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Behavior is guided by the compatibility of expectations based on past experience and the outcome. In a recent study, Fouragnan and colleagues report that absolute prediction error (PE)-related heart-evoked potentials (HEPs) differ according to the cardiac cycle phase at outcome, and that the magnitude of this effect positively correlates with reward learning in healthy adults., Competing Interests: Declaration of interests None declared by authors., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Hippocampus is essential for episodic memory formation, lesion studies demonstrating its role especially in processing spatial and temporal information. Further, adult hippocampal neurogenesis (AHN) in the dentate gyrus (DG) has also been linked to learning. To study hippocampal neuronal activity during events like learning, in vivo calcium imaging has become increasingly popular. It relies on the use of adeno-associated viral (AAV) vectors, which seem to lead to a decrease in AHN when applied on the DG. More notably, imaging requires the implantation of a relatively large lens into the tissue. Here, we examined how injection of an AAV vector and implantation of a 1-mm-diameter lens into the dorsal DG routinely used to image calcium activity impact the behavior of adult male C57BL/6 mice. To this aim, we conducted open-field, object-recognition and object-location tasks at baseline, after AAV vector injection, and after lens implantation. Finally, we determined AHN from hippocampal slices using a doublecortin-antibody. According to our results, the operations needed for in vivo imaging of the dorsal DG did not have adverse effects on behavior, although we noticed a decrease in AHN ipsilaterally to the operations. Thus, our results suggest that in vivo imaging can be safely used to, for example, correlate patterns of calcium activity with learned behavior. One should still keep in mind that the defects on the operated side might be functionally compensated by the (hippocampus in the) contralateral hemisphere., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The ability to accurately assess one's own memory performance during learning is essential for adaptive behavior, but the brain mechanisms underlying this metamemory function are not well understood. We investigated the neural correlates of memory accuracy and retrospective memory confidence in a face-name associative learning task using magnetoencephalography in healthy young adults (n = 32). We found that high retrospective confidence was associated with stronger occipital event-related fields during encoding and widespread event-related fields during retrieval compared to low confidence. On the other hand, memory accuracy was linked to medial temporal activities during both encoding and retrieval, but only in low-confidence trials. A decrease in oscillatory power at alpha/beta bands in the parietal regions during retrieval was associated with higher memory confidence. In addition, representational similarity analysis at the single-trial level revealed distributed but differentiable neural activities associated with memory accuracy and confidence during both encoding and retrieval. In summary, our study unveiled distinct neural activity patterns related to memory confidence and accuracy during associative learning and underscored the crucial role of parietal regions in metamemory., (© The Author(s) 2024. Published by Oxford University Press.)

Learning outcome is modified by the degree to which the subject responds and pays attention to specific stimuli. Our recent research suggests that presenting stimuli in contingency with a specific phase of the cardiorespiratory rhythm might expedite learning. Specifically, expiration-diastole (EXP-DIA) is beneficial for learning trace eyeblink conditioning (TEBC) compared with inspiration-systole (INS-SYS) in healthy young adults. The aim of this study was to investigate whether the same holds true in healthy elderly adults ( n = 50, aged >70 yr). Participants were instructed to watch a silent nature film while TEBC trials were presented at either INS-SYS or EXP-DIA (separate groups). Learned responses were determined as eyeblinks occurring after the tone conditioned stimulus (CS), immediately preceding the air puff unconditioned stimulus (US). Participants were classified as learners if they made at least five conditioned responses (CRs). Brain responses to the stimuli were measured by electroencephalogram (EEG). Memory for the film and awareness of the CS-US contingency were evaluated with a questionnaire. As a result, participants showed robust brain responses to the CS, acquired CRs, and reported awareness of the CS-US relationship to a variable degree. There was no difference between the INS-SYS and EXP-DIA groups in any of the above. However, when only participants who learned were considered, those trained at EXP-DIA ( n = 11) made more CRs than those trained at INS-SYS ( n = 13). Thus, learned performance could be facilitated in those elderly who learned. However, training at a specific phase of cardiorespiratory rhythm did not increase the proportion of participants who learned. NEW & NOTEWORTHY We trained healthy elderly individuals in trace eyeblink conditioning, either at inspiration-systole or at expiration-diastole. Those who learned exhibited more conditioned responses when trained at expiration-diastole rather than inspiration-systole. However, there was no difference between the experimental groups in the proportion of individuals who learned or did not learn.

Trace eyeblink conditioning (TEBC) has been widely used to study associative learning in both animals and humans. In this paradigm, conditioned responses (CRs) to conditioned stimuli (CS) serve as a measure for retrieving learned associations between the CS and the unconditioned stimuli (US) within a trial. Memory consolidation, that is, learning over time, can be quantified as an increase in the proportion of CRs across training sessions. However, how hippocampal oscillations differentiate between successful memory retrieval within a session and consolidation across TEBC training sessions remains unknown. To address this question, we recorded local field potentials (LFPs) from the rat dorsal hippocampus during TEBC and investigated hippocampal oscillation dynamics associated with these two functions. We show that transient broadband responses to the CS were correlated with memory consolidation, as indexed by an increase in CRs across TEBC sessions. In contrast, induced alpha (8-10 Hz) and beta (16-20 Hz) band responses were correlated with the successful retrieval of the CS-US association within a session, as indexed by the difference in trials with and without CR., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Kim et al.)

