Hippocampal Oscillations Research Articles

Marco Capogna, a pioneering neuroscientist and true European

Marco Capogna, a pioneering neuroscientist and true European

Optogenetic modulation of hippocampal oscillations ameliorates spatial cognition and hippocampal dysrhythmia following early-life seizures

There is increasing human and animal evidence that brain oscillations play a critical role in the development of spatial cognition. In rat pups, disruption of hippocampal rhythms via optogenetic stimulation during the critical period for memory development impairs spatial cognition. Early-life seizures are associated with long-term deficits in spatial cognition and aberrant hippocampal oscillatory activity. Here we asked whether modulation of hippocampal rhythms following early-life seizures can reverse or improve hippocampal connectivity and spatial cognition. We used optogenetic stimulation of the medial septum to induce physiological 7 Hz theta oscillations in the hippocampus during the critical period of spatial cognition following early-life seizures.Optogenetic stimulation of the medial septum in control and rats subjected to early-life seizures resulted in precisely regulated frequency-matched hippocampal oscillations. Rat pups receiving active blue light stimulation performed better than the rats receiving inert yellow light in a test of spatial cognition. The improvement in spatial cognition in these rats was associated with a faster theta frequency and higher theta power, coherence and phase locking value in the hippocampus than rats with early-life seizures receiving inert yellow light. These findings indicate that following early life seizures, modification of hippocampal rhythms may be a potential novel therapeutic modality.

Status epilepticus induces chronic silencing of burster and dominance of regular firing neurons during sharp wave-ripples in the mouse subiculum

Sharp wave-ripples (SWRs) are hippocampal oscillations associated with memory consolidation. The subiculum, as the hippocampal output structure, ensures that hippocampal memory representations are transferred correctly to the consolidating neocortical regions. Because patients with temporal lobe epilepsy often develop memory deficits, we hypothesized that epileptic networks may disrupt subicular SWRs. We therefore investigated the impact of experimentally induced status epilepticus (SE) on subicular SWRs and contributing pyramidal neurons using electrophysiological recordings in mouse hippocampal slices. Subicular SWRs expressed hyperexcitable features post-SE, including increased ripple and unit activity. While regular firing neurons normally remain silent during SWRs, selective disinhibition recruited more regular firing neurons for action potential generation during SWRs post-SE. By contrast, burster neurons generated fewer action potential bursts during SWRs post-SE. Furthermore, altered timing of postsynaptic and action potentials suggested distorted neuronal recruitment during SWRs. Distorted subicular SWRs may therefore impair information processing and memory consolidation in epilepsy.

TREM2 Deficiency Disrupts Network Oscillations Leading to Epileptic Activity and Aggravates Amyloid-β-Related Hippocampal Pathophysiology in Mice.

Genetic mutations in triggering receptor expressed on myeloid cells-2 (TREM2) have been strongly associated with increased risk of developing Alzheimer's disease (AD) and other progressive dementias. In the brain, TREM2 protein is specifically expressed on microglia suggesting their active involvement in driving disease pathology. Using various transgenic AD models to interfere with microglial function through TREM2, several recent studies provided important data indicating a causal link between TREM2 and underlying amyloid-β (Aβ) and tau pathology. However, mechanisms by which TREM2 contributes to increased predisposition to clinical AD and influences its progression still remain largely unknown. Our aim was to elucidate the potential contribution of TREM2 on specific oscillatory dynamic changes associated with AD pathophysiology. Spontaneous and brainstem nucleus pontis oralis stimulation-induced hippocampal oscillation paradigm was used to investigate the impact of TREM2 haploinsufficiency TREM2(Het) or total deficiency TREM2(Hom) on hippocampal network function in wild-type and Aβ overproducing Tg2576 mice under urethane anesthesia. Partial (TREM2(Het)) or total (TREM2(Hom)) deletion of TREM2 led to increased incidence of spontaneous epileptiform seizures in both wild-type and Tg2576 mice. Importantly, deficiency of TREM2 in Tg2576 mice significantly diminished power of theta oscillation in the hippocampus elicited by brainstem-stimulation compared to wild-type mice. However, it did not affect hippocampal theta-phase gamma-amplitude coupling significantly, since over a 60%reduction was found in coupling in Tg2576 mice regardless of TREM2 function. Our findings indicate a role for TREM2-dependent microglial function in the hippocampal neuronal excitability in both wild type and Aβ overproducing mice, whereas deficiency in TREM2 function exacerbates disruptive effects of Aβ on hippocampal network oscillations.

