Task-dependent effects of intracranial hippocampal stimulation on human memory and hippocampal theta power

BackgroundDespite its potential to revolutionize the treatment of memory dysfunction, the efficacy of direct electrical hippocampal stimulation for memory performance has not yet been well characterized. One of the main challenges to cross-study comparison in this area of research is the diversity of the cognitive tasks used to measure memory performance.ObjectiveWe hypothesized that the tasks that differentially engage the hippocampus may be differentially influenced by hippocampal stimulation and the behavioral effects would be related to the underlying hippocampal activity.MethodsTo investigate this issue, we recorded intracranial EEG from and directly applied stimulation to the hippocampus of 10 epilepsy patients while they performed two different verbal memory tasks – a word pair associative memory task and a single item memory task.ResultsHippocampal stimulation modulated memory performance in a task-dependent manner, improving associative memory performance, while impairing item memory performance. In addition, subjects with poorer baseline cognitive function improved much more with stimulation. iEEG recordings from the hippocampus during non-stimulation encoding blocks revealed that the associative memory task elicited stronger theta oscillations than did item memory and that stronger theta power was related to memory performance.ConclusionsWe show here for the first time that stimulation-induced associative memory enhancement was linked to increased theta power during retrieval. These results suggest that hippocampal stimulation enhances associative memory but not item memory because it engages more hippocampal theta activity and that, in general, increasing hippocampal theta may provide a neural mechanism for successful memory enhancement.     

Anterior thalamic stimulation improves working memory precision judgments

BackgroundThe anterior nucleus of thalamus (ANT) has been suggested as an extended hippocampal system. The circuit of ANT and hippocampus has been widely demonstrated to be associated with memory function. Both lesions to each region and disrupting inter-regional information flow can induce working memory impairment. However, the role of this circuit in working memory precision remains unknown.ObjectiveTo test the role of the hippocampal-anterior thalamic pathway in working memory precision, we delivered intracranially electrical stimulation to the ANT. We hypothesize that ANT stimulation can improve working memory precision.MethodsPresurgical epilepsy patients with depth electrodes in ANT and hippocampus were recruited to perform a color-recall working memory task. Participants were instructed to point out the color they were supposed to recall by clicking a point on the color wheel, while the intracranial EEG data were synchronously recorded. For randomly selected half trials, a bipolar electrical stimulation was delivered to the ANT electrodes.ResultsWe found that compared to non-stimulation trials, working memory precision judgements were significantly improved for stimulation trials. ANT electrical stimulation significantly increased spectral power of gamma (30–100 Hz) oscillations and decreased interictal epileptiform discharges (IED) in the hippocampus. Moreover, the increased gamma power during the pre-stimulus and retrieval period predicted the improvement of working memory precision judgements.ConclusionANT electrical stimulation can improve working memory precision judgements and modulate hippocampal gamma activity, providing direct evidence on the role of the human hippocampal-anterior thalamic axis in working memory precision.     

Corticosterone and corticotropin‐releasing factor acutely facilitate gamma oscillations in the hippocampus in vitro

Stressful experiences do not only cause peripheral changes in stress hormone levels, but also affect central structures such as the hippocampus, implicated in spatial orientation, stress evaluation, and learning and memory. It has been suggested that formation of memory traces is dependent on hippocampal gamma oscillations observed during alert behaviour and rapid eye movement sleep. Furthermore, during quiescent behaviour, sharp wave‐ripple (SW‐R) activity emerges. These events provide a temporal window during which reactivation of memory ensembles occur. We hypothesized that stress‐responsive modulators, such as corticosterone (CORT), corticotropin‐releasing factor (CRF) and the neurosteroid 3α, 21‐dihydroxy‐5α‐pregnan‐20‐one (THDOC) are able to modulate gamma oscillations and SW‐Rs. Using in vitro hippocampal slices, we studied acute and subacute (2 h) impact of these agents on gamma oscillations in area cornu ammonis 3 of the ventral hippocampus induced by acetylcholine (10 μm ) combined with physostigmine (2 μm ). CORT increased the gamma oscillations in a dose‐dependent fashion. This effect was mediated by glucocorticoid receptors. Likewise, CRF augmented gamma oscillations via CRF type 1 receptor. Lastly, THDOC was found to diminish cholinergic gamma oscillations in a dose‐dependent manner. Neither CORT, CRF nor THDOC modulated gamma power when pre‐applied for 1 h, 2 h before the induction of gamma oscillations. Interestingly, stress‐related neuromodulators had rather mild effects on spontaneous SW‐R compared with their effects on gamma oscillations. These data suggest that the alteration of hippocampal gamma oscillation strength in vitro by stress‐related agents is an acute process, permitting fast adaptation to new attention‐requiring situations in vivo.     