Good aerobic and metabolic fitness associates with better cognitive performance and brain health. Conversely, poor metabolic health predisposes to neurodegenerative diseases. Our previous findings indicate that rats selectively bred for Low Capacity for Running (LCR) show less synaptic plasticity and more inflammation in the hippocampus and perform worse in tasks requiring flexible cognition than rats bred for High Capacity for Running (HCR). Here we aimed to determine whether hippocampal electrophysiological activity related to learning and memory would be impaired in LCR compared to HCR rats. We also studied whether an exercise intervention could even out the possible differences. We conducted in vivo recordings from the dorsal hippocampus under terminal urethane anesthesia in middle-aged sedentary males and female rats, and in females allowed to access running wheels for 6 weeks. Our results indicate stronger long-term potentiation (LTP) in the CA3-CA1 synapse in HCR than LCR rats, and in female than male rats. Compared to LCR rats, HCR rats had more dentate spikes and more gamma epochs, the occurrence of which also correlated positively with the magnitude of LTP. Voluntary running reduced the differences between female LCR and HCR rats. In conclusion, low innate fitness links to reduced hippocampal function and plasticity which can seems to improve with voluntary aerobic exercise even in middle age., (Copyright © 2024. Published by Elsevier B.V.)

Breathing and heartbeat synchronize to each other and to brain function and affect cognition in humans. However, it is not clear how cardiorespiratory rhythms modulate such basic processes as synaptic plasticity thought to underlie learning. Thus, we studied if respiration and cardiac cycle phases at burst stimulation onset affect hippocampal long-term potentiation (LTP) in the CA3-CA1 synapse in urethane-anesthetized adult male Sprague-Dawley rats. In a between-subjects design, we timed burst stimulation of the ventral hippocampal commissure (vHC) to systole or diastole either during expiration or inspiration and recorded responses throughout the hippocampus with a linear probe. As classical conditioning in humans seems to be most efficient at expiration-diastole, we also expected LTP to be most efficient if burst stimulation was targeted to expiration-diastole. However, LTP was induced equally in all four groups and respiration and cardiac cycle phase did not modulate CA1 responses to vHC stimulation overall. This could be perhaps because we bypassed all natural routes of external influences on the CA1 by directly stimulating the vHC. In the future, the effect of cardiorespiratory rhythms on synaptic plasticity could also be studied in awake state and in other parts of the hippocampal tri-synaptic loop., (© 2023 The Authors. Hippocampus published by Wiley Periodicals LLC.)

Good aerobic fitness associates positively with cognitive performance and brain health and conversely, low aerobic fitness predisposes to neurodegenerative diseases. To study how genotype together with exercise, started at older age, affects brain and behavior, we utilized rats that differ in inherited aerobic fitness. Rats bred for Low Capacity for Running (LCR) are shown to display less synaptic plasticity and more inflammation in the hippocampus and perform worse than rats bred for a High Capacity for Running (HCR) in tasks requiring flexible cognition. Here we used middle-aged (∼ 16 months) HCR and LCR rats to study how genotype and sex associate with anxiety and neural information filtering, termed sensory gating. Further, we assessed how inherited aerobic capacity associates with hippocampus-dependent learning, measured with contextual fear conditioning task. In females, we also investigated the effects of voluntary wheel running (5 weeks) on these characteristics. Our results indicate that independent of sex or voluntary running, HCR rats were more anxious in open-field tasks, exhibited lower sensory gating and learned more efficiently in contextual fear conditioning task than LCR rats. Voluntary running did not markedly affect innate behavior but slightly decreased the differences between female LCR and HCR rats in fear learning. In conclusion, inherited fitness seems to determine cognitive and behavioral traits independent of sex. Although the traits proved to be rather resistant to change at adult age, learning was slightly improved following exercise in LCR females, prone to obesity and poor fitness., Competing Interests: Competing interests None., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Dentate gyrus (DG) is important for pattern separation and spatial memory, and it is thought to gate information flow to the downstream hippocampal subregions. Dentate spikes (DSs) are high-amplitude, fast, positive local-field potential events taking place in the DG during immobility and sleep, and they have been connected to memory consolidation in rodents. DSs are a result of signaling from the entorhinal cortex (EC) to the DG, and they suppress firing of pyramidal cells in the CA3 and CA1. To study the effects of DSs to signaling in the hippocampal tri-synaptic loop, we electrically stimulated the afferent fibers of the DG, CA3, and CA1 in adult male Sprague-Dawley rats at different delays from DSs. Responses to stimulation were increased in the EC-DG synapse during DSs, and the effect was amplified after theta-burst stimulation. We concluded that DSs strengthen the excitatory signal from the EC to the DG, which is reinforced by synapse potentiation and increased excitability of granule cells after theta-burst stimulation. This signal boosting may function in enhancing plastic changes in the DG-CA3 synapse. As responses in the CA3 and CA1 remained unaffected by the DS, the DS-contingent silencing of pyramidal cells seems to be a result of a decrease in excitatory input rather than a decrease in the excitability of the pyramidal cells themselves. In addition, we found that the DSs occur asynchronously in the left and right hippocampi, giving novel evidence of lateralization of the rodent hippocampus., (© 2022 The Authors. Hippocampus published by Wiley Periodicals LLC.)

The body is, in essence, an ensemble of interacting systems with biorhythms nested at multiple timescales. Traditionally, the focus in the study of body-brain interaction has been on clarifying the ways by which our brain orchestrates the functions of the body. During recent decades theories building on the opposite causal direction, namely how the different body systems influence the brain and mind, have been dramatically increasing. Despite influential theories, direct research evidence about the link between bodily rhythms, brain and cognition are scattered. Here, we review existing evidence on how the electrophysiological activity of the brain on one hand, and perception or cognition on the other hand depend on the phase of the physiological cycles of the body, specifically those of the heartbeat and respiration. We summarize the accumulated evidence from human and animal studies and their implication for the theoretical reasoning. Last, besides elaborating how the cycles of bodily rhythms influence brain signaling and perceptual cognitive functions, we present potential explanations and answers to why this link might exist., (Copyright © 2022. Published by Elsevier Ltd.)

