Publications by authors named "Menno P Witter"

122 Publications

Task-dependent mixed selectivity in the subiculum.

Cell Rep 2021 May;35(8):109175

Kavli Institute for Systems Neuroscience and Centre for Neural Computation, Norwegian University of Science and Technology, Olav Kyrre s gate 9, MTFS, 7489 Trondheim, Norway. Electronic address:

CA1 and subiculum (SUB) connect the hippocampus to numerous output regions. Cells in both areas have place-specific firing fields, although they are more dispersed in SUB. Weak responses to head direction and running speed have been reported in both regions. However, how such information is encoded in CA1 and SUB and the resulting impact on downstream targets are poorly understood. Here, we estimate the tuning of simultaneously recorded CA1 and SUB cells to position, head direction, and speed. Individual neurons respond conjunctively to these covariates in both regions, but the degree of mixed representation is stronger in SUB, and more so during goal-directed spatial navigation than free foraging. Each navigational variable could be decoded with higher precision, from a similar number of neurons, in SUB than CA1. The findings point to a possible contribution of mixed-selective coding in SUB to efficient transmission of hippocampal representations to widespread brain regions.
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http://dx.doi.org/10.1016/j.celrep.2021.109175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170370PMC
May 2021

Development of the Entorhinal Cortex Occurs via Parallel Lamination During Neurogenesis.

Front Neuroanat 2021 5;15:663667. Epub 2021 May 5.

Group of Brain Development and Disease, Section Pathobiological Sciences, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

The entorhinal cortex (EC) is the spatial processing center of the brain and structurally is an interface between the three layered paleocortex and six layered neocortex, known as the periarchicortex. Limited studies indicate peculiarities in the formation of the EC such as early emergence of cells in layers (L) II and late deposition of LIII, as well as divergence in the timing of maturation of cell types in the superficial layers. In this study, we examine developmental events in the entorhinal cortex using an understudied model in neuroanatomy and development, the pig and supplement the research with BrdU labeling in the developing mouse EC. We determine the pig serves as an excellent anatomical model for studying human neurogenesis, given its long gestational length, presence of a moderate sized outer subventricular zone and early cessation of neurogenesis during gestation. Immunohistochemistry identified prominent clusters of OLIG2 oligoprogenitor-like cells in the superficial layers of the lateral EC (LEC) that are sparser in the medial EC (MEC). These are first detected in the subplate during the early second trimester. MRI analyses reveal an acceleration of EC growth at the end of the second trimester. BrdU labeling of the developing MEC, shows the deeper layers form first and prior to the superficial layers, but the LV/VI emerges in parallel and the LII/III emerges later, but also in parallel. We coin this lamination pattern parallel lamination. The early born Reln stellate cells in the superficial layers express the classic LV marker, Bcl11b (Ctip2) and arise from a common progenitor that forms the late deep layer LV neurons. In summary, we characterize the developing EC in a novel animal model and outline in detail the formation of the EC. We further provide insight into how the periarchicortex forms in the brain, which differs remarkably to the inside-out lamination of the neocortex.
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http://dx.doi.org/10.3389/fnana.2021.663667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139189PMC
May 2021

Local projections of layer Vb-to-Va are more prominent in lateral than in medial entorhinal cortex.

Elife 2021 03 26;10. Epub 2021 Mar 26.

Kavli institute for Systems Neuroscience, Center for Computational Neuroscience, Egil and Pauline Braathen and Fred Kavli Center for Cortical Microcircuits, NTNU Norwegian University of Science and Technology, Trondheim, Norway.

The entorhinal cortex, in particular neurons in layer V, allegedly mediate transfer of information from the hippocampus to the neocortex, underlying long-term memory. Recently, this circuit has been shown to comprise a hippocampal output recipient layer Vb and a cortical projecting layer Va. With the use of in vitro electrophysiology in transgenic mice specific for layer Vb, we assessed the presence of the thus necessary connection from layer Vb-to-Va in the functionally distinct medial (MEC) and lateral (LEC) subdivisions; MEC, particularly its dorsal part, processes allocentric spatial information, whereas the corresponding part of LEC processes information representing elements of episodes. Using identical experimental approaches, we show that connections from layer Vb-to-Va neurons are stronger in dorsal LEC compared with dorsal MEC, suggesting different operating principles in these two regions. Although further in vivo experiments are needed, our findings imply a potential difference in how LEC and MEC mediate episodic systems consolidation.
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http://dx.doi.org/10.7554/eLife.67262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8051944PMC
March 2021

Re-emphasizing early Alzheimer's disease pathology starting in select entorhinal neurons, with a special focus on mitophagy.

Ageing Res Rev 2021 05 20;67:101307. Epub 2021 Feb 20.

Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, 1478, Lørenskog, Norway; The Norwegian Centre on Healthy Ageing (NO-Age), Norway. Electronic address:

The entorhinal-hippocampal system contains distinct networks subserving declarative memory. This system is selectively vulnerable to changes of ageing and pathological processes. The entorhinal cortex (EC) is a pivotal component of this memory system since it serves as the interface between the neocortex and the hippocampus. EC is heavily affected by the proteinopathies of Alzheimer's disease (AD). These appear in a stereotypical spatiotemporal manner and include increased levels of intracellular amyloid-beta Aβ (iAβ), parenchymal deposition of Aβ plaques, and neurofibrillary tangles (NFTs) containing abnormally processed Tau. Increased levels of iAβ and the formation of NFTs are seen very early on in a population of neurons belonging to EC layer II (EC LII), and recent evidence leads us to believe that this population is made up of highly energy-demanding reelin-positive (RE+) projection neurons. Mitochondria are fundamental to the energy supply, metabolism, and plasticity of neurons. Evidence from AD postmortem brain tissues supports the notion that mitochondrial dysfunction is one of the initial pathological events in AD, and this is likely to take place in the vulnerable RE + EC LII neurons. Here we review and discuss these notions, anchored to the anatomy of AD, and formulate a hypothesis attempting to explain the vulnerability of RE + EC LII neurons to the formation of NFTs. We attempt to link impaired mitochondrial clearance to iAβ and signaling involving both apolipoprotein 4 and reelin, and argue for their relevance to the formation of NFTs specifically in RE + EC LII neurons during the prodromal stages of AD. We believe future studies on these interactions holds promise to advance our understanding of AD etiology and provide new ideas for drug development.
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http://dx.doi.org/10.1016/j.arr.2021.101307DOI Listing
May 2021

