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On the Mechanisms Behind Hippocampal Theta Oscillations: The role of OLMα2 interneurons
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Theta activity is one of the most prominent rhythms in the brain and appears to be conserved among mammals.  These 4-12 Hz oscillations have been predominantly studied in the dorsal hippocampus where they are correlated with a broad range of voluntary and exploratory behaviors. Theta activity has been also implicated in a number of mnemonic processes, long-term potentiation (LTP) induction and even acting as a global synchronizing mechanism. Moving along the dorso-ventral axis theta activity is reduced in power and desynchronized from the dorsal part. However, theta activity can also be generated in the ventral hippocampus itself during anxiety- and fear-related behaviors. Until now it was unknown which hippocampal cell population was capable to generate theta activity and it was controversial if its origin was local, in the hippocampus, or driven by other brain regions. In this thesis I present compelling in vitro and in vivo  evidence that   a subpopulation of OLM interneurons (defined by the Chrna2-cre line)  distinctively enriched  in the CA1 region of  the ventral hippocampus is implicated in LTP function (paper I,II), information control (paper V) and the induction of theta activity that is under cholinergic  control (paper IV). Importantly, a concomitant effect of the optogenetically induced theta activity is reduction in anxiety (Paper IV). Another innovation of this work was the development of a methodological approach to avoid artefactual signals when combining electrophysiology with light activation during optogenetic experiments (Paper III). In summary, the work presented in this thesis elucidates the role of a morphologically and electrophysiologially identified cell population, OLMα2 interneurons, first on the cellular, then on the circuit and ultimately on the behavioral level.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. , 47 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1206
Keyword [en]
hippocampus, interneuron, optogenetics, theta oscillations, anxiety
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:uu:diva-282144ISBN: 978-91-554-9542-8 (print)OAI: oai:DiVA.org:uu-282144DiVA: diva2:916518
Public defence
2016-05-28, A1:111a, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2016-05-04 Created: 2016-04-03 Last updated: 2016-05-12
List of papers
1. Novel markers for OLM interneurons in the hippocampus
Open this publication in new window or tab >>Novel markers for OLM interneurons in the hippocampus
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2015 (English)In: Frontiers in Cellular Neuroscience, ISSN 1662-5102, E-ISSN 1662-5102, Vol. 9, 201Article in journal, Editorial material (Other academic) Published
Keyword
interneuron, OLM, somatostatin, hippocampus, Chrna2
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-259200 (URN)10.3389/fncel.2015.00201 (DOI)000357611600001 ()26082683 (PubMedID)
Available from: 2015-07-30 Created: 2015-07-29 Last updated: 2017-12-04Bibliographically approved
2. Ventral hippocampus OLMα2 interneurons control type 2 theta oscillations and anxiety responses to predator odor
Open this publication in new window or tab >>Ventral hippocampus OLMα2 interneurons control type 2 theta oscillations and anxiety responses to predator odor
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

The 4-12 Hz oscillations have been predominantly studied in the dorsal hippocampus where they appear to be strongly correlated with movements and explorative behavior. However, moving along the septotemporal axis theta activity during movements is reduced in power and desynchronized from the dorsal part. In fact, theta activity can also be generated in the ventral hippocampus itself in anxiety, stress and fear-related behaviors. These functional differences are similarly reflected in local hippocampal circuit properties and anatomy. We found a specific subpopulation of oriens-lacunosum moleculare (OLM) interneurons expressing nicotinic acetylcholine receptor α2 subunit (Chrna2) differentially distributed along the dorso-ventral hippocampal axis, OLMα2 cells. The activation of OLMα2 cells is sufficient to induce theta activity in anesthetized mice and it is abolished by the application of atropine. While the induced theta rhythm did not affect frequency ranges related to animals movements (8-10 Hz), it significantly influenced lower frequency range, 6-8 Hz. It has been suggested that the low range theta activity corresponds to type 2 theta and is associated with innate responses to the predator smell. We conducted this test and observed that OLMα2 cells stimulation leads to a significant increase of mice risk-taking behavior. In summary, our data suggest that vHipp OLMα2 cells control hippocampal type 2 theta activity and innate anxiety responses to predator odor. 