Functions of the brain and body are oscillatory in nature and organized according to a logarithmic scale. Brain oscillations and bodily functions such as respiration and heartbeat appear nested within each other and coupled together either based on phase or based on phase and amplitude. This facilitates communication in wide-spread neuronal networks and probably also between the body and the brain. It is a widely accepted view, that nested electrophysiological brain oscillations involving the neocortex, thalamus, and the hippocampus form the basis of memory consolidation. This applies especially to declarative memories, that is, memories of life events, for example. Here, we present our view of hippocampal contribution to the process of memory consolidation based on the general ideas stated above and on some recent findings on the topic by us and by other research groups. We propose that in addition to the interplay between neocortical slow oscillations, spindles, and hippocampal sharp-wave ripples during sleep, there are also additional mechanisms available in the hippocampus to control memory consolidation: a rather non-oscillatory hippocampal electrophysiological phenomenon called the dentate spike might provide a means to not only consolidate but to also modify the neural representation of declarative memories. Further, we suggest that memory consolidation in the hippocampus might be in part paced by breathing. These considerations might open new possibilities for regulating memory consolidation in rest and sleep., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Nokia and Penttonen.)

Rhythms of breathing and heartbeat are linked to each other as well as to the rhythms of the brain. Our recent studies suggest that presenting conditioned stimulus during expiration or during the diastolic phase of the cardiac cycle facilitates neural processing of that stimulus and improves learning in a conditioning task. To date, it has not been examined whether using information from both respiration and cardiac cycle phases simultaneously allows even more efficient modulation of learning. Here, we studied whether the timing of the conditioned stimulus to different cardiorespiratory rhythm phase combinations affects learning in a conditioning task in healthy young adults. The results were consistent with previous reports: timing the conditioned stimulus to diastole during expiration was more beneficial for learning than timing it to systole during inspiration. Cardiac cycle phase seemed to explain most of this variation in learning at the behavioral level. Brain-evoked potentials (N1) elicited by the conditioned stimulus and recorded using electroencephalogram were larger when the conditioned stimulus was presented to diastole during expiration than when it was presented to systole during inspiration. Breathing phase explained the variation in the N1 amplitude. To conclude, our findings suggest that noninvasive monitoring of bodily rhythms combined with closed-loop control of stimulation can be used to promote learning in humans. The next step will be to test if performance can also be improved in humans with compromised cognitive ability, such as in older people with memory impairments. NEW & NOTEWORTHY We report, for the first time, that the rhythms of breathing and the beating of the heart have a phase combination that is indicative of a neural state beneficial for cognition. This suggests that bodily rhythms not only modulate cognition but that this phenomenon can also be noninvasively harnessed to improve learning in humans.

Optogenetics, a field concentrating on controlling cellular functions by means of light-activated proteins, has shown tremendous potential in neuroscience. It possesses superior spatiotemporal resolution compared to the surgical, electrical, and pharmacological methods traditionally used in studying brain function. A multitude of optogenetic tools for neuroscience have been created that, for example, enable the control of action potential generation via light-activated ion channels. Other optogenetic proteins have been used in the brain, for example, to control long-term potentiation or to ablate specific subtypes of neurons. In in vivo applications, however, the majority of optogenetic tools are operated with blue, green, or yellow light, which all have limited penetration in biological tissues compared to red light and especially infrared light. This difference is significant, especially considering the size of the rodent brain, a major research model in neuroscience. Our review will focus on the utilization of red light-operated optogenetic tools in neuroscience. We first outline the advantages of red light for in vivo studies. Then we provide a brief overview of the red light-activated optogenetic proteins and systems with a focus on new developments in the field. Finally, we will highlight different tools and applications, which further facilitate the use of red light optogenetics in neuroscience., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lehtinen, Nokia and Takala.)

Background: Increasing evidence shows obesity and poor metabolic health are associated with cognitive deficits, but the mechanistic connections have yet to be resolved. We studied rats selectively bred for low and high intrinsic aerobic capacity in order to test the association between low physical fitness, a genetic predisposition for obesity, and brain health. We hypothesized that low-capacity runner (LCR) rats with concurrently greater levels of adiposity would have increased hippocampal inflammation and reduced plasticity compared to the more physically fit high-capacity runner (HCR) rats., Methods: We examined markers for inflammation and brain plasticity in the hippocampi of LCR rats and compared them to HCR rats. The effect of age was determined by studying the rats at a young age (8 weeks) and later in life (40 weeks). We used western blots and immunohistochemistry to quantify the expression of target proteins., Results: Our study showed that the number of adult-born new neurons in the hippocampus was significantly lower in LCR rats than it was in HCR rats already at a young age and that the difference became more pronounced with age. The expression of synaptic proteins was higher in young animals relative to older ones. Brain inflammation tended to be higher in LCR rats than it was in the HCR rats, and more prominent in older rats than in young ones., Conclusion: Our study is the first to demonstrate that low intrinsic aerobic fitness that is associated with obesity and poor metabolic health is also linked with reduced hippocampal structural plasticity at a young age. Our results also suggest that inflammation of the brain could be one factor mediating the link between obesity and poor cognitive performance., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Metabolic syndrome (MetS) is a known risk factor for cognitive decline. Using polygenic rat models selectively bred for high and low intrinsic exercise capacity and simultaneously modelling as low and high innate risk factor for MetS respectively, we have previously shown that adult animals with lower exercise capacity/higher MetS risk perform poorly in tasks requiring flexible cognition. However, it is not known whether these deficits in cognition are present already at young age. Also, it is unclear whether the high risk genome is related also to lower-level cognition, such as sensory gating measured as prepulse inhibition. In this study, young and adult (5-8 weeks and ~9 months) rats selectively bred for 36 generations as High-Capacity Runners (HCR) or Low-Capacity Runners (LCR) were tested for behavior in an open field task, modulation of startle reflex, and spatial learning in a T-maze. HCR rats were more active in the open field than LCR rats independent of age. Responses to the startle stimulus habituated to the same extent in LCR compared to HCR rats when young, but as adults, stronger habituation was seen in the HCR animals. The prepulse inhibition of startle response was equally strong in young HCR and LCR animals but the effect was shorter lasting in HCR animals. In T-maze, adult HCR animals unexpectedly showed attenuated learning, but we interpret this finding to stem from differences in motivation rather than learning ability. Overall, in the LCR rats with the risk genome for poor aerobic fitness and MetS, indications of compromised cognitive function are present already at a young age., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Understanding brain operation demands linking basic behavioral traits to cell-type specific dynamics of different brain-wide subcircuits. This requires a system to classify the basic operational modes of neurons and circuits. Single-cell phenotyping of firing behavior during ongoing oscillations in vivo has provided a large body of evidence on entorhinal-hippocampal function, but data are dispersed and diverse. Here, we mined literature to search for information regarding the phase-timing dynamics of over 100 hippocampal/entorhinal neuron types defined in Hippocampome.org. We identified missing and unresolved pieces of knowledge (e.g., the preferred theta phase for a specific neuron type) and complemented the dataset with our own new data. By confronting the effect of brain state and recording methods, we highlight the equivalences and differences across conditions and offer a number of novel observations. We show how a heuristic approach based on oscillatory features of morphologically identified neurons can aid in classifying extracellular recordings of single cells and discuss future opportunities and challenges towards integrating single-cell phenotypes with circuit function., Competing Interests: The authors have declared that no competing interests exist.

