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Memorizing the locations of environmental cues is crucial for survival and depends on the hippocampus. We recorded local field potentials (LFPs) from the hippocampus of freely moving mice during an object location task. The power of beta-band (23-30 Hz) oscillations increased immediately before approaching objects in a memory-encoding phase. The exploration-induced beta oscillations gradually decreased during the memory-encoding session. Mice that exhibited stronger beta oscillation power exhibited better performance in the subsequent memory-retrieval test. These results suggest that beta oscillations in the hippocampal CA1 region are involved in the memory encoding of object-location associations.

Dopaminergic neurons in the ventral tegmental area (VTA) play a crucial role in the processing of reward-related information. Recent studies with pharmacological manipulations of VTA neuronal activity demonstrated a VTA-induced immunoenhancement in peripheral organs. Here, to examine the detailed physiological dynamics, we took an optogenetic approach in which VTA dopaminergic neurons were selectively activated with millisecond precision. Optogenetic phasic, rather than tonic, stimulation of VTA dopaminergic neurons increased serum cytokine levels, such as IL-2, IL-4 and TNF-α. These results provide direct evidence to link dopaminergic neuronal phasic firing to peripheral immunity. Next, we tested whether cytokine induction in male mice was boosted by female encounters, a natural condition that induces increased active VTA neurons and gamma power. Female encounters increased serum IL-2 levels, which were abolished by pharmacological inhibition of VTA neuronal activity. Taken together, our results highlight the importance of the brain reward system in the treatment and management of immune-related disorders.

The brain-gut axis which is an interaction between recognition and emotion and the gut sensory system for food and microbiota is important for health. However, there is no real-time monitoring system of the brain and the gut simultaneously so far. We attempted to establish a dual real-time monitoring system for the brain-gut axis by a combination of intravital Ca2+ imaging of the gut and electroencephalogram. Using a conditional Yellow Cameleon 3.60 expression mouse line, we performed intravital imaging of the gut, electrophysiological recordings of the vagus nerve, and electroencephalogram recordings of the various cortical regions simultaneously upon capsaicin stimuli as a positive control. Upon capsaicin administration into the small intestinal lumen, a simultaneous response of Ca2+ signal in the enteric nervous system and cortical local field potentials (LFPs) was successfully observed. Both of them responded immediately upon capsaicin stimuli. Capsaicin triggered a significant increase in the frequency of vagus nerve spikes and a significant decrease in the slow-wave power of cortical LFPs. Furthermore, capsaicin induced delayed and sustained Ca2+ signal in intestinal epithelial cells and then suppressed intestinal motility. The dual real-time monitoring system of the brain and the gut enables to dissect the interaction between the brain and the gut over time with precision.

SUMMARYThe medial prefrontal cortex and amygdala are involved in the regulation of social behavior and associated with psychiatric diseases but their detailed neurophysiological mechanisms at a network level remain unclear. We recorded local field potentials (LFPs) from the dorsal medial PFC (dmPFC) and basolateral amygdala (BLA) while mice engaged on social behavior. We found that in wild-type mice, both the dmPFC and BLA increased 4–7 Hz oscillation power and decreased 30–60 Hz power when they needed to attend to another target mouse. In mouse models with reduced social interactions, dmPFC 4–7 Hz power further increased especially when they exhibited social avoidance behavior. In contrast, dmPFC and BLA decreased 4–7 Hz power when wild-type mice socially approached a target mouse. Frequency-specific optogenetic manipulations of replicating social approach-related LFP patterns restored social interaction behavior in socially deficient mice. These results demonstrate a neurophysiological substrate of the prefrontal cortex and amygdala related to social behavior and provide a unified pathophysiological understanding of neuronal population dynamics underlying social behavioral deficits.

Senescence affects various aspects of sleep, and it remains unclear how sleep-related neuronal network activity is altered by senescence. Here, we recorded local field potential signals from multiple brain regions covering the forebrain in young (10-week-old) and aged (2-year-old) mice. Interregional LFP correlations across these brain regions showed smaller differences between awake and sleep states in aged mice. Multivariate analyses with machine learning algorithms with uniform manifold approximation and projection (UMAP) and robust continuous clustering (RCC) demonstrated that these LFP correlational patterns in aged mice less represented awake/sleep states than those in young mice. By housing aged mice in an enriched environment, the LFP patterns were restored to those observed in young mice. Our results demonstrate senescence-induced changes in neuronal activity at the network level and provide insight into the prevention of pathological symptoms associated with sleep disturbance in senescence.