Hippocampal intracerebral evoked potentials as a marker of its functionality in drug-resistant epilepsy

ObjectivesTo assess hippocampal function during stereoelectroencephalography (SEEG) investigations through the study of the medial temporal lobe event-related potential (ERP) MTL-P300.MethodsWe recorded the MTL-P300 during a visual oddball task, using hippocampal electrodes implanted for SEEG in 71 patients, in a preoperative epilepsy investigation. The presence of an MTL-P300 and its amplitude were correlated with hippocampal involvement during seizures and memory function.ResultsAnalysis using ROC curves revealed that an MTL-P300 amplitude below -46 µV, has a specificity of 93.3% in detecting the epileptogenic zone, and absence of the MTL-P300 in the left hippocampus of patients with typical language organization was associated with marked alteration of verbal memory scores. There was a significant correlation between performance in non-verbal memory tests and the amplitude of the MTL-P300 in the right hippocampus of patients with left hemispheric seizures (immediate visual recall: r = 0.67, p = 0.005; delayed visual recall: r = 0.56, p = 0.025). Using a linear regression, we confirmed that the absence of the MTL-P300 in the left hippocampus, the involvement of the left hippocampus during seizures, and the duration of epilepsy were predictors of verbal memory deficits.ConclusionAnalysis of the MTL-P300 during SEEG recording provides relevant information for the analysis of hippocampal functionality and can help to localize the epileptogenic zone.     

Activation of immobility-related hippocampal theta by cholinergic septohippocampal neurons during vestibular stimulation

The vestibular system has been suggested to participate in spatial navigation, a function ascribed to the hippocampus. Vestibular stimulation during spatial navigation activates a hippocampal theta rhythm (4-10 Hz), which may enhance spatial processing and motor response. We hypothesize that a cholinergic, atropine-sensitive theta is generated during passive whole-body rotation in freely behaving rats. Hippocampal EEGs were recorded by implanted electrodes in CA1 while rats were rotated on a vertical axis, for a minute or longer, at different angular velocities. Rotation induced a continuous hippocampal theta rhythm while the rat was immobile, in both light and dark conditions. Theta peak frequency showed a significant increase during high (50-70 rpm) as compared with a lower (20-49 rpm) rotational velocity. Rotation-induced theta was abolished by muscarinic receptor antagonist atropine sulfate (50 mg/kg i.p.) but not by atropine methyl nitrate (50 mg/kg i.p.), which did not pass the blood-brain barrier. Theta was attenuated in rats in which cholinergic neurons in the medial septum (MS) were lesioned with 192 IgG-saporin (0.14 μg in 0.4 μl), as confirmed by depletion of MS cells immunoreactive to choline acetyltransferase and an absence of acetylcholinesterase staining in the hippocampus. Bilateral lesion of the vestibular receptors by sodium arsanilate (30 mg in 0.1 ml, intratympanically) also attenuated the rotation-induced theta rhythm. In intact rats, field excitatory postsynaptic potentials (fEPSPs) in CA1 evoked by commissural stimulation were smaller during walking or rotation as compared with during immobility. Modulation of fEPSP was absent following atropine sulfate in intact rats and in 192 IgG-saporin lesion rats. In summary, this is the first report of a continuous atropine-sensitive hippocampal theta in the rat induced by vestibular stimulation during rotation, and accompanied by cholinergic modulation of hippocampal synaptic transmission. Vestibular-activated septohippocampal cholinergic activity could be an important component in sensorimotor processing and spatial memory.     

