Separation or binding? Role of the dentate gyrus in hippocampal mnemonic processing

As a major component of the hippocampal trisynaptic circuit, the dentate gyrus (DG) relays inputs from the entorhinal cortex to the CA3 subregion. Although the anatomy of the DG is well characterized, its contribution to hippocampal mnemonic processing is still unclear. A currently popular theory proposes that the primary function of the DG is to orthogonalize incoming input patterns into non-overlapping patterns (pattern separation). We critically review the available data and conclude that the theoretical support and empirical evidence for this theory are not strong. We then review an alternative theory that posits a role for the DG in binding together different types of incoming sensory information. We conclude that ‘binding’ better captures the contribution of the DG to memory encoding than ‘pattern separation’.     

Neurogliaform cells in the molecular layer of the dentate gyrus as feed-forward γ-aminobutyric acidergic modulators of entorhinal-hippocampal interplay

Feed-forward inhibition from molecular layer interneurons onto granule cells (GCs) in the dentate gyrus is thought to have major effects regulating entorhinal-hippocampal interactions, but the precise identity, properties, and functional connectivity of the GABAergic cells in the molecular layer are not well understood. We used single and paired intracellular patch clamp recordings from post-hoc-identified cells in acute rat hippocampal slices and identified a subpopulation of molecular layer interneurons that expressed immunocytochemical markers present in members of the neurogliaform cell (NGFC) class. Single NGFCs displayed small dendritic trees, and their characteristically dense axonal arborizations covered significant portions of the outer and middle one-thirds of the molecular layer, with frequent axonal projections across the fissure into the CA1 and subicular regions. Typical NGFCs exhibited a late firing pattern with a ramp in membrane potential prior to firing action potentials, and single spikes in NGFCs evoked biphasic, prolonged GABA(A) and GABA(B) postsynaptic responses in GCs. In addition to providing dendritic GABAergic inputs to GCs, NGFCs also formed chemical synapses and gap junctions with various molecular layer interneurons, including other NGFCs. NGFCs received low-frequency spontaneous synaptic events, and stimulation of perforant path fibers revealed direct, facilitating synaptic inputs from the entorhinal cortex. Taken together, these results indicate that NGFCs form an integral part of the local molecular layer microcircuitry generating feed-forward inhibition and provide a direct GABAergic pathway linking the dentate gyrus to the CA1 and subicular regions through the hippocampal fissure.     

What are the effects of prolonged seizures in the brain?

Convulsive status epilepticus is the most common neurological emergency in children and is associated with significant morbidity and mortality. The morbidities include later development of epilepsy, cognitive impairment, and psychiatric impairments. There has been a long‐standing hypothesis that these outcomes are, at least in part, a function of brain injury induced by the status epilepticus. There is evidence from animal models and prospective human studies that the hippocampus may be injured during febrile status epilepticus although this pathophysiological sequence remains uncommon. Potential mechanisms include excitotoxicity, ischaemia, and inflammation. Neuroprotective drugs reduce brain injury but have little impact on epileptogenesis or cognitive impairments. Anti‐inflammatory treatments have given mixed results to date. Broad‐spectrum anti‐inflammatory agents, such as steroids, are potentially harmful, whereas prevention of leucocyte diapedesis across the blood brain barrier appears to have a positive outcome. Therefore, more studies dissecting the inflammatory process are required to establish the most effective strategies for translation into clinical practice. In addition to neuronal loss, cognitive impairments are related to neuronal re‐organisation and disruption of neural networks underpinning cognition. Further understanding of these mechanisms may lead to novel therapies that prevent brain injury, but also therapies that may improve outcomes even if injury has occurred.     

