance between retrieval and memory differentiation processes by controlling the reactivation of specific memory traces. While an increase in CA3 NMDAR activity boosts memory retrieval, dentate gyrus NMDAR activity enhances memory differentiation. Our results contribute to understanding how the hippocampal circuit sustains a flexible balance between memory formation and retrieval depending on the environmental cues and the internal representations of the individual. They also provide new insights into the molecular mechanisms underlying the contributions of hippocampal subregions to generate this balance.

Cumulative lifetime stressor exposure impairs stimulus-response but not contextual learning.

Greater exposure to stressors over the life course is believed to promote striatum-dependent over hippocampus-dependent learning and memory processes under stressful conditions. However, little research in this context has actually assessed lifetime stressor exposure and, moreover, it remains unknown whether greater cumulative lifetime stressor exposure exerts comparable effects on striatum-dependent learning and hippocampus-dependent learning in non-stressful contexts. To investigate this issue, we used the Stress and Adversity Inventory for Adults (Adult STRAIN) and Multicued Search Task to investigate the relation between cumulative lifetime stressor exposure and striatum-dependent stimulus-response learning and hippocampus-dependent contextual learning under non-stressful conditions among healthcare professionals (N = 205; 157 females, 48 males; Age: M = 34.23, SD 9.3, range 20-59 years). Individuals with moderate, but not low, cumulative lifetime stressor exposure exhibited impaired learning for stimulus-response associations. In contrast, learning for context associations was unrelated to participants' lifetime stressor exposure profiles. These results thus provide first evidence that cumulative lifetime stressor exposure may have negative consequences on human striatum-dependent stimulus-response learning under non-stressful environmental conditions.

Investigating Morphological Changes of the Hippocampus After Prolonged Aerobic Exercise in Mice: Neural Function and Learning Capabilities / Investigación de los Cambios Morfológicos del Hipocampo Después De un Ejercicio Aeróbico Prolongado en Ratones: Función Neuronal y Capacidades de Aprendizaje

SUMMARY: Both the academic and popular worlds have paid close attention to the link between exercise and cognitive performance. It is increasingly important to understand the numerous mechanisms by which exercise might influence cognitive abilities in view of the continuous societal issues caused by aging populations and the prevalence of disorders associated to cognitive decline. A rising amount of evidence showing a favorable association between physical activity and cognitive well-being serves as the foundation for the justification for studying the effects of exercise on cognitive function and learning ability. The study employed an 8-week treadmill based on exercise on male adults C57BL/6 mice. The exercise group were engaged in 5 sessions a week gradually increasing the intensity of the protocol by 5 % each week. The Mice cognitive assessments were done using Morris Water Maze and Novel Object Recognition tests. The long term-impact on learning ability were further assessed through immmohistochemistry and molecular analysis of the hippocampal and prefrontal cortex tissues of the animals' brain tissues. The findings showed improved spatial learning abilities, recognition memory, and heighted synaptic plasticity indicated by elevated synaptic makers. The study underscores the role of long-term aerobic exercise in augmenting cognitive performance. It not only contributes to the understanding of the interplay between neuroplasticity and cognitive benefits but also the growing body of research on the impact of exercise on cognitive function.

Tanto el mundo académico como el popular han prestado mucha atención al vínculo entre el ejercicio y el rendimiento cognitivo. Es cada vez más importante comprender los numerosos mecanismos por los cuales el ejercicio podría influir en las capacidades cognitivas en vista de los continuos problemas sociales causados por el envejecimiento de la población y la prevalencia de trastornos asociados al deterioro cognitivo. Una cantidad cada vez mayor de evidencia que muestra una asociación favorable entre la actividad física y el bienestar cognitivo sirve como base para justificar el estudio de los efectos del ejercicio sobre la función cognitiva y la capacidad de aprendizaje. El estudio se realizó en ratones machos adultos C57BL/6 utilizándose en los ejercicios una cinta rodante durante 8 semanas. El grupo de ejercicio realizó 5 sesiones por semana aumentando gradualmente la intensidad del protocolo en un 5 % cada semana. Las evaluaciones cognitivas de los ratones se realizaron utilizando las pruebas Morris Water Maze y Novel Object Recognition. El impacto a largo plazo en la capacidad de aprendizaje se evaluó mediante inmunohistoquímica y análisis molecular de los tejidos del hipocampo y la corteza prefrontal de los tejidos cerebrales de los animales. Los hallazgos mostraron mejoras en las habilidades de aprendizaje espacial, la memoria de reconocimiento y una mayor plasticidad sináptica indicada por unos creadores sinápticos elevados. El estudio subraya el papel del ejercicio aeróbico a largo plazo para aumentar el rendimiento cognitivo. No sólo contribuye a la comprensión de la interacción entre la neuroplasticidad y los beneficios cognitivos, sino también al creciente conjunto de investigaciones sobre el impacto del ejercicio en la función cognitiva.