Disruption of ripple‐associated hippocampal activity during rest impairs spatial learning in the rat

The hippocampus plays a key role in the acquisition of new memories for places and events. Evidence suggests that the consolidation of these memories is enhanced during sleep. At the neuronal level, reactivation of awake experience in the hippocampus during sharp‐wave ripple events, characteristic of slow‐wave sleep, has been proposed as a neural mechanism for sleep‐dependent memory consolidation. However, a causal relation between sleep reactivation and memory consolidation has not been established. Here we show that disrupting neuronal activity during ripple events impairs spatial learning. We trained rats daily in two identical spatial navigation tasks followed each by a 1‐hour rest period. After one of the tasks, stimulation of hippocampal afferents selectively disrupted neuronal activity associated with ripple events without changing the sleep‐wake structure. Rats learned the control task significantly faster than the task followed by rest stimulation, indicating that interfering with hippocampal processing during sleep led to decreased learning. © 2009 Wiley‐Liss, Inc.     

The form and function of hippocampal context representations

Context is an essential component of learning and memory processes, and the hippocampus is critical for encoding contextual information. However, connecting hippocampal physiology with its role in context and memory has only recently become possible. It is now clear that contexts are represented by coherent ensembles of hippocampal neurons and new optogenetic stimulation studies indicate that activity in these ensembles can trigger the retrieval of context appropriate memories. We interpret these findings in the light of recent evidence that the hippocampus is critically involved in using contextual information to prevent interference, and propose a theoretical framework for understanding contextual influence on memory retrieval. When a new context is encountered, a unique hippocampal ensemble is recruited to represent it. Memories for events that occur in the context become associated with the hippocampal representation. Revisiting the context causes the hippocampal context code to be re-expressed and the relevant memories are primed. As a result, retrieval of appropriate memories is enhanced and interference from memories belonging to other contexts is minimized.     

Physostigmine reverses memory deficits produced by pretraining electrical stimulation of the dorsal hippocampus in mice

The aim of the present experiments was to test the validity of the hypothesis that presynaptic cholinergic activity has a functional significance for memory formation. The results show that electrical stimulation of the dorsal hippocampus delivered before learning in BALB/c mice which induces a decrease of about 40% in hippocampal choline acetyltransferase (ChAT) activity at the time of learning results in deficits in retention scores in two appetitive learning tasks (operant conditioning in the Skinner box or a spatial memory task using a 4-hole board). In both behavioral tasks intraventricular injection of 1 microgram of physostigmine 20 min before the acquisition session reverses the disruptive effect of pretraining hippocampal stimulation. Our results seem to indicate that the memory deficits produced by pretraining electrical stimulation of the hippocampus result from both a decrease in ChAT activity and a corresponding reduction of acetylcholine availability in the hippocampal formation.     

Neuronal responses to focused ultrasound are gated by pre-stimulation brain rhythms

BackgroundOwing to its high spatial resolution and penetration depth, transcranial focused ultrasound stimulation (tFUS) is one of the most promising approaches to non-invasive neuromodulation. Identifying the impact of endogenous neural activity on neuromodulation outcome is critical to harnessing the potential of tFUS.ObjectiveHere we sought to identify the relationship between pre-stimulation neural activity and the neuronal response to tFUS.MethodsWe applied 3 min of continuous-wave tFUS to the hippocampal region of the rat while recording local field potentials (LFP) and multi-unit activity (MUA) from the target. We also tested the application of tFUS but with an air gap separating the transducer and the skull, as well as active stimulation of the contralateral olfactory bulb.ResultsWe observed a modest but significant increase in firing rate during hippocampal tFUS, but not during stimulation of the olfactory bulb or when an air gap was present. Importantly, the observed firing rate increase was significantly modulated by the power of baseline oscillations in the LFP, with low levels of delta (1–3 Hz) and high levels of theta (4–10 Hz) and gamma (30–250 Hz) power producing significantly larger firing rate increases. Firing rate increases were also amplified by a factor of 7× when stimulation was applied during periods of frequent sharp-wave ripple (SWR) activity.ConclusionOur findings suggest that baseline brain rhythms may effectively “gate” the response to tFUS.     