Densities and numbers of calbindin and parvalbumin positive neurons across the rat and mouse brain.

iScience 2021 Jan 8;24(1):101906. Epub 2020 Dec 8.

Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.

The calcium-binding proteins parvalbumin and calbindin are expressed in neuronal populations regulating brain networks involved in spatial navigation, memory processes, and social interactions. Information about the numbers of these neurons across brain regions is required to understand their functional roles but is scarcely available. Employing semi-automated image analysis, we performed brain-wide analysis of immunohistochemically stained parvalbumin and calbindin sections and show that these neurons distribute in complementary patterns across the mouse brain. Parvalbumin neurons dominate in areas related to sensorimotor processing and navigation, whereas calbindin neurons prevail in regions reflecting behavioral states. We also find that parvalbumin neurons distribute according to similar principles in the hippocampal region of the rat and mouse brain. We validated our results against manual counts and evaluated variability of results among researchers. Comparison of our results to previous reports showed that neuron numbers vary, whereas patterns of relative densities and numbers are consistent.
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http://dx.doi.org/10.1016/j.isci.2020.101906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770605PMC
January 2021

Developmental, cellular, and behavioral phenotypes in a mouse model of congenital hypoplasia of the dentate gyrus.

Elife 2020 10 21;9. Epub 2020 Oct 21.

Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, United States.

In the hippocampus, a widely accepted model posits that the dentate gyrus improves learning and memory by enhancing discrimination between inputs. To test this model, we studied conditional knockout mice in which the vast majority of dentate granule cells (DGCs) fail to develop - including nearly all DGCs in the dorsal hippocampus - secondary to eliminating () in a subset of cortical progenitors with . Other cells in the hippocampus were minimally affected, as determined by single nucleus RNA sequencing. CA3 pyramidal cells, the targets of DGC-derived mossy fibers, exhibited normal morphologies with a small reduction in the numbers of synaptic spines. mice have a modest performance decrement in several complex spatial tasks, including active place avoidance. They were also modestly impaired in one simpler spatial task, finding a visible platform in the Morris water maze. These experiments support a role for DGCs in enhancing spatial learning and memory.
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http://dx.doi.org/10.7554/eLife.62766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577738PMC
October 2020

A Brainstem Locomotor Circuit Drives the Activity of Speed Cells in the Medial Entorhinal Cortex.

Cell Rep 2020 09;32(10):108123

Kavli Institute for Systems Neuroscience and Centre for Neural Computation, Norwegian University of Science and Technology, Olav Kyrres Gate 9, 7491 Trondheim, Norway. Electronic address:

Locomotion activates an array of sensory inputs that may help build the self-position map of the medial entorhinal cortex (MEC). In this map, speed-coding neurons are thought to dynamically update representations of the animal's position. A possible origin for the entorhinal speed signal is the mesencephalic locomotor region (MLR), which is critically involved in the activation of locomotor programs. Here, we describe, in rats, a circuit connecting the pedunculopontine tegmental nucleus (PPN) of the MLR to the MEC via the horizontal limb of the diagonal band of Broca (HDB). At each level of this pathway, locomotion speed is linearly encoded in neuronal firing rates. Optogenetic activation of PPN cells drives locomotion and modulates activity of speed-modulated neurons in HDB and MEC. Our results provide evidence for a pathway by which brainstem speed signals can reach cortical structures implicated in navigation and higher-order dynamic representations of space.
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http://dx.doi.org/10.1016/j.celrep.2020.108123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487772PMC
September 2020

The entorhinal cortex of the monkey: VI. Organization of projections from the hippocampus, subiculum, presubiculum, and parasubiculum.

J Comp Neurol 2021 03 4;529(4):828-852. Epub 2020 Aug 4.

Department of Psychiatry and Behavioral Sciences, The MIND Institute and the California National Primate Research Center, Davis, California, USA.

The organization of projections from the macaque monkey hippocampus, subiculum, presubiculum, and parasubiculum to the entorhinal cortex was analyzed using anterograde and retrograde tracing techniques. Projections exclusively originate in the CA1 field of the hippocampus and in the subiculum, presubiculum, and parasubiculum. The CA1 and subicular projections terminate most densely in Layers V and VI of the entorhinal cortex, with sparser innervation of the deep portion of Layers III and II. Entorhinal projections from CA1 and the subiculum are topographically organized such that a rostrocaudal axis of origin is related to a medial-to-lateral axis of termination. A proximodistal axis of origin in CA1 and distoproximal axis in subiculum are related to a rostrocaudal axis of termination in the entorhinal cortex. The presubiculum sends a dense, bilateral projection to caudal parts of the entorhinal cortex. This projection terminates most densely in Layer III with sparser termination in Layers I, II, and V. The same parts of entorhinal cortex receive a dense projection from the parasubiculum. This projection terminates in Layers III and II. Both presubicular and parasubicular projections demonstrate the same longitudinal topographic organization as the projections from CA1 and the subiculum. These studies demonstrate that: (a) hippocampal and subicular inputs to the entorhinal cortex in the monkey are organized similar to those described in nonprimate species; (b) the topographic organization of the projections from the hippocampus and subicular areas matches that of the reciprocal projections from the entorhinal cortex to the hippocampus and the subicular areas.
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http://dx.doi.org/10.1002/cne.24983DOI Listing
March 2021

Development and topographic organization of subicular projections to lateral septum in the rat brain.