Treatment of brain cancer, glioma, can cause cognitive impairment as a side-effect, possibly because it disrupts the integrity of the hippocampus, a structure vital for normal memory. Radiotherapy is commonly used to treat glioma, but the effects of irradiation on the brain are still poorly understood, and other biological effects have not been extensively studied. Here, we exposed healthy adult male rats to moderate-dose irradiation of the head. We found no effect of irradiation on systemic inflammation, weight gain or gut microbiota diversity, although it increased the abundance of Bacteroidaceae family, namely Bacteroides genus in the gut microbiota. Irradiation had no effect on long-term potentiation in the CA3-CA1 synapse or endogenous hippocampal electrophysiology, but it did reduce adult hippocampal neurogenesis and impaired short-term spatial recognition memory. However, no overall cognitive impairment was observed. To summarize, our results suggest that in adult male rats head irradiation does not compromise health or cognition overall even though the number of new, adult-born hippocampal neurons is decreased. Thus, the sole effects of head irradiation on the body, brain and cognition might be less harmful than previously thought, and the cognitive decline experienced by cancer patients might originate from physiological and mental effects of the disease itself. Therefore, to increase the translational value of animal studies, the effects of irradiation should be studied together with cancer, in older animals, using varying irradiation protocols and doses., (© 2020 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Hippocampus forms neural representations of real-life events including multimodal information of spatial and temporal context. These representations, i.e., organized sequences of neuronal firing, are repeated during following rest and sleep, especially when so-called sharp-wave ripples (SPW-Rs) characterize hippocampal local field potentials. This SPW-R -related replay is thought to underlie memory consolidation. Here, we set out to explore how hippocampal CA1 pyramidal cells respond to the conditioned stimulus during trace eyeblink conditioning and how these responses manifest during SPW-Rs in awake adult female New Zealand White rabbits. Based on reports in rodents, we expected SPW-Rs to take place in bursts, possibly according to a slow endogenous rhythm. In awake rabbits, half of all SPW-Rs took place in bursts, but no endogenous slow rhythm appeared. Conditioning trials suppressed SPW-Rs while increasing theta for a period of several seconds. As expected based on previous findings, only a quarter of the putative CA1 pyramidal cells increased firing in response to the conditioned stimulus. Compared with other cells, rate-increasing cells were more active during spontaneous epochs of hippocampal theta while response profile during conditioning did not affect firing during SPW-Rs. Taken together, CA1 pyramidal cell firing during SPW-Rs is not limited to cells that fired during the preceding experience. Furthermore, the importance of possible reactivations taking place during theta epochs on memory consolidation warrants further investigation. NEW & NOTEWORTHY We studied hippocampal sharp-wave ripples and theta and CA1 pyramidal cell activity during trace eyeblink conditioning in rabbits. Conditioning trials suppressed ripples while increasing theta for a period of several seconds. A quarter of the cells increased firing in response to the conditioned stimulus and fired extensively during endogenous theta as well as ripples. The role of endogenous theta epochs in off-line memory consolidation should be studied further.

Rhythmic variation in heart rate and respiratory pattern are coupled in a way that optimizes the level of oxygen in the blood stream of the lungs and the body as well as saves energy in pulmonary gas exchange. It has been suggested that the cardiac cycle and respiratory pattern are coupled to neural oscillations of the brain. Yet, studies on how this rhythmic coupling is related to behavior are scarce. There is some evidence that, for example, the phase of respiration affects memory retrieval and the electrophysiological oscillatory state of the limbic system. It is also known that the phase of the cardiac cycle and hippocampal electrophysiological oscillations alone affect learning. Here, we studied whether the timing of training trials to different phases of respiration affects learning trace eyeblink conditioning in healthy adult humans. Trials consisting of a neutral conditioned stimulus (200-ms tone) and a slightly aversive unconditioned stimulus (100-ms air puff toward the eye), presented with a 600-ms trace interval, were timed to either inspiration or expiration. A control group was trained regardless of respiratory phase. We found that, at the end of training, the rate of conditioned responses was higher in the group trained at expiration than it was in the other two groups. That is, brain state seems to fluctuate as a function of respiratory rhythm, and this fluctuation is also behaviorally relevant, exerting its effect on, at the least, a simple form of associative learning., (© 2019 Society for Psychophysiological Research.)