Proximal CA1 20-40 Hz power dynamics reflect trial-specific information processing supporting nonspatial sequence memory.

The hippocampus is known to play a critical role in processing information about temporal context. However, it remains unclear how hippocampal oscillations are involved, and how their functional organization is influenced by connectivity gradients. We examined local field potential activity in CA1 as rats performed a nonspatial odor sequence memory task. We found that odor sequence processing epochs were characterized by distinct spectral profiles and proximodistal CA1 gradients of theta and 20-40 Hz power than track running epochs. We also discovered that 20-40 Hz power was predictive of sequence memory performance, particularly in proximal CA1 and during the plateau of high power observed in trials in which animals had to maintain their decision until instructed to respond. Altogether, these results provide evidence that dynamics of 20-40 Hz power along the CA1 axis are linked to trial-specific processing of nonspatial information critical to order judgments and are consistent with a role for 20-40 Hz power in gating information processing.

Bidirectional Communication between the Pontine Nucleus Incertus and the Medial Septum Is Carried Out by Electrophysiologically-Distinct Neuronal Populations.

Theta oscillations are key brain rhythm involved in memory formation, sensorimotor integration, and control of locomotion and behavioral states. Generation and spatiotemporal synchronization of theta oscillations rely on interactions between brain nuclei forming a large neural network, which includes pontine nucleus incertus (NI). Here we identified distinct populations of NI neurons, based on the relationship of their firing to hippocampal waves, with a special focus on theta oscillations, and the direction and type of interaction with the medial septum (MS) in male, urethane-anesthetized rats. By recording NI neuronal firing and hippocampal LFP, we described NI neurons that fire action potentials in a theta phase-independent or theta phase-locked and delta wave-independent or delta wave-locked manner. Among hippocampal activity-independent NI neurons, irregular, slow-firing, and regular, fast-firing cells were observed, while hippocampal oscillation-/wave-locked NI neurons were of a bursting or nonbursting type. By projection-specific optotagging, we revealed that only fast-firing theta phase-independent NI neurons innervate the MS, rarely receiving feedback information. In contrast, the majority of theta-bursting NI neurons were inhibited by MS stimulation, and this effect was mediated by direct GABAergic input. Described NI neuronal populations differ in reciprocal connections with the septohippocampal system, plausibly forming separate neuronal loops. Our results suggest that theta phase-independent NI neurons participate in theta rhythm generation through direct innervation of the MS, while theta-bursting NI neurons further transmit the rhythmic signal received from the MS to stabilize and/or strengthen rhythmic activity in other structures.SIGNIFICANCE STATEMENT The generation and spatiotemporal synchronization of theta oscillations rely on interactions between nuclei forming a large neural network, part of which is the pontine nucleus incertus (NI). Here we describe that within NI there are populations of neurons that can be distinguished based on the relationship of their firing to hippocampal theta oscillations and delta waves. We show that these neuronal populations largely do not have reciprocal connections with the septohippocampal system, but form separate neuronal loops. Our results suggest that medial septum (MS)-projecting, fast-firing, theta phase-independent NI neurons may participate in theta rhythm generation through direct innervation of the MS, while theta-bursting NI neurons may further transmit the rhythmic signal received from the MS to other structures.

Utility of 7,8-dihydroxyflavone in preventing astrocytic and synaptic deficits in the hippocampus elicited by PTSD

