Kavli Institute for Systems Neuroscience / Centre for Neural Computation
Phone: +47 73598249
I accepted a professorship at the Kavli Institute in 2007, after having worked as a visiting member of CBM for 6 years. Since 2007, I have built up an active state-of-the-art neuroanatomy group of approximately 10 post-docs and PhD students.
Over the years my work on the architecture of the entorhinal-hippocampal system carried out at VU University Medical Center Amsterdam, has led to a number of testable hypotheses that still are at the core of the ongoing quest to understand the functional contributions of the system to learning and memory processes.
In one of my first publications (Witter and Groenewegen, 1984), I postulated the concept of functional differentiation along the long axis of the hippocampus, which I further elaborated on in my 1989 review (Witter et al. 1989). This idea still strongly influences ongoing research.
In a conceptual paper published in 2000, I summarized a body of work from my lab, substantiating the concept put forward in my 1989 paper of parallel processing of spatial and object information, mediated by the two subdivisions of the entorhinal cortex and the notion that these are differently processed in the different subdivisions of the hippocampus (Witter et al. 2000). This postulate eventually led to an influential series of collaborative papers with Edvard and May-Britt Mosers on grid cells.
Recent selected publications
- Couey JJ, Witoelar A, Zhang S-J, Jing Y, Dunn B, Czajkowski R, Moser M-B, Moser EI, Roudi Y, Witter MP (2013) Recurrent inhibitory circuitry as a mechanism for grid cell formation. Nat Neurosci 16:318-324.
- Rowland D, Weible A, Wickersham I, Wu H, Mayford M, Witter MP, Kentros C (2013) Transgenically-targeted rabies virus demonstrates a major monosynaptic projection from hippocampal area CA2 to medial entorhinal layer II neurons. J. Neurosci, 33: 14889-14898.
- O'Reilly KC, Dahl AG, Kruge IU, Witter MP (2013). Subicular-parahippocampal projections revisited. The development of a complex topography in the rat. J Comp Neurol. 521:4248-4299.
- Czajkowski R, Sugar J, Zhang S-J, Couey JJ, Ying J, Witter MP (2013) Superficially projecting principal neurons in layer V of medial entorhinal cortex in the rat receive excitatory retrosplenial input. J. Neurosci, 33:15779-15792.
- Ohara S, Sato S, Tsutsui K, Witter MP, Iijima T (2013) Organization of multisynaptic inputs to the dorsal and ventral dentate gyrus: retrograde trans-synaptic tracing with rabies virus vector in the rat. PLoS One. 8:e78928.
- Kondo H, Witter MP (2014) Topographic organization of orbitofrontal projections to the parahippocampal region in rats. J Comp Neurol. 522:772–793.
- Witter MP, Canto CB, Couey JJ, Koganezawa N, O’Reilly K (2014) Architecture of Spatial Circuits in the Hippocampal Region. Phil Trans R Soc B 369: 20120515.
- Moser EI, Roudi Y, Witter MP, Kentros C, Bonhoeffer T, Moser MB .(2014) Grid cells and cortical representation. Nat Rev Neurosci 15: 466-481.
- Strange B, Witter MP, Moser EI, Lein E (2014) Functional organization of the hippocampal longitudinal axis. Nat Rev Neurosci 15: 655-669.
- Evensmoen HR, Ladstein J, Hansen TI, Møller JA, Witter MP, Nadel L, Håberg AK (2015) From details to large scale: The representation of environmental positions follows a granularity gradient along the human hippocampal and entorhinal anterior-posterior axis. Hippocampus 25:119-135.
- Kjonigsen LJ, Lillehaug S, Bjaalie JG, Witter MP, Leergaard TB (2015) Waxholm Space atlas of the rat brain hippocampal region: Three-dimensional delineations based on magnetic resonance and diffusion tensor imaging. Neuroimage 108: 441-449
- Boccara CB, Kjonigsen LJ, Hammer IM, Bjaalie JG, Leergaard TB, Witter MP (2015) A three plane architectonic atlas of the rat hippocampal region. Hippocampus, 25: 838-857
- Mathiasen ML, Hansen L, Witter MP (2015). Insular Projections to the Parahippocampal Region in the Rat. J Comp Neurol 523: 1379-1398.
- Ito HT, Zhang S-J, Witter MP, Moser EI, Moser M-B (2015) A prefrontal-thalamo-hippocampal circuit for goal-directed spatial coding. Nature 522:50-55.
- Heggland I, Storkaas I, Soligard HT, Kobro-Flatmoen A, Witter MP (2015) Stereological estimation of neuron number and plaque load in the hippocampal region of a transgenic rat model of Alzheimer’s disease. Eur J Neurosci 41: 1245-1262.
- O'Reilly KC, Flatberg A, Islam S, Olsen LC, Kruge IU, Witter MP (2015). Identification of dorsal-ventral hippocampal differentiation in neonatal rats. Brain Struct Funct 220: 2873-2893.