Hippocampal dentate spikes (DSs) are short-duration, large-amplitude fluctuations in hilar local field potentials and take place while resting and sleeping. During DSs, dentate gyrus granule cells increase firing while CA1 pyramidal cells decrease firing. Recent findings suggest DSs play a significant role in memory consolidation after training on a hippocampus-dependent, nonspatial associative learning task. Here, we aimed to find out whether DSs are important in other types of hippocampus-dependent learning tasks as well. To this end, we trained adult male Sprague-Dawley rats in a spatial reference memory task, a fixed interval task, and a pattern separation task. During a rest period immediately after each training session, we either let neural activity to take place as usual, timed electrical stimulation of the ventral hippocampal commissure (vHC) to immediately follow DSs, or applied the vHC stimulation during a random neural state. We found no effect of vHC stimulation on performance in the spatial reference memory task or in the fixed interval task. Surprisingly, vHC stimulation, especially contingent on DSs, improved performance in the pattern separation task. In conclusion, the behavioral relevance of hippocampal processing and DSs seems to depend on the task at hand. It could be that in an intact brain, offline memory consolidation by default involves associating neural representations of temporally separate but related events. In some cases this might be beneficial for adaptive behavior in the future (associative learning), while in other cases it might not (pattern separation). NEW & NOTEWORTHY The behavioral relevance of dentate spikes seems to depend on the learning task at hand. We suggest that dentate spikes are related to associating neural representations of temporally separate but related events within the dentate gyrus. In some cases this might be beneficial for adaptive behavior in the future (associative learning), while in other cases it might not (pattern separation).

Cardiac cycle phase is known to modulate processing of simple sensory information. This effect of the heartbeat on brain function is likely exerted via baroreceptors, the neurons sensitive for changes in blood pressure. From baroreceptors, the signal is conveyed all the way to the forebrain and the medial prefrontal cortex. In the two experiments reported, we examined whether learning, as a more complex form of cognition, can be modulated by the cardiac cycle phase. Human participants ( experiment 1) and rabbits ( experiment 2) were trained in trace eyeblink conditioning while neural activity was recorded. The conditioned stimulus was presented contingently with either the systolic or diastolic phase of the cycle. The tone used as the conditioned stimulus evoked amplified responses in both humans (electroencephalogram from "vertex," Cz) and rabbits (hippocampal CA1 local field potential) when its onset was timed at systole. In humans, the cardiac cycle phase did not affect learning, but rabbits trained at diastole learned significantly better than those trained at a random phase of the cardiac cycle. In summary, our results suggest that neural processing of external stimuli and also learning can be affected by targeting stimuli on the basis of cardiac cycle phase. These findings might be useful in applications aimed at maximizing or minimizing the effects of external stimulation. NEW & NOTEWORTHY It has been shown that rapid changes in bodily states modulate neural processing of external stimulus in brain. In this study, we show that modulation of neural processing of external stimulus and learning about it depends on the phase of the cardiac cycle. This is a novel finding that can be applied to optimize associative learning.

Hippocampal theta oscillations (3-12Hz) play a prominent role in learning. It has been suggested that encoding and retrieval of memories are supported by different phases of the theta cycle. Our previous study on trace eyeblink conditioning in rabbits suggests that the timing of the conditioned stimulus (CS) in relation to theta phase affects encoding but not retrieval of the memory trace. Here, we directly tested the effects of hippocampal theta phase on memory retrieval in two experiments conducted on adult female New Zealand White rabbits. In Experiment 1, animals were trained in trace eyeblink conditioning followed by extinction, and memory retrieval was tested by presenting the CS at troughs and peaks of the theta cycle during different stages of learning. In Experiment 2, animals were trained in delay conditioning either contingent on a high level of theta or at a random neural state. Conditioning was then followed by extinction conducted either at a random state, contingent on theta trough or contingent on theta peak. Our current results indicate that the phase of theta at CS onset has no effect on the performance of the behavioral learned response at any stage of classical eyeblink conditioning or extinction. In addition, theta-contingent trial presentation does not improve learning during delay eyeblink conditioning. The results are consistent with our earlier findings and suggest that the theta phase alone is not sufficient to affect learning at the behavioral level. It seems that the retrieval of recently acquired memories and consequently performing a learned response is moderated by neural mechanisms other than hippocampal theta., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Host genetic factors affecting the gut microbiome play an important role in obesity, yet limited attention has been paid on the host genetic factors linked to physical fitness in modifying the microbiome. This study determined whether sibling-matched pairs of rats selectively bred for high (HCR) and low (LCR) aerobic capacity differ in their microbiome age-dependently and which taxa associate with differential in metabolism. Several taxa in young adult rats (hereafter young) linked to inherited aerobic capacity, while in older adult (hereafter old) rats most of the differences between the lines associated with body weight. Despite the absence of weight differential between LCR and HCR when young, the LCR microbiome contained more Actinobacteria, Veillonellaceae, Coriobacteriaceae, Phascolarctobacterium, and Ruminococcus; taxa previously linked to obesity. This raises the question whether the microbiome contributes to the later development of obesity in LCR. Age-related differences were detected in almost all taxa in both rat lines. The young HCR measured higher for serum glycerol and free fatty-acids and lower for cholesterol, HDL, LDL, and triglycerides than LCR. The old HCR differed from the old LCR by lower LDL. Several metabolites, including LDL, are associated age and genetic background-dependently with the microbiome, which might explain the metabolic differences between the lines. While old lines did not differ in visceral adipose tissue gene expression, the young HCR expressed more inflammatory genes than LCR, and several taxa including Proteobacteria associated with these genes. In conclusion, intrinsic aerobic capacity governs the microbiome, which may influence body weight, metabolism, and gene expression.

