bluuebunny/crossref_metadata_2025 huggingface dataset:
Lamprey as an evo‐devo model: Lessons from comparative embryology and molecular phylogenetics
Authors: Kuratani Shigeru , Kuraku Shigehiro , Murakami Yasunori
Published: October 2002

Lamprey, the living jawless vertebrate, has been regarded as one of the most primitive groups of vertebrates. The evolutionary phylogenetic position of the lamprey promises to provide hints about the origin of the vertebrate genome as well as the origin of the body plan, a part of which may be written in the genome. Since the lamprey split from the gnathostome lineage early in the history of vertebrates, the shared developmental mechanisms in lampreys and gnathostomes can be regarded as possessed by the hypothetical common ancestor of these animals, whereas the gnathostome‐specific developmental mechanisms that are absent from lampreys indicate that they are relatively new, added to the developmental program only after the split of gnathostomes. Thus, the sequential establishment of the gnathostome body plan is inherently related to the history of genomic duplication events. In this review, recent molecular developmental and evolutionary molecular research on the living lampreys are summarized and discussed, taking vertebrate comparative morphology and embryology into consideration. genesis 34:175–183, 2002. © 2002 Wiley‐Liss, Inc.
Abnormalities in cloned mice are not transmitted to the progeny
Authors: Shimozawa Nobuhiro , Ono Yukiko , Kimoto Shingo , Hioki Kyoji , Araki Yoshihiko , Shinkai Yoichi , Kono Tomohiro , Ito Mamoru
Published: October 2002

Cloned animals suffer a wide range of severe fetal and placental malformations. Whether these malformations arise from insufficient epigenetic modifications or mutations has not yet been determined. To address this question, we examined siblings from both cloned XO and XY parents. These parents, which exhibited hypertrophic placentas, increased body weights, and open eyelids at birth, were created from the same ES cell sublines. The siblings from all three cloned pairs showed normal body and placenta weights and no open eyelids at birth. The results clearly showed that the phenotypic abnormalities seen in cloned mice were not transmitted to the progeny, a finding that suggests that abnormalities in cloned mice are responsible for insufficient epigenetic modifications/reprogramming. genesis 2:203–207, 2002. © 2002 Wiley‐Liss, Inc.
ER‐based double icre fusion protein allows partial recombination in forebrain
Authors: Casanova Emilio , Fehsenfeld Sandra , Lemberger Thomas , Shimshek Derya R. , Sprengel Rolf , Mantamadiotis Theo
Published: October 2002

Here we describe the generation of a new tamoxifen‐inducible double Cre fusion protein generated by fusing two ERT2 domains onto both ends of the iCre recombinase (a codon improved Cre recombinase). This Cre fusion protein (ERiCreER) had a twofold increased activity in cell culture assays than the previously described MerCreMer Cre double fusion protein. ERiCreER was targeted to the brain by placing it under the control of the promoter from the CamKIIα gene using a 170 kb BAC. The fusion protein was detected in hippocampus, cortex, striatum, thalamus, and hypothalamus but not in cerebellum. The ERiCreER was cytoplasmatic in the absence of tamoxifen and translocated into the nucleus upon tamoxifen administration. The activity of the ERiCreER was tested in vivo by mating the CamKIIα ERiCreER transgenic line with mice harbouring exon 10 of the CREB gene flanked by two LoxP sites. In the absence of tamoxifen, no background activity was detected in mice older than 6 months. After tamoxifen administration, most if not all of the ERiCreER fusion protein translocated from the cytoplasm to the nucleus; however, only 5–10% of the “floxed” CREB allele was recombined. Recombination was also visualised at the cellular level by following the upregulation of the CREM protein, which corresponds precisely with CREB loss/recombination. Unlike in other tissues (Sohal et al., 2001; Tannour‐Louet et al., 2002), it appears that in brain, although ERiCreER can bind tamoxifen, the Cre‐recombinase cannot be fully activated. genesis 34:208–214, 2002. © 2002 Wiley‐Liss, Inc.
Visualization of rod photoreceptor development using GFP‐transgenic zebrafish
Authors: Hamaoka Takanori , Takechi Masaki , Chinen Akito , Nishiwaki Yuko , Kawamura Shoji
Published: October 2002

Summary: Zebrafish retina contains five morphologically distinct classes of photoreceptors, each expressing a distinct type of opsin gene. Molecular mechanisms underlying specification of opsin expression and differentiation among the cell types are largely unknown. This is partly because mutants affected with expression of a particular class of opsin gene are difficult to find. In this study we established the transgenic lines of zebrafish carrying green fluorescent protein (GFP) gene under the 1.1‐kb and 3.7‐kb upstream regions of the rod‐opsin gene. In transgenic fish, GFP expression initiated and proceeded in the same spatiotemporal pattern with rod‐opsin gene. The retinal section from adult transgenic fish showed GFP expression throughout the rod cell layer. These results indicate that the proximal 1.1‐kb region is sufficient to drive gene expression in all rod photoreceptor cells. These transgenic fish should facilitate screening of mutants affected specifically with rod‐opsin expression or rod cell development by visualization of rod cells by GFP. genesis 34:215–220, 2002. © 2002 Wiley‐Liss, Inc.
Statistical parametric mapping of LORETA using high density EEG and individual MRI: Application to mismatch negativities in Schizophrenia
Authors: Park Hae‐Jeong , Kwon Jun Soo , Youn Tak , Pae Ji Soo , Kim Jae‐Jin , Kim Myung‐Sun , Ha Kyoo‐Seob
Published: October 2002

