bluuebunny/crossref_metadata_2025 huggingface dataset:
Estradiol and dihydrotestosterone regulate endothelial cell barrier function after hypergravity-induced alterations in MAPK activity
Authors: Sumanasekera Wasana K. , Sumanasekera Gamini U. , Mattingly Kathleen A. , Dougherty Susan M. , Keynton Robert S. , Klinge Carolyn M.
Published: March 2007

Postflight orthostatic intolerance (POI) was reported to be higher in female than male astronauts and may result from sex-dependent differences in endothelial cell (EC) barrier permeability. Here the effect of 17β-estradiol (E2) and dihydrotestosterone (DHT) on the expression of the tight junction protein occludin, EC barrier function, and MAPK activation over time was tested after subjecting human umbilical vein EC (HUVEC) to brief hypergravity identical to that experienced by astronauts during liftoff (LO) into space. After LO hypergravity, HUVEC showed a time-dependent decrease in occludin correlating with an increase in paracellular permeability and a decrease in transendothelial electrical resistance, indicating a decrease in EC barrier function. LO hypergravity inhibited MAPK activation, which remained suppressed 4 h after LO. Inhibition of MAPK activation correlated with decreased phosphotyrosine occludin, decreased cytochrome- c oxidase activity, and increased paracellular permeability, suggesting a mechanism by which LO hypergravity decreased EC barrier function. Time-dependent differences in MAPK activation, decreased occludin, and EC barrier function between HUVEC treated with E2 vs. DHT were observed. HUVEC showed delayed activation of MAPK with DHT, i.e., 4 h rather than 2 h for E2, which correlated with decreased paracellular permeability and the observed sex differences in POI in astronauts. These data temporally separate E2 and DHT effects in HUVEC and provide evidence for the possible protective roles of sex steroids on EC function after brief exposure to low hypergravity.
Effects of ATP, Mg2+, and redox agents on the Ca2+ dependence of RyR channels from rat brain cortex
Authors: Bull Ricardo , Finkelstein José Pablo , Humeres Alexis , Behrens María Isabel , Hidalgo Cecilia
Published: March 2007

Despite their relevance for neuronal Ca2+-induced Ca2+ release (CICR), activation by Ca2+ of ryanodine receptor (RyR) channels of brain endoplasmic reticulum at the [ATP], [Mg2+], and redox conditions present in neurons has not been reported. Here, we studied the effects of varying cis-(cytoplasmic) free ATP concentration ([ATP]), [Mg2+], and RyR redox state on the Ca2+ dependence of endoplasmic reticulum RyR channels from rat brain cortex. At pCa 4.9 and 0.5 mM adenylylimidodiphosphate (AMP-PNP), increasing free [Mg2+] up to 1 mM inhibited vesicular [3H]ryanodine binding; incubation with thimerosal or dithiothreitol decreased or enhanced Mg2+ inhibition, respectively. Single RyR channels incorporated into lipid bilayers displayed three different Ca2+ dependencies, defined by low, moderate, or high maximal fractional open time (Po), that depend on RyR redox state, as we have previously reported. In all cases, cis-ATP addition (3 mM) decreased threshold [Ca2+] for activation, increased maximal Po, and shifted channel inhibition to higher [Ca2+]. Conversely, at pCa 4.5 and 3 mM ATP, increasing cis-[Mg2+] up to 1 mM inhibited low activity channels more than moderate activity channels but barely modified high activity channels. Addition of 0.5 mM free [ATP] plus 0.8 mM free [Mg2+] induced a right shift in Ca2+ dependence for all channels so that [Ca2+] <30 μM activated only high activity channels. These results strongly suggest that channel redox state determines RyR activation by Ca2+ at physiological [ATP] and [Mg2+]. If RyR behave similarly in living neurons, cellular redox state should affect RyR-mediated CICR.
Basal and angiotensin II-inhibited neuronal delayed-rectifier K+ current are regulated by thioredoxin
Authors: Matsuura Tomokazu , Harrison Rachael A. , Westwell Andrew D. , Nakamura Hajime , Martynyuk Anatoly E. , Sumners Colin
Published: March 2007

In previous studies, we determined that macrophage migration inhibitory factor (MIF), acting intracellularly via its intrinsic thiol-protein oxidoreductase (TPOR) activity, stimulates basal neuronal delayed-rectifier K+ current ( IKv) and inhibits basal and angiotensin (ANG) II-induced increases in neuronal activity. These findings are the basis for our hypothesis that MIF is a negative regulator of ANG II actions in neurons. MIF has recently been recategorized as a member of the thioredoxin (Trx) superfamily of small proteins. In the present study we have examined whether Trx influences basal and ANG II-modulated IKv in an effort to determine whether the Trx superfamily can exert a general regulatory influence over neuronal activity and the actions of ANG II. Intracellular application of Trx (0.8–80 nM) into rat hypothalamic/brain stem neurons in culture increased neuronal IKv, as measured by voltage-clamp recordings. This effect of Trx was abolished in the presence of the TPOR inhibitor PMX 464 (800 nM). Furthermore, the mutant protein recombinant human C32S/C35S-Trx, which lacks TPOR activity, failed to alter neuronal IKv. Trx applied at a concentration (0.08 nM) that does not alter basal IKv abolished the inhibition of neuronal IKv produced by ANG II (100 nM). Given our observation that ANG II increases Trx levels in neuronal cultures, it is possible that Trx (like MIF) has a negative regulatory role over basal and ANG II-stimulated neuronal activity via modulation of IKv. Moreover, these data suggest that TPOR may be a general mechanism for negatively regulating neuronal activity.
Altered inflammatory gene expression underlies increased susceptibility to murine postoperative ileus with advancing age
Authors: Moore Beverley A. , Albers Kathryn M. , Davis Brian M. , Grandis Jennifer R. , Tögel Sandra , Bauer Anthony J.
Published: March 2007

