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PubMed1992

cFos labeling in rat superior colliculus: activation by normal retinal pathways and pathways from intracranial retinal transplants.

Previous studies in this laboratory have shown that intracranial retinal transplants can establish both anatomical and functional connections with the host brain. Embryonic rat retinae transplanted intracranially into neonatal host brains are capable of evoking appropriate physiological and behavioral responses when illuminated. The present study employs the specific expression of the cFos protein to identify brain regions in which immediate-early gene activation can be recognized in response to flash stimuli delivered to retinal transplants and to normal intact retinae. Stimulation of the intact eye induced significant cFos expression in various visual centers, including the stratum griseum superficiale of the superior colliculus and the pretectal area, but not in the dLGN, suprachiasmatic nucleus, or retina. Animals with functional transplants expressed cFos throughout the depth of the stratum griseum superficiale and stratum opticum of the superior colliculus, thus apparently activating an additional population of superior collicular cells. Like the eye-stimulated animals, animals with functional transplants failed to elicit significant cFos expression in the dLGN or transplanted retina. This study indicates that intracranial retinal transplants are capable of forming functional connections with the host superior colliculus which not only mediate transient changes in electrical activity but also may affect gene expression through the induction of the c-fos gene.

Animals↗
PubMed2004

Phase-locking characteristics of limbic P3 responses in hippocampal sclerosis.

Amplitudes of the P3 recorded invasively from the medial temporal lobe (MTL-P3) have been reported to be reduced on the side of a mediotemporal epileptogenic focus. This reduction has been attributed to the massive cell loss within the hippocampus associated with hippocampal sclerosis. It has remained unclear how functional connectivity between the hippocampus and rhinal cortex, as well as within the hippocampus, is altered in hippocampal sclerosis. To investigate this issue, we analyzed to what extent stimulus-related phase-locking and power changes within the low-frequency range (2-30 Hz) and within the gamma band (32-48 Hz), as well as rhinal-hippocampal phase synchronization contribute to the averaged MTL-P3 potentials. Event-related responses were recorded via bilateral depth electrodes in epilepsy patients with unilateral hippocampal sclerosis, who performed a visual oddball experiment. On the contralateral (nonsclerotic) side, successful target detection was associated with an increase of power and phase locking of hippocampal activity in both the low-frequency range and in the gamma range. Besides, there were rhinal-hippocampal synchronization enhancements in the theta and gamma range. On the ipsilateral (sclerotic) side, the event-related power increase in the low-frequency range had almost disappeared, a finding likely to be explained by the loss of principle neurons. However, low-frequency phase-locking, rhinal-hippocampal synchronization, as well as event-related power changes in the gamma range persisted ipsilaterally, although there were differences in temporal and spectral characteristics. These findings support the hypothesis that functional connectivity between hippocampus and rhinal cortex, as well as intrahippocampal connectivity, are partially preserved in hippocampal sclerosis.

Adult↗
PubMed1994

Spinal cord-skeletal muscle cografts: trophic and functional interactions.

Skeletal muscle from embryonic day 20 (E20) was combined with E15 rat spinal cord in the anterior chamber of the eye of adult albino rats. The two grafts were either transplanted concomitantly or sequentially, in which case muscle tissue was added 4 months after the spinal cord. Control groups received a single graft of either spinal cord or skeletal muscle. Survival and intraocular growth were observed through the cornea. After maturation in oculo, the double grafts were examined immunohistologically utilizing antisera to neurofilament (NF) and acetylcholinesterase (AChE). The grafts were also evaluated using electrical stimulation to determine functional connectivity. The spinal cord and skeletal muscle grafts were found to exert reciprocal trophic effects on each other, evidenced as a larger muscle mass in skeletal muscle grafts allowed to develop in the presence of spinal cord tissue, and a larger volume of spinal cord grafts allowed to develop together with a skeletal muscle graft, respectively. Immunohistochemistry revealed NF-positive nerve fibers leaving the spinal cord graft and entering the muscle tissue. AChE-positive endplates developed in the muscle grafts. Electrical stimulation of the spinal cord part of double-graft combinations generally elicited contractile responses in specific areas of the muscle cograft. These results demonstrate both structural and functional connections between grafts of spinal cord and skeletal muscle tissue in vivo. The fact that such connections were also established between a mature (adult) spinal cord graft and fetal skeletal muscle tissue suggests that some alpha-motoneurons are able to survive for many months in the intraocular grafts without an appropriate target, and that they are able to subsequently innervate skeletal muscle targets.