- Koganezawa, N, Gisetstad R, Husby E, Doan T, Witter MP (2015) Excitatory postrhinal projections to principal cells in the medial entorhinal cortex. J. Neurosci, in press
Functional neuroanatomy aims to understand the relationships between the wiring of neuronal networks and their function. The research of my group focuses on the architecture of the parahippocampal and hippocampal networks mediating learning and memory.
The central hypothesis for my research is that striking differences in functional properties of the lateral and medial entorhinal cortex emerge from subtle differences in intrinsic wiring combined with differences in input and output relationships.
- Laminar and cellular terminal distribution of main inputs to the medial entorhinal cortex, such as inputs from the pre- and parasubiculum, the retrosplenial, parietal, and postrhinal cortices.
- Laminar and cellular terminal distribution of inputs from orbital, medial prefrontal, and insular cortices to the lateral entorhinal cortex.
- The comparative architecture of local networks of the lateral and medial entorhinal cortex.
- The postnatal development of the cortico-parahippocampal-hippocampal network.
We use advanced methodologies, including retrogradely and transsynaptically transported rabies virus that express different fluorophores, and multiple whole cell recordings (>3 cells) as a superior method to quantify local microcircuitry in the cortex in vitro. These approaches are complemented with a new advanced technique to express photo-inducible molecular channels such as channelrhodopsin-2 in specific input pathways, which allows to stimulate specific sets of axons that cannot be easily maintained or recognized in an in vitro slice preparation.
This application builds on the group's recently developed approach of in vivo tracing of input-output connectivity followed by in vitro recording. With the use of voltage sensitive dye imaging, we can assess efficiently whether the connectivity of interest is maintained in the slice, and we developed efficient methods to combine all these approaches.
These new methods are complemented with traditional, yet powerful, anterograde and retrograde tracing of input and output pathways and newly developed confocal analyses in thick slices using sequential immunohistochemical staining procedures on intracellularly filled neurons as well as analyses at the electronmicroscopical level.
The functional anatomy toolbox
A. Two injections of rabies virus expressing different fluorophores in dorsal CA1.
B. Single (red and green) and double labeled (yellow) retrogradely infected cells in layer III of LEC following injections shown in A (Ohara and Witter).
C. In vitro patch of a neuron in layer III of MEC, receiving anterogradely labeled input from presubiculum. Left: low power image of section with injection site in PRS (yellow) and recorded and filled neuron (blue). Right: high power image of the same neuron which is clearly embedded in the labelled PrS axonal plexus; inset: response of layer III cell (Canto et al. 2012).
D. Retrogradely labelled neurons in layers II and III of MEC following an injection in dorsal hippocampus (white/fluorogold) and in ventral hippocampus (blue/fast blue) in a P2 animal.
E.Voltage sensitive dye imaging of presubicular activation of entorhinal cortex in adult rat (Koganezawa & Witter).
F. Four layer II cells intracellularly filled with spectral variants of Alexa (red and green: stellate cells, blue and yellow: pyramidal cells (Couey et al. 2012).
G. Sequential confocal analysis of synaptic connectivity of retrosplenial axons onto identified layer III neurons in presubiculum (Color code represents distance between elements of a potential synaps). Inset: bouton is characterized with the vesicular marker synaptophysin, postsynaptic element with PSD95 (Kononenko and Witter 2011).
H. Single cell patch clamp recording of a layer V neuron in MEC showing EPSP's evoked by laser stimulation of axons from the retrosplenial cortex infected with rAAVthat contained a mutant of the light-gated channelrhodopsin (ChiEF) together with mCherry as a fluorescent tag. Inset indicates stimulated area and evoked responses are on the left (Czajkowski et al, in prep).
In order to make our research data available to the scientific community, we have initiated a collaborative digital brain atlas on the parahippocampal-hippocampal region (Univ. Oslo; http://rbwb.org), and published a collaborative connectional database (http://www.temporal-lobe.com; van Strien et al., 2009, Nat Rev. Neurosci). The latter activities are embedded in the activities of the International Neuroinformatics Coordinating Facility (INCF; http://www.incf.org).
The research is embedded in active local interactions with May-Britt and Edvard Moser with respect to functional relevance of characteristic architecture, with Yasser Roudi regarding theoretical aspects of our observations and with incoming Cliff Kentros, currently at the University of Oregon, USA. We also have collaborations with a number of international investigators including Toshio Iijima, Tohoku Univ, Sendai, Japan, Yuchio Yanagawa, Gunma University Japan, Cliff Kentros, Claudio Cuello at McGill University, Montreal, Scott Small, Columbia Univ, and John Gigg, Univ Manchester, UK.
Translational promises are now also on the research agenda. While the primary goal of my research is to contribute to our understanding of cognition in the normal brain, the activity has considerable potential for translation to clinical applications. Because the entorhinal cortex is one of the first brain regions to be affected in patients with Alzheimer's disease, functional insight into the underpinning entorhinal functions may ultimately provide clinical neurologists and health workers with essential tools for early diagnostics, prevention and treatment of Alzheimer's disease. We have taken initiatives to explore this promising potential.