Amphibian spatial cognition, medial pallium and other supporting telencephalic structures.

Vertebrate hippocampal formation is central to conversations on the comparative analysis of spatial cognition, especially in light of variation found in different vertebrate classes. Assuming the medial pallium (MP) of extant amphibians resembles the hippocampal formation (HF) of ancestral stem tetrapods, we propose that the HF of modern amniotes began with a MP characterized by a relatively undifferentiated cytoarchitecture, more direct thalamic/olfactory sensory inputs, and a more generalized role in associative learning-memory processes. As such, hippocampal evolution in amniotes, especially mammals, can be seen as progressing toward a cytoarchitecture with well-defined subdivisions, regional connectivity, and a functional specialization supporting map-like representations of space. We then summarize a growing literature on amphibian spatial cognition and its underlying brain organization. Emphasizing the MP/HF, we highlight that further research into amphibian spatial cognition would provide novel insight into the role of the HF in spatial memory processes, and their supporting neural mechanisms. A more complete reconstruction of hippocampal evolution would benefit from additional research on non-mammalian vertebrates, with amphibians being of particular interest.

5-MeO-DMT induces sleep-like LFP spectral signatures in the hippocampus and prefrontal cortex of awake rats.

5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a potent classical psychedelic known to induce changes in locomotion, behaviour, and sleep in rodents. However, there is limited knowledge regarding its acute neurophysiological effects. Local field potentials (LFPs) are commonly used as a proxy for neural activity, but previous studies investigating psychedelics have been hindered by confounding effects of behavioural changes and anaesthesia, which alter these signals. To address this gap, we investigated acute LFP changes in the hippocampus (HP) and medial prefrontal cortex (mPFC) of freely behaving rats, following 5-MeO-DMT administration. 5-MeO-DMT led to an increase of delta power and a decrease of theta power in the HP LFPs, which could not be accounted for by changes in locomotion. Furthermore, we observed a dose-dependent reduction in slow (20-50 Hz) and mid (50-100 Hz) gamma power, as well as in theta phase modulation, even after controlling for the effects of speed and theta power. State map analysis of the spectral profile of waking behaviour induced by 5-MeO-DMT revealed similarities to electrophysiological states observed during slow-wave sleep (SWS) and rapid-eye-movement (REM) sleep. Our findings suggest that the psychoactive effects of classical psychedelics are associated with the integration of waking behaviours with sleep-like spectral patterns in LFPs.

Neurogenesis and pesticides: news of no new neurons.

New hippocampal neurons are continuously generated in the adult human brain. Several studies have demonstrated that the proliferation of hippocampal cells is strongly influenced by a variety of stimuli, including pesticides exposure. These effects are particularly important because neurogenesis dysregulation could be associated with the decline of neuronal and cognitive functions and the possible development of neuropsychiatric disorders.

Novos neurônios hipocampais são gerados continuamente no cérebro humano adulto. Vários estudos têm demonstrado que a proliferação de células do hipocampo é influenciada por uma variedade de estímulos, incluindo a exposição a pesticidas. Estes efeitos são particularmente importantes porque a desregulação da neurogênese pode estar associada ao declínio das funções neuronais e cognitivas e ao possível desenvolvimento de doenças neuropsiquiátricas.