We describe a method for the statistical parametric mapping of low resolution electromagnetic tomography (LORETA) using high‐density electroencephalography (EEG) and individual magnetic resonance images (MRI) to investigate the characteristics of the mismatch negativity (MMN) generators in schizophrenia. LORETA, using a realistic head model of the boundary element method derived from the individual anatomy, estimated the current density maps from the scalp topography of the 128‐channel EEG. From the current density maps that covered the whole cortical gray matter (up to 20,000 points), volumetric current density images were reconstructed. Intensity normalization of the smoothed current density images was used to reduce the confounding effect of subject specific global activity. After transforming each image into a standard stereotaxic space, we carried out statistical parametric mapping of the normalized current density images. We applied this method to the source localization of MMN in schizophrenia. The MMN generators, produced by a deviant tone of 1,200 Hz (5% of 1,600 trials) under the standard tone of 1,000 Hz, 80 dB binaural stimuli with 300 msec of inter‐stimulus interval, were measured in 14 right‐handed schizophrenic subjects and 14 age‐, gender‐, and handedness‐matched controls. We found that the schizophrenic group exhibited significant current density reductions of MMN in the left superior temporal gyrus and the left inferior parietal gyrus (P < 0. 0005). This study is the first voxel‐by‐voxel statistical mapping of current density using individual MRI and high‐density EEG. Hum. Brain Mapping 17:168–178, 2002. © 2002 Wiley‐Liss, Inc.
Changes in neural circuitry of language before and after treatment of major depression
Authors: Abdullaev Yalçin , Kennedy Barbara L. , Tasman Allan
Published: October 2002

Language tasks requiring semantic analysis of word meaning activate distinct brain areas including the anterior cingulate gyrus at about 200 msec after the stimulus onset, the left lateral prefrontal cortex at about 250 msec, and the left temporo‐parietal (Wernicke's) area at 500–600 msec. Reading the same words activate the insula around 800 msec and left occipital cortex around 200 msec stronger than the semantic analysis in normal subjects. Many of these brain areas also show abnormal activity in resting state in patients with major unipolar depression. We measured 128‐channel event‐related brain potentials (ERPs) and statistical probability mapping in the use generation task carried out with single visual nouns to explore the topography and time course of these cortical activations related to semantic processing in 11 patients with major unipolar depression before and 8 weeks after treatment with the selective serotonin reuptake inhibitor (SSRI) citalopram. Before treatment in depressed state, the time course for the left prefrontal cortex activation did not show slowing, but was accompanied by the right prefrontal activation with a similar time course. The left posterior temporo‐parietal activation appeared later than in normals. Treatment was accompanied by the complete elimination of the right prefrontal activation in the same use generation task. Time course of the posterior left temporo‐parietal area showed a trend toward normalization. Insula‐related activation in reading task was not seen in depressed state, but was evident in the same patient group after the depression has lifted, presumably as a result of treatment with citalopram. Hum. Brain Mapping 17:156–167, 2002. © 2002 Wiley‐Liss, Inc.
Validating the boundary element method for forward and inverse EEG computations in the presence of a hole in the skull
Authors: Oostenveld Robert , Oostendorp Thom F.
Published: October 2002

Holes in the skull may have a large influence on the EEG and ERP. Inverse source modeling techniques such as dipole fitting require an accurate volume conductor model. This model should incorporate holes if present, especially when either a neuronal generator or the electrodes are close to the hole, e.g., in case of a trephine hole in the upper part of the skull. The boundary element method (BEM) is at present the preferred method for inverse computations using a realistic head model, because of its efficiency and availability. Using a simulation approach, we have studied the accuracy of the BEM by comparing it to the analytical solution for a volume conductor without a hole, and to the finite difference method (FDM) for one with a hole. Furthermore, we have evaluated the influence of holes on the results of forward and inverse computations using the BEM. Without a hole and compared to the analytical model, a three‐sphere BEM model was accurate up to 5–10%, while the corresponding FDM model had an error <0.5%. In the presence of a hole, the difference between the BEM and the FDM was, on average, 4% (1.3–11.4%). The FDM turned out to be very accurate if no hole is present. We believe that the difference between the BEM and the FDM represents the inaccuracy of the BEM. This inaccuracy in the BEM is very small compared to the effect that holes can have on the scalp potential (up to 450%). In regard to the large influence of holes on forward and inverse computations, we conclude that holes in the skull can be treated reliably by means of the BEM and should be incorporated in forward and inverse modeling. Hum. Brain Mapping 17:179–192, 2002. © 2002 Wiley‐Liss, Inc.
Fast robust automated brain extraction
Authors: Smith Stephen M.
Published: October 2002