Astrocytic functions and brain-derived neurotrophic factor (BDNF)-tyrosine kinase receptor B (TrkB) signaling pathways are impaired in stress-related neuropsychiatric diseases. Previous studies have reported neuroprotective effects of 7,8-dihydroxyflavone (7,8-DHF), a TrkB activator. Here, we investigated the molecular mechanisms underlying pathogenesis of post-traumatic stress disorder (PTSD) using a modified single-prolonged stress (SPS&S) model and the potential beneficial effects of 7,8-DHF. SPS&S reduced the hippocampal expression of glial fibrillary acidic protein (GFAP), a marker of astrocytes, and induced morphological changes in astrocytes. From the perspective of synaptic function, the SPS&S model displayed reduced expression of BDNF, p-TrkB, postsynaptic density protein 95 (PSD95), AMPA receptor subunit GluR1 (GluA1), NMDA receptor subunit N2A/N2B ratio, calpain-1, phosphorylated protein kinase B (Akt) and phosphorylated mammalian target of rapamycin (mTOR) and conversely, higher phosphatase and tension homolog (PTEN) expression in the hippocampus. Acute or continuous intraperitoneal administration of 7,8-DHF (5 mg/kg) after SPS&S procedures prevented SPS&S-induced fear memory generalization and anxiety-like behaviors as well as abnormalities of hippocampal oscillations. Most importantly, 7,8-DHF attenuated SPS&S-induced abnormal BDNF-TrkB signaling and calpain-1-dependent cascade of synaptic deficits. Furthermore, treatment with a TrkB inhibitor completely blocked while an mTOR inhibitor partially blocked the effects of 7,8-DHF on behavioral changes of SPS&S model mice. Our collective findings suggest that 7,8-DHF effectively alleviates PTSD-like symptoms, including fear generalization and anxiety-like behavior, potentially by preventing astrocytic and synaptic deficits in the hippocampus through targeting of TrkB.

Looking for the neural basis of memory.

Memory neuroscientists often measure neural activity during task trials designed to recruit specific memory processes. Behavior is championed as crucial for deciphering brain-memory linkages but is impoverished in typical experiments that rely on summary judgments. We criticize this approach as being blind to the multiple cognitive, neural, and behavioral processes that occur rapidly within a trial to support memory. Instead, time-resolved behaviors such as eye movements occur at the speed of cognition and neural activity. We highlight successes using eye-movement tracking with in vivo electrophysiology to link rapid hippocampal oscillations to encoding and retrieval processes that interact over hundreds of milliseconds. This approach will improve research on the neural basis of memory because it pinpoints discrete moments of brain-behavior-cognition correspondence.

When shared concept cells support associations: Theory of overlapping memory engrams.

Assemblies of neurons, called concepts cells, encode acquired concepts in human Medial Temporal Lobe. Those concept cells that are shared between two assemblies have been hypothesized to encode associations between concepts. Here we test this hypothesis in a computational model of attractor neural networks. We find that for concepts encoded in sparse neural assemblies there is a minimal fraction cmin of neurons shared between assemblies below which associations cannot be reliably implemented; and a maximal fraction cmax of shared neurons above which single concepts can no longer be retrieved. In the presence of a periodically modulated background signal, such as hippocampal oscillations, recall takes the form of association chains reminiscent of those postulated by theories of free recall of words. Predictions of an iterative overlap-generating model match experimental data on the number of concepts to which a neuron responds.

Activity and Coupling to Hippocampal Oscillations of Median Raphe GABAergic Cells in Awake Mice.

Ascending serotonergic/glutamatergic projection from the median raphe region (MRR) to the hippocampal formation regulates both encoding and consolidation of memory and the oscillations associated with them. The firing of various types of MRR neurons exhibits rhythmic modulation coupled to hippocampal oscillatory activity. A possible intermediary between rhythm-generating forebrain regions and entrained ascending modulation may be the GABAergic circuit in the MRR, known to be targeted by a diverse array of top-down inputs. However, the activity of inhibitory MRR neurons in an awake animal is still largely unexplored. In this study, we utilized whole cell patch-clamp, single cell, and multichannel extracellular recordings of GABAergic and non-GABAergic MRR neurons in awake, head-fixed mice. First, we have demonstrated that glutamatergic and serotonergic neurons receive both transient, phasic, and sustained tonic inhibition. Then, we observed substantial heterogeneity of GABAergic firing patterns but a marked modulation of activity by brain states and fine timescale coupling of spiking to theta and ripple oscillations. We also uncovered a correlation between the preferred theta phase and the direction of activity change during ripples, suggesting the segregation of inhibitory neurons into functional groups. Finally, we could detect complementary alteration of non-GABAergic neurons’ ripple-coupled activity. Our findings support the assumption that the local inhibitory circuit in the MRR may synchronize ascending serotonergic/glutamatergic modulation with hippocampal activity on a subsecond timescale.