Eur J Neurosci 2020 08 23;52(4):3140-3159. Epub 2020 Feb 23.

Kavli institute for Systems Neuroscience, Centre for Computational Neuroscience, Egil and Pauline Braathen and Fred Kavli Centre for Cortical Microcircuits, NTNU Norwegian University of Science and Technology, Trondheim, Norway.

One of the main subcortical targets of hippocampal formation efferents is the lateral septum. Previous studies on the subicular projections, as a main output structure of the hippocampus, have shown a clear topographic organization of septal innervation, related to the origin of the fibres along the dorsoventral axis of the subiculum in the adult brain. In contrast, studies on the developing brain depict an extensive rearrangement of subicular projections during the prenatal period, shifting from the medial septum to the lateral septum. Our study aimed to describe the postnatal development of subicular projections to the septum. We injected anterograde tracers into the subiculum of 57 pups of different postnatal ages. Injections covered the proximodistal and dorsoventral axis of the subiculum. The age of the pups at day of tracer injection ranged from the day of birth to postnatal day 30. Analyses revealed that from the first postnatal day projections from subiculum preferentially target the lateral septum. Sparse innervation in the lateral septum was already present in the first few postnatal days, and during the following 3 weeks, the axonal distribution gradually expanded. Subicular projections to the lateral septum are topographically organized depending on the origin along the dorsoventral axis of the subiculum, in line with the adult innervation pattern. Different origins along the proximodistal axis of the subiculum are reflected in changes in the strength of septal innervation. The findings demonstrate that in case of the development of subicular projections, axonal expansion is more prominent than axonal pruning.
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http://dx.doi.org/10.1111/ejn.14696DOI Listing
August 2020

Entorhinal Layer II Calbindin-Expressing Neurons Originate Widespread Telencephalic and Intrinsic Projections.

Front Syst Neurosci 2019 15;13:54. Epub 2019 Oct 15.

Kavli Institute for Systems Neuroscience, Center for Computational Neuroscience, Egil and Pauline Braathen and Fred Kavli Centre for Cortical Microcircuits, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.

In the present study we provide the first systematic and quantitative hodological study of the calbindin-expressing (CB+) principal neurons in layer II of the entorhinal cortex and compared the respective projections of the lateral and medial subdivisions of the entorhinal cortex. Using elaborate quantitative retrograde tracing, complemented by anterograde tracing, we report that the layer II CB+ population comprises neurons with diverse, mainly excitatory projections. At least half of them originate local intrinsic and commissural projections which distribute mainly to layer I and II. We further show that long-range CB+ projections from the two entorhinal subdivisions differ substantially in that MEC projections mainly target field CA1 of the hippocampus, whereas LEC CB+ projections distribute much more widely to a substantial number of known forebrain targets. This connectional difference between the CB+ populations in LEC and MEC is reminiscent of the overall projection pattern of the two entorhinal subdivisions.
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http://dx.doi.org/10.3389/fnsys.2019.00054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6803526PMC
October 2019

Convergent Projections from Perirhinal and Postrhinal Cortices Suggest a Multisensory Nature of Lateral, but Not Medial, Entorhinal Cortex.

Cell Rep 2019 10;29(3):617-627.e7

Kavli Institute for Systems Neuroscience, Centre for Computational Neuroscience, Egil and Pauline Braathen and Fred Kavli Centre for Cortical Microcircuits, NTNU Norwegian University of Science and Technology, Trondheim, Norway. Electronic address:

The current model of the organization of the medial temporal lobe (MTL) episodic memory system assumes that two functionally different "where" and "what" pathways enter MTL as parallel parahippocampal cortex (PHC)-medial entorhinal cortex (MEC) and perirhinal cortex (PER)-lateral entorhinal cortex (LEC) streams, respectively. With the use of tract tracing and in vitro electrophysiological recordings, we show that, in the rat LEC, all main principal neuron types in layer II receive convergent inputs from PER and postrhinal cortex (POR), homologous to PHC in primates. Projections to MEC from POR are much less prominent than previously assumed. These findings thus challenge the prevailing concept that LEC and MEC are defined by different inputs from the PER and PHC/POR, respectively. Our findings point to LEC as the main parahippocampal multimodal integrative structure whose unique set of external sensory-derived inputs allows its network to represent a continuously fluctuating extrinsic environment.
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http://dx.doi.org/10.1016/j.celrep.2019.09.005DOI Listing
October 2019

Postnatal Development of Functional Projections from Parasubiculum and Presubiculum to Medial Entorhinal Cortex in the Rat.

J Neurosci 2019 10 11;39(44):8645-8663. Epub 2019 Sep 11.