Animals↗
PubMed2003

Frontal and parietal participation in problem solving in the Tower of London: fMRI and computational modeling of planning and high-level perception.

This study triangulates executive planning and visuo-spatial reasoning in the context of the Tower of London (TOL) task by using a variety of methodological approaches. These approaches include functional magnetic resonance imaging (fMRI), functional connectivity analysis, individual difference analysis, and computational modeling. A graded fMRI paradigm compared the brain activation during the solution of problems with varying path lengths: easy (1 and 2 moves), moderate (3 and 4 moves) and difficult (5 and 6 moves). There were three central findings regarding the prefrontal cortex: (1) while both the left and right prefrontal cortices were equally involved during the solution of moderate and difficult problems, the activation on the right was differentially attenuated during the solution of the easy problems; (2) the activation observed in the right prefrontal cortex was highly correlated with individual differences in working memory (measured independently by the reading span task); and (3) different patterns of functional connectivity were observed in the left and right prefrontal cortices. Results obtained from the superior parietal region also revealed left/right differences; only the left superior parietal region revealed an effect of difficulty. These fMRI results converged upon two hypotheses: (1) the right prefrontal area may be more involved in the generation of a plan, whereas the left prefrontal area may be more involved in plan execution; and (2) the right superior parietal region is more involved in attention processes while the left homologue is more of a visuo-spatial workspace. A 4CAPS computational model of the cognitive processes and brain activation in the TOL task integrated these hypothesized mechanisms, and provided a reasonably good fit to the observed behavioral and brain activation data. The multiple research approaches presented here converge on a deepening understanding of the combination of perceptual and conceptual processes in this type of visual problem solving.

Adolescent↗
PubMed1999

Comparison of impaired subcortico-frontal metabolic networks in normal aging, subcortico-frontal dementia, and cortical frontal dementia.

Normal aging, progressive supranuclear palsy (PSP), and frontotemporal dementia (FTD) are characterized by different degrees of decline in frontal lobe functions. We used (18)FDG-PET and statistical parametric mapping (SPM96) to compare relative subcorticofrontal metabolic impairment at rest in 21 healthy elderly subjects (HES), 20 PSP patients, and 6 FTD patients. When HES were compared to 22 healthy young subjects, widespread decrease in metabolism was observed in bilateral medial prefrontal areas including anterior cingulate cortices, in dorsolateral prefrontal areas, in left lateral premotor area, in Broca's area, and in left insula. In PSP compared to the 43 healthy subjects (HS), we observed subcorticofrontal metabolic impairment including both motor and cognitive neural networks. Impairment of functional connections between midbrain tegmentum and cerebellar, temporal and pallidal regions was demonstrated in PSP as compared to HS. When comparing FTD to HS, glucose uptake was primarily reduced in dorsolateral and ventrolateral prefrontal cortices and in frontopolar and anterior cingulate regions. There was also bilateral anterior temporal, right inferior parietal, and bilateral striatal hypometabolism. Finally, FTD showed more severe striatofrontal metabolic impairment than PSP, while mesencephalothalamic involvement was only observed in PSP. Our data suggest that subcorticofrontal metabolic impairment is distributed in distinct subcorticocortical networks in normal aging, PSP, and FTD. Subcorticofrontal dementia in PSP is related to hypometabolism in discrete frontal areas, which are probably disconnected from certain subcortical structures. The concept of subcortical dementia is reinforced by our data, which show disrupted functional connections between mesencephalon and cerebellar cortex, inferior and medial temporal regions, and pallidum.

Adult↗
PubMed2005

From anatomic standardization analysis of perfusion SPECT data to perfusion pattern modeling: evidence of functional networks in healthy subjects and temporal lobe epilepsy patients.

RATIONALE AND OBJECTIVES: In the general context of perfusion pattern modeling from single-photon emission computed tomographic (SPECT) data, the purpose of this study is to characterize interindividual functional variability and functional connectivity between anatomic structures in a set of SPECT data acquired from a homogeneous population of subjects. MATERIALS AND METHODS: From volume of interest (VOI)-perfusion measurements performed on anatomically standardized SPECT data, we proposed to use correspondence analysis (CA) and hierarchical clustering (HC) to explore the structure of statistical dependencies among these measurements. The method was applied to study the perfusion pattern in two populations of subjects; namely, SPECT data from 27 healthy subjects and ictal SPECT data from 10 patients with mesio-temporal lobe epilepsy (MTLE). RESULTS: For healthy subjects, anatomic structures showing statistically dependent perfusion patterns were classified into four groups; namely, temporomesial structures, internal structures, posterior structures, and remaining cortex. For patients with MTLE, they were classified as temporomesial structures, surrounding temporal structures, internal structures, and remaining cortex. Anatomic structures of each group showed similar perfusion behavior so that they may be functionally connected and may belong to the same network. Our main result is that the temporal pole and lenticular nucleus seemed to be highly relevant to characterize ictal perfusion in patients with MTLE. This exploratory analysis suggests that a network involving temporal structures, lenticular nucleus, brainstem, and cerebellum seems to be involved during MTLE seizures. CONCLUSION: CA followed by HC is a promising approach to explore brain perfusion patterns from SPECT VOI measurements.