Effect of topiramate on partial excitatory amino acids in hippocampal dentate gyrus of rats after alcohol withdrawal

IN T R O D U C T IO NA lcohol is a com m on addictive substance, and long-term ethanol drinking m ay lead to alcoholdependence. O nce the drinking am ount of alcohol is reduced or w ithdraw n suddenly, specific w ithdraw al sym ptom s w illoccur, such as …     

Effects of exercise on neurogenesis in the dentate gyrus and ability of learning and memory after hippocampus lesion in adult rats

Objective To explore the effects of exercise on dentate gyrus (DG) neurogenesis and the ability of learning and memory in hippocampus-lesioned adult rats. Methods Hippocampus lesion was produced by intrahippocampal microinjection of kainic acid (KA). Bromodeoxyuridine (BrdU) was used to label dividing cells. Y maze test was used to evaluate the ability of learning and memory. Exercise was conducted in the form of forced running in a motor-driven running wheel. The speed of wheel revolution was regulated at 3 kinds of intensity: lightly running, moderately running, or heavily running. Results Hippocampus lesion could increase the number of BrdU-labeled DG cells, moderately running after lesion could further enhance the number of BrdU-labeled cells and decrease the error number (EN) in Y maze test, while neither lightly running, nor heavily running had such effects. There was a negative correlation between the number of DG BrdU-labeled cells and the EN in the Y maze test after running. Conclusion Moderate exercise could enhance the DG neurogenesis and ameliorate the ability of learning and memory in hippocampus-lesioned rats.     

What is the role of the hippocampus and parahippocampal gyrus in the persistence of tinnitus?

The hippocampus and parahippocampal gyrus have been implicated as part of a tinnitus network by a number of studies. These structures are usually considered in the context of a “limbic system,” a concept typically invoked to explain the emotional response to tinnitus. Despite this common framing, it is not apparent from current literature that this is necessarily the main functional role of these structures in persistent tinnitus. Here, we highlight a different role that encompasses their most commonly implicated functional position within the brain—that is, as a memory system. We consider tinnitus as an auditory object that is held in memory, which may be made persistent by associated activity from the hippocampus and parahippocampal gyrus. Evidence from animal and human studies implicating these structures in tinnitus is reviewed and used as an anchor for this hypothesis. We highlight the potential for the hippocampus/parahippocampal gyrus to facilitate maintenance of the memory of the tinnitus percept via communication with auditory cortex, rather than (or in addition to) mediating emotional responses to this percept.     

Effect of electroacupuncture on synaptic transmission in dentate gyrus of the hippocampus in cerebral ischemic injured rats

IN T R O D U C T IO N Long-term potentiation (LTP ) is an essentialphenom enon concern- ing cerebral plasticity. It w as routinely used as a basic cellular m odel for the study of m em ory. LTP could be induced by m ul- ti-factors constructing the externa…     

Postnatal neurogenesis in the hippocampal dentate gyrus and subventricular zone of the Göttingen minipig

Postnatal neurogenesis is currently viewed as important for neuroplasticity and brain repair. We are, therefore, interested in animal models for neuroimaging of postnatal neurogenesis. A recent stereological study found an age-dependent increase in the number of neurons and glial cells in the neocortex of G?ttingen minipigs, suggesting that this species may be characterized by a prolonged postnatal neurogenesis. Since there is no direct evidence on this issue, the goal of our study was to quantify cell proliferation in the two major neurogenic regions of the postnatal brain - the subventricular zone of the lateral ventricle (SVZ) and the hippocampal dentate gyrus (DG) - at two separate points during the lifespan of the minipig. G?ttingen minipigs aged 6-7 and 32 weeks were injected with bromodeoxyuridine (BrdU), a marker of cycling cells, and killed after 2h. We found BrdU-positive cells numbering 165,000 in the SVZ and 35,000 in the DG at 6-7 weeks and 66,000 in the SVZ and 19,000 in the DG at 32 weeks-of-age. Stereology showed a 60% increase in the total number of DG granule cells between 6-7 and 32 weeks-of-age. Our findings show a continued postnatal neurogenesis in the major neurogenic regions of G?ttingen minipigs, thereby providing a potential animal model for studies aimed at examining ongoing neurogenesis in the living brain with molecular neuroimaging technology.     