Susceptibility to postoperative ileus following abdominal surgery increases with advancing age. The mechanisms underlying this phenomenon are unknown. This study compares functional and molecular endpoints between young-adult (2 mo old), middle-aged (15 mo old), and elderly mice (26–30 mo old) to identify potential mechanisms. Susceptibility to ileus was assessed by measuring gastrointestinal transit (geometric center) 24 h after anesthesia, laparotomy, and light manipulation (LM) of the small bowel. Proinflammatory (IL-6, COX-2, inducible nitric oxide synthase) and anti-inflammatory (IL-10, heme oxygenase-1) gene and protein expressions were determined by real time RT-PCR, Western blot, and ELISA. LM did not alter gastrointestinal transit in young animals (geometric center = 8.8 ± 0.9), but transit was increasingly delayed in middle-aged (6.9 ± 0.8, P = 0.03) and elderly animals (4.7 ± 0.6, P = 0.013). Despite the lack of LM effect on transit in young mice, IL-6 and COX-2 mRNA expressions were significantly increased postoperatively (165 ± 24-fold and 2.9 ± 0.3-fold, respectively). Expressions were increased further in middle-aged mice (1,103 ± 187-fold; 4.4 ± 0.7-fold) and further still in elderly mice (1,218 ± 168-fold; 6.9 ± 0.3-fold). IL-10 and heme oxygenase-1 gene expressions were also elevated postoperatively in young mice (4.8 ± 0.5-fold and 13.0 ± 1.3-fold, respectively) and were further increased in middle-aged mice (7.5 ± 0.6-fold; 21.8 ± 3.2-fold). However, inductions in elderly mice were significantly blunted (5.8 ± 0.9-fold; 16.9 ± 0.8-fold). There is both an age-dependent increase in the proinflammatory mediator expression and an age-dependent decrease in anti-inflammatory mediator expressions following minor insult to the bowel. Such imbalances between pro- and anti-inflammatory mechanisms may form the basis for increased susceptibility to ileus and for the increased severity and duration of ileus observed in the elderly.
Dehydration increases the magnitude of selective brain cooling independently of core temperature in sheep
Authors: Fuller Andrea , Meyer Leith C. R. , Mitchell Duncan , Maloney Shane K.
Published: March 2007

By cooling the hypothalamus during hyperthermia, selective brain cooling reduces the drive on evaporative heat loss effectors, in so doing saving body water. To investigate whether selective brain cooling was increased in dehydrated sheep, we measured brain and carotid arterial blood temperatures at 5-min intervals in nine female Dorper sheep (41 ± 3 kg, means ± SD). The animals, housed in a climatic chamber at 23°C, were exposed for nine days to a cyclic protocol with daytime heat (40°C for 6 h). Drinking water was removed on the 3rd day and returned 5 days later. After 4 days of water deprivation, sheep had lost 16 ± 4% of body mass, and plasma osmolality had increased from 290 ± 8 to 323 ± 9 mmol/kg ( P < 0.0001). Although carotid blood temperature increased during heat exposure to similar levels during euhydration and dehydration, selective brain cooling was significantly greater in dehydration (0.38 ± 0.18°C) than in euhydration (−0.05 ± 0.14°C, P = 0.0008). The threshold temperature for selective brain cooling was not significantly different during euhydration (39.27°C) and dehydration (39.14°C, P = 0.62). However, the mean slope of lines of regression of brain temperature on carotid blood temperature above the threshold was significantly lower in dehydrated animals (0.40 ± 0.31) than in euhydrated animals (0.87 ± 0.11, P = 0.003). Return of drinking water at 39°C led to rapid cessation of selective brain cooling, and brain temperature exceeded carotid blood temperature throughout heat exposure on the following day. We conclude that for any given carotid blood temperature, dehydrated sheep exposed to heat exhibit selective brain cooling up to threefold greater than that when euhydrated.
Time-Varying Cortical Activations Related to Visual–Tactile Cross-Modal Links in Spatial Selective Attention
Authors: Kida Tetsuo , Inui Koji , Wasaka Toshiaki , Akatsuka Kosuke , Tanaka Emi , Kakigi Ryusuke
Published: March 2007

The neural mechanisms underlying unimodal spatial attention have long been studied, but the cortical processes underlying cross-modal links remain a matter of debate. To reveal the cortical processes underlying the cross-modal links between vision and touch in spatial attention, we recorded magnetoencephalographic (MEG) responses to electrocutaneous stimuli when subjects directed attention to an electrocutaneous or visual stimulus presented randomly in the left or right space. Neural responses recorded around the bilateral sylvian fissures at 85 and 100 ms after the electrocutaneous stimulus were significantly enhanced by spatial attention in both the touch-irrelevant and -relevant modalities. Source analysis revealed that the sylvian responses were generated in the secondary somatosensory cortex (SII). An early response, M50c, generated in the contralateral primary somatosensory cortex (SI), was not modulated by attention. There were no significant attentional changes in the source location or magnetic field distribution, suggesting attentional facilitation of the neural activity in SII itself, rather than a tonic bias effect or overlapping of separate neuronal populations. The results show that spatial attention enhances responses to tactile inputs in SII, independent of sensory modality attended. The underlying mechanism remains to be determined, but may be an increase in gain.
Synaptic Regulation of Proopiomelanocortin Neurons Can Occur Distal to the Arcuate Nucleus
Authors: Hentges Shane T.
Published: March 2007