Emotional behavior and psychological disorders are expressed through coordinated interactions across multiple brain regions. Brain electrophysiological signals are composed of diverse neuronal oscillations, representing cell-level to region-level neuronal activity patterns, and serve as a biomarker of mental disorders. Here, we review recent observations from rodents demonstrating how neuronal oscillations in the hippocampus, amygdala, and prefrontal cortex are engaged in emotional behavior and altered by psychiatric changes such as anxiety and depression. In particular, we focus mainly on theta-range (4–12 Hz) oscillations, including several distinct oscillations in this frequency range. We then discuss therapeutic possibilities related to controlling such mental disease-related neuronal oscillations to ameliorate psychiatric symptoms and disorders in rodents and humans.

Summary A major challenge in neuroscience is linking synapses to cognition and behavior. Here, we developed an experimental technique to concurrently conduct a whole-cell recording of a prefrontal neuron and a multiunit recording of hippocampal neurons from an awake rat. This protocol includes surgical steps to establish a cranial window and 3D printer-based devices to hold the rat. The data sets allow us to directly compare how subthreshold synaptic transmission is associated with suprathreshold spike patterns of neuronal ensembles. For complete details on the use and execution of this protocol, please refer to Nishimura et al. (2021)., Graphical Abstract, Highlights • A surgical craniotomy is performed on the prefrontal cortex • A microdrive is implanted on the hippocampus • A patch-clamp recording is obtained from a prefrontal neuron • Protocol allows simultaneous multiunit and whole-cell recordings, A major challenge in neuroscience is linking synapses to cognition and behavior. Here, we developed an experimental technique to concurrently conduct a whole-cell recording of a prefrontal neuron and a multiunit recording of hippocampal neurons from an awake rat. This protocol includes surgical steps to establish a cranial window and 3D printer-based devices to hold the rat. The data sets allow us to directly compare how subthreshold synaptic transmission is associated with suprathreshold spike patterns of neuronal ensembles.

The human vesicular monoamine transporter 1 (VMAT1) harbors unique substitutions (Asn136Thr/Ile) that affect monoamine uptake into synaptic vesicles. These substitutions are absent in all known mammals, suggesting their contributions to distinct aspects of human behavior modulated by monoaminergic transmission, such as emotion and cognition. To directly test the impact of these human-specific mutations, we introduced the humanized residues into mouse Vmat1 via CRISPR/Cas9-mediated genome editing and examined changes at the behavioral, neurophysiological and molecular levels. Behavioral tests revealed reduced anxiety-related traits of Vmat1Ile mice, consistent with human studies, and electrophysiological recordings showed altered oscillatory activity in the amygdala under anxiogenic conditions. Transcriptome analyses further identified amygdala-specific changes in the expression of genes involved in neurodevelopment and emotional regulation, which may corroborate the observed phenotypes. This knock-in mouse model hence provides compelling evidence that the mutations affecting monoaminergic signaling and amygdala circuits have contributed to the evolution of human socio-emotional behaviors.

The central nervous system controls the activity states of the peripheral organs in response to various environmental changes. However, the physiological interactions across multiple organs remain largely unknown. Recently, we have developed an electrophysiological recording system that simultaneously captures neuronal population activity patterns in the brain, heartbeat signals, muscle contraction signals, respiratory signals, and vagus nerve action potentials in freely moving rodents. This paper summarizes several recent insights obtained from this recording system, including the observations that some but not all brain activity patterns are associated with peripheral organ activity in a behavioral test, and that functions across cortical networks can predict stress-induced changes in cardiac function in rats. The evidence suggests that adding information on peripheral physiological signals to behavioral data assists in a more accurate estimation of animals' mental states. The concept of such a research approach opens a new field of large-scale analysis of systemic physiological signals, termed "physiolomics," which is expected to unveil further physiological issues involving mind-body associations in health and disease.

The ventromedial prefrontal cortex (vmPFC) plays key roles in higher cognitive abilities, including mental representations and the regulation of emotion. Previous studies have reported that vmPFC activity is altered in depressed human patients, highlighting this subregion as a major site of dysfunction in neuropsychiatric diseases. To examine how neuronal activity at spike levels in the vmPFC is altered by social defeat stress, we performed electrophysiological multiunit recordings along the dorsoventral axis of the mPFC of freely moving mice. Chronic social defeat stress-susceptible mice showing an impairment in social interaction exhibited significant reductions in the overall spike frequencies of neurons in the vmPFC, but not in the dorsal mPFC. Analysis of local field potentials revealed that the vmPFC generated spatially constrained 20–40 Hz events lasting hundreds of milliseconds, with an average event frequency of 0.05 Hz; during these events, a subset of neurons were transiently inhibited. The frequency of 20–40 Hz events in the vmPFC was reduced in defeated stress-susceptible animals, and this decrease was reversed by systemic ketamine administration. The novel neurophysiological correlates of stress-induced changes in the vmPFC advance the understanding of the neural basis of stress-induced dysregulation of social behavior.