Adult↗
PubMed2001

Differential effect of ik3-1/cables on p53- and p73-induced cell death.

ik3-1/Cables is associated with cdk3 in self-replicating cells. In postmitotic neurons, it may serve as an adaptor molecule, functionally connecting c-abl and cdk5, and supporting neurite growth. Here we report that ik3-1 binds to p53 and p73 in vivo. Ectopically expressed ik3-1 potentiates p53-induced cell death but not p73-induced cell death in U2OS cells. On the contrary, coexpression of ik3-1-DeltaC, an ik3-1 deletion mutant lacking the C-terminal 139 [corrected] amino acids (corresponding to the cyclin box-homologous region), inhibits p73-induced cell death but not p53-induced cell death. ik3-1-DeltaC-mediated inhibition of p73-induced cell death are partially attenuated by overexpression of ik3-1. These data indicate that ik3-1 is not only a regulator for p53-induced cell death but also an essential regulator for p73-induced cell death, and ik3-1-DeltaC competes with ik3-1 only in p73-induced cell death. Furthermore, functional domains of p53 responsible for its interaction with ik3-1 are partially different from those of p73. In conclusion, we found that ik3-1, a putative component of cell cycle regulation, is functionally connected with p53 and p73, but in distinct fashions.

Adenoviridae↗
PubMed1993

Neurophysiological basis of functional recovery in the neonatal spinalized rat.

It had been shown previously that, following spinalization of the neonatal rat on postnatal day 7 (PN7), at the middle thoracic level, there was spontaneous recovery of coordinated stepping in the hindlimbs, enabling the animal to execute quadrupedal locomotion, with an ataxic gait. No significant recovery occurred in rats that were similarly spinalized on PN14. Despite the functional recovery in the PN7 group, their hindlimbs were paralyzed when not in contact with a surface. In the present experiments, at 16-18 weeks after spinalization, muscle spindle GpIa and cutaneous afferents were tested for functional connectivity to the alpha motoneurons (a-MNs) that innervate the right triceps surae (TS) muscles. The Hoffmann reflex (H-reflex), the tonic stretch reflex (TSR), and cutaneous reflexes were recorded from the right TS muscles in the nonanesthetized, intercollicular decerebrate preparation. The H-reflex and the TSR were readily elicited from the PN7 animals, but not from the PN14 animals. The PN14 preparations were characterized by prolonged (> 18 h in 3/8 cases), spontaneous discharge of motor units, and prominent M responses. There was widespread, bilateral convergence of cutaneous afferents from the hindquarters to the a-MNs of the TS muscles in both the PN7 and the PN14 preparations. In the nonspinalized, control preparation, only ipsilateral, cutaneous afferents activated the right TS a-MNs. These results demonstrate that in the chronic (> 3 months after spinalization), spinalized PN7 rat, but not in the PN14 rat, there is a tight functional connectivity between the hindlimb GpIa afferents and their homonymous a-MNs.

Animals↗
PubMed2001

ik3-1/Cables is associated with Trap and Pctaire2.

ik3-1/Cables is associated with and phosphorylated by cdk3 in self-replicating cells. In postmitotic neurons, it may serve as an adaptor molecule, functionally connecting c-abl and cdk5, and supporting neurite growth. Here, we cloned cDNAs coding for mouse Trap (tudor repeat associator with Pctaire 2) to interact with ik3-1. ik3-1 interacts with a region of mouse Trap containing the C-terminal tudor repeat domains 4 and 5 (corresponding to amino acids 881-1086 of mouse Trap). Furthermore, the N-terminal 93-amino-acid domain of ik3-1 is essential for ik3-1 interaction with Trap. Moreover, ik3-1 is coimmunoprecipitated with Pctaire 2 from COS7 cells, although we could not clarify whether ik3-1 is directly associated with Pctaire 2 or indirectly associated with Pctaire 2 through Trap. In vitro kinase assay indicated that ik3-1 does not activate phosphorylation of myelin basic protein or histione H 1 by the Pctaire 2-mediated kinase. These findings led us to speculate that through ik3-1, the Pctaire family and Trap may be functionally connected with cdk3 or cdk5.

