Biomedical subjects

Christian Hölscher

Publications and source records attributed to Christian Hölscher.

13 recordsLinked to original sources

PubMed2006

Impairments of hippocampal synaptic plasticity induced by aggregated beta-amyloid (25-35) are dependent on stimulation-protocol and genetic background.

The aggregation of beta-amyloid to plaques in the brain is one of the hallmarks of Alzheimer disease (AD). Numerous studies have tried to elucidate to what degree amyloid peptides play a role in the neurodegenerative developments seen in AD. While most studies report an effect of amyloid on neural activity and cognitive abilities of rodents, there have been many inconsistencies in the results. This study investigated to what degree the different genetic backgrounds affect the outcome of beta-amyloid fragment (25-35) on synaptic plasticity in vivo in the rat hippocampus. Two strains, Wistar and Lister hooded rats, were tested. In addition, the effects of a strong (600 stimuli) and a weak stimulation protocol (100 stimuli) on impairments of LTP were analysed. Furthermore, since the state of amyloid aggregation appears to play a role in the induction of toxic processes, it was tested by dual polarisation interferometry to what degree and at what speed beta-amyloid (25-35) can aggregate in vitro. It was found that 100 nmol beta-amyloid (25-35) injected icv did impair LTP in Wistar rats when using the weak but not the strong stimulation protocol (P < 0.001). One-hundred nano mole of the reverse sequence amyloid (35-25) had no effect. LTP in Lister Hooded rats was not impaired by amyloid at any stimulation protocol. The aggregation studies showed that amyloid (25-35) aggregated within hours, while amyloid (35-25) did not. These results show that the genetic background and the stimulation protocol are important variables that greatly influence the experimental outcome. The fact that amyloid (25-35) aggregated quickly and showed neurophysiological effects, while amyloid (35-25) did not aggregate and did not show any effects indicates that the state of aggregation plays an important role in the physiological effects.

Alzheimer Disease↗

PubMed2006

Abeta42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology.

We have generated a novel transgenic mouse model on a C57BL/6J genetic background that coexpresses KM670/671NL mutated amyloid precursor protein and L166P mutated presenilin 1 under the control of a neuron-specific Thy1 promoter element (APPPS1 mice). Cerebral amyloidosis starts at 6-8 weeks and the ratio of human amyloid (A)beta42 to Abeta40 is 1.5 and 5 in pre-depositing and amyloid-depositing mice, respectively. Consistent with this ratio, extensive congophilic parenchymal amyloid but minimal amyloid angiopathy is observed. Amyloid-associated pathologies include dystrophic synaptic boutons, hyperphosphorylated tau-positive neuritic structures and robust gliosis, with neocortical microglia number increasing threefold from 1 to 8 months of age. Global neocortical neuron loss is not apparent up to 8 months of age, but local neuron loss in the dentate gyrus is observed. Because of the early onset of amyloid lesions, the defined genetic background of the model and the facile breeding characteristics, APPPS1 mice are well suited for studying therapeutic strategies and the pathomechanism of amyloidosis by cross-breeding to other genetically engineered mouse models.

Amyloid beta-Peptides↗

PubMed2005

Inactivation of the rat dorsal striatum impairs performance in spatial tasks and alters hippocampal theta in the freely moving rat.

We analysed the interaction between the dorsal striatum (motor coordination and planning) and the hippocampus (sensory information processing and integration) during performance of goal-directed tasks. The performance of rats that had been injected with different doses of the D(2)-antagonist Sulpiride into the dorsal striatum was tested in an egocentric 4-arm maze task that tests striatal functions. Furthermore, hippocampal EEGs were recorded before, during and after inactivation of the dorsal striatum via injections of Sulpiride of rats that were performing a continuous alternation task. Injection of 5 microl of 100 mM Sulpiride increased the number of errors committed in the egocentric 4-arm maze (p < 0.01), indicating that the dorsal striatum is involved in motor control and motor memory recall in such a task. In the recording study, the same dose of Sulpiride injected into the dorsal striatum had powerful effects on the hippocampal EEG. The main activity in the theta range (5-10 Hz) was shifted from higher frequencies in the 8-10 Hz range to lower frequencies in the 5-7 Hz range (p < 0.005). The impairment in the behavioural egocentric task after Sulpiride injection, and the effects of Sulpiride on hippocampal theta shows that there is a functional interaction between the dorsal striatum and the hippocampus. While the dorsal striatum coordinates the execution of complex motor programs, the hippocampus integrates spatial and other sensory information required for the planning and execution of goal-directed movements.