Energy homeostasis is controlled to a large extent by various signals that are integrated in the hypothalamus. It is generally considered that neurons in each of the hypothalamic nuclei are regulated by afferent projections that terminate within the cell body region of the nucleus. However, here it is shown that hypothalamic proopiomelanocortin (POMC) neurons receive synaptic inputs onto distal dendrites that reside outside of the cell body region in the arcuate nucleus. Previous studies using whole cell recordings from identified neurons in brain slices have shown that cannabinoids reduce GABA release from inhibitory synapses onto the POMC cells. Here it was found that endocannabinoids inhibited GABAergic inhibitory postsynaptic currents in POMC neurons only in intact sagittal brain slices, but not coronal, horizontal, or sagittal slices that were truncated rostrally at the level of the optic chiasm. Thus endocannabinoids inhibited presynaptic GABA release only at an anatomically distinct subset of POMC–neuron dendrites that extends rostrally beyond the arcuate nucleus into preoptic hypothalamic regions. There are two key results. First, the activity of POMC neurons can be regulated by afferent input at sites much farther from the soma than previously recognized. Second, endocannabinoids can act to inhibit inputs only at selective dendrites. POMC neurons play a critical role in the maintenance of body weight. Therefore these data suggest that energy balance may be regulated, in part, by modulation of POMC neuron activity at sites outside of the arcuate nucleus.
Comparison Between Offset and Onset Responses of Primary Auditory Cortex on–off Neurons in Awake Cats
Authors: Qin Ling , Chimoto Sohei , Sakai Masashi , Wang JingYu , Sato Yu
Published: March 2007

Primary auditory cortex (A1) neurons are believed not to carry much information about tonal offsets because A1 neurons in barbiturate-anesthetized animals are usually described as having only onset responses. We investigated tonal offset responses in comparison with onset responses in the caudal part of A1 of awake cats. Cells responding to both onsets and offsets were commonly found (59.2% of recorded cells). Offset responses usually co-occurred with phasic onset responses or phasic components of sustained responses. These on–off cells had diverse combinations of offset- and onset-frequency-receptive field (FRF): offset-FRF was similar to onset-FRF, or narrower, wider, lower, or higher than onset-FRF. The distribution of FRF patterns was diffuse with no boundaries between the different FRF-pattern groups. The onset- versus offset-FRF pattern of each cell remained unchanged across multiple stimulus intensities. Mean offset response showed similar peak latency (19.5 vs. 21.5ms), longer half-decay time (74.5 vs. 48.5 ms), and lower peak amplitude (20.4 vs. 35.9 spikes/s) compared with the mean onset response. Although offset responses were facilitated when preceded by the suppression of spike activity, they were still elicited without preceding spike suppression. It is concluded that neurons showing paired onset and offset responses are predominant in the caudal A1. Their frequency-filtering property is usually not static but dynamic, changing between sound onsets and offsets. Offset responses are similarly precise and salient as onset responses for effectively encoding sound offsets. They may be elicited as active spike responses to sound offset rather than simple rebound facilitation.
Neural Correlations Increase Between Consecutive Processing Levels in the Auditory System of Locusts
Authors: Vogel A. , Ronacher B.
Published: March 2007

Nervous systems may encode information about sensory stimuli using the temporal relations in spiking patterns between neurons. By conducting simultaneous intracellular recordings on pairs of auditory neurons we measured the strength of correlations between elements of the first three processing levels in the metathoracic auditory network of the locust. We quantified the degree of spike synchronization and rate covariations that occur among auditory neurons during acoustic stimulation. In addition to the acoustic stimulation, current pulses were injected into both neurons to study the connectivity within this network. Our findings support the view that the metathoracic auditory system is a hierarchically organized feedforward network. Strong synaptic connections were observed only between consecutive processing levels, whereas there was no indication for strong connections between elements of the same processing level. Both spike synchronization and rate covariations were increased among neurons on higher processing levels. We further investigated the consequences that correlations may have on the common estimates of neuronal variability. For example, rate covariations caused by strong synaptic coupling between two neurons may lead to an overestimation if the variability is measured trial by trial with respect to only single neurons. For the vast majority of cell pairs tested, however, no strong synaptic coupling could be demonstrated. Thus we could show that in most cases no serious errors are made if one determines variability by following the usual procedure on the basis of single-cell recordings.
Two-Dimensional Mapping of the Central and Parafoveal Visual Field to Human Visual Cortex
Authors: Schira Mark M. , Wade Alex R. , Tyler Christopher W.
Published: March 2007

