AG Gloveli

The goal of our research is to understand how information is processed and encoded in the brain. The framework for such information processing on the network level is the temporal binding of neuronal cell ensembles resulting in coherent oscillatory activity in humans and animals especially in the theta, gamma and ripple frequency range.

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Cellular physiology and pathophysiology

Our group is active in the field of cellular physiology and pathophysiology. We use a combination of electrophysiological, anatomical and immunohistological approaches to address the following research questions:

  • Role of interneurons in hippocampal sharp wave-ripple and gamma frequency network oscillations
  • Hippocampal pyramidal cell axonal activity, network dynamic and plasticity
  • Entorhinal cortex-hippocampal physiology and pathophysiology
  • Functional and structural alterations in hippocampal inhibitory innervations in temporal lobe epilepsy

Methods

  • In vitro field, intracellular and Patch clamp techniques
  • Dual somatic and axonal patch-clamp recordings from identified cells
  • In vivo LFP recordings
  • Neuromorphology and Immunohistochemistry
  • Mouse model of temporal lobe epilepsy

Research Fields:

Information flow in the brain is not a "one-way street"

Fig. 1 High frequency discharge of the axon but not the soma of hippocampal CA3 pyramidal cells during gamma frequency oscillations in vitro. Dual somatic and axonal cell-attached recoding directly demonstrate that high frequency axonal spikes (‘axon’) fail to invade the soma (‘soma’) during gamma frequency oscillations (‘LFP’). (from Dugladze et al., Science 2012)
Fig. 1 High frequency discharge of the axon but not the soma of hippocampal CA3 pyramidal cells during gamma frequency oscillations in vitro. Dual somatic and axonal cell-attached recoding directly demonstrate that high frequency axonal spikes (‘axon’) fail to invade the soma (‘soma’) during gamma frequency oscillations (‘LFP’). (from Dugladze et al., Science 2012)

A longstanding question in brain research is how information is processed in the brain. Until now it has been assumed that information flow in nerve cells proceeds along a "one-way street". Electrical impulses are initiated close to the cell body and propagate along the axon to the next neuron. However, we discovered that signals can also be initiated in axons, i.e. outside the cell body. This happens during highly synchronous neuronal activity as, for example, in a state of heightened attention. Moreover, these axonally generated signals flow bidirectionally and represent a new principle of information processing: on the one hand, impulses propagate from their origin towards other nerve cells; on the other hand, the signals also backpropagate towards the cell body, i.e. in the "wrong direction" down the one-way street.

A potential problem is that backpropagating signals could lead to excessive cell activation. However, we found that backpropagating signals do not reach the cell body under normal conditions. Axo-axonic cells, an inhibitory cell type, regulate signal propagation and thus occupy an outstanding strategic position. Through the filter function, these cells allow signals initiated close to the cell body to pass, but suppress backpropagating impulses generated in the axon. By this means, excessive activation of the cell body is prevented. Indeed, when this filter function is deactivated, backpropagating signals are allowed to pass, resulting in higher cell activation.

These filter cells can become damaged in various neurological diseases. The consequent misregulation of signal flow, in turn, has fatal effects on information processing in the brain. Therefore, these findings could help us better understand the development and progress of neuronal diseases such as epilepsy, which involves excessive hypersynchronous activity of large sets of neurons.

Inhibitory interneurons and hippocampal network rhythms

O-LM cells posses higher axonal projections in the longitudinal direction of the CA3 area. Neurolucida reconstructed biocytin-filled O-LM cell in area CA3 from transverse (Left) and longitudinal slices (Right). The soma and dendrites are drawn in red, whereas the axon is in green. Hippocampal layers are depicted schematically. CA3, CA3 area; str. or., stratum oriens; str. pyr., stratum pyramidale; str. rad., stratum radiatum; str. l.-m., stratum lacunosum-moleculare. (from Tort et al. PNAS 2007)
O-LM cells posses higher axonal projections in the longitudinal direction of the CA3 area. Neurolucida reconstructed biocytin-filled O-LM cell in area CA3 from transverse (Left) and longitudinal slices (Right). The soma and dendrites are drawn in red, whereas the axon is in green. Hippocampal layers are depicted schematically. CA3, CA3 area; str. or., stratum oriens; str. pyr., stratum pyramidale; str. rad., stratum radiatum; str. l.-m., stratum lacunosum-moleculare. (from Tort et al. PNAS 2007)

As a structure involved in learning and memory, the hippocampus functions as a network. It is widely accepted that phasic inhibition is important for the generation of behavioural specific rhythmic oscillatory activity in the gamma and theta frequency range. However, the function of the various inhibitory interneuron types in shaping distinct network activities in the hippocampus is largely unknown. Using combined electrophysiological, anatomical and immunohistological approaches we demonstrated that the firing properties of certain types of hippocampal inhibitory interneurons and therefore their impact on synchronized network activity were clearly different, which appeared to correspond mainly to the intrinsic membrane properties of these interneurons.