National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-282141 (URN)
Available from: 2016-04-03 Created: 2016-04-03 Last updated: 2016-05-12
3. On the photovoltaic effect in localfield potential recordings
Open this publication in new window or tab >>On the photovoltaic effect in localfield potential recordings
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2016 (English)In: Neurophotonics, ISSN 2329-423X, Vol. 3, no 1, 015002Article in journal (Refereed) Published
Abstract [en]

ptogenetics allows light activation of genetically defined cell populations and the study of their link to specific brain functions. While it is a powerful method that has revolutionized neuroscience in the last decade, the shortcomings of directly stimulating electrodes and living tissue with light have been poorly characterized. Here, we assessed the photovoltaic effects in local field potential (LFP) recordings of the mouse hippocampus. We found that light leads to several artifacts that resemble genuine LFP features in animals with no opsin expression, such as stereotyped peaks at the power spectrum, phase shifts across different recording channels, coupling between low and high oscillation frequencies, and sharp signal deflections that are detected as spikes. Further, we tested how light stimulation affected hippocampal LFP recordings in mice expressing channelrhodopsin 2 in parvalbumin neurons (PV/ChR2 mice). Genuine oscillatory activity at the frequency of light stimulation could not be separated from light-induced artifacts. In addition, light stimulation in PV/ChR2 mice led to an overall decrease in LFP power. Thus, genuine LFP changes caused by the stimulation of specific cell populations may be intermingled with spurious changes caused by photovoltaic effects. Our data suggest that care should be taken in the interpretation of electrophysiology experiments involving light stimulation.

National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-279326 (URN)10.1117/1.NPh.3.1.015002 (DOI)000373771200006 ()26835485 (PubMedID)
Available from: 2016-02-29 Created: 2016-02-29 Last updated: 2016-06-20Bibliographically approved
4. OLMα2 and basket interneurons participate in distinct pacemaker networks in vitro
Open this publication in new window or tab >>OLMα2 and basket interneurons participate in distinct pacemaker networks in vitro
(English)Manuscript (preprint) (Other academic)
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-282142 (URN)
Available from: 2016-04-03 Created: 2016-04-03 Last updated: 2016-05-12
5. OLM interneurons differentially modulate CA3 and entorhinal inputs to hippocampal CA1 neurons
Open this publication in new window or tab >>OLM interneurons differentially modulate CA3 and entorhinal inputs to hippocampal CA1 neurons
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2012 (English)In: Nature Neuroscience, ISSN 1097-6256, E-ISSN 1546-1726, Vol. 15, no 11, 1524-1530 p.Article in journal (Refereed) Published
Abstract [en]

The vast diversity of GABAergic interneurons is believed to endow hippocampal microcircuits with the required flexibility for memory encoding and retrieval. However, dissection of the functional roles of defined interneuron types has been hampered by the lack of cell-specific tools. We identified a precise molecular marker for a population of hippocampal GABAergic interneurons known as oriens lacunosum-moleculare (OLM) cells. By combining transgenic mice and optogenetic tools, we found that OLM cells are important for gating the information flow in CA1, facilitating the transmission of intrahippocampal information (from CA3) while reducing the influence of extrahippocampal inputs (from the entorhinal cortex). Furthermore, we found that OLM cells were interconnected by gap junctions, received direct cholinergic inputs from subcortical afferents and accounted for the effect of nicotine on synaptic plasticity of the Schaffer collateral pathway. Our results suggest that acetylcholine acting through OLM cells can control the mnemonic processes executed by the hippocampus.

National Category
Basic Medicine
Identifiers
urn:nbn:se:uu:diva-184961 (URN)10.1038/nn.3235 (DOI)000310424900012 ()
Available from: 2012-11-15 Created: 2012-11-15 Last updated: 2017-12-07Bibliographically approved

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