Waveform-based classification of dentate spikes.

Synchronous excitatory discharges from the entorhinal cortex (EC) to the dentate gyrus (DG) generate fast and prominent patterns in the hilar local field potential (LFP), called dentate spikes (DSs). As sharp-wave ripples in CA1, DSs are more likely to occur in quiet behavioral states, when memory consolidation is thought to take place. However, their functions in mnemonic processes are yet to be elucidated. The classification of DSs into types 1 or 2 is determined by their origin in the lateral or medial EC, as revealed by current source density (CSD) analysis, which requires recordings from linear probes with multiple electrodes spanning the DG layers. To allow the investigation of the functional role of each DS type in recordings obtained from single electrodes and tetrodes, which are abundant in the field, we developed an unsupervised method using Gaussian mixture models to classify such events based on their waveforms. Our classification approach achieved high accuracies (> 80%) when validated in 8 mice with DG laminar profiles. The average CSDs, waveforms, rates, and widths of the DS types obtained through our method closely resembled those derived from the CSD-based classification. As an example of application, we used the technique to analyze single-electrode LFPs from apolipoprotein (apo) E3 and apoE4 knock-in mice. We observed that the latter group, which is a model for Alzheimer's disease, exhibited wider DSs of both types from a young age, with a larger effect size for DS type 2, likely reflecting early pathophysiological alterations in the EC-DG network, such as hyperactivity. In addition to the applicability of the method in expanding the study of DS types, our results show that their waveforms carry information about their origins, suggesting different underlying network dynamics and roles in memory processing.

The Neuroprotective Role of Quinoa (Chenopodium quinoa, Wild) Supplementation in Hippocampal Morphology and Memory of Adolescent Stressed Rats.

Brain physiology and morphology are vulnerable to chronic stress, impacting cognitive performance and behavior. However, functional compounds found in food may alleviate these alterations. White quinoa (Chenopodium quinoa, Wild) seeds contain a high content of n-3 fatty acids, including alpha-linolenic acid. This study aimed to evaluate the potential neuroprotective role of a quinoa-based functional food (QFF) in rats. Prepubertal male Sprague-Dawley rats were fed with rat chow or QFF (50% rat chow + 50% dehydrated quinoa seeds) and exposed or not to restraint stress protocol (2 h/day; 15 days). Four experimental groups were used: Non-stressed (rat chow), Non-stressed + QFF, Stressed (rat chow) and Stressed + QFF. Weight gain, locomotor activity (open field), anxiety (elevated plus maze, light-dark box), spatial memory (Y-maze), and dendritic length in the hippocampus were measured in all animals. QFF intake did not influence anxiety-like behaviors, while the memory of stressed rats fed with QFF improved compared to those fed with rat chow. Additionally, QFF intake mitigated the stress-induced dendritic atrophy in pyramidal neurons located in the CA3 area of the hippocampus. The results suggest that a quinoa-supplemented diet could play a protective role in the memory of chronically stressed rats.

Long-term calorie restriction prevented memory impairment in middle-aged male mice and increased a marker of DNA oxidative stress in hippocampal dentate gyrus.

Calorie restriction (CR) is a non-invasive and economic approachknown to increase healthspan and life expectancy, through a decrease in oxidative stress, an increase in neurotrophins, among other benefits. However, it is not clear whether its benefit could be noted earlier, as at the beginning of middle-age. Hence, weaimed to determine whether six months of long-term CR, from early adulthood to the beginning of middle age (10 months of age) could positively affect cognitive, neurochemical, and behavioral parameters. Male C57BL6/J mice were randomly distributed into Young Control (YC, ad libitum food), Old Control (OC, ad libitum food), and Old Restricted (OR, 30 % of caloric restriction) groups. To analyze the cognitive and behavioral aspects, the novel object recognition task (NOR), open field, and elevated plus maze tests were performed. In addition, immunohistochemistry targetingΔFosB (neuronal activity), brain-derived neurotrophic factor (BDNF) and the DNA oxidative damage (8OHdG) in hippocampal subfields CA1, CA2, CA3, and dentate gyrus (DG), and in basolateral amygdala and striatum were performed. Our results showed that long-term CR prevented short-term memory impairment related to aging and increased 8OHdG in hippocampal DG. BDNF was not involved in the effects of either age or CR on memory at middle-age, as it increased in CA3 of the OC group but was not altered in OR. Regarding anxiety-type behavior, no parameter showed differences between the groups. In conclusion, while the effects of long-term CR on anxiety-type behavior were inconclusive, it mitigated the memory deficit related to aging, which was accompanied by an increase in hippocampal 8OHdG in DG. Future studies should investigate whether the benefits of CR would remain if the restriction were interrupted after this long-term protocol.