Human induced-pluripotent stem cell (hiPSC)-derived neurons develop organized neuronal networks under in vitro cultivation conditions. Here, using a multielectrode array system, we examined whether the spike patterns of hiPSC-derived neuronal populations differed in a manner that depended on the proportions of glutamatergic and gamma-aminobutyric acid (GABA)ergic neurons in the cultures. Synchronous burst firing events spanning multiple electrodes became more frequent as the number of days in culture increased. However, at all developmental stages, the event rates of synchronous burst firing, the repertoires of synchronous burst firing, and the frequencies of sporadic spikes did not differ in cultures with different glutamatergic-to-GABAergic ratios. Pharmacological blockade of GABAergic synaptic transmission increased the frequencies of spike patterns specifically in cultures with lower glutamatergic-to-GABAergic ratios. These results demonstrate that a robust homeostatic property of developing hiPSC-derived neuronal networks in culture counteracts chronically imbalanced glutamatergic and GABAergic signaling.

Bridging accumulating insights from microscopic and macroscopic studies in neuroscience research requires monitoring of neuronal population dynamics and quantifying specific molecules or genes from the brain of identical animals. To this end, by minimizing the size and weight of an electrode array, we developed a method that records local field potential signals of multiple brain regions from one side of the hemisphere in a freely moving rodent. At the same time, extracellular cerebrospinal fluid for biochemical assays or a small part of brain tissue samples for gene expression assays are collected from the other side of the hemisphere. This method allows ongoing stable recordings and sample collections for at least two months. The methodological concept is applicable to a wide range of biological reactions at various spatiotemporal scales, allowing us to integrate an idea of physiolomics into existing omics analyses, leading to a new combination of multi-omics approaches. Keywords: Brain, Local field potential, Neuromodulator, Microdialysis, Genes

Behavioral tests using rodents are widely used for assessing mental states of animals and the effects of pharmacological drugs on psychiatric disorders. However, the results of behavioral tests are sometimes inconsistent due to individual differences. To evaluate animal's mental states based on internal organ activity, we recently developed a new electrophysiological method to simultaneously monitor cortical local field potentials, electrocardiograms, electromyograms, respiratory signals, and vagus nerve spikes in a freely moving rodent. Here, we introduce some results obtained from an elevated plus maze test. Both cortical activity patterns and vagus nerve spike patterns are crucially related to other peripheral organ activity rather than arm types of the maze in which animal were located, which demonstrates that combining behavioral tests with peripheral physiological makers enables a more accurate evaluation of rodent mental states. Moreover, we show that functional connection patterns across cortical regions could be predictive factors accounting for stress susceptibility defined based on the irregularity of heartbeat signals, demonstrating that cortical activity may be a mechanism that causes abnormal activity of peripheral organs in response to mental stress episodes. These observations from our recording technique are a new step for understanding of the neurophysiological correlates of mind-body associations in health and disease.

The vagus nerve serves as a central pathway for communication between the central and peripheral organs. Despite traditional knowledge of vagus nerve functions, detailed neurophysiological dynamics of the vagus nerve in naïve behavior remain to be understood. In this study, we developed a new method to record spiking patterns from the cervical vagus nerve while simultaneously monitoring central and peripheral organ bioelectrical signals in a freely moving rat. When the rats transiently elevated locomotor activity, the frequency of vagus nerve spikes was correspondingly increased, and this activity was retained for several seconds after the increase in running speed terminated. Spike patterns of the vagus nerve were not robustly associated with which arms the animals entered on an elevated plus maze. During sniffing behavior, vagus nerve spikes were nearly absent. During stopping, the vagus nerve spike patterns differed considerably depending on external contexts and peripheral activity states associated with cortical arousal levels. Stimulation of the vagus nerve altered rat's running speed and cortical arousal states depending on running speed at the instant of stimulation. These observations are a new step for uncovering the physiological dynamics of the vagus nerve modulating the visceral organs such as cardiovascular, respiratory, and gastrointestinal systems.

Behavioral and cognitive studies have demonstrated that brain functions are affected by the activity states of the peripheral organs, such as the cardiac and respiratory systems. However, detailed neurophysiological mechanisms underlying the body-brain interactions remain unknown. In this study, we developed a method for manipulating activity levels of the heart using direct cardiac stimulation and vagus nerve stimulation that can be combined with recording cerebral local field potentials using a microdrive system, electrocardiograms, electromyograms, in a freely moving rat. With this method, the electrical stimulation to the heart increases heart rates up to 14 Hz, whereas the vagus nerve stimulation decreases heart rates to 3 Hz. Transient electrical artifacts arising from the peripheral stimulation are not contaminated in cortical local field potential signals low-pass filtered at 150 Hz and distinguishable from extracellular multiunit signals. The technique will contribute to understanding the neurophysiological correlate of mind-body associations in health and disease.

