Biomedical subjects

T Bonhoeffer

Publications and source records attributed to T Bonhoeffer.

At least 19 recordsLinked to original sources

PubMed2001

Tuning and topography in an odor map on the rat olfactory bulb.

The sense of smell originates in a diverse array of receptor neurons, comprising up to 1000 different types. To understand how these parallel channels encode chemical stimuli, we recorded the responses of glomeruli in the olfactory bulbs of the anesthetized rat, by optical imaging of intrinsic signals. Odor stimulation produced two kinds of optical responses at the surface of the bulb: a broad diffuse component superposed by discrete small spots. Histology showed that the spots correspond to individual glomeruli, and that approximately 400 of them can be monitored in this way. Based on its wavelength-dependence, this optical signal appears to derive from changes in light scattering during neural activity. Pure odorants generally activated several glomeruli in a bilaterally symmetric pattern, whose extent varied greatly with concentration. A simple formalism for ligand binding accounts quantitatively for this concentration dependence and yields the effective affinity with which a glomerulus responds to an odorant. When tested with aliphatic molecules of increasing carbon chain length, many glomeruli were sharply tuned for one or two adjacent chain lengths. Glomeruli with similar tuning properties were located near each other, producing a systematic map of molecular chain length on the surface of the olfactory bulb. Given local inhibitory circuits within the olfactory bulb, this can account for the observed functional inhibition between related odors. We explore several parallels to the function and architecture of the visual system that help interpret the neural representation of odors.

Administration, Inhalation↗

PubMed2001

In vivo optical mapping of epileptic foci and surround inhibition in ferret cerebral cortex.

The population of neurons participating in an epileptiform event varies from moment to moment. Most techniques currently used to localize epileptiform events in vivo have spatial and/or temporal sampling limitations. Here we show in an animal model that optical imaging based on intrinsic signals is an excellent method for in vivo mapping of clinically relevant epileptiform events, such as interictal spikes, ictal onsets, ictal spread and secondary homotopic foci. In addition, a decrease in the optical signal correlates spatially with a decrease in neuronal activity recorded from cortex surrounding an epileptic focus. Optical mapping of epilepsy might be a useful adjunct in the surgical treatment of neocortical epilepsy, which critically depends on the precise localization of intrinsically epileptogenic neurons.

Animals↗

PubMed2001

Morphological changes in dendritic spines associated with long-term synaptic plasticity.

Dendritic spines are morphological specializations that receive synaptic inputs and compartmentalize calcium. In spite of a long history of research, the specific function of spines is still not well understood. Here we review the current status of the relation between morphological changes in spines and synaptic plasticity. Since Cajal and Tanzi proposed that changes in the structure of the brain might occur as a consequence of experience, the search for the morphological correlates of learning has constituted one of the central questions in neuroscience. Although there are scores of studies that encompass this wide field in many species, in this review we focus on experimental work that has analyzed the morphological consequences of hippocampal long-term potentiation (LTP) in rodents. Over the past two decades many studies have demonstrated changes in the morphology of spines after LTP, such as enlargements of the spine head and shortenings of the spine neck. Biophysically, these changes translate into an increase in the synaptic current injected at the spine, as well as shortening of the time constant for calcium compartmentalization. In addition, recent online studies using time-lapse imaging have reported increased spinogenesis. The currently available data show a strong correlation between synaptic plasticity and morphological changes in spines, although at the same time, there is no evidence that these morphological changes are necessary or sufficient for the induction or maintenance of LTP. Still, they highlight once more how form and function go hand in hand in the central nervous system.

Animals↗

PubMed2000

Shc-binding site in the TrkB receptor is not required for hippocampal long-term potentiation.