Kavli Institute for Systems Neuroscience, Centre for Neural Computation, and Egil and Pauline Braathen and Fred Kavli Centre for Cortical Microcircuits, NTNU Norwegian University of Science and Technology, 7491 Trondheim, Norway,

Neurons in parasubiculum (PaS), presubiculum (PrS), and medial entorhinal cortex (MEC) code for place (grid cells) and head direction. Directional input has been shown to be important for stable grid cell properties in MEC, and PaS and PrS have been postulated to provide this information to MEC. In line with this, head direction cells in those brain areas are present at postnatal day 11 (P11), having directional tuning that stabilizes shortly after eye opening, which is before premature grid cells emerge in MEC at P16. Whether functional connectivity between these structures exists at those early postnatal stages is unclear. Using anatomical tracing, voltage-sensitive dye imaging and single-cell patch recordings in female and male rat brain slices between P2 and P61, we determined when the pathways from PaS and PrS to MEC emerge, become functional, and how they develop. Anatomical connections from PaS and PrS to superficial MEC emerge between P4 and P6. Monosynaptic connectivity from PaS and PrS to superficial MEC was measurable from P9 to P10 onward, whereas connectivity with deep MEC was measurable from P11 to P12. From P14/P15 on, reactivity of MEC neurons to parasubicular and presubicular inputs becomes adult-like and continues to develop until P28-P30. The maturation of the efficacy of both inputs between P9 and P21 is paralleled by maturation of morphological properties, changes in intrinsic properties of MEC principal neurons, and changes in the GABAergic network of MEC. In conclusion, synaptic projections from PaS and PrS to MEC become functional and adult-like before the emergence of grid cells in MEC. Head direction information, crucial for grid cells in medial entorhinal cortex (MEC), is thought to enter MEC via parasubiculum (PaS) and presubiculum (PrS). Unraveling the development of functional connections between PaS, PrS, and MEC is key to understanding how spatial navigation, an important cognitive function, may evolve. To gain insight into the development, we used anatomical tracing techniques, voltage-sensitive dye imaging, and single-cell recordings. The combined data led us to conclude that synaptic projections from PaS and PrS to MEC become functional and adult-like before eye opening, allowing crucial head direction information to influence place encoding before the emergence of grid cells in rat MEC.
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http://dx.doi.org/10.1523/JNEUROSCI.1623-19.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820215PMC
October 2019

Organization of Posterior Parietal-Frontal Connections in the Rat.

Front Syst Neurosci 2019 21;13:38. Epub 2019 Aug 21.

The Faculty of Medicine, Kavli Institute for Systems Neuroscience, Centre for Neural Computation, Egil and Pauline Braathen and Fred Kavli Centre for Cortical Microcircuits, NTNU-Norwegian University of Science and Technology, Trondheim, Norway.

Recent investigations of the rat posterior parietal cortex (PPC) suggest that this region plays a central role in action control together with the frontal cortical areas. Posterior parietal-frontal cortical connections have been described in rats, but little is known about whether these connections are topographically organized as in the primate. Here, we injected retrograde and anterograde tracers into subdivisions of PPC as well as the frontal midline and orbital cortical areas to explore possible topographies within their connections. We found that PPC projects to several frontal cortical areas, largely reciprocating the densest input received from the same areas. All PPC subdivisions are strongly connected with the secondary motor cortex (M2) in a topographically organized manner. The medial subdivision (medial posterior parietal cortex, mPPC) has a dense reciprocal connection with the most caudal portion of M2 (cM2), whereas the lateral subdivision (lateral posterior parietal cortex, lPPC) and the caudolateral subdivision (PtP) are reciprocally connected with the intermediate rostrocaudal portion of M2 (iM2). Sparser reciprocal connections were seen with anterior cingulate area 24b. mPPC connects with rostral, and lPPC and PtP connect with caudal parts of 24b, respectively. There are virtually no connections with area 24a, nor with prelimbic or infralimbic cortex. PPC and orbitofrontal cortices are also connected, showing a gradient such that mPPC entertains reciprocal connections mainly with the ventral orbitofrontal cortex (OFC), whereas lPPC and PtP are preferentially connected with medial and central portions of ventrolateral OFC, respectively. Our results thus indicate that the connections of PPC with frontal cortices are organized in a topographical fashion, supporting functional heterogeneity within PPC and frontal cortices.
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http://dx.doi.org/10.3389/fnsys.2019.00038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6713060PMC
August 2019

Neurons and networks in the entorhinal cortex: A reappraisal of the lateral and medial entorhinal subdivisions mediating parallel cortical pathways.

Hippocampus 2019 12 13;29(12):1238-1254. Epub 2019 Aug 13.

Kavli Institute for Systems Neuroscience, Centre for Neural Computation, Egil and Pauline Braathen and Fred Kavli Centre for Cortical Microcircuits, NTNU Norwegian University of Science and Technology, Trondheim, Norway.

In this review, we aim to reappraise the organization of intrinsic and extrinsic networks of the entorhinal cortex with a focus on the concept of parallel cortical connectivity streams. The concept of two entorhinal areas, the lateral and medial entorhinal cortex, belonging to two parallel input-output streams mediating the encoding and storage of respectively what and where information hinges on the claim that a major component of their cortical connections is with the perirhinal cortex and postrhinal or parahippocampal cortex in, respectively, rodents or primates. In this scenario, the lateral entorhinal cortex and the perirhinal cortex are connectionally associated and likewise the postrhinal/parahippocampal cortex and the medial entorhinal cortex are partners. In contrast, here we argue that the connectivity matrix emphasizes the potential of substantial integration of cortical information through interactions between the two entorhinal subdivisions and between the perirhinal and postrhinal/parahippocampal cortices, but most importantly through a new observation that the postrhinal/parahippocampal cortex projects to both lateral and medial entorhinal cortex. We suggest that entorhinal inputs provide the hippocampus with high-order complex representations of the external environment, its stability, as well as apparent changes either as an inherent feature of a biological environment or as the result of navigating the environment. This thus indicates that the current connectional model of the parahippocampal region as part of the medial temporal lobe memory system needs to be revised.
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http://dx.doi.org/10.1002/hipo.23145DOI Listing
December 2019

Neuronal chemo-architecture of the entorhinal cortex: A comparative review.