An automated method for segmenting magnetic resonance head images into brain and non‐brain has been developed. It is very robust and accurate and has been tested on thousands of data sets from a wide variety of scanners and taken with a wide variety of MR sequences. The method, Brain Extraction Tool (BET), uses a deformable model that evolves to fit the brain's surface by the application of a set of locally adaptive model forces. The method is very fast and requires no preregistration or other pre‐processing before being applied. We describe the new method and give examples of results and the results of extensive quantitative testing against “gold‐standard” hand segmentations, and two other popular automated methods. Hum. Brain Mapping 17:143–155, 2002. © 2002 Wiley‐Liss, Inc.
Neural implementation of response selection in humans as revealed by localized effects of stimulus–response compatibility on brain activation
Authors: Schumacher Eric H. , D'Esposito Mark
Published: October 2002

Response selection, which involves choosing representations for appropriate motor behaviors given one's current situation, is a fundamental mental process central to a wide variety of human performance, yet the neural mechanisms underlying this mental process remain unclear. Research using nonhuman primates implicates ventral prefrontal and lateral premotor cortices in this process. In contrast, human neuroimaging research also highlights the role of dorsal prefrontal, anterior cingulate, and superior parietal cortices in response selection. This inconsistency may stem from the difficulty of isolating response selection within the constraints of cognitive subtraction methodology utilized in neuroimaging. We overcome this limitation by using an experimental procedure designed to selectively influence discrete mental processing stages and analyses that are less reliant on the assumptions of cognitive subtraction. We varied stimulus contrast to affect stimulus encoding and stimulus–response compatibility to affect response selection. Brain activation data suggest processing specific to response selection in superior parietal and dorsal prefrontal cortices, and not ventral prefrontal cortex. Anterior cingulate and lateral premotor cortices may also be involved in response selection, or these regions may mediate other response processes. Hum. Brain Mapping 17:193–201, 2002. © 2002 Wiley‐Liss, Inc.
Cortical and subcortical networks underlying syncopated and synchronized coordination revealed using fMRI
Authors: Mayville Justine M. , Jantzen Kelly J. , Fuchs Armin , Steinberg Fred L. , Kelso J.A. Scott
Published: October 2002

Inherent differences in difficulty between on the beat (synchronization) and off the beat (syncopation) coordination modes are well known. Synchronization is typically quite easy and, once begun, may be carried out with little apparent attention demand. Syncopation tends to be difficult, even though it has been described as a simple, phase‐shifted version of a synchronized pattern. We hypothesize that syncopation, unlike synchronization, is organized on a cycle‐by‐cycle basis, thereby imposing much greater preparatory and attentional demands on the central nervous system. To test this hypothesis we used fMRI to measure the BOLD response during syncopation and synchronization to an auditory stimulus. We found that the distribution of cortical and subcortical areas involved in intentionally coordinating movement with an external metronome depends on the timing pattern employed. Both synchronized and syncopated patterns require activation of contralateral sensorimotor and caudal supplementary motor cortices as well as the (primarily ipsilateral) cerebellum. Moving off the beat, however, requires not only additional activation of the cerebellum but also the recruitment of another network comprised of the basal ganglia, dorsolateral premotor, rostral supplementary motor, prefrontal, and temporal association cortices. No areas were found to be more active during synchronization than syncopation. The functional role of the cortical and subcortical regions areas involved in syncopation supports the hypothesis that whereas synchronization requires little preparation and monitoring, syncopated movements are planned and executed individually on each perception–action cycle. Hum. Brain Mapping 17:214–229, 2002. © 2002 Wiley‐Liss, Inc.
Determination of individual stimulus–response curves in the visual cortex
Authors: Hagenbeek Rogier E. , Rombouts Serge A.R.B. , van Dijk Bob W. , Barkhof Frederik
Published: October 2002

Activation in the visual cortex is typically studied using group average changes in an on–off paradigm for a single flicker frequency. We used functional magnetic resonance imaging (fMRI) to characterize the stimulus–response curve in the visual cortex as a function of flicker frequency in individual subjects, using LED goggles with 17 frequency steps between 0 and 30 Hz. Ten healthy young individuals were studied on two different occasions (mean interval; 22 days). In all but one subject, a third‐order polynomial curve could be fitted to the data. From the response curve we calculated the peak response (the frequency where the response amplitude was maximal), the percentage change (relative difference) of the response amplitudes between 8 Hz and the peak frequency, and the average slope of response (towards the peak). On both occasions we could determine a peak response for each subject with small within‐subject variability. The average absolute difference in peak response between both sessions was 1.37 Hz (range, 0.2–4.3 Hz), indicating that the peak frequency is rather stable for a given individual. In conclusion, our study illustrates the ability of fMRI to examine the stimulus–response curve in individual subjects in the visual cortex. Based on our findings, the peak response and the slope of response seem highly reproducible within subjects. A similar analysis of the stimulus–response curve may be applicable to other types of stimuli. Hum. Brain Mapping 17:245–251, 2002. © 2002 Wiley‐Liss, Inc.
Medial temporal lobe activation during context‐dependent relational processes in episodic retrieval: An fMRI study
Authors: Tsukiura Takashi , Fujii Toshikatsu , Takahashi Toshimitsu , Xiao Ruiting , Sugiura Motoaki , Okuda Jiro , Iijima Toshio , Yamadori Atsushi
Published: October 2002