Background Paired associative stimulation (PAS) induces long-term potentiation (LTP)-like effects when interstimulus intervals (ISIs) between electrical peripheral nerve stimulation and transcranial magnetic stimulation (TMS) to M1 are approximately 21–25 ms (PASLTP). It was previously reported that two forms of motor learning (i.e., mode-free and model-based learning) can be differentially modulated by PASLTP depending on the different synaptic inputs to corticospinal neurons (CSNs), which relate to posterior-to-anterior (PA) or anterior-to-posterior (AP) currents induced by TMS (PA or AP inputs, respectively). However, the effects of long-term depression (LTD)-inducing PAS with an ISI of approximately 10 ms (PASLTD) on motor learning and its dependency on current direction have not yet been tested. Objective To investigate whether, and how, PASLTD affects distinct types of motor learning. Methods Eighteen healthy volunteers participated. We adopted the standard PAS using suprathreshold TMS with the target muscle relaxed, as well as subthreshold PAS during voluntary contraction, which was suggested to selectively recruit PA or AP inputs depending on the orientation of the TMS coil. We examined the effects of suprathreshold and subthreshold PASLTD on the performance of model-free and model-based learning, as well as the corticospinal excitability, indexed as the amplitudes of motor evoked potentials (MEPs). Results PASLTD inhibited model-free learning and MEPs only when subthreshold AP currents were applied. The PASLTD protocols tested here showed no effects on model-based learning. Conclusions PASLTD affected model-free learning, presumably by modulating CSN excitability changes, rather than PA inputs, which are thought to be related to model-free learning.

Objective Deep brain stimulation (DBS) can provide insights into the workings of the basal ganglia (BG) by interfering with their function. In patients with Parkinson's disease (PD) treated with DBS of the subthalamic nucleus, we studied the effect of DBS on scanning eye movements. Methods In the visual memory task, subjects viewed images of various complexities for later recall. In visual search tasks, subjects looked for and fixated one odd target ring, embedded among 48 Landolt rings, which either stood out or not from the distractors. We compared the parameters of scanning saccades when DBS was on and off. Results In the visual memory task, DBS increased the amplitude of saccades scanning simple but not complex drawings. In the visual search tasks, DBS showed no effect on saccade amplitude or frequency. Conclusions Saccades when viewing simple images were affected by DBS since they are internally guided saccades, for which the involvement of BG is large. In contrast, saccades when viewing complex images or during visual search, made with the help of visual cues in the images (externally guided saccades) and less dependent on BG, were resistant to the effect of DBS. Significance DBS affects saccades differentially depending on the task.

The olfactory piriform cortex (PC) is thought to participate in olfactory associative memory. Like the hippocampus, which is essential for episodic memory, it belongs to an evolutionally conserved paleocortex and comprises a three-layered cortical structure. During slow-wave sleep, the olfactory PC becomes less responsive to external odor stimuli and instead displays sharp wave (SPW) activity similar to that observed in the hippocampus. Neural activity patterns during hippocampal SPW have been intensively studied in terms of memory consolidation; however, little is known about the activity patterns of olfactory cortical neurons during olfactory cortex sharp waves (OC-SPWs). In this study, we recorded multi-unit neural activities in the anterior PC in urethane-anesthetized mice. We found that the activity patterns of olfactory cortical neurons during OC-SPWs were non-randomly organized. Individual olfactory cortical neurons varied in the timings of their peak firing rates during OC-SPW events. Moreover, specific pairs of olfactory cortical neurons were more frequently activated together than expected by chance. On the basis of these observations, we speculate that coordinated activation of specific subsets of olfactory cortical neurons repeats during OC-SPWs, thereby facilitating synaptic plasticity underlying the consolidation of olfactory associative memories.

The vagus nerve plays a pivotal role in communication between the brain and peripheral organs involved in the sensory detection and the autonomic control of visceral activity. While the lack of appropriate experimental techniques to manipulate the physiological activity of the vagus nerve has been a long-standing problem, recent advancements in optogenetic tools, including viral vectors and photostimulation devices, during the late 2010s have begun to overcome this technical hurdle. Furthermore, identifying promoters for expressing transgenes in a cell-type-specific subpopulation of vagal neurons enables the selective photoactivation of afferent/efferent vagal neurons and specific visceral organ-innervating vagal neurons. In this chapter, we describe recent optogenetic approaches to study vagus nerve physiology and describe how these approaches have provided novel findings on the roles of vagus nerve signals in the cardiac, respiratory, and gastrointestinal systems. Compared with studies of the central nervous system, there are still few insights into vagus nerve physiology. Further studies with optogenetic tools will be useful for understanding the fundamental characteristics of vagus nerve signals transferred throughout the body.