Key Points: Dentate spikes are fast fluctuations of hilar local-field potentials that take place during rest and are thought to reflect input arriving from the entorhinal cortex to the hippocampus. During dentate spikes, neuronal firing in hippocampal input (dentate gyrus) and output (CA1/CA3) regions is uncoupled. To date, the behavioural significance of dentate spikes is unknown. Here, we provide evidence that disrupting the dentate spike-related uncoupling of the dentate gyrus and the CA1/CA3 subregions for 1 h after training retards associative learning. We suggest dentate spikes play a significant role in memory consolidation., Abstract: Hippocampal electrophysiological oscillations, namely theta and ripples, have been implicated in encoding and consolidation of new memories, respectively. According to existing literature, hippocampal dentate spikes are prominent, short-duration (<30 ms), large-amplitude (∼2-4 mV) fluctuations in hilar local-field potentials that take place during awake immobility and sleep. Interestingly, previous studies indicate that during dentate spikes dentate gyrus granule cells increase their firing while firing of CA1 pyramidal cells are suppressed, thus resulting in momentary uncoupling of the two hippocampal subregions. To date, the behavioural significance of dentate spikes is unknown. Here, to study the possible role of dentate spikes in learning, we trained adult male Sprague-Dawley rats in trace eyeblink classical conditioning. For 1 h immediately following each conditioning session, one group of animals received hippocampal stimulation via the ventral hippocampal commissure (vHC) contingent on dentate spikes to disrupt the uncoupling between the dentate gyrus and the CA1 subregions. A yoked control group was stimulated during immobility, irrespective of brain state, and another control group was not stimulated at all. As a result, learning was impaired only in the group where vHC stimulation was administered contingent on dentate spikes. Our results suggest dentate spikes and/or the associated uncoupling of the dentate gyrus and the CA1 play a significant role in memory consolidation. Dentate spikes could possibly reflect reactivation and refinement of a memory trace within the dentate gyrus triggered by input from the entorhinal cortex., (© 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.)

Key Points: Aerobic exercise, such as running, enhances adult hippocampal neurogenesis (AHN) in rodents. Little is known about the effects of high-intensity interval training (HIT) or of purely anaerobic resistance training on AHN. Here, compared with a sedentary lifestyle, we report a very modest effect of HIT and no effect of resistance training on AHN in adult male rats. We found the most AHN in rats that were selectively bred for an innately high response to aerobic exercise that also run voluntarily and increase maximal running capacity. Our results confirm that sustained aerobic exercise is key in improving AHN., Abstract: Aerobic exercise, such as running, has positive effects on brain structure and function, such as adult hippocampal neurogenesis (AHN) and learning. Whether high-intensity interval training (HIT), referring to alternating short bouts of very intense anaerobic exercise with recovery periods, or anaerobic resistance training (RT) has similar effects on AHN is unclear. In addition, individual genetic variation in the overall response to physical exercise is likely to play a part in the effects of exercise on AHN but is less well studied. Recently, we developed polygenic rat models that gain differentially for running capacity in response to aerobic treadmill training. Here, we subjected these low-response trainer (LRT) and high-response trainer (HRT) adult male rats to various forms of physical exercise for 6-8 weeks and examined the effects on AHN. Compared with sedentary animals, the highest number of doublecortin-positive hippocampal cells was observed in HRT rats that ran voluntarily on a running wheel, whereas HIT on the treadmill had a smaller, statistically non-significant effect on AHN. Adult hippocampal neurogenesis was elevated in both LRT and HRT rats that underwent endurance training on a treadmill compared with those that performed RT by climbing a vertical ladder with weights, despite their significant gain in strength. Furthermore, RT had no effect on proliferation (Ki67), maturation (doublecortin) or survival (bromodeoxyuridine) of new adult-born hippocampal neurons in adult male Sprague-Dawley rats. Our results suggest that physical exercise promotes AHN most effectively if the exercise is aerobic and sustained, especially when accompanied by a heightened genetic predisposition for response to physical exercise., (© 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.)

Hippocampal θ (3-12 Hz) oscillations are implicated in learning and memory, but their functional role remains unclear. We studied the effect of the phase of local θ oscillation on hippocampal responses to a neutral conditioned stimulus (CS) and subsequent learning of classical trace eyeblink conditioning in adult rabbits. High-amplitude, regular hippocampal θ-band responses (that predict good learning) were elicited by the CS when it was timed to commence at the fissure θ trough (Trough group). Regardless, learning in this group was not enhanced compared with a yoked control group, possibly due to a ceiling effect. However, when the CS was consistently presented to the peak of θ (Peak group), hippocampal θ-band responding was less organized and learning was retarded. In well-trained animals, the hippocampal θ phase at CS onset no longer affected performance of the learned response, suggesting a time-limited role for hippocampal processing in learning. To our knowledge, this is the first study to demonstrate that timing a peripheral stimulus to a specific phase of the hippocampal θ cycle produces robust effects on the synchronization of neural responses and affects learning at the behavioral level. Our results support the notion that the phase of spontaneous hippocampal θ oscillation is a means of regulating the processing of information in the brain to a behaviorally relevant degree., (© 2015 Nokia et al.; Published by Cold Spring Harbor Laboratory Press.)