Amino Acid Sequence↗
PubMed1987

Coincidence detection in auditory neurons: a possible mechanism to enhance stimulus specificity in the grassfrog.

It is still a matter of debate whether neurons in the higher central nervous system of anurans become progressively more sharply tuned to sounds that have a behavioral importance or that such coding is performed by (small) groups of neurons. The approach we have taken to investigate this matter comprises simultaneous single-unit recording using two microelectrodes in the auditory midbrain of the grassfrog. The present study deals with 96 pairs of units responding to an ensemble of natural and synthetic mating calls in which carrier frequency and pulse-repetition rate were varied. This ensemble was presented without noise and also with background noise of increasing intensity. The spike trains were analysed for correlations between their firings. In 34 pairs (35%) a functional connection, mostly common input, was present. By selecting one of the units of a pair as a trigger it was investigated which window for a coincidence analysis would result in enhanced specificity for the unit pair. Such an analysis based on a logical AND operation could be a model for the action of a neuron on which both units under study would converge, and which would then show an enhanced specificity in their response to a stimulus ensemble. It was found that in 20 pairs (21%) the logical AND operation was more selective than each of the component neurons. The largest time window for which the selectivity was found was evenly distributed over the values 8 ms, 32 ms and 128 ms, in one case selectivity was found only for a window of 2 ms. There was neither preference for selective pairs to be found for recordings with one electrode (45 cases) or dual electrodes (51), nor for independent (62) versus functionally connected (34) pairs. In some cases selectivity resulted in a preference for one specific call, in other cases it resulted in a loss of responsiveness to the masking noise effectively resulting in an enhanced signal-to-noise ratio. The analysis stresses the importance of spatiotemporal patterns of nervous activity for the representation of sounds in the auditory midbrain of anurans.

Animals↗
PubMed1999

Altered spatial patterns of functional thalamocortical connections in the barrel cortex after neonatal infraorbital nerve cut revealed by optical recording.

In rodents, the somatosensory cortex has a cell aggregation cluster termed the barrel, reflecting a whisker vibrissa, and this barrel formation is disrupted by infraorbital nerve cut at birth. In the present study, we prepared thalamocortical slice preparations from rats that received infraorbital nerve cut either at birth or at postnatal day (P) 7 and those from normal rats, recorded the optical response reflecting neural excitation in the somatosensory cortex with a voltage-sensitive dye (RH482) and compared the optical responses from lesioned rats with those from normal rats. In normal rats at P10, the optical response elicited electrically by thalamic stimulation propagated to the cortex, and then several patchy clusters appeared in layer IV. The size and location of these patchy responses precisely matched either barrels identified by cytochrome oxidase staining or terminal arbors of thalamocortial axons stained with biotinylated dextran amine. In contrast, at P10 in P0-lesioned rats, clusters having a wider horizontal width but smaller amplitude than those seen in normal rats appeared in layer IV. Correspondingly, neither cytochrome oxidase staining nor biotinylated dextran amine labeling of thalamocortical axons showed any barrel-like clusters or glomerular axon terminals. Likewise, at P5-P6, the tangential width of clusters in layer IV were larger than that in normal rats. At P10 in P7-lesioned rats, small cluster-matched barrels were seen in the optical response as well as in normal rats. These results suggest that P0 infraorbital nerve cut interrupted segregation of functional synapses into the barrels and retarded the maturation of thalamocortical transmission.

Animals↗
PubMed1996

Pericapillary and distant axon terminals in the nuclei of the cat amygdala: a morphometric study.

According to some ultrastructural studies, the pericapillary axon terminals in the central nervous system (CNS) are functionally connected with the capillary vessel wall. Thus, it may be expected that the population of pericapillary axon terminals will be morphologically distinct from the terminals at a further distance from the capillary walls. To test this hypothesis, morphometrical analysis of 3,048 axon terminals was performed, comparing terminals situated in the close vicinity of the capillary vessel with those at a distance from the vessels in the lateral, basal, medial, central and cortical nuclei of the amygdaloid body of eight cats. The cross-sectional area and circumference of each identified axon terminal profile were measured, and the shape of synaptic vesicles and the presence of synaptic contacts and granular vesicles were recorded. The statistical evaluation of results was performed by means of the Newman-Keuls' test, Wilcoxon's test, Fisher's contingency-table test and the test for two coefficients of structure. The morphometric examination revealed two ultrastructurally distinct groups of axon terminals, pericapillary and distant terminals, in all the nuclei of the amygdaloid body. The differentiating features were the shape of the synaptic vesicles, the number of synaptic contacts, and the size of the axon terminals. These results further support the hypothesis of a functional connection between axon terminals and the capillary vessel wall in the CNS.

