Hippocampal Commissure Research Articles

Long‐lasting hyperpolarization underlies seizure reduction by low frequency deep brain electrical stimulation

Mesial temporal lobe epilepsy (MTLE) is a common medically refractory neurological disease. Deep brain electrical stimulation (DBS) of grey matter has been used for MTLE with limited success. However, stimulation of a white matter tract connecting the hippocampi, the ventral hippocampal commissure (VHC), with low frequencies that simulate interictal discharges has shown promising results, with seizure reduction greater than 98% in bilateral hippocampi during stimulation and greater than 50% seizure reduction in bilateral hippocampi after treatment. A major hurdle to the implementation and optimization of this treatment is that the mechanisms of seizure reduction by low frequency electrical stimulation (LFS) are not known. The goal of this study is to understand how commissural fibre tract stimulation reduces bilateral hippocampal epileptic activity in an in vitro slice preparation containing bilateral hippocampi connected by the VHC. It is our hypothesis that electrical stimuli induce hyperpolarization lasting hundreds of milliseconds following each pulse which reduces spontaneous epileptic activity during each inter-stimulus interval (ISI). Stimulus-induced long-lasting-hyperpolarization (LLH) can be mediated by GABA(B) inhibitory post-synaptic potentials (IPSPs) or slow after-hyperpolarization (sAHP). To test the role of LLH in effective bilateral seizure reduction by fibre tract stimulation, we measured stimulus-induced hyperpolarization during LFS of the VHC using electrophysiology techniques. Antagonism of the GABA(B) IPSP and/or sAHP diminished stimulus-induced hyperpolarization concurrently with LFS efficacy (greater than 50% reduction). Blocking both the GABA(B) IPSP and sAHP simultaneously eliminated the effect of electrical stimulation on seizure reduction entirely. These data show that LFS of the VHC is an effective protocol for bilateral hippocampal seizure reduction and that its efficacy relies on the induction of long-lasting hyperpolarization mediated through GABA(B) IPSPs and sAHP. Based on this study, optimization of the timing of LFS and LFS-induced-LLH may lead to improved outcomes from DBS treatments for human epilepsy.

On–off control of burst high frequency electrical stimulation to suppress 4-AP induced seizures

Objective. The goal of this study was to investigate, using model simulations and animal experiments, the efficiency and the side effects of burst high frequency stimulation combined with on–off control in seizure suppression. Approach. A modified mathematical hippocampal seizure model was created to provide evidence of the eligibility of this approach. In the experimental setup, two recording electrodes were inserted into bilateral septal CA1 of the hippocampus, and a stimulation electrode was placed on the ventral hippocampal commissure of a rat. After seizures had been induced by 4-aminopyridine treatment, on–off control stimulation was used to suppress the seizures at 20 s intervals. The stimulation time, cumulative charge and post-stimulation suppression were used to assess the effects of burst duration. Main results. The results showed that burst stimulation could suppress the seizures during the control period and burst stimulation of a shorter duration could keep the seizure suppressed with less effort. By decreasing the burst duration, the cumulative stimulation time became shorter, the delivered cumulative charge became lower, and the cumulative time of post-stimulation suppression became longer. Significance. The on–off control stimulation not only prolonged the duration of suppression but also avoided the side effects of the conversion of seizure patterns. In particular, decreasing the specified burst duration increased the efficiency of the burst stimulation.

Quantitative Trait Loci for Interhemispheric Commissure Development and Social Behaviors in the BTBR T+ tf/J Mouse Model of Autism

BackgroundAutism and Agenesis of the Corpus Callosum (AgCC) are interrelated behavioral and anatomic phenotypes whose genetic etiologies are incompletely understood. We used the BTBR T+ tf/J (BTBR) strain, exhibiting fully penetrant AgCC, a diminished hippocampal commissure, and abnormal behaviors that may have face validity to autism, to study the genetic basis of these disorders.MethodsWe generated 410 progeny from an F2 intercross between the BTBR and C57BL/6J strains. The progeny were phenotyped for social behaviors (as juveniles and adults) and commisural morphology, and genotyped using 458 markers. Quantitative trait loci (QTL) were identified using genome scans; significant loci were fine-mapped, and the BTBR genome was sequenced and analyzed to identify candidate genes.ResultsSix QTL meeting genome-wide significance for three autism-relevant behaviors in BTBR were identified on chromosomes 1, 3, 9, 10, 12, and X. Four novel QTL for commissural morphology on chromosomes 4, 6, and 12 were also identified. We identified a highly significant QTL (LOD score = 20.2) for callosal morphology on the distal end of chromosome 4.ConclusionsWe identified several QTL and candidate genes for both autism-relevant traits and commissural morphology in the BTBR mouse. Twenty-nine candidate genes were associated with synaptic activity, axon guidance, and neural development. This is consistent with a role for these processes in modulating white matter tract development and aspects of autism-relevant behaviors in the BTBR mouse. Our findings reveal candidate genes in a mouse model that will inform future human and preclinical studies of autism and AgCC.