Primate visual cortex contains a set of maps of visual space. These maps are fundamental to early visual processing, yet their form is not fully understood in humans. This is especially true for the central and most important part of the visual field—the fovea. We used functional magnetic resonance imaging (fMRI) to measure the mapping geometry of human V1 and V2 down to 0.5° of eccentricity. By applying automated atlas fitting procedures to parametrize and average retinotopic measurements of eight brains, we provide a reference standard for the two-dimensional geometry of human early visual cortex of unprecedented precision and analyze this high-quality mean dataset with respect to the 2-dimensional cortical magnification morphometry. The analysis indicates that 1) area V1 has meridional isotropy in areal projection: equal areas of visual space are mapped to equal areas of cortex at any given eccentricity. 2) V1 has a systematic pattern of local anisotropies: cortical magnification varies between isopolar and isoeccentricity lines, and 3) the shape of V1 deviates systematically from the complex-log model, the fit of which is particularly poor close to the fovea. We therefore propose that human V1 be fitted by models based on an equal-area principle of its two-dimensional magnification. 4) V2 is elongated by a factor of 2 in eccentricity direction relative to V1 and has significantly more local anisotropy. We propose that V2 has systematic intrinsic curvature, but V1 is intrinsically flat.
Encoding of Reach and Grasp by Single Neurons in Premotor Cortex Is Independent of Recording Site
Authors: Stark Eran , Asher Itay , Abeles Moshe
Published: March 2007

Neural activity has been studied during reaching and grasping separately, yet little is known about their combined representation. To study the functional organization of reaching and grasping in the premotor cortex (PM), we trained two monkeys to reach in one of six directions and grasp one of three objects. During prehensile movements, activity of proximal (shoulder and elbow) muscles was mainly modulated by reach direction, whereas distal (finger) muscles were also modulated by grasp type. Using intracortical microstimulation, we identified spatially distinct PM sites from which movements of proximal or distal joints were evoked. In contrast to muscles, modulation of neural activity by reach direction was similar for single units recorded in proximal and distal sites. Similarly, grasp type encoding was the same for units recorded in the different sites. This pattern of encoding reach and grasp irrespective of recoding site was observed throughout the task: before, during, and after prehension movements. Despite the similarities between single units within different sites, we found differences between pairs of units. Pairs of directionally selective units recorded by the same electrode in the same proximal site preferred similar reach directions but not grasp types, whereas pairs of object-selective units recorded in the same distal site tended to prefer the same grasp type but not reach direction. We suggest that the unexpected “mixing neurons” encoding reach and grasp within distal and proximal sites, respectively, provide a neural substrate for coordination between reach and grasp during prehension.
The Role of the Medial Prefrontal Cortex-Amygdala Circuit in Stress Effects on the Extinction of Fear
Authors: Akirav Irit , Maroun Mouna
Published: March 2007

Stress exposure, depending on its intensity and duration, affects cognition and learning in an adaptive or maladaptive manner. Studies addressing the effects of stress on cognitive processes have mainly focused on conditioned fear, since it is suggested that fear-motivated learning lies at the root of affective and anxiety disorders. Inhibition of fear-motivated response can be accomplished by experimental extinction of the fearful response to the fear-inducing stimulus. Converging evidence indicates that extinction of fear memory requires plasticity in both the medial prefrontal cortex and the amygdala. These brain areas are also deeply involved in mediating the effects of exposure to stress on memory. Moreover, extensive evidence indicates that gamma-aminobutyric acid (GABA) transmission plays a primary role in the modulation of behavioral sequelae resulting from a stressful experience, and may also partially mediate inhibitory learning during extinction. In this review, we present evidence that exposure to a stressful experience may impair fear extinction and the possible involvement of the GABA system. Impairment of fear extinction learning is particularly important as it may predispose some individuals to the development of posttraumatic stress disorder. We further discuss a possible dysfunction in the medial prefrontal cortex-amygdala circuit following a stressful experience that may explain the impaired extinction caused by exposure to a stressor.
Intraretinal Transplantation for Rod‐Cell Replacement in Light‐Damaged Retinas
Authors: del Cerro Manuel , Notter Mary F. D. , del Cerro Coca , Wiegand Stanley J. , Grover Donald A. , Lazar Eliot
Published: March 2007

Blindness from retinal disease is often the consequence of extensive damage to the photoreceptor cell population, while other cell types which form the neural retina are relatively spared. In this setting, transplantation of photoreceptor cells could offer hope for the restoration of some degree of visual function. We testd the feasibility of this approach by transplanting immature retinal cells into the eyes of adult rats affected by late stage phototoxic retinopathy, which are almost totally devoid of photoreceptor cells.

Dissociated neuroretinal cells from newborn rats were injected into the hosts′ retinas. These cells were labelled with the fluorescent tracer Fast‐blue for identification within the host eye. Survival time ranged from 3 to 100 post‐transplantation days.

Fundus examination of light‐irradiated eyes showed pallor caused by a considerable reduction of the retino‐choroidal vascular bed after light irradiation. Histologically the hosts exhibited decimation of the elements forming the outer layers.throughout the entire retina.

As visualized by light and electron microscopic procedures, we report the differentiation of clusters of transplanted photoreceptor cells, and the integration of these cells within the adjacent areas of the host retina.