Analysis of Variance↗

PubMed2005

Development of beta-amyloid-induced neurodegeneration in Alzheimer's disease and novel neuroprotective strategies.

Alzheimer's disease (AD) is a form of dementia in which people develop rapid neurodegeneration, complete loss of cognitive abilities, and are likely to die prematurely. At present, no treatment for AD is known. One of the hallmarks in the development of AD is the aggregation of amyloid protein fragments in the brain, and much evidence points towards beta-amyloid fragments being one of the main causes of the neurodegenerative processes. This review summarises the present concepts and theories on how AD develops, and lists the evidence that supports them. A cascade of biochemical events is initiated that ultimately leads to neuronal death involving an imbalance of intracellular calcium homeostasis via activation of calcium channels, intracellular calcium stores, and subsequent production of free radicals by calcium-sensitive enzymes. Secondary processes include inflammatory responses that produce more free radicals and the induction of apoptosis. Recently, several new strategies have been proposed to try to ameliorate the neurodegenerative developments associated with AD. These include the activation of neuronal growth factor receptors and insulin-like receptors, both of which have neuroprotective properties. Furthermore, the role of cholesterol and potential protective properties of cholesterol-lowering drugs are under intense investigation. Other promising strategies include the inhibition of beta- and gamma-secretases which produce beta-amyloid, activation of proteases that degrade beta-amyloid, glutamate receptor selective drugs, antioxidants, and metal chelating agents, all of which prevent formation of plaques. Novel drugs that act at different levels of the neurodegenerative processes show great promise to reduce neurodegeneration. They could help to prolong the time of unimpaired cognitive abilities of people who develop AD, allowing them to lead an independent life.

Alzheimer Disease↗

PubMed2004

Lack of the metabotropic glutamate receptor subtype 7 selectively impairs short-term working memory but not long-term memory.

Metabotropic glutamate receptors (mGluRs), and in particular the mGluR group III receptors (subtypes 4, 6, 7, 8) are known to play a role in synaptic plasticity and learning. Here, we report the effect of mGluR7 gene ablation in different learning paradigms. In the acoustic startle response (ASR), no differences were seen between knockout (KO) mice and wildtype (WT) littermates in parameters including prepulse inhibition and habituation. In an open field test, no differences were seen between genotypes in motor activity, exploratory behaviour, and fearful behaviour. In a T-maze reinforced alternation working memory (WM) task, again no difference was seen between groups. However, when increasing the demands on working-memory in a 4-arm and 8-arm maze task, KO mice committed more WM errors than WT littermates thereby uncovering a highly significant difference between the two groups that persisted every day for the whole 9 days of the experiment. In a 4-arm maze with 2 arms baited, KO and wildtype mice committed the same number of LTM errors, whereas KOs committed more WM errors. Altogether, these findings suggest that a lack of mGluR7 mainly impairs short-term working but not long-term memory performance while having no effect on sensorimotor processing, non-associative learning, motor activity and spatial orientation. The effects on WM are task-dependent and become apparent in more complex but not simple learning tasks. We discuss how mGluR7 could influence WM.

Animals↗

PubMed2004

Learned association of allocentric and egocentric information in the hippocampus.

Single-cell recording was conducted in the hippocampus of rats that performed a spontaneous alternation task in a modified T-maze. In the central arm of the maze, 4 out of 45 cells (8%) were found that fired selectively depending on which turn the animals would take. This result is in disagreement with a previous study in which two-thirds of cells (22 out of 33) showed a clear bias for direction of turns. The interpretation was that the cells coded information of episodic memory. Our results do not support this hypothesis. Interestingly, over the course of training, an increasing number of cells were found that fired in correlation with the rats' movements. It is proposed that these cells associate egocentric motor information with allocentric spatial information rather than encode episodic memory.

Animals↗

PubMed2003

Reward modulates neuronal activity in the hippocampus of the rat.