Short-term and long-term memory deficits in handedness learning in mice with absent corpus callosum and reduced hippocampal commissure

The corpus callosum (CC) and hippocampal commissure (HC) are major interhemispheric connections whose role in brain function and behaviors is fascinating and contentious. Paw preference of laboratory mice is a genetically regulated, adaptive behavior, continuously shaped by training and learning. We studied variation with training in paw-preference in mice of the 9XCA/WahBid (‘9XCA’) recombinant inbred strain, selected for complete absence of the CC and severely reduced HC. We measured sequences of paw choices in 9XCA mice in two training sessions in unbiased test chambers, separated by one-week. We compared them with sequences of paw choices in model non-learner mice that have random unbiased paw choices and with those of C57BL/6JBid (‘C57BL/6J’) mice that have normal interhemispheric connections and learn a paw preference. Positive autocorrelation between successive paw choices during each session and change in paw-preference bias between sessions indicate that 9XCA mice have weak, but not null, learning skills. We tested the effect of the forebrain commissural defect on paw-preference learning with the independent BTBR T+ tf/J (‘BTBR’) mouse strain that has a genetically identical, non-complementing commissural trait. BTBR has weak short-term and long-term memory skills, identical to 9XCA. The results provide strong evidence that CC and HC contribute in memory function and formation of paw-preference biases.

Vertebrate Intersectin1 Is Repurposed to Facilitate Cortical Midline Connectivity and Higher Order Cognition

Invertebrate studies have highlighted a role for EH and SH3 domain Intersectin (Itsn) proteins in synaptic vesicle recycling and morphology. Mammals have two Itsn genes (Itsn1 and Itsn2), both of which can undergo alternative splicing to include DBL/PH and C2 domains not present in invertebrate Itsn proteins. To probe for specific and redundant functions of vertebrate Itsn genes, we generated Itsn1, Itsn2, and double mutant mice. While invertebrate mutants showed severe synaptic abnormalities, basal synaptic transmission and plasticity were unaffected at Schaffer CA1 synapses in mutant mice. Surprisingly, intercortical tracts-corpus callosum, ventral hippocampal, and anterior commissures-failed to cross the midline in mice lacking Itsn1, but not Itsn2. In contrast, tracts extending within hemispheres and those that decussate to more caudal brain segments appeared normal. Itsn1 mutant mice showed severe deficits in Morris water maze and contextual fear memory tasks, whereas mice lacking Itsn2 showed normal learning and memory. Thus, coincident with the acquisition of additional signaling domains, vertebrate Itsn1 has been functionally repurposed to also facilitate interhemispheric connectivity essential for high order cognitive functions.

Right-hemispheric Dominance Of Dentate Granule Cell Activity After Spatial Exploration In Split-brain Mice But Not In Acallosal Mutant Mice