Fluorescence microscopy showed these clusters to be formed by fluorescently labelled cells developing in intimate contact with the unlabelled host retina. Electron microscopically it was possible to determine that these photoreceptors had established synaptic contacts. These observations indicate that successful transplantation of immature retinal cells is feasible into adult eyes that have suffered extensive retino‐choroidal damage. These findings also support the concept that retinal transplantation is a procedure which may open new avenues into the study of retinal repair.
The Use of Bromodeoxyuridine‐Immunohistochemistry to Identify Transplanted Fetal Brain Tissue
Authors: Brown Darlene B. , Stanfield Brent B.
Published: March 2007

The immunohistochemical detection of the thymidine analog, 5‐bromo‐2′‐deoxyuridine (BrdU) is shown to be a useful and reliable method to positively identify fetal brain transplants in standard histological preparations. This technique offers several advantages over the [ 3H]thymidine autoradiographic method, including being much more rapid and avoiding the use of radionuclides.
Intraparenchymal Striatal Transplants Required for Maintenance of Behavioral Recovery in an Animal Model of Huntington′s Disease
Authors: Sanberg Paul R. , Giòrdano Magda , Henault Mark A. , Nash David R. , Ragozzino Michael E. , Hagenmeyer-Houser Starr H.
Published: March 2007

Rats which receive injections of kainic acid (KA) into the striatum show many of the anatomical, biochemical
and behavioral abnormalities seen in patients with Huntington′s disease. Recently, it has been reported that
fetal striatal transplants into the lesioned striatum could normalize the neurological and behavioral abnormalities
produced by the KA lesion. The present study examined the issue of transplant integration in producing behavioral
recovery. In one experiment, lesioned animals with transplants located within the lateral ventricle were
compared against parenchymally transplanted rats. It was found that unless the ventricular transplant grew
into the lesioned striatum there was no recovery. The second experiment demonstrated that electrolytic destruction
of a successful fetal striatal transplant could reverse the transplant‐induced behavioral recovery. These
results suggest that the integrity of the transplant is important in maintaining behavioral recovery. A continuing
functional interaction between the host brain and transplanted tissue may be a vital element in the
success of the fetal striatal transplant.
Supranumerary Barrels Develop in the Somatosensory Cortex of Mice, After the Implantation of the Vibrissal Follicle Parts Containing Large Numbers of Receptors
Authors: Andrés F. L.
Published: March 2007

In the mouse whiskerpad there is a group of vibrissal follicles arranged in five rows, which are topologically represented in the contralateral somatosensory cortex by the barrelfield.

Each vibrissal follicle is a specialized sensory organ containing a large number of receptors, mostly Merkel cells.

In these experiments, the parts of the vibrissal follicles containing most of the receptors were transplanted
to different regions of the whiskerpad of newborn mice, to know whether “new”, supranumerary barrels could develop.

The results confirm this hypothesis. However, the “new” barrels are not topologically represented in the barrelfield, as normal barrels do.
Tissue Culture Models of Myelination After Oligodendrocyte Transplantation
Authors: Seil Fredrick J.
Published: March 2007

Studies of myelination after transplantation of mature oligodendrocytes to cerebellar cultures in which
oligodendrocyte maturation and myelination had been irreversibly inhibited by exposure to cytosine
arabinoside were reviewed. Transplanted oligodendrocytes were derived from three sources, including cerebellar
explants treated with kainic acid, dissociated oligodendrocyte cultures, and optic nerve fragments.
Oligodendrocytes from all sources migrated into the host explants and myelinated appropriate axons. The
time of appearance of myelin and the percentage of host cultures myelinated differed for the three sources
of oligodendrocytes, however. Myelin was visible earliest and in the highest percentage of host explants transplanted
with cultured dissociated oligodendrocytes, which were presumably the most free to migrate into
the host tissue, and latest and in the lowest percentage of host cultures transplanted with optic nerve, from
which oligodendrocytes were presumably least free to migrate. Some myelin‐like membranes unassociated
with axons appeared in cerebellar cultures transplanted with cultured dissociated oligodendrocytes, and not
in cerebellar explants transplanted with oligodendrocytes from other sources. The formation of such myelin‐like
membranes was interpreted as a manifestation of oligodendrocyte hyperreactivity induced by culture
in isolation.
Immunization of Rats With Cholinergic Neurons Induces Behavioral Deficits
Authors: Chapman Joab , Feldon Joram , Alroy Gil , Michaelson Daniel M.
Published: March 2007

We have previously shown that sera from patients with Alzheimer′s disease (AD) contain a significantly
high level of antibodies to the cell bodies (Perikarya; PK) but not to the nerve terminals (synaptosomes)
of purely cholinergic neurons from the electric fish Torpedo. In the present study we examined the effect
of repeated immunization of rats with either of these antigens for one year. Immunoblot studies revealed
that sera of cholinergic PK immunized rats contained a high level of antibodies to cholinergic PK proteins,
in particular to a 200 kilodalton protein, to which there are specifically high levels of antibodies in AD.
Sera from rats immunized with cholinergic synaptosomes and from control rats contained very low levels
of these antibodies. Behavioral studies performed one year after the initial immunization revealed that
the cholinergic PK immunized rats were impaired in spatial learning and memory tasks (Morris swim
test and T‐maze alternation) when compared to control rats and that the synaptosome‐immunized rats
showed no such deficit. In contrast, the three groups performed similarly in general activity, active avoidance
and conditioned emotional response tests. Further experiments revealed that the cholinergic PK
immunized rats displayed a significant deficit in short term memory. The association of antibodies to cholinergic
neurons with Cognitive deficits in this rat model suggests that such antibodies may be involved in the pathogenesis of AD.
Developing Retina and PNS Segments for Transplantation Into the Adult Host Eye: Reconstruction of the Mammalian Visual System. 1. Methodology
Authors: Zanakis Michael F. , Lowe Howard F. , Jacobsen Glenn , LaCorte Michael , Lee Simone P. , Hallas Brian H.
Published: March 2007