Hippocampal local field potentials are characterized by two mutually exclusive states: one characterized by regular θ oscillations (∼4-8 Hz) and the other by irregular sharp-wave ripples. Presenting stimuli during dominant θ oscillations leads to expedited learning, suggesting that θ indexes a state in which encoding is most effective. However, ripple-contingent training also expedites learning, suggesting that any discrete brain state, much like the external context, can affect learning. We trained adult rabbits in trace eyeblink conditioning, a hippocampus-dependent nonspatial task, followed by extinction. Trials were delivered either in the presence or absence of θ or regardless of hippocampal state. Conditioning in the absence of θ led to more animals learning, although learning was slower compared with a yoked control group. Contrary to expectations, conditioning in the presence of θ did not affect learning. However, extinction was expedited both when it was conducted contingent on θ and when it was conducted in a state contrary to that used to trigger trials during conditioning. Strong phase-locking of hippocampal θ-band responses to the conditioned stimulus early on during conditioning predicted good learning. No such connection was observed during extinction. Our results suggest that any consistent hippocampal oscillatory state can potentially be used to regulate learning. However, the effects depend on the specific state and task at hand. Finally, much like the external environment, the ongoing neural state appears to act as a context for learning and memory retrieval.

Hippocampal electrophysiological oscillatory activity is undoubtedly related to learning and memory. The relative power of spontaneously occurring hippocampal theta (∼4-8 Hz) oscillations predicts how fast and how well an animal will learn: more theta predicts faster acquisition of the conditioned response in eyeblink conditioning in both rats and rabbits. Here, our aim was to study how hippocampal theta-band responses to conditioned stimuli elicited during very-long delay discrimination eyeblink conditioning relate to the accompanying conditioned behavior. We trained adult male New Zealand White rabbits using 1500-ms auditory stimuli as conditioned stimuli and a 100-ms airpuff as an unconditioned stimulus. The reinforced conditioned stimulus overlapped and co-terminated with the unconditioned stimulus whereas the non-reinforced conditioned stimulus was always presented alone. Consistent with previous results, hippocampal theta-band responses to the conditioned stimuli diminished in amplitude across training. Interestingly, hippocampal theta-band responses were most consistently time-locked when a well-trained animal failed to suppress behavioral learned responses to the non-reinforced conditioned stimulus. We suggest that phase-locking of hippocampal theta-band oscillations in response to external stimuli reflects retrieval of the dominant memory trace (adaptive or not) along with initiating the most prominent action scheme related to that memory trace., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Oscillations in hippocampal local-field potentials (LFPs) reflect the crucial involvement of the hippocampus in memory trace formation: theta (4-8 Hz) oscillations and ripples (~200 Hz) occurring during sharp waves are thought to mediate encoding and consolidation, respectively. During sharp wave-ripple complexes (SPW-Rs), hippocampal cell firing closely follows the pattern that took place during the initial experience, most likely reflecting replay of that event. Disrupting hippocampal ripples using electrical stimulation either during training in awake animals or during sleep after training retards spatial learning. Here, adult rabbits were trained in trace eyeblink conditioning, a hippocampus-dependent associative learning task. A bright light was presented to the animals during the inter-trial interval (ITI), when awake, either during SPW-Rs or irrespective of their neural state. Learning was particularly poor when the light was presented following SPW-Rs. While the light did not disrupt the ripple itself, it elicited a theta-band oscillation, a state that does not usually coincide with SPW-Rs. Thus, it seems that consolidation depends on neuronal activity within and beyond the hippocampus taking place immediately after, but by no means limited to, hippocampal SPW-Rs.

Chemotherapy, especially if prolonged, disrupts attention, working memory and speed of processing in humans. Most cancer drugs that cross the blood-brain barrier also decrease adult neurogenesis. Because new neurons are generated in the hippocampus, this decrease may contribute to the deficits in working memory and related thought processes. The neurophysiological mechanisms that underlie these deficits are generally unknown. A possible mediator is hippocampal oscillatory activity within the theta range (3-12 Hz). Theta activity predicts and promotes efficient learning in healthy animals and humans. Here, we hypothesised that chemotherapy disrupts learning via decreases in hippocampal adult neurogenesis and theta activity. Temozolomide was administered to adult male Sprague-Dawley rats in a cyclic manner for several weeks. Treatment was followed by training with different types of eyeblink classical conditioning, a form of associative learning. Chemotherapy reduced both neurogenesis and endogenous theta activity, as well as disrupted learning and related theta-band responses to the conditioned stimulus. The detrimental effects of temozolomide only occurred after several weeks of treatment, and only on a task that requires the association of events across a temporal gap and not during training with temporally overlapping stimuli. Chemotherapy did not disrupt the memory for previously learned associations, a memory independent of (new neurons in) the hippocampus. In conclusion, prolonged systemic chemotherapy is associated with a decrease in hippocampal adult neurogenesis and theta activity that may explain the selective deficits in processes of learning that describe the 'chemobrain'., (© 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.)

Animals in the natural world continuously encounter learning experiences of varying degrees of novelty. New neurons in the hippocampus are especially responsive to learning associations between novel events and more cells survive if a novel and challenging task is learned. One might wonder whether new neurons would be rescued from death upon each new learning experience or whether there is an internal control system that limits the number of cells that are retained as a function of learning. In this experiment, it was hypothesized that learning a task that was similar in content to one already learned previously would not increase cell survival. We further hypothesized that in situations in which the cells are rescued hippocampal theta oscillations (3-12 Hz) would be involved and perhaps necessary for increasing cell survival. Both hypotheses were disproved. Adult male Sprague-Dawley rats were trained on two similar hippocampus-dependent tasks, trace and very-long delay eyeblink conditioning, while recording hippocampal local-field potentials. Cells that were generated after training on the first task were labeled with bromodeoxyuridine and quantified after training on both tasks had ceased. Spontaneous theta activity predicted performance on the first task and the conditioned stimulus induced a theta-band response early in learning the first task. As expected, performance on the first task correlated with performance on the second task. However, theta activity did not increase during training on the second task, even though more cells were present in animals that had learned. Therefore, as long as learning occurs, relatively small changes in the environment are sufficient to increase the number of surviving neurons in the adult hippocampus and they can do so in the absence of an increase in theta activity. In conclusion, these data argue against an upper limit on the number of neurons that can be rescued from death by learning.