Recent evidence shows that neurotrophins are not only involved in neuronal survival and differentiation but also in modulating synaptic strength in the developing and adult nervous system. To understand how neurotrophins induce changes in synaptic strength, we have investigated signaling pathways downstream of the TrkB receptor, which binds brain-derived neurotrophic factor (BDNF) or NT-4/5. To test whether the Shc-site activated signaling pathway, which has been shown to be important for neuronal survival in vivo, also plays a role in processes like long-term potentiation (LTP), we have generated a mouse strain carrying a mutation in the Shc-binding site of the TrkB receptor. In hippocampal slices from these mice we investigated whether basal synaptic transmission, early-LTP (E-LTP) or late-LTP (L-LTP) were affected by this mutation. We found that homo- and heterozygous mutant mice show no difference in the induction-rate or magnitude of E-LTP and L-LTP induced by theta-burst or tetanus stimulation, suggesting that the Shc-binding site in the TrkB receptor and its downstream activated signaling cascade is not involved in hippocampal synaptic plasticity.

Animals↗

PubMed2000

Principal component analysis and blind separation of sources for optical imaging of intrinsic signals.

The analysis of data sets from optical imaging of intrinsic signals requires the separation of signals, which accurately reflect stimulated neuronal activity (mapping signal), from signals related to background activity. Here we show that blind separation of sources by extended spatial decorrelation (ESD) is a powerful method for the extraction of the mapping signal from the total recorded signal. ESD is based on the assumptions (i) that each signal component varies smoothly across space and (ii) that every component has zero cross-correlation functions with the other components. In contrast to the standard analysis of optical imaging data, the proposed method (i) is applicable to nonorthogonal stimulus-conditions, (ii) can remove the global signal, blood-vessel patterns, and movement artifacts, (iii) works without ad hoc assumptions about the data structure in the frequency domain, and (iv) provides a confidence measure for the signals (Z score). We first demonstrate on orientation maps from cat and ferret visual cortex, that principal component analysis, which acts as a preprocessing step to ESD, can already remove global signals from image stacks, as long as data stacks for at least two-not necessarily orthogonal-stimulus conditions are available. We then show that the full ESD analysis can further reduce global signal components and-finally-concentrate the mapping signal within a single component both for differential image stacks and for image stacks recorded during presentation of a single stimulus.

Animals↗

PubMed2000

Visual cortex maps are optimized for uniform coverage.

Cat visual cortex contains a topographic map of visual space, plus superimposed, spatially periodic maps of ocular dominance, spatial frequency and orientation. It is hypothesized that the layout of these maps is determined by two constraints: continuity or smooth mapping of stimulus properties across the cortical surface, and coverage uniformity or uniform representation of combinations of map features over visual space. Here we use a quantitative measure of coverage uniformity (c') to test the hypothesis that cortical maps are optimized for coverage. When we perturbed the spatial relationships between ocular dominance, spatial frequency and orientation maps obtained in single regions of cortex, we found that cortical maps are at a local minimum for c'. This suggests that coverage optimization is an important organizing principle governing cortical map development.

Animals↗

PubMed2000

An analysis of orientation and ocular dominance patterns in the visual cortex of cats and ferrets.

We report an analysis of orientation and ocular dominance maps that were recorded optically from area 17 of cats and ferrets. Similar to a recent study performed in primates (Obermayer & Blasdel, 1997), we find that 80% (for cats and ferrets) of orientation singularities that are nearest neighbors have opposite sign and that the spatial distribution of singularities deviates from a random distribution of points, because the average distances between nearest neighbors are significantly larger than expected for a random distribution. Orientation maps of normally raised cats and ferrets show approximately the same typical wavelength; however, the density of singularities is higher in ferrets than in cats. Also, we find the well-known overrepresentation of cardinal versus oblique orientations in young ferrets (Chapman & Bonhoeffer, 1998; Coppola, White, Fitzpatrick, & Purves, 1998) but only a weak, not quite significant overrepresentation of cardinal orientations in cats, as has been reported previously (Bonhoeffer & Grinvald, 1993). Orientation and ocular dominance slabs in cats exhibit a tendency of being orthogonal to each other (Hubener, Shoham, Grinvald, & Bonhoeffer, 1997), albeit less pronounced, as has been reported for primates (Obermayer & Blasdel, 1993). In chronic recordings from single animals, a decrease of the singularity density and an increase of the ocular dominance wavelength with age but no change of the orientation wavelengths were found. Orientation maps are compared with two pattern models for orientation preference maps: bandpass-filtered white noise and the field analogy model. Bandpass-filtered white noise predicts sign correlations between orientation singularities, but the correlations are significantly stronger (87% opposite sign pairs) than what we have found in the data. Also, bandpass-filtered noise predicts a deviation of the spatial distribution of singularities from a random dot pattern. The field analogy model can account for the structure of certain local patches but not for the whole orientation map. Differences between the predictions of the field analogy model and experimental data are smaller than what has been reported for primates (Obermayer & Blasdel, 1997), which can be explained by the smaller size of the imaged areas in cats and ferrets.