In vitro and in vivo anti-epileptic efficacy of eslicarbazepine acetate in a mouse model of KCNQ2-related self-limited epilepsy.

The KCNQ2 gene encodes for the Kv 7.2 subunit of non-inactivating potassium channels. KCNQ2-related diseases range from autosomal dominant neonatal self-limited epilepsy, often caused by KCNQ2 haploinsufficiency, to severe encephalopathies caused by KCNQ2 missense variants. In vivo and in vitro effects of the sodium channel blocker eslicarbazepine acetate (ESL) and eslicarbazepine metabolite (S-Lic) in a mouse model of self-limited neonatal epilepsy as a first attempt to assess the utility of ESL in the KCNQ2 disease spectrum was investigated. Effects of S-Lic on in vitro physiological and pathological hippocampal neuronal activity in slices from mice carrying a heterozygous deletion of Kcnq2 (Kcnq2+/- ) and Kcnq2+/+ mice were investigated. ESL in vivo efficacy was investigated in the 6-Hz psychomotor seizure model in both Kcnq2+/- and Kcnq2+/+ mice. S-Lic increased the amplitude and decreased the incidence of physiological sharp wave-ripples in a concentration-dependent manner and slightly decreased gamma oscillations frequency. 4-Aminopyridine-evoked seizure-like events were blocked at high S-Lic concentrations and substantially reduced in incidence at lower concentrations. These results were not different in Kcnq2+/+ and Kcnq2+/- mice, although the EC50 estimation implicated higher efficacy in Kcnq2+/- animals. In vivo, Kcnq2+/- mice had a lower seizure threshold than Kcnq2+/+ mice. In both genotypes, ESL dose-dependently displayed protection against seizures. S-Lic slightly modulates hippocampal oscillations and blocks epileptic activity in vitro and in vivo. Our results suggest that the increased excitability in Kcnq2+/- mice is effectively targeted by S-Lic high concentrations, presumably by blocking diverse sodium channel subtypes.

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.

Disruption of hippocampal rhythms via optogenetic stimulation during the critical period for memory development impairs spatial cognition

Objective . Investigate whether the disruption of normal hippocampal rhythms via optogenetic stimulation of the medial septum (MS) during late postnatal development has enduring effects on the allocentric memory of rat pups. Methods . Hippocampal theta oscillations were non-endogenously regulated in rat pups using blue light (465-nm) pan-neuronal optogenetic activation of the MS from postnatal day (P)21–25 using random sinewave frequencies ranging from 0.5 to 110 Hz. Non-stimulated and yellow light (590-nm) stimulated rats were used as controls, and local field potentials from the hippocampus and MS were recorded unilaterally during stimulations. In early adulthood, spatial cognition was assessed using the active avoidance task. Rats were perfused and tissue containing the MS and hippocampus was harvested and sectioned to assess cell density. Power spectrum density of both the MS and hippocampus; coherence, and voltage correlation analysis between both structures were used to compare baseline to the disruptive stimulation. Results . During late postnatal development, non-selective optogenetic activation of the MS tightly regulated hippocampal oscillations. Disruptive stimulation increased power but reduced coherence and voltage correlations; and resulted in impaired spatial learning compared with controls. Impairment of spatial cognition was not attributed to MS or hippocampal cell loss. Conclusions. These results demonstrate that hippocampal oscillations can be precisely regulated with non-selective optogenetic stimulation of the MS in weanling rats. A disruptive hippocampal stimulation protocol during the critical period of memory development results in long-standing spatial cognitive deficits that is not attributed to cell loss. Significance . Disruptive activity during postnatal development, such as occurs during early life seizures, has complex effects on developing neural circuits relevant to cognition. By mimicking disruption of MS-hippocampal entrainment in an isolated fashion, it may be possible to pinpoint mechanisms through which ELS may affect cognition.

A Machine Learning Approach for Detecting Vicarious Trial and Error Behaviors.