In the hippocampus of freely moving rats, neurons have been recorded that fire predominantly when the animal travels through a particular area while exploring the environment (so-called 'place cells'). This study investigates if the neuronal firing characteristics of such cells are modulated by attention, expectation of reward or memory load. A total of 16 electrodes were implanted in the CA1 region of the hippocampus of 3-month-old Long-Evans rats. Using a tetrode recording system, single neurons were recorded while a rat explored an 8-arm maze and retrieved pellets at the end of each arm. It was found that 31 out of 67 neurons showed place cell characteristics, while the other cells either fired in more than one place or fired along whole arms of the maze. Interestingly, 11 of the 31 neurons showed enhanced firing activity when the animal entered a baited arm but did not fire when the arm was visited again after the bait had been retrieved. In a second experiment, only four out of eight arms were baited. Firing rates of 46 neurons were analysed, and all cells (spatial or non-spatial) fired more in baited arms than in non-baited ones (P<0.001). In a reversal task in which the previously unbaited four arms were subsequently baited, neuronal activity was increased in the newly baited arms (42 cells analysed, P<0.001). Since no alterations to the maze or cues have been made, we interpret the increased firing probability of neurons in baited arms compared to unbaited arms as a correlate for 'attention' or 'expectation'.

Animals↗

PubMed2003

Perirhinal cortex neuronal activity related to long-term familiarity memory in the macaque.

Lesion studies suggest that the perirhinal cortex plays a role in object recognition memory. To analyse its role, the activity of single neurons in the perirhinal cortex was recorded in three rhesus monkeys (Macaca mulatta) performing a delayed matching-to-sample task with up to three intervening stimuli. A set of familiar visual stimuli was used. Some neurons had activity related to working memory, in that they responded more to the sample than to the match image within a trial, as shown previously. However, when a novel set of stimuli was introduced, the neuronal responses were on average only 47% of the magnitude of the responses to the familiar set of stimuli. Moreover, it was shown in eight different replications in three monkeys that the responses of the perirhinal cortex neurons gradually increased over hundreds of presentations of the new set of (initially novel) stimuli to become as large as with the already familiar stimuli. The mean number of 1.3-s presentations to induce this effect was 400 occurring over 7-13 days. These results show that perirhinal cortex neurons represent the very long-term familiarity of visual stimuli. A representation of the long-term familiarity of visual stimuli may be important for many aspects of social behaviour, and part of the impairment in temporal lobe amnesia may be related to the difficulty of building representations of the degree of familiarity of stimuli.

Action Potentials↗

PubMed2003

Time, space and hippocampal functions.

The hippocampus is one of the most researched structures of the brain. Studies of lesions in humans, primates and rodents have suggested to some that the primary role of the hippocampus is to act as a temporary memory buffer which is required for the consolidation of long-term memory. The famous case study of patient H.M., in particular, seemed to suggest that the hippocampus was of crucial importance for memory formation. However, recordings of single neurons in freely moving rodents did not support this notion. In such recordings, neurons were found that were active predominately when the animal passed through a particular area in space. Consequently, these neurons were termed 'place cells' and a theory was developed that suggested that the hippocampus acts as a 'cognitive map' that is required for spatial orientation. It was then found that H.M. had significant damage to his temporal lobes that included the amygdala, rhinal cortices, and other areas. Further case studies and selective hippocampal lesions in primates resulted in much milder amnestic symptoms, and lesions of defined cortical areas in the temporal lobes showed that a number of functions previously attributed to the hippocampus were in fact linked to these areas. Further analysis of neuronal activity in the hippocampus showed that not only is spatial information represented there, but also additional information, such as speed of movement, direction of movement, match or non-match detection, olfactorial identification, and others. In addition, it was found that selective lesions of the hippocampus in rodents impaired spatial navigation and memory formation only mildly. Only simultaneous lesions of several cortical areas in conjunction with the hippocamus could reproduce the impairments and symptoms that were previously thought to be observed after hippocampal lesions alone. In conclusion it is proposed that information processing and memory formation is shared by several brain areas that act as a functional system. This review presents evidence from many different studies that the hippocampus is part of this system and plays a supportive role in associating complex multimodal information and laying down new memory traces. In addition, the concept of allocating specific functions (such as the development of a cognitive map) exclusively to the hippocampus is rejected.

Animals↗

PubMed2002

Different strains of rats show different sensitivity to block of long-term potentiation by nitric oxide synthase inhibitors.