Event Abstract Back to Event Right-hemispheric Dominance Of Dentate Granule Cell Activity After Spatial Exploration In Split-brain Mice But Not In Acallosal Mutant Mice Hassan Ahmed1*, RYOSUKE KAWAKAMI2, Yugo FUKAZAWA3 and Ryuichi Shigemoto4 1 Faculty of veterinary Medicine, South Valley University, Physiology Department, Egypt 2 Research institute for electronic science, Hokkaido University, Laboratory of molecular and cellular biophysics, Japan 3 Nagoya University, Department of anatomy and molecular cell biology, Japan 4 National Institute for Physiological Sciences, Division of Cerebral Structure, Japan In the last decade, left/right brain asymmetry studies have been focused on the molecular level of the hippocampus. First, left/right asymmetry has been reported in GluN2B-NMDA subunit distribution and synaptic plasticity in hippocampal pyramidal cell synapses depending on the side of input (Kawakami et al, 2003). Furthermore, Shinohara et al (2008) found that GluA1-AMPA receptor subunit density, PSD size and spine head volume are larger in CA1 radiatum synapses contacting with presynaptic fibers from right than left CA3. Second, right isomerism in terms of the GluN2B asymmetry was found in inversus viscerum (iv) mice (Kawakami et al, 2008). Third, right-side dominance in spatial learning was reported in split-brain mouse (Shinohara et al, 2012). In the present study, we investigated asymmetry of hippocampal neural activity in wild-type, iv, Arc-Venus transgenic and acallosal mutant mice. Arc-Venus mice have the ability to produce destabilized form of Venus (derivative of green fluorescent protein) controlled by Arc-promoter which is activated by neural stimulation. These mice received transection of ventral hippocampal commissure and corpus callosum with unilateral eye deprivation to force each mice use predominantly either left or right hippocampus during spatial learning. Both left and right eye deprived wild-type mice showed right-side dominance of c-Fos expression in dentate gyrus with a similar tendency in CA1. Venus expression and Venus-immunopositive cells in left eye deprived Arc-Venus mice also showed right-side dominance confirming the dominance of neural activity in right hippocampus. Interestingly, c-Fos positive cells in left eye deprived iv mice also showed right-side dominance regardless of normal or inverted asymmetry in internal organs. On the other hand, left and right eye deprived acallosal mutant mice showed lack of left/right asymmetry in neural activity. These results suggest right-hemispheric dominance in spatial learning in mice and a critical role of corpus callosum for the development of this asymmetry. Keywords: split-brain, asymmetry, Dentate Gyrus, Right-dominance, Acallosal mice Conference: 4th Conference of the Mediterrarnean Neuroscience Society, Istanbul, Turkey, 30 Sep - 3 Oct, 2012. Presentation Type: Poster Presentation Topic: Abstracts Citation: Ahmed H, KAWAKAMI R, FUKAZAWA Y and Shigemoto R (2013). Right-hemispheric Dominance Of Dentate Granule Cell Activity After Spatial Exploration In Split-brain Mice But Not In Acallosal Mutant Mice. Conference Abstract: 4th Conference of the Mediterrarnean Neuroscience Society. doi: 10.3389/conf.fnhum.2013.210.00003 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 06 Feb 2013; Published Online: 11 Apr 2013. * Correspondence: Dr. Hassan Ahmed, Faculty of veterinary Medicine, South Valley University, Physiology Department, Qena, 83523, Egypt, hassan-Younes@vet.svu.edu.eg Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Hassan Ahmed RYOSUKE KAWAKAMI Yugo FUKAZAWA Ryuichi Shigemoto Google Hassan Ahmed RYOSUKE KAWAKAMI Yugo FUKAZAWA Ryuichi Shigemoto Google Scholar Hassan Ahmed RYOSUKE KAWAKAMI Yugo FUKAZAWA Ryuichi Shigemoto PubMed Hassan Ahmed RYOSUKE KAWAKAMI Yugo FUKAZAWA Ryuichi Shigemoto Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Neuroanatomical analysis of the BTBR mouse model of autism using magnetic resonance imaging and diffusion tensor imaging

Autism is a neurodevelopmental disorder characterized by abnormal reciprocal social interactions, communication deficits, and repetitive behaviors with restricted interests. Autism-relevant phenotypes in the inbred mouse strain BTBR T+tf/J (BTBR) offer translational tools to discover biological mechanisms underlying unusual mouse behaviors analogous to symptoms of autism. Two of the most consistent findings with BTBR are lack of sociability as measured by the three-chamber social approach task and increased amount of time engaged in self-grooming in an empty cage. Here we evaluated BTBR as compared to two typical inbred strains with high sociability and low self-grooming, C57BL/6J (B6) and FVB/AntJ (FVB), on both the automated three-chambered social approach task and repetitive self-grooming assays. Brains from the behaviorally tested mice were analyzed using magnetic resonance imaging and diffusion tensor imaging to investigate potential neuroanatomical abnormalities throughout the brain; specifically, to discover neuroanatomical mechanisms which could explain the autism-relevant behavioral abnormalities. Significant differences in volume and white matter microstructure were detected in multiple anatomical regions throughout the brain of BTBR compared to B6 and FVB. Further, significant correlations were found between behavioral measures and areas of the brain known to be associated with those behaviors. For example, striatal volume was strongly correlated to time spent in self-grooming across strains. Our findings suggest that neuropathology exists in BTBR beyond the previously reported white matter abnormalities in the corpus callosum and hippocampal commissure and that these brain differences may be related to the behavioral abnormalities seen in BTBR.