Algorithms↗

PubMed1999

Relative contribution of endogenous neurotrophins in hippocampal long-term potentiation.

Recent evidence has shown that brain-derived neurotrophic factor (BDNF) is involved in hippocampal long-term potentiation (LTP). Because the reagents used in acute experiments react not only with BDNF but also with neurotrophin-4/5 (NT4/5) and neurotrophin-3 (NT3), we examined the involvement of these neurotrophins in LTP using two highly specific, function-blocking monoclonal antibodies against BDNF and NT3, as well as a TrkB-IgG fusion protein. Our results show that NT3 antibodies did not have any effects on LTP. However, both TrkB-IgG fusion proteins and BDNF antibody similarly reduced LTP, suggesting that only BDNF but no other ligands of the TrkB-receptor are likely to be involved in LTP induction. The reduction in LTP depended on the inducing stimuli and was only observed with theta-burst stimulation (TBS) but not with tetanic stimulation. We further observed that LTP was only reduced if BDNF was blocked before and during TBS stimulation, and BDNF antibodies did not affect early or late stages of LTP if they were applied 10, 30, or 60 min after TBS stimulation. These results point toward a specific and unique role of endogenous BDNF but not of other neurotrophins in the process of TBS-induced hippocampal LTP. Additionally, they suggest that endogenous BDNF is required for a limited time period only shortly before or around LTP induction but not during the whole process of LTP.

Animals↗

PubMed1999

Dendritic spine changes associated with hippocampal long-term synaptic plasticity.

Long-term enhancement of synaptic efficacy in the hippocampus is an important model for studying the cellular mechanisms of neuronal plasticity, circuit reorganization, and even learning and memory. Although these long-lasting functional changes are easy to induce, it has been very difficult to demonstrate that they are accompanied or even caused by morphological changes on the subcellular level. Here we combined a local superfusion technique with two-photon imaging, which allowed us to scrutinize specific regions of the postsynaptic dendrite where we knew that the synaptic changes had to occur. We show that after induction of long-lasting (but not short-lasting) functional enhancement of synapses in area CA1, new spines appear on the postsynaptic dendrite, whereas in control regions on the same dendrite or in slices where long-term potentiation was blocked, no significant spine growth occurred.

Animals↗

PubMed1999

Development of orientation preference in the mammalian visual cortex.

Recent experiments have studied the development of orientation selectivity in normal animals, visually deprived animals, and animals where patterns of neuronal activity have been altered. Results of these experiments indicate that orientation tuning appears very early in development, and that normal patterns of activity are necessary for its normal development. Visual experience is not needed for early development of orientation, but is crucial for maintaining orientation selectivity. Neuronal activity and vision thus seem to play similar roles in the development of orientation selectivity as they do in the development of eye-specific segregation in the visual system.

Animals↗

PubMed1999

Essential role for TrkB receptors in hippocampus-mediated learning.

Brain-derived neurotrophic factor (BDNF) and its receptor TrkB regulate both short-term synaptic functions and long-term potentiation (LTP) of brain synapses, raising the possibility that BDNF/TrkB may be involved in cognitive functions. We have generated conditionally gene targeted mice in which the knockout of the trkB gene is restricted to the forebrain and occurs only during postnatal development. Adult mutant mice show increasingly impaired learning behavior or inappropriate coping responses when facing complex and/or stressful learning paradigms but succeed in simple passive avoidance learning. Homozygous mutants show impaired LTP at CA1 hippocampal synapses. Interestingly, heterozygotes show a partial but substantial reduction of LTP but appear behaviorally normal. Thus, CA1 LTP may need to be reduced below a certain threshold before behavioral defects become apparent.

