Basic paradigms

Links through basic paradigms

One possibility to successfully link different areas of neuroscientific research is to adapt paradigms that can be investigated at both the animal and the human level. This strategy permits conclusions at both the molecular and the systems levels that cannot be drawn from either approach in isolation. In particular, human medical research can benefit enormously from insights gained through the use of invasive experimental techniques in animals (including transgenic approaches) if analogous paradigms are employed.

Various methods will be combined in individual projects, including functional neuroimaging (e.g. fMRI, MEG, EEG, transcranial magnetic and DC stimulation), genetic techniques (e.g. second generation conditional knock-out/knock-in mice, viral infection), molecular biology (e.g. single gene and whole genome epigenetic profiling in mice), electrophysiology in vitro (e.g. single-cell and paired-cell recordings) and in vivo (e.g. multiple-site recordings in cortex, hippocampus and subcortical nuclei), and behavioral analysis. Often both approaches converge on selected anatomical circuits (e.g. ventromedial prefrontal cortex, hippocampus and amygdala for classical conditioning and extinction), transmitter systems (e.g. dopaminergic) and signalling principles. This strategy is intended to provide a maximum of collaborative synergy and will lead to convergent lines of evidence in the explanation of mechanisms underlying learning and memory. Although this approach is restricted to a set of common paradigms and parameters, it provides an initial basis for the combination of data from different fields and will in addition generate new, testable hypotheses for both areas.

This approach has already been successfully applied by our consortium as exemplified in the Collaborative Research Centre SFB TRR 58 in which fear learning is investigated in rodents and humans. This includes ongoing collaborations on fear conditioning in humans (Kalisch, Büchel, Engel) and rodents (Pape; Münster) and its genetics (Lesch, Deckert; Würzburg).

Current projects exploiting common paradigms:

Animal Human

Mechanisms of classical conditioning

The molecular mechanisms underlying fear conditioning and its extinction are currently being investigated in the laboratories of D. Kuhl and D. Isbrandt, using genetic tools and pharmacological manipulations or behavioral interventions. Effects are being measured at the level of behavior, endocrine responses, gene expression, protein function, and LTP induction.
Different groups in this consortium (Büchel, Kalisch) have revealed key mechanisms of classical conditioning in humans, including the role of amygdala, hippocampus and vmPFC and of the glutamatergic, opioidergic and oxytocin systems (Büchel, Kalisch). Currently, these projects focus on the influence of genetic variation on learning and memory by investigating genetic norm variants (polymorphisms) in cooperation with SFB TRR 58.

Oscillatory activity in classical conditioning

The group of A.K. Engel investigates changes of assembly dynamics in hippocampus, amygdala and neocortex during fear conditioning in transgenic mouse models. The experiments focus on oscillatory activity and dynamic coupling by neural coherence between the structures involved in fear learning.

Complementing the studies on oscillatory activity and neural coherence during fear conditioning in the mouse, these phenomena are also investigated during fear conditioning in human subjects using MEG and advanced source modelling techniques (Engel, Büchel)

Spatial learning

Aiming at the investigation of molecular mechanisms underlying hippocampus-dependent episodic-like memory D. Isbrandt and D. Kuhl have used spatial learning and memory tasks in rodents and, in particular, in transgenic mice. Specific experimental designs and protocols have been established to dissect different forms of idio- and allothetic navigation as well as other forms of learning (i.e. reversal learning, extinction).
Using virtual environments it has become possible to study simple spatial navigational skills in humans using fMRI (Büchel, May). These paradigms comprise spatial updating, path integration and ego- and allocentric spatial navigation. Studies using genetically stratified groups of volunteers or neuropharmacological challenges will further improve our understanding of the neurophysiological and neurochemical basis of the processes.

Investigation of Tau processing in Alzheimer Disease and frontotemporal dementia

Deposition of pathologically processed Tau is a hallmark feature in 100% of Alzheimer Disease (AD) and 40% of Frontotemporal dementia (FTD). Recent studies indicate that aggregated Tau protein may consist in part of proteolytically cleaved fragments of Tau, and that the aggregation process may indeed be triggered by aberrant proteolytic processing. We are investigating the role of proteolytically processed Tau in the pathophysiology of AD and FTD by analyzing sites of abnormal proteolysis of tau fragments in cell and mouse models of these diseases using sequencing and mass spectro¬metry. Furthermore, we are generating monoclonal antibodies which are specifically directed against protease specific cleavage sites within Tau.
In humans, we are assessing the amount and the distribution of specific Tau fragments within the central nervous system of individuals suffering from AD or FTD. Furthermore we are investigating the expression and the activity of a number of candidate Tau-cleaving proteases such as Caspase 3, Calpain and others. The presence of cleaved Tau and the activity of proteases is correlated to neuronal loss, apoptosis, degree of gliosis and deposition of other pathologically processed proteins.
Finally, we will focus on the development of novel diagnostic tools for the diagnosis of AD and FTD. In order to facilitate diagnostic applications we will develop ELISA based assays which will allow the identification of potentially disease specific Tau fragments or ratios of Tau fragments.