Various techniques have been explored to determine
the uses and limitations of techniques that enable the adult CNS to regenerate, but relatively
little attention has been given to the consideration of a "reconstructed" visual system.
Using this approach, one can design experiments to study the uses of exogenous tissues in
reestablishing neuronal circuits that have been damaged. Toward this end, experiments were designed
to determine whether embryonic retinal ganglion cells can project axons into a grafted
PNS "bridge", and enter adult host targets that were partially deafferented. Embryonic eyes of
E11, E14, E18 and E21 rats were sutured to peripheral nerve segments which served as bridges
between the host eye and frontal cortex. Projections between the developing retina and the host
brain could then be evaluated using HRP tracing techniques. From a methodological standpoint,
the preparations are 65% effective; i.e., a viable bridge results between the embryonic eye and
the host forebrain. The results presented in the accompanying paper demonstrate that the technique
can yield results indicative of embryonic retinal development and axonal projection
through the graft and into the host brain. This partial reconstruction of the visual system may
prove a useful tool in understanding the uses and limitations of grafting in the CNS.
Developing Retina and PNS Segments for Transplantation Into the Adult Host Eye: Reconstruction of the Mammalian Visual System. 2. Results
Authors: Hallas Brian H. , Lowe Howard F. , Jacobsen Glenn , LaCorte Michael , Lee Simone P. , Zanakis Michael F.
Published: March 2007

The previous companion paper detailed, a technique which allowed embryonic retinal ganglion cell axons to grow from the anterior eye chamber across a PNS bridge, and enter the adult host forebrain. Embryonic eyes of E11, E14, E18 and E21 animals were sutured to a PNS bridge, the embryonic eye implanted into an adult host eye, and the distal end of the bridge implanted into the host forebrain. Results indicate that when eyes of all ages are used for implantation, axons could be observed to grow from the embryonic retina, through the bridge and into the adult host forebrain. The axons extend for long distances in the host brain, reach various layers of the cortex and in a few animals enter the caudate/putamen complex. Control studies show that the bridge is used exclusively as the conduit to the brain, as opposed to the degenerated host optic nerve. Thus, the results presented in this paper indicate that successful grafting and transplantation is possible using the aforementioned technique. The results suggest that the described visual system reconstruction technique can be used for the study of development and transplantation in this system.
Analysis of an Experimental Cortical Network: i) Architectonics of VisualAreas 17 and 18 After Neonatal Injections of Ibotenic Acid;Similarities with Human Microgyria
Authors: Innocenti G. M. , Berbel P.
Published: March 2007

Lesions of cortical areas 17 and 18 have been produced in newborn kittens by local injections of the excitotoxin ibotenic acid (ibo). Twenty‐four hours after an injection on postnatal days 2 or 3, the gray matter of areas 17 and 18 near the center of the injection appears completely destroyed, with the exception of a one‐to‐two cell‐thick layer at the bottom of layer I. Intact migrating neurons and radial glia can be found light‐ and electron‐microscopically in the region affected. During the following weeks a several hundred micron thick cortex reforms. In the adult, this cortex consists of superficial layers I, II and III as proven by cytoarchitectonics, continuity with the corresponding layers of the normal cortex and cellular composition. We believe that the recovery is due to completion of migration by neurons spared by the ibo injection. More severe destruction of cerebral cortex, i.e. complete loss of the neuronal layers or their reduction to a few cell‐thick mantles can be obtained with ibo injections at the end of the second or, respectively, first postnatal week. Severity of lesion also depends on the dose of ibo injected. There are interesting similarities between the ibo‐injured cortex and two human neocortical displasias: microgyria and ulegyria.
Effects of Glutamate and γ‐Aminobutyric Acid onSpontaneously Active Intraocular Spinal Cord Graft Neurons
Authors: Broton J. G. , Yezierski R. P. , Seiger Å.
Published: March 2007

Pieces of fetal rat lumbar spinal cord were transplanted into the anterior eye chamber of adult rat hosts. At least seven months later, extracellular single‐unit recordings of spontaneously active graft neurons were made prior to and during the superfusion of either glutamate or γ‐aminobutyric acid (GABA). Superfusion of glutamate produced an increase (five cells), decrease (three cells), or had no effect (two cells) on the firing rate of neurons tested. Superfusion of GABA decreased the firing rate of all twelve neurons tested, while superfusion of the GABA receptor antagonist bicuculline increased the firing rates of all eight neurons tested. The latency and magnitude of the responses to glutamate and GABA were not related to depth of the recording electrode below the graft surface. Together, these data suggest that the intraocular spinal cord graft is suitable for the in vivo study of GABA and glutamate neuropharmacology.
Pineal Gland Transplants into the Cerebral Hemisphere of Newborn Rats: A Study of the Blood Brain Barrier and Innervation
Authors: McNulty J. A. , Fox L. M. , Shaw P. L. , Alones V. E. , Klausen B. S. , Swenson R. S. , Castro A. J.
Published: March 2007