Animals↗

PubMed1999

Influence of experience on orientation maps in cat visual cortex.

Experience is known to affect the development of ocular dominance maps in visual cortex, but it has remained controversial whether orientation preference maps are similarly affected by limiting visual experience to a single orientation early in life. Here we used optical imaging based on intrinsic signals to show that the visual cortex of kittens reared in a striped environment responded to all orientations, but devoted up to twice as much surface area to the experienced orientation as the orthogonal one. This effect is due to an instructive role of visual experience whereby some neurons shift their orientation preferences toward the experienced orientation. Thus, although cortical orientation maps are remarkably rigid in the sense that orientations that have never been seen by the animal occupy a large portion of the cortical territory, visual experience can nevertheless alter neuronal responses to oriented contours.

Animals↗

PubMed1999

Eyes wide shut.

Crowley and Katz cast doubt on the idea that correlated activity is critical for visual cortex development by showing that ocular dominance maps can emerge without any retinal input.

Animals↗

PubMed1999

Orientation topography of layer 4 lateral networks revealed by optical imaging in cat visual cortex (area 18).

The functional specificity of corticocortical connections with respect to the topography of orientation selectivity was studied by optical imaging of intrinsic signals and bulk injections of fluorescent latex beads (green and red) and biocytin into layer 4. The distributions of retrogradely labelled cells and anterogradely labelled axon terminals were histologically reconstructed from all cortical laminae, and the resulting anatomical maps compared with the optically imaged functional maps. Layer 4 injections produced extensive horizontal labelling up to 2-3 mm from the injection centres albeit without the clear patchy pattern described after layer 2/3 injections (Gilbert & Wiesel 1989, J. Neurosci., 9, 2432-2442; Kisvárday et al. 1997, Cerebral Cortex, 7, 605-618). The functional (orientation) distribution of the labelled projections was analysed according to laminar location and lateral spread. With regard to the former, no major difference in the orientation topography between supragranular- (upper tier), granular- (middle tier) and infragranular (lower tier) layers was seen. Laterally, proximal and distal projections were distinguished and further dissected into three orientation categories, iso- (+/- 30 degrees ), oblique- (+/- 30-60 degrees ) and cross-orientations (+/- 60-90 degrees ) with respect to the orientation preference at the injection sites. The majority of distal connections (retrograde and anterograde) was equally distributed across orientations (35.4% iso-, 33.7% oblique-, and 30.9% cross-orientations) that are equivalent with a preponderance to dissimilar orientations (oblique- and cross-orientations, 64.6%). In one case, distal excitatory and inhibitory connections could be morphologically distinguished. For both categories, a marked bias to dissimilar orientations was found (excitatory, 63.7%; inhibitory, 86.6%). Taken together, these results suggest that the long-range layer 4 circuitry has a different functional role from that of the iso-orientation biased (52.9%, Kisvárday et al. 1997, Cerebral Cortex, 7, 605-618) layer 2/3 circuitry, and is perhaps involved in feature difference-based mechanisms, e.g. figure ground segregation.

Animals↗

PubMed1998

Overrepresentation of horizontal and vertical orientation preferences in developing ferret area 17.

One of the fundamental principles of visual cortical organization is that neurons form a "map" in which neighboring cells have similar orientation preferences. Previous anatomical and imaging studies have shown that although the exact layouts of these orientation preference maps vary between individuals, features of iso-orientation domains such as width and spacing appear constant within a species. Using chronic optical imaging of intrinsic signals we now demonstrate that in ferret area 17 a larger proportion of cortical surface is dominated by responses to horizontal and vertical contours than to the two oblique orientations. This was true for all ferrets studied both during development and in adulthood. Interestingly, however, we found that the degree of the overrepresentation varied significantly between individual animals. In some young ferrets, responses to horizontal and vertical stimuli developed faster than responses to oblique stimuli, and a much larger percentage of the cortex responded preferentially to horizontal and vertical stimuli. In other individuals, responses to all stimuli developed at roughly the same rate, and there was relatively little overrepresentation of horizontal and vertical preferences.