Eur J Neurosci 2019 11 29;50(10):3627-3662. Epub 2019 Jul 29.

Kavli Institute for Systems Neuroscience, Centre for Neural Computation, Egil and Pauline Braathen and Fred Kavli Centre for Cortical Microcircuits, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.

The identification of neuronal markers, that is, molecules selectively present in subsets of neurons, contributes to our understanding of brain areas and the networks within them. Specifically, recognizing the distribution of different neuronal markers facilitates the identification of borders between functionally distinct brain areas. Detailed knowledge about the localization and physiological significance of neuronal markers may also provide clues to generate new hypotheses concerning aspects of normal and abnormal brain functioning. Here, we provide a comprehensive review on the distribution within the entorhinal cortex of neuronal markers and the morphology of the neurons they reveal. Emphasis is on the comparative distribution of several markers, with a focus on, but not restricted to rodent, monkey and human data, allowing to infer connectional features, across species, associated with these markers, based on what is revealed by mainly rodent data. The overall conclusion from this review is that there is an emerging pattern in the distribution of neuronal markers in the entorhinal cortex when aligning data along a comparable coordinate system in various species.
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http://dx.doi.org/10.1111/ejn.14511DOI Listing
November 2019

The nucleus reuniens of the thalamus sits at the nexus of a hippocampus and medial prefrontal cortex circuit enabling memory and behavior.

Learn Mem 2019 07 17;26(7):191-205. Epub 2019 Jun 17.

Cognitive Neuroscience Program, Department of Psychology, Florida International University, Miami, Florida 33199, USA.

The nucleus reuniens of the thalamus (RE) is a key component of an extensive network of hippocampal and cortical structures and is a fundamental substrate for cognition. A common misconception is that RE is a simple relay structure. Instead, a better conceptualization is that RE is a critical component of a canonical higher-order cortico-thalamo-cortical circuit that supports communication between the medial prefrontal cortex (mPFC) and the hippocampus (HC). RE dysfunction is implicated in several clinical disorders including, but not limited to Alzheimer's disease, schizophrenia, and epilepsy. Here, we review key anatomical and physiological features of the RE based primarily on studies in rodents. We present a conceptual model of RE circuitry within the mPFC-RE-HC system and speculate on the computations RE enables. We review the rapidly growing literature demonstrating that RE is critical to, and its neurons represent, aspects of behavioral tasks that place demands on memory focusing on its role in navigation, spatial working memory, the temporal organization of memory, and executive functions.
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http://dx.doi.org/10.1101/lm.048389.118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581009PMC
July 2019

GABA Receptor Subunit α3 in Network Dynamics in the Medial Entorhinal Cortex.

Front Syst Neurosci 2019 15;13:10. Epub 2019 Mar 15.

Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway.

Layer II of the medial entorhinal cortex (MEC LII) contains the largest number of spatially modulated grid cells and is one of the first regions in the brain to express Alzheimer's disease (AD)-related pathology. The most common principal cell type in MEC LII, reelin-expressing stellate cells, are grid cell candidates. Recently we found evidence that γ-aminobutyric acid (GABA) receptor subunits show a specific distribution in MEC LII, in which GABA α3 is selectively associated with reelin-positive neurons, with limited association with the other principal cell type, calbindin (CB)-positive pyramidal neurons. Furthermore, the expression of α3 subunit decreases in mice between P15 and P25, which coincides with the emergence of stable grid cell activity. It has been shown that the α3 subunit undergoes specific developmental changes and that it may exert pro-inflammatory actions if improperly regulated. In this review article, we evaluate the changing kinetics of α3-GABA receptors (GABARs). during development in relation to α3-subunit expression pattern in MEC LII and conclude that α3 could be closely related to the stabilization of grid cell activity and theta oscillations. We further conclude that dysregulated α3 may be a driving factor in early AD pathology.
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http://dx.doi.org/10.3389/fnsys.2019.00010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428777PMC
March 2019

Electrophysiological Characterization of Networks and Single Cells in the Hippocampal Region of a Transgenic Rat Model of Alzheimer's Disease.

eNeuro 2019 Jan-Feb;6(1). Epub 2019 Feb 22.

Kavli Institute for Systems Neuroscience and Centre for Neural Computation, Egil and Pauline Braathen and Fred Kavli Centre for Cortical Microcircuits, Norwegian University of Science and Technology (NTNU), Trondheim NO-7491, Norway.

The hippocampus and entorhinal cortex (EC) are areas affected early and severely in Alzheimer's disease (AD), and this is associated with deficits in episodic memory. Amyloid-β (Aβ), the main protein found in amyloid plaques, can affect neuronal physiology and excitability, and several AD mouse models with memory impairments display aberrant network activity, including hyperexcitability and seizures. In this study, we investigated single cell physiology in EC and network activity in EC and dentate gyrus (DG) in the McGill-R-Thy1-APP transgenic rat model, using whole-cell patch clamp recordings and voltage-sensitive dye imaging (VSDI) in acute slices. In slices from transgenic animals up to 4 months of age, the majority of the principal neurons in Layer II of EC, fan cells and stellate cells, expressed intracellular Aβ (iAβ). Whereas the electrophysiological properties of fan cells were unaltered, stellate cells were more excitable in transgenic than in control rats. Stimulation in the DG resulted in comparable patterns in both groups at three and nine months, but at 12 months, the elicited responses in the transgenic group showed a significant preference for the enclosed blade, without any change in overall excitability. Only transient changes in the local network activity were seen in the medial EC (MEC). Although the observed changes in the McGill rat model are subtle, they are specific, pointing to a differential and selective involvement of specific parts of the hippocampal circuitry in Aβ pathology.
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http://dx.doi.org/10.1523/ENEURO.0448-17.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6390198PMC
April 2019

Development and topographical organization of projections from the hippocampus and parahippocampus to the retrosplenial cortex.