Pineal glands from neonatal (0‐1 day) Long‐Evans
black‐hooded rats were transplanted into the cerebral
hemispheres of litter mates for periods of 1 to 5.5
months. Grafts exhibited differentiated pinealocytes
that were intensely immunoreactive for serotonin.
Transplant vasculature was permeable to endogenous
IgG, comprised fenestrated endothelia with wide
pericapillary spaces typical of in situ glands, and had
a volume density intermediate to that of surrounding
cortex and in situ pineals. Along the periphery,
transplant capillaries tended to have continuous
endothelia similar to those of host cortex. This peripheral zone was impermeable to endogenous IgG
and appeared to increase in size in older grafts. The
presence of noradrenergic‐like fibers within the
perivascular compartment suggested that transplants
were innervated by peripheral sympathetic neurons
from the superior cervical ganglia. In animals which
had been superior cervical ganglionectomized, noradrenergic‐like
fibers were absent or degenerating.
Neural regulation of transplant metabolic activity was
suggested by the increased frequency of pinealocyte
synaptic ribbons in denervated grafts. These findings
are consistent with the hypothesis that factors from
both graft and host influence vasculature physiology
and differentiation in neural transplants. Furthermore,
grafts appeared to receive appropriate neural
input from the peripheral sympathetic system.
Electrophysiological and Morphological Properties of Embryonic Neocortical Grafts Developing in Different Regions of the Host Rat Brain
Authors: Senatorov V. V. , Obuhova G. P. , Fülöp Z.
Published: March 2007

Parallel morphological and electrophysiological studies of embryonic neocortical tissue (primordia of anterior parietal–presumptive sensorimotor–cortex) grafted into different regions of the host adult brain (sensori‐motor cortex, caudate‐putamen, septum or thalamus) were carried out to investigate to what extent the properties of transplanted embryonic neocortex–an advanced organizational form of neuronal tissue–are affected by homotopic or heterotopic surroundings.

The results point to the importance of the host tissue environment as it influences both the size, the morphological and functional properties of the implanted embryonic cortical plate tissue. The cortical grafts were smaller in size when developed homo‐topically in sensorimotor cortex and grew larger in heterotopic environment (caudate‐putamen, septum, thalamus). The orientation of neuronal dendrites in the grafts tends to follow that seen in the surroundings. The homotopic grafts showed a better structural integration into the host brain. Differences were seen between intracortical and subcortical transplants in the spontaneous firing rate of neurons and in the ratio of units with various types of spontaneous discharge.
Microencapsulated Dopamine (DA)‐Induced Restitution of Function in 6‐OHDA‐Denervated Rat Striatum in vivo: Comparison Between Two Microsphere Excipients
Authors: McRae Amanda , Hjorth Stephan , Mason David W. , Dillon Lynn , Tice Thomas R.
Published: March 2007

Biodegradable controlled‐release microsphere
systems made with the biocompatible
biodegradable polyester excipient poly [DL
lactide‐co‐glycolide] constitute an exciting new
technology for drug delivery to the central nervous
system (CNS). The present study describes
functional observations indicating that implantation
of dopamine (DA) microspheres encapsulated
within two different polymer excipients
into denervated‐ striatal tissue assures a
prolonged release of the transmitter in vivo.
Moreover, in this regard, the results show that
there were clear cut temporal differences in the
effect of the two DA microsphere formulations
compared in this study, probably reflecting variations
in the actual composition (i.e., lactide to
glycolide ratio) of the two copolymer excipients
examined. This technology has considerable potential
for basic research with possible clinical
application.
Adrenal Medullary Autografts in Anterior Eye Chamber, Lateral Ventricle and Striatum of Adult Rats: A Long Term Study
Authors: Shetty Ashok Kumar , Gopinath Gomathy , Tandon P. N.
Published: March 2007

The neurobiological basis for the short‐term
recovery in Parkinson′s patients and experimental
animals grafted with adrenal medulla is
not yet clear. Structural details of the grafted
chromaffin cells are also not available. In the
present study, autografts of adrenal medulla in
the anterior eye chamber, lateral ventricle and
striatum of adult rats were studied for 360 days.
Though a large number of cells degenerated, a
few healthy chromaffin cells survived up to 360
days in the anterior eye chamber. In the ventricular
and striatal regions, cells degenerated
more rapidly, and a few surviving cells were seen
only up to 120 and 150 days, respectively. Degeneration
of the cells was evident from the
alteration of the cytoplasmic granules, appearance
of vacuoles and lysosomes, rapid decline
in the number of TH and DBH positive
cells and diffusion of enzymes in the intercellular
region. Only lymphocytes and connective tissue
cells were seen in the ventricle after 120 days,
while outlines of a few chromaffin cells and
background fluorescence were still evident in the
striatum up to 150 days. In some of the intrastriatal
transplants, morphologically identifiable
Schwann cells were present and, in one
transplant, there was evidence of myelination of
axons by Schwann cells. These axons were obviously
derived from the adjacent host tissue.
From the findings it has been concluded that
autografts of adrenal medulla survive for only a
Limited period of time on transplantation to the
central nervous system and anterior eye
chamber. Survival seemed to be better in the
anterior eye chamber than at the sites
preferentially chosen for treating Parkinson′s
patients or experimental animals.
Transplantation of Fetal CNS Tissue Into the Peripheral Nervous System:A Model to Study Aberrant Changes in the Neuronal Cytoskeleton
Authors: Doering Laurie C.
Published: March 2007

Defined regions (septum, substantia nigra) of the embryonic central nervous system (CNS) were transplanted into the sciatic nerves of young adult rats. Immunocytochemical techniques were used to examine the expression of neurotransmitter related enzymes and neuronal cytoskeletal proteins in the grafts.