Previous studies have reported that the medial temporal lobe (MTL) structures contribute to the processing of relations among multiple stimuli in episodic encoding. There have been few studies, however, on the episodic retrieval requiring processing of relations among multiple components that was involved in our events. We used functional magnetic resonance imaging (fMRI) to investigate neural activities during the retrieval of relations within an organized episode and the recognition of an episodic component. Healthy, normal participants memorized 50 four‐scene comic strips before fMRI scanning. In the retrieval phase with fMRI scanning, participants were engaged in three tasks: a visual identification (VI) task, a story recall (SR) task, and a picture recognition (PRe) task. In the VI task, participants were asked to judge whether they could identify at least one female character in the two scenes presented vertically. In the SR task, participants were shown the first and last scenes from strips memorized previously and asked to judge whether or not the two scenes were from the same strip. In the PRe task, participants were shown two scenes and asked to judge whether they both belonged to the memorized scenes. The two contrasts of SR with VI and PRe with VI demonstrated some commonly activated areas, such as the bilateral middle frontal gyrus and cerebellum. More importantly, the SR task differentially activated the bilateral parahippocampal gyrus, whereas the PRe task differentially activated right prefrontal areas, including the inferior frontal and precentral gyri. The results suggest that the activity of the MTL structures may be strongly associated with episodic memory retrieval requiring context‐dependent relational processing. Hum. Brain Mapping 17:203–213, 2002. © 2002 Wiley‐Liss, Inc.
Monitoring eye movements during fMRI tasks with echo planar images
Authors: Tregellas Jason R. , Tanabe Jody L. , Miller David E. , Freedman Robert
Published: October 2002

Verifying task compliance during functional magnetic resonance imaging (fMRI) experiments is an essential component of experimental design. To date, studies of oculomotor tasks such as smooth pursuit eye movements have either measured task performance outside the magnet and assumed similar performance during functional neuroimaging, or have used MR‐compatible eye movement recording devices, which can be costly and technically difficult to use. We describe a simple method to visualize and quantify eye movements during an imaging experiment using the gradient echo images. We demonstrate that local eye movements will influence whole‐head motion correction procedures, resulting in inaccurate movement parameters and potentially lowering the sensitivity to detect activations. Hum. Brain Mapping 17:238–244, 2002. © 2002 Wiley‐Liss, Inc.
Novelty detection and repetition suppression in a passive picture viewing task: A possible approach for the evaluation of neuropsychiatric disorders
Authors: Jessen Frank , Manka Christoph , Scheef Lukas , Granath Dirk‐Oliver , Schild Hans H. , Heun Reinhard
Published: October 2002

The applicability of functional magnetic resonance imaging (fMRI) in patients with Alzheimer's disease (AD) or schizophrenia is frequently limited by cognitive impairment, which prevents the adequate execution of complex tasks. An experimental design that puts only minor demands on the patients' cognitive ability but engages disease‐relevant brain structures would be of benefit. Novelty detection and repetition suppression are two basic components of memory that might be used to investigate specific brain areas under these conditions. Novelty detection has been related to hippocampal activation increases. Stimulus repetition related activation decreases (suppression) have been observed in the extrastriate cortex and have been related to perceptual priming. Both processes have been examined primarily in neuroimaging studies with complex cognitive tasks. We used event‐related fMRI to investigate novelty‐ and repetition‐related effects in an attended but passive picture‐viewing task in healthy subjects. The differential activation, detected in the novel vs. repeated contrast, was located in the bilateral anterior hippocampus and in bilateral occipital and inferior‐temporal areas. The hippocampal activation is of interest because medial temporal lobe lesions are key features in AD and schizophrenia. The repetition‐related activation decreases in the extrastriate areas are of potential value in investigating the conflicting results regarding perceptual priming impairment in both disorders. Our results indicate that activation of disease‐relevant brain regions under passive task conditions is possible. This might increase the utility of functional imaging in cognitively impaired patients. Hum. Brain Mapping 17:231–237, 2002. © 2002 Wiley‐Liss, Inc.
Activity‐induced changes of spine morphology
Authors: Nikonenko Irina , Jourdain Pascal , Alberi Stefano , Toni Nicolas , Muller Dominique
Published: October 2002

Spine morphology has been shown in recent years to exhibit a high degree of plasticity. In developing tissue such as organotypic slice cultures, shape changes in spines as well as reorganization of the postsynaptic density (PSD) occur within minutes. Furthermore, several studies have shown that these and other changes can be induced by or are dependent on synaptic activation. Formation of filopodia, enlargement of spines, formation of spines with perforated PSDs, appearance of new spines, and formation of specific types of synapses such as multiple synapse boutons (MSBs), in which two spines contact the same terminal, have all been reported to be induced in an activity‐dependent manner. The common denominator of most of these different processes is that they are calcium and NMDA receptor dependent. Their time course, however, may vary. Some appear quite rapidly after stimulation (e.g., filopodia, perforated synapses), while others are clearly more delayed (e.g., formation of spines, appearance of MSBs). How these different structural changes relate to each other, as well as their functional significance, have therefore become intriguing issues. The characteristics of these different types of morphological changes are reviewed, with a discussion of the possibility that structural plasticity contributes to changes in synaptic efficacy. Hippocampus 2002;12:585–591. © 2002 Wiley‐Liss, Inc.
A large sustained Ca2+ elevation occurs in unstimulated spines during the LTP pairing protocol but does not change synaptic strength
Authors: Conti Rossella , Lisman John
Published: October 2002