Eur J Neurosci 2019 07 25;50(1):1799-1819. Epub 2019 Mar 25.

Kavli Institute for Systems Neuroscience, Centre for Neural Computation, Egil and Pauline Braathen and Fred Kavli Center for Cortical Microcircuits, NTNU Norwegian University for Science and Technology, Trondheim, Norway.

The rat hippocampal formation (HF), parahippocampal region (PHR), and retrosplenial cortex (RSC) play critical roles in spatial processing. These regions are interconnected, and functionally dependent. The neuronal networks mediating this reciprocal dependency are largely unknown. Establishing the developmental timing of network formation will help to understand the emergence of this dependency. We questioned whether the long-range outputs from HF-PHR to RSC in Long Evans rats develop during the same time periods as previously reported for the intrinsic HF-PHR connectivity and the projections from RSC to HF-PHR. The results of a series of retrograde and anterograde tracing experiments in rats of different postnatal ages show that the postnatal projections from HF-PHR to RSC display low densities around birth, but develop during the first postnatal week, reaching adult-like densities around the time of eye-opening. Developing projections display a topographical organization similar to adult projections. We conclude that the long-range projections from HF-PHR to RSC develop in parallel with the intrinsic circuitry of HF-PHR and the projections of RSC to HF-PHR.
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http://dx.doi.org/10.1111/ejn.14395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767700PMC
July 2019

Architecture and organization of mouse posterior parietal cortex relative to extrastriate areas.

Eur J Neurosci 2019 05 14;49(10):1313-1329. Epub 2018 Dec 14.

Kavli Institute for Systems Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway.

The posterior parietal cortex (PPC) is a multifaceted region of cortex, contributing to several cognitive processes, including sensorimotor integration and spatial navigation. Although recent years have seen a considerable rise in the use of rodents, particularly mice, to investigate PPC and related networks, a coherent anatomical definition of PPC in the mouse is still lacking. To address this, we delineated the mouse PPC, using cyto- and chemoarchitectural markers from Nissl-, parvalbumin-and muscarinic acetylcholine receptor M2-staining. Additionally, we performed bilateral triple anterograde tracer injections in primary visual cortex (V1) and prepared flattened tangential sections from one hemisphere and coronal sections from the other, allowing us to co-register the cytoarchitectural features of PPC with V1 projections. This revealed that extrastriate area A was largely contained within lateral PPC, that medial PPC overlapped with the anterior portion of area AM, and that anterior RL overlapped partially with area PtP. Furthermore, triple anterograde tracer injections in PPC showed strong projections to associative thalamic nuclei as well as higher visual areas, orbitofrontal, cingulate and secondary motor cortices. Retrograde circuit mapping with rabies virus further showed that all cortical connections were reciprocal. These combined approaches provide a coherent definition of mouse PPC that incorporates laminar architecture, extrastriate projections, thalamic, and cortico-cortical connections.
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http://dx.doi.org/10.1111/ejn.14280DOI Listing
May 2019

Inhibitory Connectivity Dominates the Fan Cell Network in Layer II of Lateral Entorhinal Cortex.

J Neurosci 2018 11 24;38(45):9712-9727. Epub 2018 Sep 24.

Kavli Institute for Systems Neuroscience and Centre for Neural Computation, NTNU Norwegian University of Science and Technology, 7491 Trondheim, Norway

Fan cells in layer II of the lateral entorhinal cortex (LEC) form a main component of the projection to the dentate gyrus, CA3 and CA2 of the hippocampal formation. This projection has a counterpart originating from stellate cells in layer II of the medial entorhinal cortex (MEC). Available evidence suggests that the two pathways carry different information, exemplified by a difference in spatial tuning of cells in LEC and MEC. The grid cell, a prominent position-modulated cell type present in MEC, has been postulated to derive its characteristic hexagonal firing pattern from dominant disynaptic inhibitory connections between hippocampal-projecting stellate cells. Given that grid cells have not been described in LEC, we aim to describe the local synaptic connectivity of fan cells, to explore whether the network architecture is similar to that of the MEC stellate cell. Using a combination of multicell electrophysiological and optogenetic approaches in acute slices from rodents of either sex, we show that excitatory connectivity between fan cells is very sparse. Fan cells connect preferentially with two distinct types of inhibitory interneurons, suggesting disynaptic inhibitory coupling as the main form of communication among fan cells. These principles are similar to those reported for stellate cells in MEC, indicating an overall comparable local circuit architecture of the main hippocampal-projecting cell types in the lateral and medial entorhinal cortex. Our data provide the first description of the synaptic microcircuit of hippocampal-projecting layer II cells in the lateral entorhinal cortex. We show that these cells make infrequent monosynaptic connections with each other, and that they preferentially communicate through a disynaptic inhibitory network. This is similar to the microcircuit of hippocampal-projecting stellate cells in layer II of the medial entorhinal cortex, but dissimilar to the connectivity observed in layer 2 of neocortex. In medial entorhinal cortex, the observed network structure has been proposed to underlie the firing pattern of grid cells. This opens the possibility that layer II cells in lateral entorhinal cortex exhibit regular firing patterns in an unexplored domain.
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http://dx.doi.org/10.1523/JNEUROSCI.1290-18.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6595991PMC
November 2018

Marked Diversity of Unique Cortical Enhancers Enables Neuron-Specific Tools by Enhancer-Driven Gene Expression.

Curr Biol 2018 07 28;28(13):2103-2114.e5. Epub 2018 Jun 28.