The origin of the septal grafts was confirmed by immunoreactivity in nenrons to choline acetyltransferase and the β‐nerve growth factor receptor (192‐IgG). In substantia nigra grafts, neuronal perikarya and processes were identified with an antibody directed against tyrosine hydroxylase. Typical spatial distributions of phosphorylated (Mr 200,000)
and non phosphorylated (Mr 168,000 & 200,000) neurofilaments were observed in the short term (1‐2 months) grafts with the monoclonal antibodies RT97 and SMI‐32 respectively. Dense dendrite arbors and neuronal cell bodies were immunostained with an antibody that recognizes a high molecular weight microtubule associated protein (MAP2).

In the long term (1 year) transplants, prominent cytoskeletal changes in the somata, axons and dendrites of neurons were evident. The cells showed a shift in phosphorylated neurofilament staining from the axon to the soma accompanied by a reduction in axonal immunoreactivity in the adjacent neuropil, Other abnormal features included swollen perikarya, hypertrophied axonal segments and Short segments of kinked axons. Regression of the dendrite trees in the long standing grafts was also apparent when sections were reacted with the MAP2 antibody.

These experiments indicate that grafted fetal neurons, isolated in the peripheral nervous system, differentiate and express markers like their counterparts in situ. After extended time periods under these circumstances, cytoskeletal modifications become apparent in the neurons. These aberrant changes are similar to morphological characteristics associated with aging and neurodegenerative disorders. This experimental paradigm offers a new approach, to study cytoskeletal disturbances in neurons and provides a unique opportunity to examine conditions that
may modulate the abnormal changes.
Fetal Cortical Transplants in Adult Rats Subjected toExperimental Brain Injury
Authors: Soares Holly , McIntosh Tracy K.
Published: March 2007

Fetal cortical tissue was injected into injured adult rat brains following concussive fluid percussion (FP) brain injury. Rats subjected to moderate FP injury received E16 cortex transplant injections into lesioned motor cortex 2 days, 1 week, 2 weeks, and 4 weeks post injury. Histological assessment of transplant survival and integration was based upon Nissl staining, glial fibrillary acidic protein (GFAP) immunocytochemistry, and staining for acetylcholinesterase. In addition to histological analysis, the ability of the transplants to attenuate neurological motor deficits associated with concussive FP brain injury was also tested. Three subgroups of rats receiving transplant 1 week, 2 weeks, and 4 weeks post injury Were chosen for evaluation of neurological motor function. Fetal cortical tissue injected into the injury site 4 weeks post injury failed to incorporate with injured host brain, did not affect glial scar formation, and exhibited extensive GFAP immunoreactivity. No improvement in neurological motor function was observed in animals receiving transplants 4 weeks post injury. Conversely, transplants injected 2 days, 1 week, or 2 weeks post injury survived, incorporated with host brain, exhibited little GFAP immunoreactivity, and successfully attenuated glial scarring. However, no significant improvement in motor function was observed at the one week or two week time points. The inability of the transplants to attenuate motor function may indicate inappropriate host/transplant interaction. Our results demonstrate that there exists a temporal window in which fetal cortical transplants can attenuate glial scarring as well as be successfully incorporated into host brains following FP injury.
Motor Deficits Are Produced By Removing Some Cortical TransplantsGrafted Into Injured Sensorimotor Cortexof Neonatal Rats
Authors: Sandor Rick , Gonzalez Manuel F. , Moseley Michael , Sharp Frank R.
Published: March 2007

Fetal frontal cortex was transplanted into cavities formed in the right, motor cortex of neonatal rats. As adults, the animals were trained to press two levers in rapid succession with their left forelimb to receive food rewards. Once they had reached an optimal level of performance, the effect of removing their transplants was assessed. Surgical removal of transplants significantly impaired the performance of 2 of 4 subjects. Placing a crossstrain skin graft to induce the immunological rejection of the transplants produced a behavioral deficit in 1 of 2 subjects with complete transplant removal. Skin grafts produced no behavioral effects in four subjects that had surviving transplants. Since the motor deficit produced by transplant removal resembled those observed following the removal of normal motor cortex, we propose that these three transplants functioned within the host brain.

Histology Showed that the procedures used to remove cortical grafts did not injure any host brains. Therefore, host brain damage is unlikely to account for the behavioral deterioration that followed transplant removals.
Quantitative Estimation of the Ratio of GABA‐Immunoreactive Cells in Neocortical Grafts
Authors: Bragin A. , Takács J. , Vinogradova O. , Hámori J.
Published: March 2007

Somatosensory anlage from 17‐18 day old rat
embryos were transplanted in place of the
removed barrel cortex in adult rats. Six to eight
months after transplantation, the grafts were
either completely separated by glial scar or
partly separated and partly confluent with the
host neocortex. Each was studied histologically
and immunostained for GABA. It was found that
in partly confluent grafts the neuronal density
was similar or even higher than in the host
cortex, while the cell number in the separate
grafts was much lower than in the nearby host
cortex. The number of GABA‐positive cells,
however, was in all grafts significantly lower
(2.9% on average) than in the normal cortex
(11.8% on average).The decline in GABA‐stained
nerve cells was highest in separated
grafts, but was somewhat less marked in
transplants partly confluent with the host tissue.
The possible role of partial or total
deafferentation as well as the relative
vulnerability of the transplanted tissue by
temporary hypoxia and other metabolic
disturbances are discussed as the probable
factors in selective decline of GABA‐ergic cells in
the transplanted somatosensory cortex.