Nitric oxide is presumed to play important roles in the induction of synaptic plasticity and learning. Previous publications, however, reported contradictory results. Block of nitric oxide synthase (NOS) has been shown to impair the induction of long-term potentiation of synaptic transmission in some studies. Other studies observed a partial block of long-term potentiation depending on experimental conditions, while yet other studies did not find an effect of NOS inhibitors under any conditions tested. Some reasons for these differences had been identified, e.g. the temperature of the slice buffer, the age of the animals, and the specific stimulation protocols used. Still, even when taking these parameters into account, not all results can be explained. The present study compares three strains of rats and observes large differences in sensitivity to nitric oxide synthase (NOS) blockers on the induction of long-term potentiation. While Wistar rats showed an almost complete block of long-term potentiation when using the NOS inhibitors 7-nitro-indazole (30 mg/kg ip) or 1-(2-trifluoromethylphenyl) imidazole (TRIM; 150 nmol/5 microl icv), 117+/-5 S.E.M. of % of baseline slope values of excitatory postsynaptic potentials. Sprague-Dawley and Long-Evans rats showed no or only weak effects of drugs on the induction of long-term potentiation (166+/-17 S.E.M. of % of baseline slopes in Sprague-Dawley rats, 173+/-24 S.E.M. of % of baseline values in Long-Evans rats). The results could explain at least some of the discrepancies of the efficacy of NOS inhibitors on synaptic plasticity that is found in the literature. Such large strain differences suggest that results from studies that use laboratory rats could have strain-dependent components and should be generalised cautiously.

Animals↗

PubMed2002

Metabotropic glutamate receptors control gating of spike transmission in the hippocampus area CA1.

Signal transmission in the brain is regulated by a number of filters and modulatory systems. In particular, theta rhythm modulates local inhibition of networks and facilitates the induction of synaptic plastic processes. Additionally, the transmission of spikes in the network is controlled by pulse facilitation as a noise filter. Metabotropic glutamate receptors (mGluRs) that are found on interneurons in area CA1 of the hippocampus play a role in the fine-tuning of inhibitory circuits and in the transmission of spikes through the network. It was found that the mGluR agonist 1S,3S-1-amino-cyclo-pentyl-1,3-dicarboxylic acid (1S,3S-ACPD) blocked the induction of long-term potentiation (LTP) by high-frequency stimulation (HFS). In addition, theta-patterned stimulation was blocked by the drug. However, learning of spatial tasks in the water maze or radial arm maze was not inhibited by 1S,3S-ACPD. Yet, when stimulating with short bursts phase-locked with theta rhythm at the low inhibition phase, 1S,3S-ACPD did not inhibit the development of LTP. This suggests that burst transmission is not blocked in the network, while high-frequency trains are reduced to prevent overexcitation and the transmission of nonphysiologic stimuli patterns.

Animals↗

PubMed2002

Perirhinal cortex neuronal activity is actively related to working memory in the macaque.

Lesion studies suggest that the perirhinal cortex plays a role in object recognition memory. To analyze its role, we recorded the activity of single neurons in the perirhinal cortex in a rhesus monkey (Macaca mulatta) performing a delayed matching-to-sample task with up to four intervening stimuli. Certain neurons (40 of 90 analyzed) showed a smaller response to an image when it was shown the second time within a trial (as a match image) than when it had been shown (as a sample image) the first time. A new finding was that the perirhinal cortex neurons were actively reset between trials: when a particular image was shown as a sample on a succeeding trial, the response was much larger than when it had been shown as a match image a short time previously on the previous trial. This resetting between trials appears to reflect the operation of an active working memory process rather than a passive temporal decay in a neuronal response. The results thus provide evidence that the perirhinal cortex plays an active role in visual working memory, perhaps in association with other brain areas such as the prefrontal cortex.

Animals↗

PubMedDate not supplied

Lack of the metabotropic glutamate receptor subtype 7 selectively modulates Theta rhythm and working memory.

Metabotropic glutamate receptors (mGluRs) are known to play a role in synaptic plasticity and learning. We have previously shown that mGluR7 deletion in mice produces a selective working memory (WM) impairment, while other types of memory such as reference memory remain unaffected. Since WM has been associated with Theta activity (6-12 Hz) in EEGs, and since EEG abnormalities have been observed in these mice before, we studied the effect of mGluR7 gene ablation on EEG activity in the hippocampus, in particular in the Theta range, during performance of a WM task. In an eight-arm maze with four arms baited, mGluR7 knock-out (KO) and wild-type mice committed the same number of reference memory errors, whereas KOs committed more WM errors. While performing the task, KO mice showed substantially higher Theta amplitudes, and the ratio of Theta to overall EEG power was much increased. No change was seen in the Delta (0-5 Hz), or Gamma (30-40 Hz) EEG bands compared with controls. When recording EEGs during periods of rest in the home cages, no difference was seen between groups. These findings suggest that mGluR7 is important for modulation and control of Theta activity. Since only WM was affected, and only the Theta range of EEG activity was altered, these results show a correlation between Theta rhythm and WM performance, and therefore support the concept that Theta activity in the hippocampus is involved in WM storage.

Analysis of Variance↗