Kavli Institute for Systems Neuroscience and Centre for Neural Computation, NTNU, Trondheim, Norway; Institute of Neuroscience, University of Oregon, Eugene, OR, USA. Electronic address:

Understanding neural circuit function requires individually addressing their component parts: specific neuronal cell types. However, not only do the precise genetic mechanisms specifying neuronal cell types remain obscure, access to these neuronal cell types by transgenic techniques also remains elusive. Whereas most genes are expressed in the brain, the vast majority are expressed in many different kinds of neurons, suggesting that promoters alone are not sufficiently specific to distinguish cell types. However, there are orders of magnitude more distal genetic cis-regulatory elements controlling transcription (i.e., enhancers), so we screened for enhancer activity in microdissected samples of mouse cortical subregions. This identified thousands of novel putative enhancers, many unique to particular cortical subregions. Pronuclear injection of expression constructs containing such region-specific enhancers resulted in transgenic lines driving expression in distinct sets of cells specifically in the targeted cortical subregions, even though the parent gene's promoter was relatively non-specific. These data showcase the promise of utilizing the genetic mechanisms underlying the specification of diverse neuronal cell types for the development of genetic tools potentially capable of targeting any neuronal circuit of interest, an approach we call enhancer-driven gene expression (EDGE).
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http://dx.doi.org/10.1016/j.cub.2018.05.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7301410PMC
July 2018

Intrinsic Projections of Layer Vb Neurons to Layers Va, III, and II in the Lateral and Medial Entorhinal Cortex of the Rat.

Cell Rep 2018 07;24(1):107-116

Kavli institute for Systems Neuroscience, Center for Computational Neuroscience, Egil and Pauline Braathen and Fred Kavli Center for Cortical Microcircuits, NTNU Norwegian University of Science and Technology, 7489 Trondheim, Norway. Electronic address:

Layer V of the entorhinal cortex (EC) receives input from the hippocampus and originates main entorhinal outputs. The deep-sublayer Vb, immunopositive for the transcription factor Ctip2, is thought to be the main recipient of hippocampal projections, whereas the superficial-sublayer LVa, immunonegative for Ctip2, originates the main outputs of EC. This disrupts the proposed role of EC as mediating hippocampal-cortical interactions. With the use of specific (trans)synaptic tracing approaches, we report that, in medial entorhinal cortex, layer Vb neurons innervate neurons in layers Va, II, and III. A similar circuitry exists in the lateral entorhinal cortex. We conclude that EC-layer Vb neurons mediate two circuits in the hippocampus-memory system: (1) a hippocampal output circuit to telencephalic areas by projecting to layer Va and (2) a feedback projection, sending information back to the EC-hippocampal loop via neurons in layers II and III.
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http://dx.doi.org/10.1016/j.celrep.2018.06.014DOI Listing
July 2018

Development of Parvalbumin-Expressing Basket Terminals in Layer II of the Rat Medial Entorhinal Cortex.

eNeuro 2018 May-Jun;5(3). Epub 2018 Jun 26.

Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, NTNU Norwegian University of Science and Technology, Trondheim 7491, Norway.

Grid cells in layer II of the medial entorhinal cortex (MEC LII) generate multiple regular firing fields in response to the position and speed of an individual within the environment. They exhibit a protracted postnatal development and, in the adult, show activity differences along the dorsoventral axis (DVA). Evidence suggests parvalbumin-positive (PV) interneurons, most of which are perisomatic-targeting cells, play a crucial role in generation of the hexagonal grid cell activity pattern. We therefore hypothesized that the development and organization of PV perisomatic terminals in MEC LII reflect the postnatal emergence of the hexagonal firing pattern and dorsoventral differences seen in grid cell activity. We used immuno-electron microscopy to examine the development of PV perisomatic terminals and their target somata within dorsal and ventral MEC LII in rats of postnatal day (P)10, P15, and P30. We demonstrate that in dorsal and ventral MEC LII, the cross-sectional area of somata and number and density of perisomatic PV terminals increase between P10 and P15. A simultaneous decrease was observed in cross-sectional area of PV terminals. Between P15 and P30, both MEC regions showed an increase in PV terminal size and percentage of PV terminals containing mitochondria, which may enable grid cell activity to emerge and stabilize. We also report that dorsal somata are larger and apposed by more PV terminals than ventral somata at all stages, suggesting a protracted maturation in the ventral portion and a possible gradient in soma size and PV basket innervation along the DVA in the adult.
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http://dx.doi.org/10.1523/ENEURO.0438-17.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6019390PMC
January 2019

A transatlantic cooperation for enriched neuroscience training.

Eur J Neurosci 2018 07 4;48(2):1717-1719. Epub 2018 Jul 4.

Society for Neuroscience, Neuroscience Training Committee, Washington, District of Columbia.

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http://dx.doi.org/10.1111/ejn.14056DOI Listing
July 2018

Entorhinal fast-spiking speed cells project to the hippocampus.

Proc Natl Acad Sci U S A 2018 02 31;115(7):E1627-E1636. Epub 2018 Jan 31.

Kavli Institute for Systems Neuroscience, Norwegian University of Science and Technology, 7489 Trondheim, Norway;

The mammalian positioning system contains a variety of functionally specialized cells in the medial entorhinal cortex (MEC) and the hippocampus. In order for cells in these systems to dynamically update representations in a way that reflects ongoing movement in the environment, they must be able to read out the current speed of the animal. Speed is encoded by speed-responsive cells in both MEC and hippocampus, but the relationship between the two populations has not been determined. We show here that many entorhinal speed cells are fast-spiking putative GABAergic neurons. Using retrograde viral labeling from the hippocampus, we find that a subset of these fast-spiking MEC speed cells project directly to hippocampal areas. This projection contains parvalbumin (PV) but not somatostatin (SOM)-immunopositive cells. The data point to PV-expressing GABAergic projection neurons in MEC as a source for widespread speed modulation and temporal synchronization in entorhinal-hippocampal circuits for place representation.
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http://dx.doi.org/10.1073/pnas.1720855115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5816210PMC
February 2018

Comparative Contemplations on the Hippocampus.