Low‐frequency‐induced synaptic potentiation: A paradigm shift in the field of memory‐related plasticity mechanisms?

Long‐term potentiation (LTP) and long‐term depression (LTD) are two forms of synaptic plasticity thought to play functional roles in learning and memory processes. It is generally assumed that the direction of synaptic modifications (i.e., up‐ or down‐regulation of synaptic strength) depends on the specific pattern of afferent inputs, with high frequency activity or stimulation effectively inducing LTP, while low‐frequency patterns often elicit LTD. This dogma (“high frequency‐LTP, low frequency‐LTD”) has recently been challenged by evidence demonstrating low frequency stimulation (LFS)‐induced synaptic potentiation in the rodent hippocampus and amygdala. Extensive work in the past decades has focused on deciphering the mechanisms by which high frequency stimulation of afferent fiber systems results in LTP. With this review, we will compare and contrast the well‐known synaptic and cellular mechanisms underlying classical, high‐frequency‐induced LTP to those mediating the more recently discovered phenomena of LFS‐induced synaptic enhancement. In addition, we argue that LFS protocols provide a means to more accurately mimic some endogenous, oscillatory activity patterns present in hippocampal and extra‐hippocampal (especially neocortical) circuits during periods of memory consolidation. Consequently, LFS‐induced synaptic potentiation offers a novel and important avenue to investigate cellular and systems‐level mechanisms mediating the encoding, consolidation, and transfer of information throughout multiple forebrain networks implicated in learning and memory processes. © 2009 Wiley‐Liss, Inc.     

A comparison of the spontaneous firing patterns between principal cells and fast spiking interneurons from dentate gyrus in waking guinea pigs

Objective To explore the possible mechanisms that cause the dentate gyrus (DG) neurons to play different roles in information coding. Methods In vivo extracellular single unit recording was performed on 22 waking female guinea pigs, which were positioned in a sound-attenuated recording chamber without any muscular relaxants. The spontaneous firing patterns of the DG neurons were detected and compared. Results There were two different electrophysiological populations in the DG of guinea pigs, principal cells (PCs) and fast spiking interneurons (INs). Of the PCs, 1.3% discharged regularly, 48.1% irregularly and 50.6% in bursts; in contrast, of the INs units, 64.1% discharged regularly, 2.6% irregularly and 33.3% in bursts. The spontaneous firing patterns of PCs were significantly different from those of INs (P<0.01). In addition, the differences of several interspike interval (ISI) parameters also have been observed: (1) the ISI coefficients of variation of PCs (3.39±3.56) were significantly higher than those of INs (1.08±0.46) (P<0.01); (2) the ISI asymmetric indexes of PCs (0.047±0.059) were significantly lower than those of INs (0.569±0.238) (P<0.01). Conclusion In the DG, the spontaneous firing patterns of PCs were significantly different from those of INs. The former were prone to fire in bursts, the latter were prone to fire regularly. The different roles in information coding between PCs and INs might be caused by their different firing patterns.     

β-Estradiol unmasks metabotropic receptor-mediated metaplasticity of NMDA receptor transmission in the female rat dentate gyrus

Loss of estrogen in women following menopause is associated with increased risk for cognitive decline, dementia and depression, all of which can be prevented by estradiol replacement. The dentate gyrus plays an important role in cognition, learning and memory. The gatekeeping function of the dentate gyrus to filter incoming activity into the hippocampus is modulated by estradiol in a frequency-dependent manner and involves activation of metabotropic glutamate receptors (mGluR). In the present study, we investigated whether estradiol (EB) modulates the metaplastic effect of inducing synaptic long-term potentiation (LTP) on subsequent propensity for expression of LTP in the dentate gyrus. At medial perforant path-dentate granule cell synapses in hippocampal slices of ovariectomized female rats, EB replacement was critical for an initial induction of LTP to enhance the magnitude of subsequent LTP elicited by a second high-frequency stimulation, metaplasticity, which was not present in slices from oil-treated control animals. EB enhanced expression of group I mGluRs, and the metaplastic effect of EB on LTP required activation of group I mGluRs that led to Src-family tyrosine kinase-mediated phosphorylation of NR2B subunits of N-methyl-d-aspartate receptors (NMDAR) that enhanced the magnitude of NMDAR-dependent LTP. Our data show that EB effects on LTP in the hippocampal dentate gyrus require activation of group I mGluRs, which in turn leads to functional metaplastic regulation of NR2B subunit-containing NMDARs, as opposed to direct effects of EB on NMDARs.     