Repeated neonatal Needle-pricking stimulation alter neurodevelopment in adolescent rats

ObjectiveTo explore the repeated pain stimulation in neonatal rats affects their cognitive and memory abilities during puberty, and the proliferation expression of hippocampal neurons.MethodsPostnatal 1 day (P1) SD rats were randomly divided into two groups, and the skin of the needle group was pricked for seven days consecutively while the skin of the control group was stroked for the same period of time. The rats in both groups were weighed every week, and the Morris water maze experiment was performed from P44 to P49 to test the cognitive and memory abilities of the rats. On P50, the hippocampal tissue was extracted for observation of pathological features and the expressions of Ki-67 and caspase 3 were determined.ResultsWith the increase of the days, the body weight of the rats in the needle group increased slightly slower than that of the control group. The escape latency of the needle group was significantly higher than that of the control group in the water maze test at P45 and P48, and the number of times the rats crossing the platform in the needle group was lower than that of the control group. The HE staining of the hippocampal tissue showed that the cells in the needle group were disorganized, with irregular morphology. Under the electron microscope, the structure of neuron cells and organelles is changed in the hippocampal CA1 region of rats. It showed a decrease in the Ki-67 expression and an increase in caspase 3 in the needle group.ConclusionRepeated experience of needle-pricking stimulation in neonatal rats can cause cognitive impairment and memory loss in puberty, disrupt hippocampal organization, and diminish neuronal proliferation.     

A potential entanglement between the spinal cord and hippocampus: Theta rhythm correlates with neurogenesis deficiency following spinal cord injury in male rats

Cognitive deficits due to spinal cord injury (SCI) have been elucidated in both animals and humans with SCI. Such disorders may cause concomitant oscillatory changes in regions of the brain involving in cognition; a subject that has not been directed mechanistically. One of the crucial oscillations, having a prominent role in cognition, particularly spatial memory, is hippocampal theta rhythm. Our research revealed that SCI could induce changes not only in the neurogenesis and apoptosis rate of the hippocampus but also in theta power as well as receptors involving in the generation of this rhythm. Herein we used 24 male Wistar rats (Sham/SCI = 12) and examined the effect of spinal cord contusion on hippocampal theta rhythm, spatial memory, and neurodegeneration. We proved that SCI eliminates hippocampus-dependent theta power through spatial working memory, and correlates significantly with neurodegeneration and expression of receptors (NMDA, GABAA, Muscarinic1/M1), which are in turn essential in generation of theta rhythm. The immunohistochemistry analysis also demonstrated a significant decrease in DCX+ and BrdU+ cells; however, according to TUNEL assay, apoptosis is significantly higher in SCI-induced animals. The western blotting analysis further showed a significant reduction of the abovementioned receptors in the hippocampus. We also verified that SCI impairs the spatial memory, proved by poor performance in the Y-maze task. As well as, based on the local field potential recordings analysis, SCI decreases the power of theta rhythm. Eventually, this study demonstrated that chronic brain neurodegeneration occurs after SCI accompanied by theta rhythm and cognitive deficiency.     

The perirhinal cortex and long-term spatial memory in rats

Two experiments examined the effects of perirhinal cortex and hippocampal neurotoxic lesions on the retention of allocentric information. Perirhinal (Expt. 1) and hippocampal rats (Expt. 2) were trained on an allocentric task until they reached a performance equal to that of the control groups. Results showed that 24 days after acquisition, during a retraining period, only the hippocampal rats presented a deficit in retention. These results suggest that the perirhinal cortex and the hippocampus can be functionally dissociated in terms of their participation in the formation of long-term spatial memory. Also, the allocentric spatial memory functions of the hippocampus seem not to depend on their afferent connections with the perirhinal cortex.     