On the participation of adenosinergic receptors in the reconsolidation of spatial long-term memory in male rats.

To date, there is insufficient evidence to explain the role of adenosinergic receptors in the reconsolidation of long-term spatial memory. In this work, the role of the adenosinergic receptor family (A1, A2A, A2B, and A3) in this process has been elucidated. It was demonstrated that when infused bilaterally into the hippocampal CA1 region immediately after an early nonreinforced test session performed 24 h posttraining in the Morris water maze task, adenosine can cause anterograde amnesia for recent and late long-term spatial memory. This effect on spatial memory reconsolidation was blocked by A1 or A3 receptor antagonists and mimicked by A1 plus A3 receptor agonists, showing that this effect occurs through A1 and A3 receptors simultaneously. The A3 receptor alone participates only in the reconsolidation of late long-term spatial memory. When the memory to be reconsolidated was delayed (reactivation 5 d posttraining), the amnesic effect of adenosine became transient and did not occur in a test performed 5 d after the reactivation of the mnemonic trace. Finally, it has been shown that the amnesic effect of adenosine on spatial memory reconsolidation depends on the occurrence of protein degradation and that the amnesic effect of inhibition of protein synthesis on spatial memory reconsolidation is dependent on the activation of A3 receptors.

Memory persistence induced by environmental enrichment is dependent on different brain structures.

Environmental enrichment (EE) has been demonstrated to have a beneficial effect on different functions of the central nervous system in several mammal species, being used to improve behavior and cell damage in various neurological and psychiatric diseases. However, little has been investigated on the effect of EE in healthy animals, particularly regarding its impact on memory persistence and the brain structures involved. Therefore, here we verified in male Wistar rats that contextual fear conditioning (CFC) memory persistence, tested 28 days after the CFC training session, was facilitated by 5 weeks of exposure to EE, with no effect in groups tested 7 or 14 days after CFC training. However, a two-week exposure to EE did not affect memory persistence. Moreover, we investigated the role of specific brain regions in mediating the effect of EE on memory persistence. We conducted inactivation experiments using the GABAergic agonist Muscimol to target the basolateral amygdala (BLA), medial prefrontal cortex (mPFC), and CA1 region of the hippocampus (CA1). Inactivation of the BLA immediately and 12 h after CFC training impaired the effect of EE on memory persistence. Similarly, inactivation of the CA1 region and mPFC 12 h after training, but not immediately, also impaired the effect of EE on memory persistence. These results have important scientific implications as they shed new light on the effect of an enriched environment on memory persistence and the brain structures involved, thereby helping elucidate how an environment rich in experiences can modify the persistence of learned information.

A scoping review of the relationship between alcohol, memory consolidation and ripple activity: An overview of common methodologies to analyse ripples.

Alcohol abuse is not only responsible for 5.3% of the total deaths in the world but also has a substantial impact on neurological and memory disabilities throughout the population. One extensively studied brain area involved in cognitive functions is the hippocampus. Evidence in several rodent models has shown that ethanol produces cognitive impairment in hippocampal-dependent tasks and that the damage is varied according to the stage of development at which the rodent was exposed to ethanol and the dose. To the authors' knowledge, there is a biomarker for cognitive processes in the hippocampus that remains relatively understudied in association with memory impairment by alcohol administration. This biomarker is called sharp wave-ripples (SWRs) which are synchronous neuronal population events that are well known to be involved in memory consolidation. Methodologies for facilitated or automatic identification of ripples and their analysis have been reported for a wider bandwidth than SWRs. This review is focused on communicating the state of the art about the relationship between alcohol, memory consolidation and ripple activity, as well as the use of the common methodologies to identify SWRs automatically.