Significance The hippocampus is crucial for spatial learning but their neuronal mechanisms remain unknown. Here, we found that hippocampal cell ensembles preferentially replayed salient reward-related locations as rats learned a new behavioral trajectory for reward. The contents of these hippocampal replays progressively varied with learning. Especially during learning, hippocampal neurons even replayed an optimized path that had never been exploited by the animals. The learning-related hippocampal activity was necessary for the stabilization of spatial behavior. These results suggest prioritized replays of significant experiences on a predictive map by hippocampal neurons., Hippocampal cells are central to spatial and predictive representations, and experience replays by place cells are crucial for learning and memory. Nonetheless, how hippocampal replay patterns dynamically change during the learning process remains to be elucidated. Here, we designed a spatial task in which rats learned a new behavioral trajectory for reward. We found that as rats updated their behavioral strategies for a novel salient location, hippocampal cell ensembles increased theta-sequences and sharp wave ripple-associated synchronous spikes that preferentially replayed salient locations and reward-related contexts in reverse order. The directionality and contents of the replays progressively varied with learning, including an optimized path that had never been exploited by the animals, suggesting prioritized replays of significant experiences on a predictive map. Online feedback blockade of sharp wave ripples during a learning process inhibited stabilizing optimized behavior. These results implicate learning-associated experience replays that act to learn and reinforce specific behavioral strategies.

Acute alcohol exposure impairs hippocampus-dependent spatial memory. However, there is little evidence for the effects of ethanol on the spike patterns of hippocampal cell populations. Here, we examined how the spatial firing patterns of place cells, neurons that encode specific locations, were altered in rats that were intraperitoneally injected with 1.5 g/kg ethanol. Ethanol administration partly reduced or abolished place-selective spiking of a subset of place cells during running periods in a spatial task, whereas a subset of place fields newly emerged, suggesting a partial reorganization of hippocampal spatial maps by ethanol. On the other hand, ethanol administration did not significantly alter the frequency of hippocampal sharp-wave ripple (SWRs) and synchronous spike patterns during resting periods, suggesting that offline memory consolidation and retrieval mechanisms underpinned by hippocampal neuronal synchronization are not strongly affected by ethanol. These results indicate that acute ethanol intake mainly affects the encoding of external information but has little impact on internal memory processing.

Summary: Cooperative reactivation of hippocampal and prefrontal neurons is considered crucial for mnemonic processes. To directly record synaptic substances supporting the interregional interactions, we develop concurrent spike recordings of hippocampal neuronal ensembles and whole-cell patch-clamp recordings of medial prefrontal neurons in awake rats. We find that medial prefrontal neurons depolarize when hippocampal neurons synchronize. The depolarization in medial prefrontal neurons is larger when hippocampal place cells that encoded overlapping place fields and place cells that encoded a novel environment are synchronously reactivated. Our results suggest a functional circuit-synapse association that enables prefrontal neurons to read out specific memory traces from the hippocampus.

Urethane, an anesthetic utilized for animal experiments, induces neocortical slow oscillations in which a large number of neurons emit rhythmic synchronized activity. However, it remains unclear how urethane affects neuronal activity in the hippocampus. In this study, we obtained in vivo patch-clamp recordings from dorsal hippocampal CA1 neurons in mice and found a reduction in the fluctuation of subthreshold membrane potentials during urethane anesthesia, implying reduced synaptic activity in the hippocampus. We then performed spike unit recordings from dorsal hippocampal CA1 neuronal ensembles in rats and found prominent reductions in the spike rates of the majority of hippocampal units, especially spatially selective units, during urethane anesthesia, whereas a subset of nonspatial units exhibited increased spike rates. The overall reductions in neuronal spike rates induced by urethane led to prominent decreases in spike synchronization across neuronal units. Consistently, the magnitude of hippocampal sharp wave ripples was also reduced by urethane. The suppression of hippocampal neuronal synchronization by urethane may lead to the disruption of offline memory reactivation mechanisms.