Synapses in the CA1 region of the hippocampus undergo bidirectional synaptic modification in response to different patterns of activity. Postsynaptic Ca2+ elevation can trigger either synaptic strengthening or weakening, depending on the properties of the local Ca2+ signal. During the pairing protocol for long‐term potentiation (LTP) induction, the cell is depolarized under voltage‐clamp and is given low‐frequency synaptic stimulation. As an initial step toward understanding the Ca2+ dynamics during this process, we used confocal microscopy to study the Ca2+ signals in spines evoked by the depolarization itself. This depolarization activates voltage‐dependent Ca2+ channels (VDCC), but whether these channels inactivate rapidly or remain functional throughout the long depolarizations used in the pairing protocol remains unknown. Cells were depolarized to 0 mV for 2–3 min. This depolarization led to a large initial elevation of Ca2+ in spines that never decayed back to resting levels. The maintained signal was close to the Kd of the low‐affinity (5 μM) Ca2+ dye, Magnesium Green. We attempted to determine the functional role of this elevation, using the Ca2+‐channel blocker D‐890. The addition of D‐890 in the internal solution produced a nearly complete abolition of the Ca2+ elevation during depolarization. Under these conditions, the NMDA conductance was normal, but LTP was almost completely blocked. This might suggest the importance of VDCC in LTP; however, we found that high concentrations of D‐890 can directly inhibit calmodulin protein kinase II (CaMKII), an enzyme required for LTP induction. Thus, whereas D‐890 is a useful tool for blocking postsynaptic VDCC, it cannot be used to study the contribution of these channels to plasticity. We conclude that the activation of VDCC produces a large and persistent elevation of Ca2+ in all spines, but does not produce either LTP or long‐term depression (LTD) in the absence of synaptic stimulation. The possible reasons for this are discussed. Hippocampus 2002;12:667–679. © 2002 Wiley‐Liss, Inc.
Learning and memory of cue–reward association meaning by modifications of synaptic efficacy in dentate gyrus and piriform cortex
Authors: Truchet B. , Chaillan F.A. , Soumireu‐Mourat B. , Roman F.S.
Published: October 2002

This article begins with a review of recent experiments investigating the synaptic efficacy changes occurring in rat dentate gyrus and piriform cortex during an associative olfactory task. In all these experiments, animals were trained to discriminate among an artificial cue, a patterned electrical stimulation distributed to the lateral olfactory tract associated with a water reward, and a natural odor associated with a flash of light. Monosynaptic field potential responses evoked by single electrical stimuli to the lateral olfactory tract were recorded in the ipsilateral piriform cortex before and just after each training session. Monosynaptic field and polysynaptic field potentials evoked by single electrical stimuli applied respectively to the lateral perforant pathway and lateral olfactory tract were also recorded in ipsilateral dentate gyrus. The results showed an increase in synaptic efficacy subsequent to the first training session in the dentate gyrus network when compared with piriform cortex at the later stage of the learning. The early increase of monosynaptic response in the dentate gyrus was observed immediately after the first learning session but disappeared 24 h later. Inversely, a synaptic depression developed across sessions, becoming significant at the onset of the last (fifth) session. The polysynaptic potential recorded in this structure increased substantially when rats began to discriminate the learning cues, usually after the second or third learning session. Then, from the third to the fifth session, an LTP like‐phenomenon appeared in piriform cortex when rats perfectly mastered the associations. Experiments using high‐frequency stimulation to prevent changes in gyrus dentatus indicated that the onset of the observed depression was necessary for the learning of the olfactory associations. The fact that hippocampal and cortical neuronal networks exhibited different timing in synaptic efficacy changes could physiologically explain learning and memory processes. Hippocampus 2002;12:600–608. © 2002 Wiley‐Liss, Inc.
Hippocampal function during behaviorally silent associative learning: Dissociation of memory storage and expression
Authors: Talk Andrew C. , Gandhi Chetan C. , Matzel Louis D.
Published: October 2002

In laboratory studies, the assessment of memory is typically associated with overt behavioral responses. Thus, it has been difficult to determine whether the enhancement of hippocampal sensory‐evoked potentials that often accompany memory formation are the neurophysiological manifestation of a memory “trace” or are a secondary product of the behavioral expression of the memory. We addressed this issue by examining changes in evoked hippocampal field potentials during sensory preconditioning, a form of behaviorally silent relational learning that requires an intact hippocampus for execution. Rats were exposed to presentations of a white noise (S1) that terminated with a tone (S2). These pairings of ostensibly “neutral” stimuli supported no change in the behavior elicited by the noise. However, if the tone was subsequently paired with mild footshock (US), suppression of ongoing licking behavior (indicative of fear) was elicited by the noise, indicating that the animal had associated the noise with tone (S1‐S2), and had represented the noise‐tone‐shock (S1‐S2‐US) relationship. Pre‐training neurotoxic lesions of the hippocampus had no effect on conditioned suppression to tone after tone‐shock (S2‐US) pairings, but disrupted the expression of continued suppression to noise (S1) after tone‐shock pairings. In a second experiment, sensory‐evoked field potentials in the dorsal hippocampus were recorded with extracellular electrodes. No changes in the hippocampal response evoked by white noise were observed after pairings of noise and tone, i.e., no evidence for a memory trace could be detected. In contrast, after tone was paired with footshock, two short‐latency negative potentials within the noise‐evoked field response increased in amplitude, a response often presumed to reflect a neurophysiological correlate of memory storage. In total, these results suggest that although the hippocampus critically contributes to the processing of a behaviorally silent associative memory, there may be no role for changes in the amplitude of hippocampal sensory‐evoked field potentials in storing representations of the relationships between sensory experiences. Hippocampus 2002;12:648–656. © 2002 Wiley‐Liss, Inc.
Long‐term potentiation as a substrate for memory: Evidence from studies of amygdaloid plasticity and Pavlovian fear conditioning
Authors: Goosens Ki A. , Maren Stephen
Published: October 2002