Increased hippocampal CREB phosphorylation after retrieval of remote contextual fear memories in Carioca high-conditioned freezing rats.

The participation of the hippocampal formation in consolidation and reconsolidation of contextual fear memories has been widely recognized and known to be dependent on the activation of the cAMP response element (CRE) binding protein (CREB) pathway. Recent findings have challenged the prevailing view that over time contextual fear memories migrate to neocortical circuits and no longer require the hippocampus for retrieval of remote fearful memories. It has also recently been found that this brain structure is important for the maintenance and recall of remote fear memories associated with aversive events, a common trait in stress-related disorders such as generalized anxiety disorder (GAD), major depression, and post-traumatic stress disorder. In view of these findings, here we examined the putative role of CREB in the hippocampus of an animal model of GAD during the retrieval of remote contextual fear memories. Specifically, we evaluated CREB phosphorylation in the hippocampus of male Carioca High- and Low-conditioned Freezing rats (CHF and CLF, respectively) upon re-exposure of animals to contextual cues associated to footshocks weeks after fear conditioning. Age-matched male rats from a randomized crossbreeding population served as controls (CTL). Adrenal catecholamine levels were also measured as a biological marker of stress response. Seven weeks after contextual fear conditioning, half of the sample of CHF (n = 9), CLF (n = 10) and CTL (n = 10) rats were randomly assigned to return to the same context chamber where footshocks were previously administrated (Context condition), while the remaining animals were individually placed in standard housing cages (Control condition). Western blot results indicated that pCREB levels were significantly increased in the hippocampus of CHF rats for both Context and Control conditions when compared to the other experimental groups. CHF rats in the Context condition also exhibited significant more freezing than that observed for both CLF and CTL rats. Lastly, CHF animals in the Context condition displayed significantly higher adrenal catecholamine levels than those in the Control condition, whereas no differences in catecholamine levels were observed between Context and Control conditions for CLF and CTL rats. These findings are discussed from a perspective in which the hippocampus plays a role in the maintenance and recall of remote contextual fear memories via the CREB pathway.

Unique potential of immature adult-born neurons for the remodeling of CA3 spatial maps.

Mammalian hippocampal circuits undergo extensive remodeling through adult neurogenesis. While this process has been widely studied, the specific contribution of adult-born granule cells (aGCs) to spatial operations in the hippocampus remains unknown. Here, we show that optogenetic activation of 4-week-old (young) aGCs in free-foraging mice produces a non-reversible reconfiguration of spatial maps in proximal CA3 while rarely evoking neural activity. Stimulation of the same neuronal cohort on subsequent days recruits CA3 neurons with increased efficacy but fails to induce further remapping. In contrast, stimulation of 8-week-old (mature) aGCs can reliably activate CA3 cells but produces no alterations in spatial maps. Our results reveal a unique role of young aGCs in remodeling CA3 representations, a potential that can be depleted and is lost with maturation. This ability could contribute to generate orthogonalized downstream codes supporting pattern separation.

Awake Hippocampal-Cortical Co-reactivation Is Associated with Forgetting.