Rebalancing mechanisms during sleep Synapses are often strengthened during wake periods and thus need to be homeostatically readjusted during sleep. During slow-wave sleep, synaptic depression is dominant. Sharp wave and ripple events are transient high-frequency field oscillations that occur spontaneously during slow-wave sleep in the brain. Norimoto et al. found that these events induced long-term depression of hippocampal synapses and may thus help to refine recently acquired memories (see the Perspective by Draguhn). Science , this issue p. 1524 ; see also p. 1461

Animals process temporal information in an ever-changing environment, but the neuronal mechanisms of this process, especially on timescales longer than seconds, remain unresolved. Here, we designed a hippocampus-dependent task in which rats prospectively increased their reward-seeking behavior over a duration of minutes. During this timing behavior, hippocampal and striatal neurons represented successive time points on the order of minutes by gradually changing their firing rates and transiently increasing their firing rates at specific time points. These minute-encoding patterns progressively developed as the rats learned a time-reward relationship, and the patterns underwent flexible scaling in parallel with timing behavior. These observations suggest a neuronal basis in the hippocampal-striatal circuits that enables temporal processing and formation of episodic memory on a timescale of minutes.

Mental stress-induced biological responses considerably differ across animals, which may be explained by intrinsic brain activity patterns. To address this hypothesis, we recorded local field potential signals from six cortical areas, electrocardiograms, and electromyograms from freely moving rats. Based on their stress-induced changes in cardiac signals, individual defeated rats were classified into stress susceptible and resilient groups. Rats with lower correlations in theta power across wide ranges of cortical regions before the stress challenge had higher probability to be stress-susceptible rats as defined based on the irregularity of heartbeat signals. A combination of principal component analysis and the support vector machine algorithm revealed that functional connections across cortical regions could be predictive factors accounting for individual differences in future stress susceptibility. These results suggest that individual differences in cortical activity may be a mechanism that causes abnormal activity of peripheral organs in response to mental stress episodes. This evidence will advance the understanding of the neurophysiological correlates of mind-body associations during mental stress exposure.

The transplantation of human-induced pluripotent stem cell (hiPSC)-derived cells has emerged as a potential clinical approach for the treatment of brain diseases. Recent studies with animal disease models have shown that hiPSC-derived neurons transplanted into the brain, especially the nigrostriatal area, could restore degenerated brain functions. Further works are required to test whether hiPSC-derived neurons can also gain functional properties for other cortical areas. In this study, hiPSC-derived neurospheres were transplanted into the adult mouse hippocampus and sensory cortex. Most transplanted hiPSC-derived neurons expressed both Nestin and NeuN at 7 weeks after transplantation. Whole-cell patch-clamp recordings from brain slices indicated that transplanted cells showed no action potentials upon current injection and few small inward currents, indicating that hiPSC-derived neurons did not become functionally mature within these time periods.

We present a new technique for the simultaneous capture of bioelectrical time signals from the brain and peripheral organs of freely moving rodents. The recording system integrates all systemic signals into an electrical interface board that is mounted on an animal's head for an extended period. The interface board accommodates up to 48 channels, enabling us to analyze neuronal activity patterns in multiple brain regions by comparing a variety of physiological body states over weeks and months. This technique will advance the understanding of the neurophysiological correlate of mind–body associations in health and disease.

Current research on stress pathology has revealed a set of molecular and cellular mechanisms through which psychosocial stress impairs brain function. However, there are few studies that have examined how chronic stress exposure alters neuronal activity patterns at a network level. Here, we recorded ensemble neuronal activity patterns of the cortico-hippocampal network from urethane-anesthetized mice that were subjected to repeated social defeat stress. In socially defeated mice, the magnitudes of local field potential signals, including theta, slow gamma, and fast gamma oscillations, were significantly reduced in the dentate gyrus, whereas they remained unchanged in the hippocampus and somatosensory cortex. In accordance with the vast majority of histological and biochemical studies, our evidence from electrophysiological investigations highlights the dentate gyrus as a key brain area that is primarily susceptible to stress-induced dysfunction.

Neuronal activity is highly sensitive to changes in oxygen tension. In this study, we examined the impact of hypoxic/ischemic conditions on neuronal ensemble activity patterns in the mouse brain using in vivo extracellular electrophysiological recordings from up to 8 sites in the thalamus, dorsal hippocampus, and neocortex, while cerebral hypoperfusion was induced by unilateral carotid artery occlusion. After a few minutes, the occlusion triggered a rapid change in the power of the local field oscillations. In the hippocampus, but not in the neocortex, the absolute power changes at all frequency ranges (relative to the baseline) became less pronounced with time, and no significant changes were observed 30min after the occlusion-induced hypoperfusion. We also tested whether continuous hypoperfusion induced by the occlusion for up to 1 week alters neuronal activity. In the hippocampus and the thalamus, the chronic occlusion did not lead to a reduction in the power of the local field oscillations. These results indicate that certain neuronal populations have the ability to maintain internal neurophysiological homeostasis against continuous hypoperfusion.