Recent reports have raised concerns about the ability of long‐term potentiation (LTP) to account for associative learning and memory. In this paper, we review the many mechanistic similarities between one form of associative learning, Pavlovian fear conditioning, and amygdaloid LTP. We then address many of the criticisms levied against LTP within the framework of fear conditioning. We believe that many of the apparent discrepancies between LTP and behavior can be generally accounted for by a failure to appreciate that learned behavior is supported by multiple synapses in an extensive network of brain structures. We conclude that LTP remains a viable substrate for memory. Hippocampus 2002;12:592–599. © 2002 Wiley‐Liss, Inc.
Regulated transcription of the immediate‐early gene Zif268: Mechanisms and gene dosage‐dependent function in synaptic plasticity and memory formation
Authors: Bozon Bruno , Davis Sabrina , Laroche Serge
Published: October 2002

The immediate‐early gene Zif268 is a member of the Egr family of inducible transcription factors. Data from gene expression studies have suggested that this gene may play a critical role in initial triggering of the genetic machinery that has long been considered a necessary mechanism for maintenance of the later phases of LTP and also for the consolidation or stabilization of long‐lasting memories. Until recently, however, the data supporting this assumption have been based primarily on circumstantial evidence, with no direct evidence to suggest that Zif268 is required for long‐lasting synaptic plasticity and memory. In this report, we review our own data using Zif268 mutant mice; we show that although the early phase of dentate gyrus LTP is normal in these mice, the later phases are not present, and the ability of the mice to maintain learned information over a 24‐h period is deficient. In addition, we present new information showing a task‐dependent gene dosage effect in Zif268 heterozygous mice. We show that spatial learning is particularly sensitive to reduced levels of Zif268, as one‐half of the complement of Zif268 in heterozygous mice is insufficient to maintain spatial long‐term memories. Hippocampus 2002;12:570–577. © 2002 Wiley‐Liss, Inc.
Hippocampal LTP and memory in mouse strains: Is there evidence for a causal relationship?
Authors: Gerlai Robert
Published: October 2002

The mechanisms underlying memory are under intense investigation. One of the most promising candidates at the cellular level is long‐term potentiation (LTP). Numerous pharmacological and molecular genetic manipulations have led to alteration in both LTP and memory. However, the causal relationship between these phenotypical changes is debated. The problem of causality can be addressed in numerous ways. One suggestion is to investigate natural variation in both LTP and memory performance in mouse strains. If variation in synaptic and behavioral phenomena is found, correlation between these traits may be investigated. The advantages and disadvantages of this approach are discussed. An empirical example using four mouse strains is also presented to highlight some general problems. The following arguments are made. First, multiple electrophysiological and behavioral paradigms with idiosyncratic condition characteristics should be conducted to avoid false‐positive findings due to alterations unrelated to memory and its mechanisms. Multiple stimulation and memory protocols may also allow one to study the complexity and multiplicity of processes. Second, analysis of a large number of mouse strains may be needed to avoid false interpretation of results due to spurious gene associations and/or linkage disequilibrium. Third, quantitative genetic analysis using, for example, diallele crosses, may be employed to properly investigate biologically meaningful, i.e., genetic, effects. It is concluded that with the use of additional methods (e.g., QTL analysis, gene expression arrays, and biochemical analysis) providing converging evidence, analysis of mouse strains will be instrumental in addressing the question regarding the role LTP may play in memory. Hippocampus 2002;12:657–666. © 2002 Wiley‐Liss, Inc.
Synaptic reentry reinforcement based network model for long‐term memory consolidation
Authors: Wittenberg Gayle M. , Sullivan Megan R. , Tsien Joe Z.
Published: October 2002

The conversion of newly formed declarative memories into long‐term memories is known to be dependent on the hippocampus. Recent experiments suggest that memory consolidation requires reactivation of the NMDA receptor in CA1 during the initial week(s) after training. This led to the hypothesis that the repeated post‐learning reinforcement of synaptic modifications, termed synaptic reentry reinforcement (SRR), is essential for long‐term memory consolidation and storage. Based on experimental observations, we have built a computational model to further illustrate and explore the effect of the SRR process on the formation of long‐term memory. We show that SRR is capable of strengthening and maintaining memory traces despite inherent variability in the system due to such processes as the turnover of synaptic receptors and their associated signaling and structural proteins. Furthermore, we demonstrate that new rounds of synaptic modification triggered by memory reactivation, either during conscious recall or sleep, could lead to the selective consolidation of a subset of memory traces. Finally, we show why the SRR process in the hippocampus is required during the initial post‐training weeks for synaptic reinforcement based memory consolidation in the cortex. Hippocampus 2002;12:637–647. © 2002 Wiley‐Liss, Inc.
Neurogenesis may relate to some but not all types of hippocampal‐dependent learning
Authors: Shors Tracey J. , Townsend David A. , Zhao Mingrui , Kozorovitskiy Yevgenia , Gould Elizabeth
Published: October 2002

