Navegando por Autor "Mikulovic, Sanja"

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Chrna2-OLM interneurons display different membrane properties and h-current magnitude depending on dorsoventral location
(2019-07) Hilscher, Markus M.; Nogueira, Ingrid; Mikulovic, Sanja; Kullander, Klas; Leão, Richardson Naves; Leão, Emelie Katarina Svahn
The hippocampus is an extended structure displaying heterogeneous anatomical cell layers along its dorsoventral axis. It is known that dorsal and ventral regions show different integrity when it comes to functionality, innervation, gene expression, and pyramidal cell properties. Still, whether hippocampal interneurons exhibit different properties along the dorsoventral axis is not known. Here, we report electrophysiological properties of dorsal and ventral oriens lacunosum moleculare (OLM) cells from coronal sections of the Chrna2‐cre mouse line. We found dorsal OLM cells to exhibit a significantly more depolarized resting membrane potential compared to ventral OLM cells, while action potential properties were similar between the two groups. We found ventral OLM cells to show a higher initial firing frequency in response to depolarizing current injections but also to exhibit a higher spike‐frequency adaptation than dorsal OLM cells. Additionally, dorsal OLM cells displayed large membrane sags in response to negative current injections correlating with our results showing that dorsal OLM cells have more hyperpolarization‐activated current (Ih) compared to ventral OLM cells. Immunohistochemical examination indicates the h‐current to correspond to hyperpolarization‐activated cyclic nucleotide‐gated subunit 2 (HCN2) channels. Computational studies suggest that Ih in OLM cells is essential for theta oscillations in hippocampal circuits, and here we found dorsal OLM cells to present a higher membrane resonance frequency than ventral OLM cells. Thus, our results highlight regional differences in membrane properties between dorsal and ventral OLM cells allowing this interneuron to differently participate in the generation of hippocampal theta rhythms depending on spatial location along the dorsoventral axis of the hippocampus.
Novel markers for OLM interneurons in the hippocampus
(2015-06-02) Mikulovic, Sanja; Restrepo, C. Ernesto; Hilscher, Markus M.; Kullander, Klas; Leão, Richardson Naves
Oriens-lacunosum moleculare (OLM) cells are a major subclass of hippocampal interneurons involved in controlling synaptic plasticity in Shaffer collateral synapses (Leão et al., 2012) and electrogenesis in pyramidal cell (PC) dendrites (Lovett-Barron et al., 2012). Their firing phase is locked with theta oscillations, which imply a role for these cells in theta rhythmogenesis (Klausberger and Somogyi, 2008; Forro et al., 2015). OLM interneurons also appear to be key in the pathophysiology of epilepsy (Dugladze et al., 2007) and is the most vulnerable interneuron population in models of epilepsy (Dinocourt et al., 2003). Somatostatin has been frequently used as a molecular marker for identification of OLM cells (Forro et al., 2015). Two recent studies suggest that the OLM cell population is heterogeneous. First, the expression of cholinergic receptor, nicotinic, alpha polypeptide 2 (Chrna2) seems to be restricted to OLM interneurons neurons of CA1 (Leão et al., 2012). Second, a subset of OLM interneurons that expresses the 5HT3a receptor is derived from the caudal ganglionic eminence and do not entrain to gamma oscillations. In contrast, OLM interneurons derived from the medial ganglionic eminence partially phase lock to in vitro gamma oscillations and do not express 5HT3a receptors (Chittajallu et al., 2013). Further, other dendritic targeting interneurons in the hippocampus also express somatostatin (Lovett-Barron et al., 2014). Hence, functional studies of OLM cell in hippocampal function have been targeting a relatively heterogenous cell population.
OLM interneurons differentially modulate CA3 and entorhinal inputs to hippocampal CA1 neurons
(2012-11) Leão, Richardson Naves; Mikulovic, Sanja; Leão, Emelie Katarina Svahn; Munguba, Hermany; Gezelius, Henrik; Enjin, Anders; Patra, Kalicharan; Eriksson, Anders; Loew, Leslie M; Tort, Adriano Bretanha Lopes; Kullander, Klas
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.