Fiber tract stimulation can reduce epileptiform activity in an in-vitro bilateral hippocampal slice preparation

Mesial temporal lobe epilepsy (MTLE) is a common medically refractory neurological disease that has been treated with electrical stimulation of gray matter with limited success. However, stimulation of a white matter tract connecting the hippocampi could maximize treatment efficacy and extent. We tested low-frequency stimulation (LFS) of a novel target that enables simultaneous targeting of bilateral hippocampi: the ventral hippocampal commissure (VHC) with a novel in-vitro slice preparation containing bilateral hippocampi connected by the VHC. The goal of this study is to understand the role of hippocampal interplay in seizure propagation and reduction by commissural fiber tract stimulation. LFS is applied to the VHC as extracellular and intracellular recording techniques are combined with signal processing to estimate several metrics of epilepsy including: (1) total time occupied by seizure activity (%); (2) seizure duration (s); (3) seizures per minute (#); and (4) power in the ictal (V2Hz−1); as well as (5) interictal spectra (V2Hz−1). Bilateral epileptiform activity in this preparation is highly correlated between hippocampi. Application of LFS to the VHC reduces all metrics of epilepsy during treatment in an amplitude and frequency dependent manner. This study lends several insights into the mechanisms of bilateral seizure reduction by LFS of the VHC, including that depolarization blocking, LTD/LTP and GABAA are not involved. Importantly, enhanced post-stimulation 1-Hz spiking correlates with long-lasting seizure reduction and both are heightened by targeting bilateral hippocampi via the VHC. Therefore, stimulating bilateral hippocampi via a single electrode in the VHC may provide an effective MTLE treatment.

Artificial Theta Stimulation Impairs Encoding of Contextual Fear Memory

Several experiments have demonstrated an intimate relationship between hippocampal theta rhythm (4–12 Hz) and memory. Lesioning the medial septum or fimbria-fornix, a fiber track connecting the hippocampus and the medial septum, abolishes the theta rhythm and results in a severe impairment in declarative memory. To assess whether there is a causal relationship between hippocampal theta and memory formation we investigated whether restoration of hippocampal theta by electrical stimulation during the encoding phase also restores fimbria-fornix lesion induced memory deficit in rats in the fear conditioning paradigm. Male Wistar rats underwent sham or fimbria-fornix lesion operation. Stimulation electrodes were implanted in the ventral hippocampal commissure and recording electrodes in the septal hippocampus. Artificial theta stimulation of 8 Hz was delivered during 3-min free exploration of the test cage in half of the rats before aversive conditioning with three foot shocks during 2 min. Memory was assessed by total freezing time in the same environment 24 h and 28 h after fear conditioning, and in an intervening test session in a different context. As expected, fimbria-fornix lesion impaired fear memory and dramatically attenuated hippocampal theta power. Artificial theta stimulation produced continuous theta oscillations that were almost similar to endogenous theta rhythm in amplitude and frequency. However, contrary to our predictions, artificial theta stimulation impaired conditioned fear response in both sham and fimbria-fornix lesioned animals. These data suggest that restoration of theta oscillation per se is not sufficient to support memory encoding after fimbria-fornix lesion and that universal theta oscillation in the hippocampus with a fixed frequency may actually impair memory.

Coexpression of high-voltage-activated ion channels Kv3.4 and Cav1.2 in pioneer axons during pathfinding in the developing rat forebrain