The hippocampal formation generates new neurons throughout adulthood. Recent studies indicate that these cells possess the morphology and physiological properties of more established neurons. However, the function of adult generated neurons is still a matter of debate. We previously demonstrated that certain forms of associative learning can enhance the survival of new neurons and a reduction in neurogenesis coincides with impaired learning of the hippocampal‐dependent task of trace eyeblink conditioning. Using the toxin methylazoxymethanol acetate (MAM) for proliferating cells, we tested whether reduction of neurogenesis affected learning and performance associated with different hippocampal dependent tasks: spatial navigation learning in a Morris water maze, fear responses to context and an explicit cue after training with a trace fear paradigm. We also examined exploratory behavior in an elevated plus maze. Rats were injected with MAM (7 mg/kg) or saline for 14 days, concurrent with BrdU, to label new neurons on days 10, 12, and 14. After treatment, groups of rats were tested in the various tasks. A significant reduction in new neurons in the adult hippocampus was associated with impaired performance in some tasks, but not with others. Specifically, treatment with the antimitotic agent reduced the amount of fear acquired after exposure to a trace fear conditioning paradigm but did not affect contextual fear conditioning or spatial navigation learning in the Morris water maze. Nor did MAM treatment affect exploration in the elevated plus maze. These results combined with previous ones suggest that neurogenesis may be associated with the formation of some but not all types of hippocampal‐dependent memories. Hippocampus 2002;12:578–584. © 2002 Wiley‐Liss, Inc.
Contribution of NMDA receptor channels to the expression of LTP in the hippocampal dentate gyrus
Authors: Wang Zhuo , Song Dong , Berger Theodore W.
Published: October 2002

The role of glutamatergic NMDA receptor channels (NMDARs) in the induction of long‐term potentiation (LTP) has been well established. In contrast, whether or not NMDARs contribute to the expression of LTP has been an issue of debate. In this study, we investigated the contribution of NMDARs to LTP expression in the hippocampal dentate gyrus (DG) by stimulating perforant path afferents with short bursts of pulses delivered at a moderate frequency (40 Hz), instead of using the traditional protocol of a single stimulus at a low frequency (<0.1 Hz). The synaptic summation provided by the “burst” protocol enabled us to measure the NMDAR‐mediated component of synaptic responses (NMDA component), defined as the NMDAR antagonist D‐2‐amino‐5‐phosphonovalerate (APV)‐sensitive component, in the presence of physiological concentrations of Mg2+ (1 mM). Intracellular recordings were obtained from DG granule cells of rabbit hippocampal slices, and excitatory postsynaptic potentials (EPSPs) were measured in terms of the integrated area of their profiles. At 40 Hz, frequency facilitation of the evoked EPSPs was observed. The NMDA component gradually increased during the five‐pulse train and frequency facilitation was significantly reduced after the application of APV. We tested the hypothesis that NMDARs undergo potentiation in LTP by comparing the NMDA/non‐NMDA ratio of the synaptic responses in control and LTP groups. An increase in the ratio was observed in the LTP group, strongly suggesting potentiation of NMDARs. To infer changes in conductance at individual synapses based on EPSPs recorded at the soma, we constructed a compartmental model of a morphologically reconstructed DG granule cell. The effect on the NMDA/non‐NMDA ratio of changes in AMPA and NMDA component synaptic conductance, and of differences in the distribution of activated synapses, was studied with computer simulations. The results confirmed that NMDARs are potentiated after the induction of LTP and contribute significantly to the expression of potentiation under physiological conditions. Hippocampus 2002;12:680–688. © 2002 Wiley‐Liss, Inc.
Contribution of T‐type VDCC to TEA‐induced long‐term synaptic modification in hippocampal CA1 and dentate gyrus
Authors: Song Dong , Wang Zhuo , Berger Theodore W.
Published: October 2002