Astrocytes generate calcium signals throughout their fine processes, which are assumed to locally regulate neighbouring neurotransmission and blood flow. The intercellular morphological relationships mature during juvenile periods when astrocytes elongate highly ramified processes. In this study, we examined developmental changes in calcium activity patterns of single hippocampal astrocytes using a transgenic mouse line in which astrocytes selectively express a genetically encoded calcium indicator, Yellow Cameleon-Nano50. Compared with postnatal day 7, astrocytes at postnatal day 30 showed larger subcellular calcium events and a greater proportion of somatic events. At both ages, the calcium activity was abolished by removal of extracellular calcium ions. Calcium events in late juvenile astrocytes were not affected by spontaneously occurring sharp waves that trigger synchronized neuronal spikes, implying the independence of astrocyte calcium signals from neuronal synchronization. These results demonstrate that astrocytes undergo dynamic changes in their activity patterns during juvenile development.

The olfactory piriform cortex is thought to participate in olfactory associative memory. Like the hippocampus, which is essential for episodic memory, it belongs to an evolutionally conserved paleocortex and comprises a three-layered cortical structure. During slow-wave sleep, the olfactory piriform cortex becomes less responsive to external odor stimuli and instead displays sharp wave (SPW) activity similar to that observed in the hippocampus. Neural activity patterns during hippocampal SPW have been intensively studied in terms of memory consolidation; however, little is known about the activity patterns of olfactory cortical neurons during olfactory cortex sharp waves (OC-SPWs). In this study, we recorded multi-unit neural activities in the anterior piriform cortex in urethane-anesthetized mice. We found that the activity patterns of olfactory cortical neurons during OC-SPWs were non-randomly organized. Individual olfactory cortical neurons varied in the timings of their peak firing rates during OC-SPW events. Moreover, specific pairs of olfactory cortical neurons were more frequently activated together than expected by chance. On the basis of these observations, we speculate that coordinated activation of specific subsets of olfactory cortical neurons repeats during OC-SPWs, thereby facilitating synaptic plasticity underlying the consolidation of olfactory associative memories.

The hippocampal network generates synchronized spikes of a large population of pyramidal neurons associated with sharp-wave ripples in local field potential signals. Ample evidence demonstrates that the synchronized spikes are created by sequential activation of hippocampal place cells that correspond to the animal's past or future trajectories and are hypothesized to play instrumental roles in mnemonic functions. However, not all place-cell spike sequences are precisely organized, and some sequences are composed of spikes from non-spatial cells, implying that not all hippocampal synchronized events directly replicate learned behavioral episodes. While less attention has been given to such non-ordered spike sequences, variable and dynamic selection of active neuronal assemblies may be optimal mechanisms for rapidly reorganizing functional circuits and self-developing novel representations to enable flexible decision-making processes. We recently showed that specific neurons, including both spatial and non-spatial cells, are preferentially recruited in synchronous events for particular time periods, suggesting that there are temporally fluctuating background states of the hippocampal network that determine active neuronal ensembles. Based on recent reports, this review discusses potential roles of the low-fidelity, heterogeneous repertoire of synchronized spike sequences of hippocampal neurons.

Elevated plus maze (EPM) tests have been used to assess animal anxiety levels. Little information is known regarding how physiological activity patterns of the brain-body system are altered during EPM tests. Herein, we monitored cortical local field potentials (LFPs), electrocardiograms (ECGs), electromyograms (EMGs), and respiratory signals in individual mice that were repeatedly exposed to EPM tests. On average, mouse heart rates were higher in open arms. In closed arms, the mice occasionally showed decreased heart and respiratory rates lasting for several seconds or minutes, characterized as low-peripheral activity states of peripheral signals. The low-activity states were observed only when the animals were in closed arms, and the frequencies of the states increased as the testing days proceeded. During the low-activity states, the delta and theta powers of cortical LFPs were significantly increased and decreased, respectively. These results demonstrate that cortical oscillations crucially depend on whether an animal exhibits low-activity states in peripheral organs rather than the EPM arm in which the animal is located. These results suggest that combining behavioral tests with physiological makers enables a more accurate evaluation of rodent mental states.