Brain Behav Evol 2017 4;90(1):15-24. Epub 2017 Sep 4.

Kavli Institute for Systems Neuroscience, Center for Computational Neuroscience, Egil and Pauline Braathen and Fred Kavli Center for Cortical Microcircuits, NTNU Norwegian University of Science and Technology, Trondheim, Norway.

The hippocampus in mammals is a morphologically well-defined structure, and so are its main subdivisions. To define the homologous structure in other vertebrate clades, using these morphological criteria has been difficult, if not impossible, since the typical mammalian morphology is absent. Although there seems to be consensus that the most medial part of the pallium represents the hippocampus in all vertebrates, there is no consensus on whether all mammalian hippocampal subdivisions are present in the derivatives of the medial pallium in all vertebrate groups. The aim of this paper is to explore the potential relevance of connections to define the hippocampus across vertebrates, with a focus on mammals, reptiles, and birds.
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http://dx.doi.org/10.1159/000475703DOI Listing
April 2018

Architecture of the Entorhinal Cortex A Review of Entorhinal Anatomy in Rodents with Some Comparative Notes.

Front Syst Neurosci 2017 28;11:46. Epub 2017 Jun 28.

Division of Systems Neuroscience, Tohoku University Graduate School of Life ScienceSendai, Japan.

The entorhinal cortex (EC) is the major input and output structure of the hippocampal formation, forming the nodal point in cortico-hippocampal circuits. Different division schemes including two or many more subdivisions have been proposed, but here we will argue that subdividing EC into two components, the lateral EC (LEC) and medial EC (MEC) might suffice to describe the functional architecture of EC. This subdivision then leads to an anatomical interpretation of the different phenotypes of LEC and MEC. First, we will briefly summarize the cytoarchitectonic differences and differences in hippocampal projection patterns on which the subdivision between LEC and MEC traditionally is based and provide a short comparative perspective. Second, we focus on main differences in cortical connectivity, leading to the conclusion that the apparent differences may well correlate with the functional differences. Cortical connectivity of MEC is features interactions with areas such as the presubiculum, parasubiculum, retrosplenial cortex (RSC) and postrhinal cortex, all areas that are considered to belong to the "spatial processing domain" of the cortex. In contrast, LEC is strongly connected with olfactory areas, insular, medial- and orbitofrontal areas and perirhinal cortex. These areas are likely more involved in processing of object information, attention and motivation. Third, we will compare the intrinsic networks involving principal- and inter-neurons in LEC and MEC. Together, these observations suggest that the different phenotypes of both EC subdivisions likely depend on the combination of intrinsic organization and specific sets of inputs. We further suggest a reappraisal of the notion of EC as a layered input-output structure for the hippocampal formation.
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http://dx.doi.org/10.3389/fnsys.2017.00046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5488372PMC
June 2017

Perirhinal firing patterns are sustained across large spatial segments of the task environment.

Nat Commun 2017 05 26;8:15602. Epub 2017 May 26.

Swammerdam Institute for Life Sciences, Center for Neuroscience, Faculty of Science, University of Amsterdam, 1098 XH Amsterdam, The Netherlands.

Spatial navigation and memory depend on the neural coding of an organism's location. Fine-grained coding of location is thought to depend on the hippocampus. Likewise, animals benefit from knowledge parsing their environment into larger spatial segments, which are relevant for task performance. Here we investigate how such knowledge may be coded, and whether this occurs in structures in the temporal lobe, supplying cortical inputs to the hippocampus. We found that neurons in the perirhinal cortex of rats generate sustained firing patterns that discriminate large segments of the task environment. This contrasted to transient firing in hippocampus and sensory neocortex. These spatially extended patterns were not explained by task variables or temporally discrete sensory stimuli. Previously it has been suggested that the perirhinal cortex is part of a pathway processing object, but not spatial information. Our results indicate a greater complexity of neural coding than captured by this dichotomy.
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http://dx.doi.org/10.1038/ncomms15602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5458559PMC
May 2017

MicroRNAs contribute to postnatal development of laminar differences and neuronal subtypes in the rat medial entorhinal cortex.

Brain Struct Funct 2017 Sep 4;222(7):3107-3126. Epub 2017 Mar 4.

Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.

The medial entorhinal cortex (MEC) is important in spatial navigation and memory formation and its layers have distinct neuronal subtypes, connectivity, spatial properties, and disease susceptibility. As little is known about the molecular basis for the development of these laminar differences, we analyzed microRNA (miRNA) and messenger RNA (mRNA) expression differences between rat MEC layer II and layers III-VI during postnatal development. We identified layer and age-specific regulation of gene expression by miRNAs, which included processes related to neuron specialization and locomotor behavior. Further analyses by retrograde labeling and expression profiling of layer II stellate neurons and in situ hybridization revealed that the miRNA most up-regulated in layer II, miR-143, was enriched in stellate neurons, whereas the miRNA most up-regulated in deep layers, miR-219-5p, was expressed in ependymal cells, oligodendrocytes and glia. Bioinformatics analyses of predicted mRNA targets with negatively correlated expression patterns to miR-143 found that miR-143 likely regulates the Lmo4 gene, which is known to influence hippocampal-based spatial learning.
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http://dx.doi.org/10.1007/s00429-017-1389-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5585308PMC
September 2017
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