We have previously reported that exposure to the K+ channel blocker tetraethylammonium (TEA), 25 mM, induces long‐term potentiation (LTP) in CA1, but not in the dentate gyrus (DG), of the rat hippocampal slice. During TEA application, stimulation of excitatory afferents results in a strong depolarizing potential after the fast excitatory postsynaptic potential (EPSP) in CA1, but not in DG. We hypothesized that the differential effect of TEA on long‐term synaptic modification in CA1 and DG results from different levels of TEA‐elicited depolarization in the two cell types. Additional pharmacological studies showed that blockade of T‐type voltage‐dependent calcium channels (VDCCs) decreased both the magnitude of LTP and the late, depolarizing potential in CA1. Blockade of L‐type VDCCs had no such effect. Using computer models of morphologically reconstructed CA1 pyramidal cells and DG granule cells, we tested our hypothesis by simulating the relative intracellular Ca2+ accumulation and membrane potential changes mediated by T‐type and L‐type VDCCs. Simulation results using pyramidal cell models showed that, with decreased maximum conductance of TEA‐sensitive potassium channels, synaptic inputs elicited strong depolarizing potentials similar to those observed with intracellular recording. During this depolarization, VDCCs were opened and resulted in a large intracellular Ca2+ accumulation that presumably caused LTP. When T‐type VDCCs were blocked, the magnitudes of both the Ca2+ accumulation and the late depolarizing potential were decreased substantially. Simulated blockade of L‐type VDCCs had only a minor effect. Together, our modeling and experimental studies indicate that T‐type VDCCs, rather than L‐type VDCCs, are primarily responsible for facilitating the depolarizing potential caused by TEA and for the consequent Ca2+ influx. Thus, our findings strongly suggest that the induction of TEA‐LTP in CA1 depends primarily on T‐type, rather than L‐type, VDCCs. Simulation results using modeled granule cells suggests that the failure of TEA to induce LTP in DG is partly due to a low density of T‐type VDCCs in granule cell membranes. Hippocampus 2002;12:689–697. © 2002 Wiley‐Liss, Inc.
Hierarchical model of the population dynamics of hippocampal dentate granule cells
Authors: Chauvet G.A. , Berger T.W.
Published: October 2002

A hierarchical modeling approach is used as the basis for a mathematical representation of the population activity of hippocampal dentate granule cells. Using neural field equations, the variation in time and space of dentate granule cell activity is derived from the summed synaptic potential and summed action potential responses of a population of granule cells evoked by monosynaptic excitatory input from entorhinal cortical afferents. In this formulation of the problem, we have considered a two‐level hierarchy: the synapses of entorhinal cortical axons define the first level of organization, and dentate granule cells, which include these synapses, define the second, higher level of organization. The model is specified by two state field variables, for membrane potential and for synaptic efficacy, respectively, with both evolving according to different time scales. The two state field variables introduce new parameters, physiological and anatomical, which characterize the dentate from the point of view of neuronal and synaptic populations: (1) a set of geometrical constraints corresponding to the morphological properties of granule cells and anatomical characteristics of entorhinal‐dentate connections; and (2) a set of neuronal parameters corresponding to physiological mechanisms. Assuming no interaction between granule cells, i.e., neither ephaptic nor synaptic coupling, the model is shown to be mathematically tractable and allows solution of the field equations leading to the determination of activity. This treatment leads to the definition of two state variables, volume of stimulated synapses and firing time, which describe observed activity. Numerical simulations are used to investigate the populational characterization of the dentate by individual parameters: (1) the relationship between the conditions of stimulation of active perforant path fibers, e.g., stimulating intensity, and activity in the granule cell layer; and (2) the influence of geometry on the generation of activity, i.e., the influence of neuron density and synaptic density‐connectivity. As an example application of the model, the granule cell population spike is reconstructed and compared with experimental data. Hippocampus 2002;12:698–712. © 2002 Wiley‐Liss, Inc.
New life in an old idea: The synaptic plasticity and memory hypothesis revisited
Authors: Martin S.J. , Morris R.G.M.
Published: October 2002

The notion that changes in synaptic efficacy underlie learning and memory processes is now widely accepted, although definitive proof of the synaptic plasticity and memory hypothesis is still lacking. This article reviews recent evidence relevant to the hypothesis, with particular emphasis on studies of experience‐dependent plasticity in the neocortex and hippocampus. In our view, there is now compelling evidence that changes in synaptic strength occur as a consequence of certain forms of learning. A major challenge will be to determine whether such changes constitute the memory trace itself or play a less specific supporting role in the information processing that accompanies memory formation. Hippocampus 2002;12:609–636. © 2002 Wiley‐Liss, Inc.
A new method of implanting orthotopic rat bladder tumor for experimental therapies
Authors: Bisson Jean‐François , Parache Robert M. , Droulle Pierre , Notter Dominique , Vigneron Claude , Guillemin François
Published: October 2002

We developed a model of orthotopic transplantation of bladder tumor cells in female Fischer rats using a new reproducible technique. After first performing the mechanical abrasion of a portion of the bladder urothelium with an Abrader© inserted transurethrally via a catheter, we administered a suspension of 5–40 × 106 viable AY‐27 tumor cells in sterile phosphate‐buffered saline to the bladder cavity. This rapidly led to a tumor growth incidence of approximately 100%. The induced bladder tumors grew expansively into the bladder cavity from the surface (mucosa) and gradually invaded the submucosa, muscles, serosa and surrounding tissue (high‐stage invasive transitional cell carcinoma). Size and staging were related to the quantity of tumor cells instilled into the bladder cavity. This model matches the characteristics of human bladder tumor more closely than other bladder cancer models induced with tumor cells. Moreover, it presents many advantages: the method is reproducible, tumors grow rapidly, they are directly attached to the bladder surface and they are always located on the bladder wall, in line with the urethra. This proves especially helpful for evaluating chemotherapeutic agents by different means such as in vivo fluorescence spectroscopy, a noninvasive method used in photodynamic therapy, or other methods designed to detect and treat transitional cell carcinoma. © 2002 Wiley‐Liss, Inc.