Precise axon pathfinding is crucial for establishment of the initial neuronal network during development. Pioneer axons navigate without the help of preexisting axons and pave the way for follower axons that project later. Voltage-gated ion channels make up the intrinsic electrical activity of pioneer axons and regulate axon pathfinding. To elucidate which channel molecules are present in pioneer axons, immunohistochemical analysis was performed to examine 14 voltage-gated ion channels (Kv1.1-Kv1.3, Kv3.1-Kv3.4, Kv4.3, Cav1.2, Cav1.3, Cav2.2, Nav1.2, Nav1.6, and Nav1.9) in nine axonal tracts in the developing rat forebrain, including the optic nerve, corpus callosum, corticofugal fibers, thalamocortical axons, lateral olfactory tract, hippocamposeptal projection, anterior commissure, hippocampal commissure, and medial longitudinal fasciculus. We found A-type K⁺ channel Kv3.4 in both pioneer axons and early follower axons and L-type Ca²⁺ channel Cav1.2 in pioneer axons and early and late follower axons. Spatially, Kv3.4 and Cav1.2 were colocalized with markers of pioneer neurons and pioneer axons, such as deleted in colorectal cancer (DCC), in most fiber tracts examined. Temporally, Kv3.4 and Cav1.2 were expressed abundantly in most fiber tracts during axon pathfinding but were downregulated beginning in synaptogenesis. By contrast, delayed rectifier Kv channels (e.g., Kv1.1) and Nav channels (e.g., Nav1.2) were absent from these fiber tracts (except for the corpus callosum) during pathfinding of pioneer axons. These data suggest that Kv3.4 and Cav1.2, two high-voltage-activated ion channels, may act together to control Ca²⁺ -dependent electrical activity of pioneer axons and play important roles during axon pathfinding.

Hippocampal commissure defects in crosses of four inbred mouse strains with absent corpus callosum

It is known that four common inbred mouse strains show defects of the forebrain commissures. The BALB/cJ strain has a low frequency of abnormally small corpus callosum, whereas the 129 strains have many animals with deficient corpus callosum. The I/LnJ and BTBR T+ tf/J strains never have a corpus callosum, whereas half of I/LnJ and almost all BTBR show severely reduced size of the hippocampal commissure. Certain F1 hybrid crosses among these strains are known to be less severely abnormal than the inbred parents, suggesting that the parent strains have different genetic causes of commissure defects. In this study, all hybrid crosses among the four strains were investigated. The BTBR × I/Ln hybrid expressed almost no defects of the hippocampal commissure, unlike its inbred parent strains. Numerous three-way crosses among the four strains yielded many mice with no corpus callosum and severely reduced hippocampal commissure, which shows that the phenotypic defect can result from several different combinations of genetic alleles. The F2 and F3 hybrid crosses of BTBR and I/LnJ had almost 100% absence of the corpus callosum but about 50% frequency of deficient hippocampal commissure. The four-way hybrid cross among all four abnormal strains involved highly fertile parents and yielded a very wide phenotypic range of defects from almost no hippocampal commissure to totally normal forebrain commissures. The F2 and F3 crosses as well as the four-way cross provide excellent material for studies of genetic linkage and behavioral consequences of commissure defects.

A NOVEL ELECTRICAL STIMULATION PARADIGM FOR THE SUPPRESSION OF EPILEPTIFORM ACTIVITY IN ANIN VIVOMODEL OF MESIAL TEMPORAL LOBE STATUS EPILEPTICUS

In this study, we present a novel low-frequency electrical stimulation paradigm for mesial temporal lobe epilepsy (MTLE). The paradigm utilizes the hippocampal commissure as a unique stimulation target to simultaneously influence large portions of the bilateral hippocampal network. When applied to an acute rat model of MTLE, animals that received stimulation exhibited an 88% reduction in the signal power of the bilateral epileptiform activity relative to the control group. In addition, the stimulation entrained the hippocampal network's spontaneous epileptiform activity and disrupted its bilateral synchrony.

Low Frequency Electrical Stimulation of White Matter Tracts in Intractable Mesial Temporal Lobe Epilepsy (IN5-1.010)