Emotional stress–induced seizures: Another reflex epilepsy?

Multiple triggers have been shown to provoke seizures in reflex epilepsy. Among these are external stimuli (flickering light, hot water), actions (chewing, reading), and even mental tasks. We present a 9-year-old girl whose seizures were provoked mainly by emotional stress. In most cases of emotional stress-related seizures, especially when a specific confrontational incidence preceded the seizure, the suspicion for a nonepileptic event is high. In our patient we were able to show that the seizures were epileptic. Further investigation to clarify the pathophysiology of stress-related seizures is needed.     

Modulation by the BK accessory β4 subunit of phosphorylation-dependent changes in excitability of dentate gyrus granule neurons

Large-conductance voltage- and calcium-activated potassium (BK) channels are large-conductance calcium- and voltage-activated potassium channels critical for neuronal excitability. Some neurons express so called fast-gated, type I BK channels. Other neurons express BK channels assembled with the accessory β4 subunit conferring slow gating of type II BK channels. However, it is not clear how protein phosphorylation modulates these two distinct BK channel types. Using β4-knockout mice, we compared fast- or slow-gated BK channels in response to changes in phosphorylation status of hippocampus dentate gyrus granule neurons. We utilized the selective PP2A/PP4 phosphatase inhibitor Fostriecin to study changes in action potential shape and firing properties of the neurons. In β4-knockout neurons, Fostriecin increases BK current, speeds up BK channel activation and reduces action potential amplitudes. Fostriecin increases spiking during early components of an action potential train. In contrast, inhibition of BK channels through β4 in wild-type neurons or by the BK channel inhibitor Paxilline opposes Fostriecin effects. Voltage clamp recordings of neurons reveal that Fostriecin increases both calcium and BK currents. However, Fostriecin does not activate BK α channels in transfected HEK293 cells lacking calcium channels. In summary, these results suggest that fast-gating, type I BK channels lacking β4 can increase neuronal excitability in response to reduced phosphatase activity and activation of calcium channels. By opposing BK channel activation, the β4 subunit plays an important role in moderating firing frequency regardless of changes in phosphorylation status.     

Is the dentate gyrus an independent generator of in vitro recorded theta rhythm?

In this study we investigated the ability of the dentate gyrus to independently generate cholinergically induced theta rhythm in vitro. Two different experiments were performed. In Experiment I, new laminar profiles of theta phase, amplitude, and current sources and sinks were constructed. In this experiment a gradual phase shift of theta waves in the CA1 stratum radiatum was observed. Simultaneously, two amplitude maxima were detected: the first in the CA1 stratum oriens, and the second in the CA1 stratum lacunosum-moleculare. Moreover, during the positive peak of theta in the CA1 stratum oriens, two large sinks were observed: the first localized in the stratum oriens and the second in the stratum lacunosum-moleculare. In Experiment II the EEG activity of three different transected hippocampal slices (CA1 transected slices, CA3c transected slices, and DG transected slices) was recorded. It was demonstrated that the dentate gyrus granular cell body layer was not able to independently produce in vitro theta rhythm. Data obtained in both experiments provide strong evidence that in cholinegically treated hippocampal formation maintained in vitro there is no independent generator of theta rhythm in the region of the dentate gyrus granular cell layer.