Monitoring the physiological dynamics of the brain and peripheral tissues is necessary for addressing a number of questions about how the brain controls body functions and internal organ rhythms when animals are exposed to emotional challenges and changes in their living environments. In general experiments, signals from different organs, such as the brain and the heart, are recorded by independent recording systems that require multiple recording devices and different procedures for processing the data files. This study describes a new method that can simultaneously monitor electrical biosignals, including tens of local field potentials in multiple brain regions, electrocardiograms that represent the cardiac rhythm, electromyograms that represent awake/sleep-related muscle contraction, and breathing signals, in a freely moving rat. The recording configuration of this method is based on a conventional micro-drive array for cortical local field potential recordings in which tens of electrodes are accommodated, and the signals obtained from these electrodes are integrated into a single electrical board mounted on the animal's head. Here, this recording system was improved so that signals from the peripheral organs are also transferred to an electrical interface board. In a single surgery, electrodes are first separately implanted into the appropriate body parts and the target brain areas. The open ends of all of these electrodes are then soldered to individual channels of the electrical board above the animal's head so that all of the signals can be integrated into the single electrical board. Connecting this board to a recording device allows for the collection of all of the signals into a single device, which reduces experimental costs and simplifies data processing, because all data can be handled in the same data file. This technique will aid the understanding of the neurophysiological correlates of the associations between central and peripheral organs.

The hippocampus contains place cells representing spaces in an environment, and these place cells have been suggested to play a fundamental role in the formation of a cognitive map for spatial processing. However, how alterations in the firing patterns of place cells in response to aversive events encode the locations tied to these aversive events is unknown. Here, we analyzed spiking patterns of place cell ensembles in the dorsal hippocampal CA1 region of rats performing a T-maze alternation task with an aversive air-puff stimulation applied at a specific location on one side of a trajectory. The intensity of the air puff was adjusted so that the rats decreased their running speed before passing the aversive location. The addition of the aversive stimulus induced reorganization of place cell ensembles on both left and right trajectories with and without the aversive stimulus, respectively. Specifically, the animals showed a more abundant spatial representation in the vicinity of the aversive location. Removing the aversive stimulus induced new spatial firing patterns on both of the trajectories that differed from those both before and during application of the aversive stimulus. These results demonstrate that hippocampal spatial maps are flexibly reorganized to represent particular aversive events.

The large capacity of episodic memory is thought to be supported by the emergence of distinct hippocampal cell assemblies for unrelated memories, such that interference is minimized. In large-scale population recordings, the orthogonal nature of hippocampal representations across environments is evident in the complete reorganization of the firing locations of hippocampal place cells. Entorhinal grid cells provide inputs to the hippocampus, and their firing patterns shift relative to each other across different environments. Although this suggests that altered grid cell firing could generate distinct hippocampal population codes, it has recently been shown that new and distinct hippocampal place fields emerge while grid cell firing is compromised. We therefore propose that separate circuits within the medial entorhinal cortex are specialized for performing either spatial or memory-related computations.

Spike rates of a hippocampal place cell are not constant and vary even when an animal visits an identical place field with nearly identical behavior. As one potential neurophysiological source underlying place cell spiking variability, we focused on the temporally fluctuating activity states of neuronal ensembles. Spike patterns of hippocampal neurons were recorded from rats performing a linear track task. Within a single consummatory period, similar sets of neurons were more frequently recruited in synchronous firing events, whereas different synchronized firing patterns of neuronal populations tended to be identified in different consummatory periods. A linear regression analysis indicated that the time-varying activation patterns of neuronal populations during consummatory periods are correlated with the spike rates of a place cell within its place field during running. These findings suggest that place cell in-field spiking is not only triggered by static inputs that represent external environments but also strongly depends on the time-varying internal states of neuronal populations.

Complex spatial working memory tasks have been shown to require both hippocampal sharp-wave ripple (SWR) activity and dentate gyrus (DG) neuronal activity. We therefore asked whether DG inputs to CA3 contribute to spatial working memory by promoting SWR generation. Recordings from DG and CA3 while rats performed a dentate-dependent working memory task on an eight-arm radial maze revealed that the activity of dentate neurons and the incidence rate of SWRs both increased during reward consumption. We then found reduced reward-related CA3 SWR generation without direct input from dentate granule neurons. Furthermore, CA3 cells with place fields in not-yet-visited arms preferentially fired during SWRs at reward locations, and these prospective CA3 firing patterns were more pronounced for correct trials and were dentate-dependent. These results indicate that coordination of CA3 neuronal activity patterns by DG is necessary for the generation of neuronal firing patterns that support goal-directed behavior and memory. Fil: Sasaki, Takuya. University of California at San Diego; Estados Unidos. The University of Tokyo; Japón. Japan Science and Technology Agency; Japón Fil: Piatti, Veronica del Carmen. University of California at San Diego; Estados Unidos Fil: Hwaun, Ernie. University of California at San Diego; Estados Unidos Fil: Ahmadi, Siavash. University of California at San Diego; Estados Unidos Fil: Lisman, John E.. Brandeis University; Estados Unidos Fil: Leutgeb, Stefan. University of California at San Diego; Estados Unidos Fil: Leutgeb, Jill K.. University of California at San Diego; Estados Unidos