Vicarious trial and error behaviors (VTEs) indicate periods of indecision during decision-making, and have been proposed as a behavioral marker of deliberation. In order to understand the neural underpinnings of these putative bridges between behavior and neural dynamics, researchers need the ability to readily distinguish VTEs from non-VTEs. Here we utilize a small set of trajectory-based features and standard machine learning classifiers to identify VTEs from non-VTEs for rats performing a spatial delayed alternation task (SDA) on an elevated plus maze. We also show that previously reported features of the hippocampal field potential oscillation can be used in the same types of classifiers to separate VTEs from non-VTEs with above chance performance. However, we caution that the modest classifier success using hippocampal population dynamics does not identify many trials where VTEs occur, and show that combining oscillation-based features with trajectory-based features does not improve classifier performance compared to trajectory-based features alone. Overall, we propose a standard set of features useful for trajectory-based VTE classification in binary decision tasks, and support previous suggestions that VTEs are supported by a network including, but likely extending beyond, the hippocampus.

To Stop the Seizure, You Must Become the Seizure: Closed-Loop Stimulation Phase Locked to Seizure Waves Disrupts Kindled Seizures While Open-Loop Stimulation Fails.

Closed-Loop Stimulation of the Medial Septum Terminates Epileptic Seizures Takeuchi Y, Harangozó M, Pedraza L, Földi T, Kozák G, Li Q, Berényi A. Brain. 2021;144(3):885-908. doi:10.1093/brain/awaa450Temporal lobe epilepsy with distributed hippocampal seizure foci is often intractable and its secondary generalization might lead to sudden death. Early termination through spatially extensive hippocampal intervention is not feasible directly, because of the large size and irregular shape of the hippocampus. In contrast, the medial septum is a promising target to govern hippocampal oscillations through its divergent connections to both hippocampi. Combining this “proxy intervention” concept and precisely timed stimulation, we report here that closed-loop medial septum electrical stimulation can quickly terminate intrahippocampal seizures and suppress secondary generalization in a rat kindling model. Precise stimulus timing governed by internal seizure rhythms was essential. Cell type-specific stimulation revealed that the precisely timed activation of medial septum GABAergic neurons underlaid the effects. Our concept of time-targeted proxy stimulation for intervening pathological oscillations can be extrapolated to other neurological and psychiatric disorders, and has potential for clinical translation.

Aging-Related Neural Disruption Might Predispose to Postoperative Cognitive Impairment Following Surgical Trauma

Accumulating evidence has demonstrated that aging is associated with an exaggerated response to surgical trauma together with cognitive impairments. This has significant implications for the development of clinical phenotype such as perioperative neurocognitive disorders (PND), which is a common complication following surgery, especially for the elderly. However, the mechanism by which aging brain is vulnerable to surgical trauma remains to be elucidated. To test whether age-related alterations in hippocampal network activities contribute to increased risk of PND following surgery. Thirty-two adult and seventy-two aged male C57BL/6 mice undergone sevoflurane anesthesia and exploratory laparotomy were used to mimic human abdominal surgery. For the interventional study, mice were treated with minocycline. Behavioral tests were performed post-surgery with open field, novel object recognition and fear conditioning tests, respectively. The brain tissues were then harvested and subjected to biochemistry studies. Local field potential (LFP) recording was performed in another separate experiment. Aged mice displayed signs of neuroinflammation, as reflected by significantly increased proinflammatory mediators in the hippocampus. Also, aged mice displayed persistently decreased oscillation activities under different conditions, both before and after surgery. Further correlation analysis suggested that theta power was positively associated with time with novel object, while γ oscillation activity was positively associated with freezing time to context. Of note, downregulation of neuroinflammation by microglia inhibitor minocycline reversed some of these abnormities. Our study highlights that age-related hippocampal oscillation dysregulation increases the risk of PND incidence, which might provide diagnostic/prognostic biomarkers for PND and possible other neurodegenerative diseases.

The actin binding protein drebrin helps to protect against the development of seizure-like events in the entorhinal cortex

The actin binding protein drebrin plays a key role in dendritic spine formation and synaptic plasticity. Decreased drebrin protein levels have been observed in temporal lobe epilepsy, suggesting the involvement of drebrin in the disease. Here we investigated the effect of drebrin knockout on physiological and pathophysiological neuronal network activities in mice by inducing gamma oscillations, involved in higher cognitive functions, and by analyzing pathophysiological epileptiform activity. We found that loss of drebrin increased the emergence of spontaneous gamma oscillations suggesting an increase in neuronal excitability when drebrin is absent. Further analysis showed that although the kainate-induced hippocampal gamma oscillations were unchanged in drebrin deficient mice, seizure like events measured in the entorhinal cortex appeared earlier and more frequently. The results suggest that while drebrin is not essential for normal physiological network activity, it helps to protect against the formation of seizure like activities during pathological conditions. The data indicate that targeting drebrin function could potentially be a preventive or therapeutic strategy for epilepsy treatment.