Role of cortico-hippocampal interactions in sleep dependent memory consolidation

In a series of comparative studies in rodents, the project will investigate how applied slow oscillation stimulation modulates not only neocortical but also hippocampal activity. Modulatory effects on electrophysiological activity will be compared with behavioural performance on learning and memory tasks. Eventually this project aims at clarifying how the oscillatory electrical phenomena of interest mediate the transfer of intermediate memories from hippocampal to neocortical circuitries for long term storage. Additionally, electrical stimulation techniques will be developed to improve this transfer of memories to the long-term store.
The sleep-dependent consolidation of declarative memory relies on a hippocampo-neocortical interaction including neocortical slow oscillation (~ 1 Hz) and sleep spindles, and hippocampal sharp-wave ripple events. Their interaction and the corresponding fine tuning of neuronal activity is presumed decisive for the consolidation of hippocampus-dependent memories. In humans we use transcranial anodal slow oscillation stimulation (~ 0.75 Hz) and obtained enhanced retention on a declarative memory task accompanied by an increase in endogenous EEG slow oscillatory and spindle activity.

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Animal	Human
Mechanisms of classical conditioning
The molecular mechanisms underlying fear conditioning and its extinction are currently being investigated in the laboratories of D. Kuhl and D. Isbrandt, using genetic tools and pharmacological manipulations or behavioral interventions. Effects are being measured at the level of behavior, endocrine responses, gene expression, protein function, and LTP induction.	Different groups in this consortium (Büchel, Kalisch) have revealed key mechanisms of classical conditioning in humans, including the role of amygdala, hippocampus and vmPFC and of the glutamatergic, opioidergic and oxytocin systems (Büchel, Kalisch). Currently, these projects focus on the influence of genetic variation on learning and memory by investigating genetic norm variants (polymorphisms) in cooperation with SFB TRR 58.
Oscillatory activity in classical conditioning
The group of A.K. Engel investigates changes of assembly dynamics in hippocampus, amygdala and neocortex during fear conditioning in transgenic mouse models. The experiments focus on oscillatory activity and dynamic coupling by neural coherence between the structures involved in fear learning.	Complementing the studies on oscillatory activity and neural coherence during fear conditioning in the mouse, these phenomena are also investigated during fear conditioning in human subjects using MEG and advanced source modelling techniques (Engel, Büchel)
Spatial learning
Aiming at the investigation of molecular mechanisms underlying hippocampus-dependent episodic-like memory D. Isbrandt and D. Kuhl have used spatial learning and memory tasks in rodents and, in particular, in transgenic mice. Specific experimental designs and protocols have been established to dissect different forms of idio- and allothetic navigation as well as other forms of learning (i.e. reversal learning, extinction).	Using virtual environments it has become possible to study simple spatial navigational skills in humans using fMRI (Büchel, May). These paradigms comprise spatial updating, path integration and ego- and allocentric spatial navigation. Studies using genetically stratified groups of volunteers or neuropharmacological challenges will further improve our understanding of the neurophysiological and neurochemical basis of the processes.
Investigation of Tau processing in Alzheimer Disease and frontotemporal dementia
Deposition of pathologically processed Tau is a hallmark feature in 100% of Alzheimer Disease (AD) and 40% of Frontotemporal dementia (FTD). Recent studies indicate that aggregated Tau protein may consist in part of proteolytically cleaved fragments of Tau, and that the aggregation process may indeed be triggered by aberrant proteolytic processing. We are investigating the role of proteolytically processed Tau in the pathophysiology of AD and FTD by analyzing sites of abnormal proteolysis of tau fragments in cell and mouse models of these diseases using sequencing and mass spectro¬metry. Furthermore, we are generating monoclonal antibodies which are specifically directed against protease specific cleavage sites within Tau.	In humans, we are assessing the amount and the distribution of specific Tau fragments within the central nervous system of individuals suffering from AD or FTD. Furthermore we are investigating the expression and the activity of a number of candidate Tau-cleaving proteases such as Caspase 3, Calpain and others. The presence of cleaved Tau and the activity of proteases is correlated to neuronal loss, apoptosis, degree of gliosis and deposition of other pathologically processed proteins. Finally, we will focus on the development of novel diagnostic tools for the diagnosis of AD and FTD. In order to facilitate diagnostic applications we will develop ELISA based assays which will allow the identification of potentially disease specific Tau fragments or ratios of Tau fragments.
Role of cortico-hippocampal interactions in sleep dependent memory consolidation
In a series of comparative studies in rodents, the project will investigate how applied slow oscillation stimulation modulates not only neocortical but also hippocampal activity. Modulatory effects on electrophysiological activity will be compared with behavioural performance on learning and memory tasks. Eventually this project aims at clarifying how the oscillatory electrical phenomena of interest mediate the transfer of intermediate memories from hippocampal to neocortical circuitries for long term storage. Additionally, electrical stimulation techniques will be developed to improve this transfer of memories to the long-term store.	The sleep-dependent consolidation of declarative memory relies on a hippocampo-neocortical interaction including neocortical slow oscillation (~ 1 Hz) and sleep spindles, and hippocampal sharp-wave ripple events. Their interaction and the corresponding fine tuning of neuronal activity is presumed decisive for the consolidation of hippocampus-dependent memories. In humans we use transcranial anodal slow oscillation stimulation (~ 0.75 Hz) and obtained enhanced retention on a declarative memory task accompanied by an increase in endogenous EEG slow oscillatory and spindle activity.

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Links through basic paradigms