Systems consolidation theories posit that consolidation occurs primarily through a coordinated communication between hippocampus and neocortex [Moscovitch, M., & Gilboa, A. Systems consolidation, transformation and reorganization: Multiple trace theory, trace transformation theory and their competitors. PsyArXiv, 2021; Kumaran, D., Hassabis, D., & McClelland, J. L. What learning systems do intelligent agents need? Complementary learning systems theory updated. Trends in Cognitive Sciences, 20, 512-534, 2016; McClelland, J. L., & O'Reilly, R. C. Why there are complementary learning systems in the hippocampus and neocortex: Insights from the successes and failures of connectionist models of learning and memory. Psychological Review, 102, 419-457, 1995]. Recent sleep studies in rodents have shown that hippocampus and visual cortex replay the same information at temporal proximity ("co-replay"; Lansink, C. S., Goltstein, P. M., Lankelma, J. V., McNaughton, B. L., & Pennartz, C. M. A. Hippocampus leads ventral striatum in replay of place-reward information. PLoS Biology, 7, e1000173, 2009; Peyrache, A., Khamassi, M., Benchenane, K., Wiener, S. I., & Battaglia, F. P. Replay of rule-learning related neural patterns in the prefrontal cortex during sleep. Nature Neuroscience, 12, 919-926, 2009; Wierzynski, C. M., Lubenov, E. V., Gu, M., & Siapas, A. G. State-dependent spike-timing relationships between hippocampal and prefrontal circuits during sleep. Neuron, 61, 587-596, 2009; Ji, D., & Wilson, M. A. Coordinated memory replay in the visual cortex and hippocampus during sleep. Nature Neuroscience, 10, 100-107, 2007). We developed a novel repetition time (TR)-based co-reactivation analysis method to study hippocampal-cortical co-replays in humans using fMRI. Thirty-six young adults completed an image (face or scene) and location paired associate encoding task in the scanner, which were preceded and followed by resting state scans. We identified post-encoding rest TRs (± 1) that showed neural reactivation of each image-location trials in both hippocampus (HPC) and category-selective cortex (fusiform face area [FFA]). This allowed us to characterize temporally proximal coordinated reactivations ("co-reactivations") between HPC and FFA. Moreover, we found that increased HPC-FFA co-reactivations were associated with incorrectly recognized trials after a 1-week delay (p = .004). Finally, we found that these HPC-FFA co-reactivations were also associated with trials that were initially correctly recognized immediately after encoding but were later forgotten in 1-day (p = .043) and 1-week delay period (p = .031). We discuss these results from a trace transformation perspective [Sekeres, M. J., Winocur, G., & Moscovitch, M. The hippocampus and related neocortical structures in memory transformation. Neuroscience Letters, 680, 39-53, 2018; Winocur, G., & Moscovitch, M. Memory transformation and systems consolidation. Journal of the International Neuropsychological Society, 17, 766-780, 2011] and speculate that HPC-FFA co-reactivations may be integrating related events, at the expense of disrupting event-specific details, hence leading to forgetting.

Hippocampal 4-Hz oscillations emerge during stationary running in a wheel and are resistant to medial septum inactivation.

Recent studies described 2-4 Hz oscillations in the hippocampus of rats performing stationary locomotion on treadmills and other apparatus. Since the 2-4 Hz rhythm shares common features with theta (5-12 Hz) oscillations-such as a positive amplitude-running speed relationship and modulation of spiking activity-many have questioned whether these rhythms are related or independently generated. Here, we analyzed local field potentials and spiking activity from the dorsal CA1 of rats executing a spatial alternation task and running for ~15 s in a wheel during the intertrial intervals both before and after muscimol injection into the medial septum. We observed remarkable 4-Hz oscillations during wheel runs, which presented amplitude positively correlated with running speed. Surprisingly, the amplitude of 4-Hz and theta oscillations were inversely related. Medial septum inactivation abolished hippocampal theta but preserved 4-Hz oscillations. It also affected the entrainment of pyramidal cells and interneurons by 4-Hz rhythmic activity. In all, these results dissociate the underlying mechanism of 4-Hz and theta oscillations in the rat hippocampus.

Contextual fear conditioning with a time interval induces CREB phosphorylation in the dorsal hippocampus and amygdala nuclei that depend on prelimbic cortex activity.