Fluoxetine tunes the abnormal hippocampal oscillations in association with cognitive impairments in 6-OHDA lesioned rats

Cognitive decline is a common clinical symptom in Parkinson’s disease (PD) patients. Fluoxetine (FLU), a selective serotonin reuptake inhibitor, can improve cognitive deficits in demented patients. The present study investigated the effects of FLU on spatial learning and memory cognitions in 6-OHDA lesioned rats. Morris water maze (MWM) test showed that FLU significantly improved spatial cognitive deficits in rats with unilateral 6-OHDA injection at 4 and 7 weeks after 6-OHDA injection. Electrophysiological recordings demonstrated that the number and duration of high voltage spindles(HVSs)in the ipsilateral hippocampus of 6-OHDA lesioned rats were decreased by the administration of FLU. Furthermore, the spectral analysis of per frequency revealed increases in δ and θ rhythm power and decreases in α, β and γ rhythm power in the ipsilateral hippocampus of 6-OHDA lesioned rats in contrast to the saline-treated rats. Acute FLU treatment can reduce δ and θ rhythm power, and enhance α, β and γ rhythm power in the ipsilateral hippocampus of 6-OHDA lesioned rats. These findings suggest that FLU improves impaired cognition by tuning oscillatory activities in the hippocampus of 6-OHDA lesioned rats.

Melamine Disrupts Acetylcholine-Mediated Neural Information Flow in the Hippocampal CA3-CA1 Pathway.

Considering the cognitive and synaptic deficits following intragastric administration of melamine, the aim of the current investigation was to test whether the hippocampal oscillations were affected. The local field potential (LFP) was recorded in the hippocampal CA3–CA1 pathway of Wistar rats during a spatial-dependent Y-maze task. The general partial directed coherence (gPDC) method was used to assess the directionality of neural information flow (NIF) between the CA3 and CA1 regions. The levels of acetylcholine (ACh) and its esterolytic protease, acetylcholinesterase (AChE), were detected in the hippocampus (HPC) following the behavioral test. The values of phase synchronization between the CA3 and CA1 regions in delta, low theta, and high theta oscillations were reduced significantly in the melamine-treated group. Moreover, the coupling directional index and the strength of CA3 driving CA1 were critically decreased in the above three frequency bands as well. Meanwhile, a reduction in ACh expression and an enhancement in AChE activity were found in the HPC of melamine-treated rats. Intrahippocampal infusion with ACh could mitigate the weakened neural coupling and directional NIF in parallel with spatial learning improvements. However, infusion of scopolamine, an acetylcholine receptor antagonist, could block the mitigative effects of ACh treatment in melamine rats. These findings provide first evidence that ACh-mediated neuronal coupling and NIF in the CA3–CA1 pathway are involved in spatial learning deficits induced by chronic melamine exposure.

Closed-loop stimulation of the medial septum terminates epileptic seizures.

Temporal lobe epilepsy with distributed hippocampal seizure foci is often intractable and its secondary generalization might lead to sudden death. Early termination through spatially extensive hippocampal intervention is not feasible directly, because of the large size and irregular shape of the hippocampus. In contrast, the medial septum is a promising target to govern hippocampal oscillations through its divergent connections to both hippocampi. Combining this 'proxy intervention' concept and precisely timed stimulation, we report here that closed-loop medial septum electrical stimulation can quickly terminate intrahippocampal seizures and suppress secondary generalization in a rat kindling model. Precise stimulus timing governed by internal seizure rhythms was essential. Cell type-specific stimulation revealed that the precisely timed activation of medial septum GABAergic neurons underlaid the effects. Our concept of time-targeted proxy stimulation for intervening pathological oscillations can be extrapolated to other neurological and psychiatric disorders, and has potential for clinical translation.