Theta band power increases in the posterior hippocampus predict successful episodic memory encoding in humans

Functional differences in the anterior and posterior hippocampus during episodic memory processing have not been examined in human electrophysiological data. This is in spite of strong evidence for such differences in rodent data, including greater place cell specificity in the dorsal hippocampus, greater sensitivity to the aversive or motivational content of memories in ventral regions, connectivity analyses identifying preferential ventral hippocampal connections with the amygdala, and gene expression analyses identifying a dorsal–ventral gradient. We asked if memory‐related oscillatory patterns observed in human hippocampal recordings, including the gamma band and slow‐theta (2.5–5 Hz) subsequent memory effects, would exhibit differences along the longitudinal axis and between hemispheres. We took advantage of a new dataset of stereo electroencephalography patients with simultaneous, robotically targeted anterior, and posterior hippocampal electrodes to directly compare oscillatory subsequent memory effects during item encoding. This same data set allowed us to examine left–right connectivity and hemispheric differences in hippocampal oscillatory patterns. Our data suggest that a power increase during successful item encoding in the 2.5–5 Hz slow‐theta frequency range preferentially occurs in the posterior hippocampus during the first 1,000 ms after item presentation, while a gamma band power increase is stronger in the dominant hemisphere. This dominant–nondominant pattern in the gamma range appears to reverse during item retrieval, however. Intrahippocampal phase coherence was found to be stronger during successful item encoding. Our phase coherence data are also consistent with existing reports of a traveling wave for theta oscillations propagating along the septotemporal (longitudinal) axis of the human hippocampus. We examine how our findings fit with theories of functional specialization along the hippocampal axis.     

Hippocampal lesioned rats are able to learn a spatial position using non-spatial strategies

In the last two decades, many experiments have demonstrated that the hippocampus plays a role in the learning and processing of spatial and contextual information. Despite these demonstrations, some recent publications have indicated that the hippocampus is not the only structure involved in spatial learning and that even after hippocampal lesions, rats can perform spatial tasks. However, it is not well established whether animals with hippocampal dysfunction still have some spatial learning capacities or develop non-spatial solutions; these may require lengthier acquisition training. We now report the effects of conventional, dorsal hippocampal ablation on rats' performance on the water maze. We tested rats using a short (4 days) versus a long (16 days) acquisition period. We demonstrated that animals with dorsal hippocampal lesions have some residual capacity for learning the localization of a hidden escape platform in a pool during both a reference memory task and a working memory task. The animals with dorsal hippocampal lesions learned to escape at a fixed location, but only with extended training. It is suggested that these animals used non-spatial strategies to compensate for a spatial memory impairment. The results are discussed with respect to the experimental procedure and the strategy applied by the lesioned rats.     

Improved object recognition memory using post-encoding repetitive transcranial magnetic stimulation

BackgroundBrain stimulation is known to affect canonical pathways and proteins involved in memory. However, there are conflicting results on the ability of brain stimulation to improve to memory, which may be due to variations in timing of stimulation.HypothesisWe hypothesized that repetitive transcranial magnetic stimulation (rTMS) given following a learning task and within the time period before retrieval could help improve memory.MethodsWe implanted male B6129SF2/J mice (n = 32) with a cranial attachment to secure the rTMS coil so that the mice could be given consistent stimulation to the frontal area whilst freely moving. Mice then underwent the object recognition test sampling phase and given treatment +3, +24, +48 h following the test. Treatment consisted of 10 min 10 Hz rTMS stimulation (TMS, n = 10), sham treatment (SHAM, n = 11) or a control group which did not do the behavior test or receive rTMS (CONTROL n = 11). At +72 h mice were tested for their exploration of the novel vs familiar object.ResultsAt 72-h's, only the mice which received rTMS had greater exploration of the novel object than the familiar object. We further show that promoting synaptic GluR2 and maintaining synaptic connections in the perirhinal cortex and hippocampal CA1 are important for this effect. In addition, we found evidence that these changes were linked to CAMKII and CREB pathways in hippocampal neurons.ConclusionBy linking the known biological effects of rTMS to memory pathways we provide evidence that rTMS is effective in improving memory when given during the consolidation and maintenance phases.     