In temporal associations, a conditioned stimulus (CS) is separated by a time interval from the unconditioned stimulus (US), which activates the prelimbic cortex (PL) to maintain a CS representation over time. However, it is unknown whether the PL participates, besides the encoding, in the memory consolidation, and thus directly, with activity-dependent changes or indirectly, by modulation of activity-dependent changes in other brain regions. We investigated brain regions supporting the consolidation of associations with intervals and the influence of PL activity in this consolidation process. For this, we observed in Wistar rats the effect of pre-training PL inactivation by muscimol in CREB (cAMP response element-binding protein) phosphorylation, which is essential for memory consolidation, in subdivisions of the medial prefrontal cortex (mPFC), hippocampus, and amygdala 3 h after the training in the contextual fear conditioning (CFC) or CFC with 5-s interval (CFC-5s), fear associations without or with an interval between the CS and US, respectively. Both the CFC-5s and CFC training increased phosphorylation of CREB in the PL and infralimbic cortex (IL); lateral (LA) and basolateral (BLA) amygdala; dorsal CA1 (dCA1); dorsal (dDG), and ventral dentate gyrus, and the CFC-5s training in the central amygdala (CEA). PL activity was necessary for the CREB phosphorylation in the PL, BLA, CEA, dCA1, and dDG only in animals trained in the CFC-5s. The cingulate cortex, ventral CA1, and ventral subiculum did not have learning-induced phosphorylation of CREB. These results suggest that the mPFC, hippocampus, and amygdala support the consolidation of associations with or without intervals and that PL activity influences consolidation in the dorsal hippocampus and amygdala in temporal associations. Thereby, the PL contributes directly and indirectly by modulation to memory consolidation. The time interval engaged the PL early in recent memory consolidation. Results expanded PL's role beyond the time interval and remote memory consolidation.

Human motor sequence learning drives transient changes in network topology and hippocampal connectivity early during memory consolidation.

In the last decade, the exclusive role of the hippocampus in human declarative learning has been challenged. Recently, we have shown that gains in performance observed in motor sequence learning (MSL) during the quiet rest periods interleaved with practice are associated with increased hippocampal activity, suggesting a role of this structure in motor memory reactivation. Yet, skill also develops offline as memory stabilizes after training and overnight. To examine whether the hippocampus contributes to motor sequence memory consolidation, here we used a network neuroscience strategy to track its functional connectivity offline 30 min and 24 h post learning using resting-state functional magnetic resonance imaging. Using a graph-analytical approach we found that MSL transiently increased network modularity, reflected in an increment in local information processing at 30 min that returned to baseline at 24 h. Within the same time window, MSL decreased the connectivity of a hippocampal-sensorimotor network, and increased the connectivity of a striatal-premotor network in an antagonistic manner. Finally, a supervised classification identified a low-dimensional pattern of hippocampal connectivity that discriminated between control and MSL data with high accuracy. The fact that changes in hippocampal connectivity were detected shortly after training supports a relevant role of the hippocampus in early stages of motor memory consolidation.

Facial nerve axotomy induces morphological changes in hippocampal pyramidal neurons.

Facial nerve injury in rats have been widely used to study functional and structural changes that occur in the injured motoneurons and other central nervous system structures related with sensorimotor processing. A decrease in long-term potentiation of hippocampal CA3-to-CA1 commissural synapse has recently been reported related to this peripheral injury. Additionally, it has been found increased corticosterone plasmatic levels, impairment in spatial memory consolidation, and hippocampal microglial activation in animals with facial nerve axotomy. In this work, we analyzed the neuronal morphology of hippocampal CA1 and CA3 pyramidal neurons in animals with either reversible or irreversible facial nerve injury. For this purpose, brain tissues of injured animals sacrificed at different postlesion times, were stained with the Golgi-Cox method and compared with control brains. It was found that both reversible and irreversible facial nerve injury-induced significant decreases in dendritic tree complexity, dendritic length, branch points, and spine density of hippocampal neurons. However, such changes' timing varied according to hippocampal area (CA1 vs. CA3), dendritic area (apical vs. basal), and lesion type (reversible vs. irreversible). In general, the observed changes were transient when animals had the possibility of motor recovery (reversible injury), but perdurable if the recovery from the lesion was impeded (irreversible injury). CA1 apical and CA3 basal dendritic tree morphology were more sensible to irreversible injury. It is concluded that facial nerve injury induced significant changes in hippocampal CA1 and CA3 pyramidal neurons morphology, which could be related to LTP impairments and microglial activation in the hippocampal formation, previously described.