Any occasional changes in the acoustic environment are of potential importance for survival. In humans, the preattentive detection of such changes generates the mismatch negativity (MMN) component of event-related brain potentials. MMN is elicited to rare changes ('deviants') in a series of otherwise regularly repeating stimuli ('standards'). Deviant stimuli are detected on the basis of a neural comparison process between the input from the current stimulus and the sensory memory trace of the standard stimuli. It is, however, unclear to what extent animals show a similar comparison process in response to auditory changes. To resolve this issue, epidural potentials were recorded above the primary auditory cortex of urethane-anesthetized rats. In an oddball condition, tone frequency was used to differentiate deviants interspersed randomly among a standard tone. Mismatch responses were observed at 60-100 ms after stimulus onset for frequency increases of 5% and 12.5% but not for similarly descending deviants. The response diminished when the silent inter-stimulus interval was increased from 375 ms to 600 ms for +5% deviants and from 600 ms to 1000 ms for +12.5% deviants. In comparison to the oddball condition the response also diminished in a control condition in which no repetitive standards were presented (equiprobable condition). These findings suggest that the rat mismatch response is similar to the human MMN and indicate that anesthetized rats provide a valuable model for studies of central auditory processing.

There are at least two distinct oscillatory states of the hippocampus that are related to distinct behavioral patterns. Theta (4-12 Hz) oscillation has been suggested to indicate selective attention during which the animal concentrates on some features of the environment while suppressing reactivity to others. In contrast, sharp-wave ripples ( approximately 200 Hz) can be seen in a state in which the hippocampus is at its most responsive to any kind of afferent stimulation. In addition, external stimulation tends to evoke and reset theta oscillation, the phase of which has been shown to modulate synaptic plasticity in the hippocampus. Theoretically, training on a hippocampus-dependent learning task contingent upon ripples could enhance learning rate due to elevated responsiveness and enhanced phase locking of the theta oscillation. We used a brain-computer interface to detect hippocampal ripples in rabbits to deliver trace eyeblink conditioning and extinction trials selectively contingent upon them. A yoked control group was trained regardless of their ongoing neural state. Ripple-contingent training expedited acquisition of the conditioned response early in training and evoked stronger theta-band phase locking to the conditioned stimulus. Surprisingly, ripple-contingent training also resulted in slower extinction in well trained animals. We suggest that the ongoing oscillatory activity in the hippocampus determines the extent to which a stimulus can induce a phase reset of the theta oscillation, which in turn is the determining factor of learning rate in trace eyeblink conditioning.

The relative power of the hippocampal theta-band ( approximately 6 Hz) activity (theta ratio) is thought to reflect a distinct neural state and has been shown to affect learning rate in classical eyeblink conditioning in rabbits. We sought to determine if the theta ratio is mostly related to the detection of the contingency between the stimuli used in conditioning or also to the learning of more complex inhibitory associations when a highly demanding delay discrimination-reversal eyeblink conditioning paradigm is used. A high hippocampal theta ratio was not only associated with a fast increase in conditioned responding in general but also correlated with slow emergence of discriminative responding due to sustained responding to the conditioned stimulus not paired with an unconditioned stimulus. The results indicate that the neural state reflected by the hippocampal theta ratio is specifically linked to forming associations between stimuli rather than to the learning of inhibitory associations needed for successful discrimination. This is in line with the view that the hippocampus is responsible for contingency detection in the early phase of learning in eyeblink conditioning., ((c) 2009 Wiley-Liss, Inc.)

The authors examined the relationship between hippocampal theta activity and trace eyeblink conditioning. Hippocampal electrophysiological local field potentials were recorded before, during, and after conditioning or explicitly unpaired training sessions in adult male New Zealand White rabbits. As expected, a high relative power of theta activity (theta ratio) in the hippocampus predicted faster acquisition of the conditioned response during trace conditioning but, contrary to previous results obtained using the delay paradigm, only in the initial stage of learning. The presentation of the conditioned stimulus overall elicited an increase in the hippocampal theta ratio. The theta ratio decreased in the unpaired group as a function of training, remained high throughout conditioning in the fast learners, and rapidly increased in the slow learners initially showing a low theta ratio. Our results indicate a reciprocal connection between the hippocampal oscillatory activity and associative learning. The hippocampal theta ratio seems to reflect changes and differences in the subjects' alertness and responsiveness to external stimuli, which affect the rate of learning and are, in turn, affected by both conditioning and unpaired training., (Copyright (c) 2009 APA, all rights reserved.)

In 1978, Berry and Thompson showed that the amount of theta (3-8Hz) activity in the spontaneous hippocampal EEG predicted learning rate in subsequent eyeblink conditioning in rabbits. More recently, the absence of theta activity during the training trial has been shown to have a detrimental effect on learning rate. Here, we aimed to further explore the relationship between theta activity and classical eyeblink conditioning by determining how the relative power of hippocampal theta activity [theta/(theta+delta) ratio] changes during both unpaired control and paired training phases. We found that animals with a higher hippocampal theta ratio immediately before conditioning learned faster and also that in these animals the theta ratio was higher throughout both experimental phases. In fact, while the hippocampal theta ratio remained stable in the fast learners as a function of training, it decreased in the slow learners already during unpaired training. In addition, the presence of hippocampal theta activity enhanced the hippocampal model of the conditioned response (CR) and seemed to be beneficial for CR performance in terms of peak latency during conditioning, but did not have any effect when the animals showed asymptotic learning. Together with earlier findings, these results imply that the behavioral state in which hippocampal theta activity is absent is detrimental for learning, and that the behavioral state in which hippocampal theta activity dominates is beneficial for learning, at least before a well-learned state is achieved.