Amygdala↗
PubMed1987

Coherent neural activity in the auditory midbrain of the grassfrog.

With a dual-electrode configuration separable few-unit activity was recorded both on one electrode as well as on two electrodes in the auditory midbrain of the grassfrog to a large variety of stimuli. Activity recorded on one electrode was separated by a pattern recognition technique through the use of features of the action potential waveform. Functional connections between units were established on basis of cross-correlation histograms of pairs of simultaneously recorded units. A hierarchical scheme was adopted to describe the various manifestations of neural correlation. If a peak or trough was observed in the simultaneous cross-correlation histogram, irrespective of stimulus conditions, this was called neural synchrony. If this peak or trough was not equal to its shift predictor estimating the stimulus contribution, neural correlation was considered to be present. About 60% of the pairs exhibited neural synchrony, mostly due to shared stimulus influences, independent of mutual distance of units. About 15% of the unit pairs showed neural correlation indicating a functional neural connection. Neural correlation was observed only in units with a distance smaller than 300 micron. The majority (approximately 85%) of the cases showing neural correlation could be ascribed to neural shared input. Unidirectional excitation was observed only in unit pairs recorded on the same electrode. Unidirectional inhibition could not be demonstrated. The dependency of occurrence of neural correlation on unit distance has implications for models of the functional organization of the auditory midbrain. About half of the neurally correlated pairs showed stimulus dependencies of their functional connections. Together with the observed lack of stimulus invariance of single-unit spectrotemporal sensitivities this indicates a dynamic stimulus dependency of functional neuronal organization in the auditory midbrain of the grassfrog. Neuron pairs with a large overlap of their spectrotemporal sensitivities on average had neurally correlated activities more often than pairs with a smaller amount of overlap. In comparison to single-unit coding, ensemble coding by populations of neurons may show an enhanced selectivity to stimulus characteristics.

Animals↗
PubMed1979

Synaptic connections and functional organization in Aplysia buccal ganglia.

The buccal ganglion of Aplysia contains three morpho-functional groups (A, B, and C) of large cells and two groups (s1 and s2) of small cells. The A cells evoke monoxynaptic IPSPs in the B cells. We found that s1 cells can evoke large EPSPs in the A cells, IEPSPs in the B cells, and EIIPSPs in the C cells; several s1 cells are able to evoke all three types of responses. Many s2 cells can evoke these same responses, but only in the A and B cells. Furthermore, the s cells can evoke depolarizing PSPs in other s cells; this relation is often reciprocal. All these responses may also be contralateral. Their monosynaptic nature is shown by the consistent 1:1 relationship with the presynaptic spike, and also by the effects of intracellular tetraethylammonium and of high Mg2+ concentration in the bathing medium. d-tubocurarine reversibly suppresses the I phase of the IEPSP evoked by the s cells in the B cells. All the responses evoked by the s cells undergo depression with repetition. The network formed by all these relations is outlined, and a double relationship proposed between s cells and B cells. By electrophysiological tracing of axonal pathways it is shown that the A cells send axons into the 3rd buccal nerve, the B cells into the 2nd and/or 3rd buccal nerve and in two cases into the radular nerve, and the C cells into the gastro-oesophageal nerve. Spontaneous synaptic activity of the buccal neurons appears to be formed mostly by the described PSPs. Spontaneous firing inside the isolated ganglion corresponds well to the alternate pattern of muscular contractions of the buccal mass.

Animals↗
PubMed2001

Reflections on the scope and the future of metabolic engineering and its connections to functional genomics and drug discovery.

Concepts, experience, and tools from metabolic engineering are immediately applicable to the challenge of understanding how the genome influences phenotype. However, new experimental approaches and mathematical and computational resources are needed to maximize the contributions of metabolic engineering to general questions in functional genomics. Among the priorities are systems for studying physiology on a microscale, theoretical tools for understanding biological control systems, and metabolic simulators "in silico" which provide reasonable predictions of stimulus-response relationships at engineering and medical resolution, with incomplete information on cellular mechanisms and their parameters. Approaching cells as complex systems, already a well-established principle in metabolic engineering, is essential to surmount stagnation in the rate of pharmaceutical discovery which is still based on a naive single-target paradigm.

Cells, Cultured↗