Aging↗

PubMed1998

The layout of orientation and ocular dominance domains in area 17 of strabismic cats.

In the primary visual cortex of strabismic cats, the elimination of correlated activity between the two eyes enhances the segregation of the geniculocortical afferents into alternating ocular dominance domains. In addition, both tangential intracortical fibres and neuronal synchronization are severely reduced between neurons activated by different eyes. Consequently, ocular dominance columns belonging to different eyes are functionally rather independent. We wondered whether this would also affect the organization of orientation preference maps. To this end, we visualized the functional architecture of area 17 of strabismic cats with both optical imaging based on intrinsic signals and double labelling of orientation and ocular dominance columns with [14C]2-deoxyglucose and [3H]proline. As expected, monocular iso-orientation domains had a patchy appearance and differed for the two eyes, leading to a clear segregation of the ocular dominance domains. Comparison of 'angle maps' revealed that orientation domains exhibit a pinwheel organization as in normally reared cats. Interestingly, the map of orientation preferences did not show any breaks at the borders between ocular dominance columns: iso-orientation domains were continuous across these borders. In addition, iso-orientation contours tended to cross the borders of adjacent ocular dominance columns at right angles. These data suggest that the basic relations between the layout of orientation maps and ocular dominance columns are not disturbed by artificial decorrelation of binocular input. Therefore in cat area 17, the orientation map does not seem to be modified by experience-dependent changes of thalamic input connections. This suggests the possibility that use-dependent rearrangement of geniculocortical afferents into ocular dominance columns is due to Hebbian modifications whereby postsynaptic responsivity is constrained by the scaffold of the orientation map.

Animals↗

PubMed1997

Spatial relationships among three columnar systems in cat area 17.

In the primary visual cortex, neurons with similar response properties are arranged in columns. As more and more columnar systems are discovered it becomes increasingly important to establish the rules that govern the geometric relationships between different columns. As a first step to examine this issue we investigated the spatial relationships between the orientation, ocular dominance, and spatial frequency domains in cat area 17. Using optical imaging of intrinsic signals we obtained high resolution maps for each of these stimulus features from the same cortical regions. We found clear relationships between orientation and ocular dominance columns: many iso-orientation lines intersected the borders between ocular dominance borders at right angles, and orientation singularities were concentrated in the center regions of the ocular dominance columns. Similar, albeit weaker geometric relationships were observed between the orientation and spatial frequency domains. The ocular dominance and spatial frequency maps were also found to be spatially related: there was a tendency for the low spatial frequency domains to avoid the border regions of the ocular dominance columns. This specific arrangement of the different columnar systems might ensure that all possible combinations of stimulus features are represented at least once in any given region of the visual cortex, thus avoiding the occurrence of functional blind spots for a particular stimulus attribute in the visual field.

Animals↗

PubMed1997

Synapse specificity of long-term potentiation breaks down at short distances.

Long-term potentiation (LTP), the long-lasting increase in synaptic transmission, has been proposed to be a cellular mechanism essential for learning and memory, neuronal development, and circuit reorganization. In the original theoretical and experimental work it was assumed that only synapses that had experienced concurrent pre- and postsynaptic activity are subject to synaptic modification. It has since been shown, however, that LTP is also expressed in synapses on neighbouring neurons that have not undergone the induction procedure. Yet, it is still believed that this spread of LTP is limited to adjacent postsynaptic cells, and does not occur for synapses on neighbouring input fibres. However, for technical reasons, tests for 'input specificity' were always done for synapses relatively far apart. Here we have used a new local superfusion technique, which allowed us to assess the synaptic specificity of LTP with a spatial resolution of approximately 30 microm. Our results indicate that there is no input specificity at a distance of less than 70 microm. Synapses in close proximity to a site of potentiation are also potentiated regardless of their own history of activation, whereas synapses far away show no potentiation.

Animals↗