Transcranial Slow Oscillation Stimulation During Sleep Enhances Memory Consolidation in Rats

BackgroundThe importance of slow-wave sleep (SWS), hallmarked by the occurrence of sleep slow oscillations (SO), for the consolidation of hippocampus-dependent memories has been shown in numerous studies. Previously, the application of transcranial direct current stimulation, oscillating at the frequency of endogenous slow oscillations, during SWS enhanced memory consolidation for a hippocampus dependent task in humans suggesting a causal role of slowly oscillating electric fields for sleep dependent memory consolidation.ObjectiveHere, we aimed to replicate and extend these findings to a rodent model.MethodsSlow oscillatory direct transcranial current stimulation (SO-tDCS) was applied over the frontal cortex of rats during non-rapid eye movement (NREM) sleep and its effects on memory consolidation in the one-trial object-place recognition task were examined. A retention interval of 24 h was used to investigate the effects of SO-tDCS on long-term memory.ResultsAnimals' preference for the displaced object was significantly greater than chance only when animals received SO-tDCS. EEG spectral power indicated a trend toward a transient enhancement of endogenous SO activity in the SO-tDCS condition.ConclusionsThese results support the hypothesis that slowly oscillating electric fields causal affect sleep dependent memory consolidation, and demonstrate that oscillatory tDCS can be a valuable tool to investigate the function of endogenous cortical network activity.     

Optogenetic activation of melanin‐concentrating hormone neurons increases non‐rapid eye movement and rapid eye movement sleep during the night in rats

Neurons containing melanin‐concentrating hormone (MCH) are located in the hypothalamus. In mice, optogenetic activation of the MCH neurons induces both non‐rapid eye movement (NREM) and rapid eye movement (REM) sleep at night, the normal wake‐active period for nocturnal rodents [R. R. Konadhode et al. (2013) J. Neurosci., 33, 10257–10263]. Here we selectively activate these neurons in rats to test the validity of the sleep network hypothesis in another species. Channelrhodopsin‐2 (ChR2) driven by the MCH promoter was selectively expressed by MCH neurons after injection of rAAV‐MCHp‐ChR2‐EYFP into the hypothalamus of Long–Evans rats. An in vitro study confirmed that the optogenetic activation of MCH neurons faithfully triggered action potentials. In the second study, in Long–Evans rats, rAAV‐MCH‐ChR2, or the control vector, rAAV‐MCH‐EYFP, were delivered into the hypothalamus. Three weeks later, baseline sleep was recorded for 48 h without optogenetic stimulation (0 Hz). Subsequently, at the start of the lights‐off cycle, the MCH neurons were stimulated at 5, 10, or 30 Hz (1 mW at tip; 1 min on – 4 min off) for 24 h. Sleep was recorded during the 24‐h stimulation period. Optogenetic activation of MCH neurons increased both REM and NREM sleep at night, whereas during the day cycle, only REM sleep was increased. Delta power, an indicator of sleep intensity, was also increased. In control rats without ChR2, optogenetic stimulation did not increase sleep or delta power. These results lend further support to the view that sleep‐active MCH neurons contribute to drive sleep in mammals.     

Spatial Memory Sequence Encoding and Replay During Modeled Theta and Ripple Oscillations

Spatial learning involves the storage and replay of temporally ordered spatial information. The hippocampus is a key brain structure involved in spatial learning in rats. Temporally ordered spatial memories are encoded and replayed by the firing rate and phase of hippocampal pyramidal cells and inhibitory interneurons with respect to ongoing network theta and ripple oscillations paced by intra- and extrahippocampal areas. Theta oscillations (4–7 Hz) may contribute to memory formation, whereas fast ripple oscillations to temporally compressed forward and reverse replay of previously stored memories. Different classes of CA1 excitatory and inhibitory neurons and medial septal inhibitory neurons have been shown to differentially phase their activities with respect to theta and ripples. Understanding how the different hippocampal and extrahippocampal areas and their neuronal classes interact during these network oscillations and how they facilitate the storage and replay of spatiotemporal memories is of great importance. A computational model of the hippocampal CA1 microcircuit that uses biophysical representations of the major cell types, including pyramidal cells and four types of inhibitory interneurons, is extended. Inputs to the network come from the entorhinal cortex (EC), the CA3 Schaffer collaterals and the medial septum. A biophysical mechanism of spike timing-dependent plasticity (STDP) is used for learning spatial memory patterns in the correct order. The model addresses two important issues: (1) How are the storage and replay (forward and reverse) of temporally ordered memory patterns controlled in the CA1 microcircuit during theta and ripples? (2) What roles do the various types of inhibitory interneurons play in these processes?     