The range of output profiles observed was accompanied by specific axonal arborization patterns and terminal field profiles in the different cell types. The fast spiking interneurons, trilaminar, bistratified and basket cells generated a predominantly gamma frequency output and targeted proximal dendritic and perisomatic compartments of pyramidal cells. Thus, the anatomical and electrophysiological properties make these neurones ideally suited for generating gamma rhythms.

In contrast to fast spiking interneurons, distal dendrite inhibiting oriens lacunosum-moleculare (O-LM) cells discharged in the theta frequency range during network oscillations and therefore are likely to provide a theta-frequency patterned output to distal dendritic segments of pyramidal cells. In vivo, gamma oscillatory activity, which has been implicated in memory formation, is frequently nested within the theta rhythm in the hippocampus. Examination of the connectivity pattern and the functional differentiation within the hippocampus provided anatomical and physiological evidence for the conclusion that these prominent rhythmic network activities occur along the transverse and longitudinal axes, respectively.

This orthogonal relationship is the result of the axonal field trajectories and the consequential interaction of the principal cells and major interneuron subtypes involved in generating each rhythm. Thus, the axonal arborisation patterns of hippocampal inhibitory cells may represent a structural framework for the spatiotemporal distribution of activity observed within the hippocampus.

Impaired hippocampal rhythmogenesis in TLE

Figure 1: Histopathological changes in hippocampus of the KA-injected mouse model of TLE include hippocampal sclerosis (asterisk) and granule cell dispersion (arrows). Note that the changes are restricted to the dorsal hippocampus, whereas the ventral parts appear histologically intact. (from Dugladze et al., PNAS 2007).
Figure 1: Histopathological changes in hippocampus of the KA-injected mouse model of TLE include hippocampal sclerosis (asterisk) and granule cell dispersion (arrows). Note that the changes are restricted to the dorsal hippocampus, whereas the ventral parts appear histologically intact. (from Dugladze et al., PNAS 2007).

The chronic kainate (KA) model of mesial temporal lobe epilepsies (mTLE) gained rapid acceptance since it reproduces well the symptoms and the neuroanatomical changes associated with human mTLE:. (1) hippocampal sclerosis with selective neuronal loss and reactive gliosis affecting in particular the CA1, CA3 and hilar regions; (2) granule cell dispersion and the emergence of ectopic granule cells; and (3) sprouting of hippocampal mossy fibers.

While the injected dorsal hippocampus is characterized by progressive anatomical changes, the ventral hippocampus appears to remain largely intact in terms of its macroscopic and histological. However, there is strong evidence that functional changes in the intrinsic and synaptic properties of various interneuron types result in enhanced excitability and population activity in ventral hippocampus circuits. Using this mouse model of mTLE we have found an altered rhythmogenesis in the epileptic network, resulting in abolishment of theta and an enhancement of gamma network activity both in vivo and in vitro. This was correlated with an increased discharge frequency of oriens/lacunosum-moleculare (O-LM) interneuons.

In addition, we found a differentially altered sensitivity of the synaptic output of the two major BC types (PV+ and CCK+ BCs) in this mouse model of TLE. The altered rhythmogenesis could reflect a hypersynchronous, hyperexcitable state of the hippocampal network which facilitate transition into pathological discharge pattern.

Funding

Information about funding

DFG GL 254/5-2:
Dynamic of axonal activity during fast network oscillations and plasticity

Einstein Foundation Berlin A-2013-176:
The axonal code of information processing

NeuroCure Postdoctoral Researcher Fellowship (T. Dugladze):
Neuronal network dynamics in the normal and epileptic brain

BMBF-EpilepCure: Establishment of pre-surgical epilepsy diagnostics in Georgia

Berstein Center for Computational Neuroscience Berlin (BCCN)

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