Objective: To explore the tolerability and efficacy of low-frequency stimulation (LFS) of white matter tracts (WMT) in patients with intractable mesial temporal lobe epilepsy (MTLE). Background Deep brain stimulation has had limited success in epilepsy. However, WMTs have not been stimulated, and low frequencies have not been adequately explored for treatment of epilepsy. Design/Methods: Seven adult patients with MTLE underwent implantation of depth electrodes in WMTs: the corpus of the fornix (n=2) and lateral to the splenium of the corpus callosum where fibers of the dorsal hippocampal commissure travel with the crus of the fornix (n=5). All patients had hippocampal electrodes. 1-Hz stimulation of the WMT in all subjects elicited hippocampal evoked potentials (EPs), confirming connectivity. The EP duration was approximately 200 msec suggesting that 5-Hz stimulation would elicit continuous interference of hippocampal activity. LFS-WMT occurred in 4-hour sessions (1-3 sessions/patient at 5Hz, current 8mA, pulse width 0.2msec) while in the video-EEG unit. Results: There were no complications, and hourly mini-mental status examination scores showed a mean increase of 0.917 during LFS-WMT (P Conclusions: Our data show that LFS-WMT activates the hippocampus and other areas of Papez circuit, and reduces epileptiform discharges and seizures, without affecting memory. Stimulation of WMTs appears to be attractive because it interferes with spontaneous electrical activity of a relatively extensive cortical area, and requires less current injection, implying more safety and a longer battery life. Our data illustrate the need for an exploratory trial to confirm safety and tolerability of LFS-WMT using different parameters using a chronic implantable pulse generator. Disclosure: Dr. Koubeissi has received personal compensation for activities with UCB Pharma and Pfizer Inc as a speaker. Dr. Durand has nothing to disclose. Dr. Kahriman has nothing to disclose. Dr. Syed has nothing to disclose. Dr. Miller has nothing to disclose. Dr. Luders has nothing to disclose.

Low frequency stimulation of ventral hippocampal commissures reduces seizures in a rat model of chronic temporal lobe epilepsy

To investigate the effects of low frequency stimulation (LFS) of a fiber tract for the suppression of spontaneous seizures in a rat model of human temporal lobe epilepsy. Stimulation electrodes were implanted into the ventral hippocampal commissure (VHC) in a rat post-status epilepticus (SE) model of human temporal lobe epilepsy (n = 7). Two recording electrodes were placed in the CA3 regions bilaterally and neural data were recorded for a minimum of 6 weeks. LFS (60 min train of 1 Hz biphasic square wave pulses, each 0.1 ms in duration and 200 μA in amplitude, followed by 15 min of rest) was applied to the VHC for 2 weeks, 24 h a day. The baseline mean seizure frequency of the study animals was 3.7 seizures per day. The seizures were significantly reduced by the application of LFS in every animal (n = 7). By the end of the 2-week period of stimulation, there was a significant, 90% (<1 seizure/day) reduction of seizure frequencies (p < 0.05) and a 57% reduction during the period following LFS (p < 0.05) when compared to baseline. LFS also resulted in a significant reduction of hippocampal interictal spike frequency (71%, p < 0.05), during 2 weeks of LFS session. The hippocampal histologic analysis showed no significant difference between rats that received LFS and SE induction and those that had received only SE-induction. None of the animals showed any symptomatic hemorrhage, infection, or complication. Low frequency stimulation applied at a frequency of 1 Hz significantly reduced both the excitability of the neural tissue as well as the seizure frequency in a rat model of human temporal lobe epilepsy. The results support the hypothesis that LFS of fiber tracts can be an effective method for the suppression of spontaneous seizures in a temporal lobe model of epilepsy in rats and could lead to the development of a new therapeutic modality for human patients with temporal lobe epilepsy.

Demyelination and remyelination in anatomically distinct regions of the corpus callosum following cuprizone intoxication

Multiple sclerosis is a chronic demyelinating disease of the central nervous system. Spontaneous remyelination during early disease stages is thought to preserve and partially restore function. However, this process ceases in later stages despite the presence of pre-oligodendrocytes. Cuprizone-induced demyelination is a useful model with which to study the remyelination process. Previous studies have demonstrated heterogeneities in demyelination in individual animals. Here we investigated regional differences in demyelination and remyelination within the corpus callosum. C57BL/6 mice were fed 0.2% cuprizone for 5 weeks to induce demyelination. Remyelination was examined 2–5 weeks after cuprizone withdrawal. Immunohistochemistry and electron microscopy were used to quantify regional differences in demyelination, gliosis, and remyelination. We found that, while demyelination was limited in the rostral region of corpus callosum, nearly complete demyelination occurred in the caudal callosum, beginning at approximately −0.5 mm from bregma. Astrogliosis and microgliosis were correlated with demyelination and differed between the rostral and caudal callosal structures. Remyelination upon cessation of cuprizone ensued at different rates with splenium remyelinating faster than dorsal hippocampal commissure. Our data show anatomical differences of cuprizone-induced demyelination and remyelination in the corpus callosum and the importance of examining specific callosal regions in myelin repair studies using this model.