Dysfunctional prefrontal cortical network activity and interactions following cannabinoid receptor activation

Coordinated activity spanning anatomically distributed neuronal networks underpins cognition and mediates limbic-cortical interactions during learning, memory, and decision-making. We used CP55940, a potent agonist of brain cannabinoid receptors known to disrupt coordinated activity in hippocampus, to investigate the roles of network oscillations during hippocampal and medial prefrontal cortical (mPFC) interactions in rats. During quiet wakefulness and rest, CP55940 dose-dependently reduced 0.1-30 Hz local field potential power in CA1 of the hippocampus while concurrently decreasing 30-100 Hz power in mPFC; these contrasting population-level effects were paralleled by differential effects on underlying single-unit activity in the two structures. During decision-making phases of a spatial working memory task, CP5540-induced deficits in hippocampal theta and prefrontal gamma oscillations were observed alongside disrupted theta-frequency coherence between the two structures. These changes in coordinated limbic-cortical network activities correlated with (1) reduced accuracy of task performance, (2) impaired phase-locking of prefrontal single-unit spiking to the local gamma and hippocampal theta rhythms, and (3) impaired task-dependent activity in a subset of mPFC units. In addition to highlighting the importance of CA1-mPFC network oscillations for cognition, these results implicate disrupted theta-frequency coordination of CA1-mPFC activity in the cognitive deficits caused by exogenous activation of brain cannabinoid receptors.     

Long-Range Respiratory and Theta Oscillation Networks Depend on Spatial Sensory Context

Neural oscillations can couple networks of brain regions, especially at lower frequencies. The nasal respiratory rhythm, which elicits robust olfactory bulb oscillations, has been linked to episodic memory, locomotion, and exploration, along with widespread oscillatory coherence. The piriform cortex is implicated in propagating the olfactory-bulb-driven respiratory rhythm, but this has not been tested explicitly in the context of both hippocampal theta and nasal respiratory rhythm during exploratory behaviors. We investigated systemwide interactions during foraging behavior, which engages respiratory and theta rhythms. Local field potentials from the olfactory bulb, piriform cortex, dentate gyrus, and CA1 of hippocampus, primary visual cortex, and nasal respiration were recorded simultaneously from male rats. We compared interactions among these areas while rats foraged using either visual or olfactory spatial cues. We found high coherence during foraging compared with home cage activity in two frequency bands that matched slow and fast respiratory rates. Piriform cortex and hippocampus maintained strong coupling at theta frequency during periods of slow respiration, whereas other pairs showed coupling only at the fast respiratory frequency. Directional analysis shows that the modality of spatial cues was matched to larger influences in the network by the respective primary sensory area. Respiratory and theta rhythms also coupled to faster oscillations in primary sensory and hippocampal areas. These data provide the first evidence of widespread interactions among nasal respiration, olfactory bulb, piriform cortex, and hippocampus in awake freely moving rats, and support the piriform cortex as an integrator of respiratory and theta activity.SIGNIFICANCE STATEMENT Recent studies have shown widespread interactions between the nasally driven respiratory rhythm and neural oscillations in hippocampus and neocortex. With this study, we address how the respiratory rhythm interacts with ongoing slow brain rhythms across olfactory, hippocampal, and visual systems in freely moving rats. Patterns of network connectivity change with behavioral state, with stronger interactions at fast and slow respiratory frequencies during foraging as compared with home cage activity. Routing of interactions between sensory cortices depends on the modality of spatial cues present during foraging. Functional connectivity and cross-frequency coupling analyses suggest strong bidirectional interactions between olfactory and hippocampal systems related to respiration and point to the piriform cortex as a key area for mediating respiratory and theta rhythms.