RA-GEF-1 (Rapgef2) is essential for proper development of the midline commissures

The cerebral hemispheres are directly connected by three major interhemispheric fibers: the corpus callosum, the anterior commissure, and the hippocampal commissure. RA-GEF-1 (also termed Rapgef2) is a guanine nucleotide exchange factor responsible for sustained activation of Rap1. We previously reported anatomical defects of the major forebrain commissures in the adult dorsal telencephalon-specific RA-GEF-1 conditional knockout (cKO) mice. In this study, we use neuroanatomical tracing and immunohistochemistry to study the formation of the commissural fibers during early postnatal development. DiI anterograde tracing reveals the inability of the callosal axons to cross the midline in cKO mice, thereby forming Probst bundles on the ipsilateral side, which is associated with the absence of the indusium griseum glia and the glial sling at the cortical midline. Wheat germ agglutinin-conjugated horseradish peroxidase retrograde tracing verifies the agenesis of the anterior commissure in cKO mice, and DiI anterograde tracing confirms the deviation of the fibers from their original tract. As for the hippocampal commissure, agenesis and hypoplasia are observed in its dorsal and ventral parts, respectively. These results indicate the essential role of RA-GEF-1 in the proper formation of the cerebral midline commissures.

The Dorsal Hippocampal Commissure: When Functionality Matters

The Dorsal Hippocampal Commissure: When Functionality Matters

PA.01 The dorsal hippocampal commissure: when the functionality matters

AimsThe human hippocampal phylogeny is manifested by near or total disappearance of ventral hippocampal commissure. In contrast, the dorsal hippocampal commissure, although considered controversial and vehemently disputed by some groups,...

Right‐hemispheric dominance of spatial memory in split‐brain mice

Left-right asymmetry of human brain function has been known for a century, although much of molecular and cellular basis of brain laterality remains to be elusive. Recent studies suggest that hippocampal CA3-CA1 excitatory synapses are asymmetrically arranged, however, the functional implication of the asymmetrical circuitry has not been studied at the behavioral level. In order to address the left-right asymmetry of hippocampal function in behaving mice, we analyzed the performance of "split-brain" mice in the Barnes maze. The "split-brain" mice received ventral hippocampal commissure and corpus callosum transection in addition to deprivation of visual input from one eye. In such mice, the hippocampus in the side of visual deprivation receives sensory-driven input. Better spatial task performance was achieved by the mice which were forced to use the right hippocampus than those which were forced to use the left hippocampus. In two-choice spatial maze, forced usage of left hippocampus resulted in a comparable performance to the right counterpart, suggesting that both hippocampal hemispheres are capable of conducting spatial learning. Therefore, the results obtained from the Barnes maze suggest that the usage of the right hippocampus improves the accuracy of spatial memory. Performance of non-spatial yet hippocampus-dependent tasks (e.g. fear conditioning) was not influenced by the laterality of the hippocampus.

Low frequency stimulation decreases seizure activity in a mutation model of epilepsy

To investigate brain electrical activity in Q54 mice that display spontaneous seizures because of a gain-of-function mutation of the Scn2a sodium channel gene, and to evaluate the efficacy of low frequency deep brain stimulation (DBS) for seizure frequency reduction. Electroencephalography (EEG), electromyography (EMG), and hippocampal deep electrodes were implanted into Q54 mice expressing an epileptic phenotype (n = 6). Chronic six channel recordings (wideband, 0.1-300 Hz) were stored 24 h a day for more than 12 days. Low frequency stimulation (LFS) (3 Hz, square wave, biphasic, 100 μs, 400 μA) was applied to the ventral hippocampal commissure (VHC) in alternating 5 min cycles (on or off) 24 h a day for a period of 4 days. LFS (3 Hz) resulted in a significant reduction in seizure frequency and duration (21% and 35%, p < 0.05), when applied to the VHC of epileptic Q54 mice (n = 6). Seizure frequency was not directly affected by stimulation state ("on" vs. "off"). LFS applied at a frequency of 3 Hz significantly reduced seizure frequency and duration in the Q54 model. Furthermore, the reduction of seizure frequency and duration by LFS was not immediate but had a delayed and lasting effect, supporting complex, indirect mechanisms of action.