OLMα2 cells bidirectionally modulate learning
(2018-07) Siwani, Samer; França, Arthur S. C.; Mikulovic, Sanja; Reis, Amilcar; Hilscher, Markus M.; Edwards, Steven J.; Leão, Richardson Naves; Tort, Adriano Bretanha Lopes; Kullander, Klas
Inhibitory interneurons participate in mnemonic processes. However, defined roles for identified interneuron populations are scarce. A subpopulation of oriens lacunosum-moleculare (OLM) interneurons genetically defined by the expression of the nicotinic receptor α2 subunit has been shown to gate information carried by either the temporoammonic pathway or Schaffer collaterals in vitro. Here we set out to determine whether selective modulation of OLMα2 cells in the intermediate CA1 affects learning and memory in vivo. Our data show that intermediate OLMα2 cells can either enhance (upon their inhibition) or impair (upon their activation) object memory encoding in freely moving mice, thus exerting bidirectional control. Moreover, we find that OLMα2 cell activation inhibits fear-related memories and that OLMα2 cells respond differently to nicotine in the dorsoventral axis. These results suggest that intermediate OLMα2 cells are an important component in the CA1 microcircuit regulating learning and memory processes.
On the photovoltaic effect in local field potential recordings
(Society of Photo-optical Instrumentation Engineers, 2016-01-19) Mikulovic, Sanja; Pupe, Stefano; Peixoto, Helton Maia; Nascimento, George Carlos; Kulander, Klas; Tort, Adriano Bretanha Lopes; Leão, Richardson Naves
Optogenetics 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
Salicylate induces anxiety-like behaviour and slow theta oscillation and abolishes the relationship between running speed and fast theta oscillation frequency
(2018-08-28) Winne, Jessica; Franzon, Rafael; Miranda, Aron; Malfatti, Thawann; Patriota, João; Mikulovic, Sanja; Leão, Emelie Katarina Svahn; Leão, Richardson Naves
Salicylate intoxication is a cause of tinnitus in humans and it is often used to produce tinnitus‐like perception in animal models. Here we assess whether salicylate induces anxiety‐like electrophysiological and behavioural signs. Using microwire electrode arrays, we recorded local field potential in the ventral and, in some experiments dorsal hippocampus, in an open field arena 1 hour after salicylate (300mg/kg) injection. We found that animals treated with salicylate moved dramatically less than saline treated animals. Salicylate‐treated animals showed a strong 4‐6Hz (type 2) oscillation in the ventral hippocampus (with smaller peaks in dorsal hippocampus electrodes). Coherence in the 4‐6Hz‐theta band was low in the ventral and dorsal hippocampus when compared to movement‐related theta coherence (7‐10Hz). Moreover, movement related theta oscillation frequency decreased and its dependency on running speed was abolished. Our results suggest that salicylate‐induced theta is mostly restricted to the ventral hippocampus. Slow theta has been classically associated to anxiety‐like behaviours. Here we show that salicylate application can consistently generate low frequency theta in the ventral hippocampus. Tinnitus and anxiety show strong comorbidity and the increase in ventral hippocampus low frequency theta could be part of this association.
Ventral hippocampal OLM cells control type 2 theta oscillations and response to predator odor
(2018-09) Mikulovic, Sanja; Restrepo, Carlos Ernesto; Siwani, Samer; Bauer, Pavol; Pupe, Stefano; Tort, Adriano Bretanha Lopes; Kullander, Klas; Leão, Richardson Naves
Dorsal and ventral hippocampus regions exert cognition and emotion-related functions, respectively. Since both regions display rhythmic activity, specific neural oscillatory pacemakers may underlie their functional dichotomy. Type 1 theta oscillations are independent of cholinergic transmission and are observed in the dorsal hippocampus during movement and exploration. In contrast, type 2 theta depends on acetylcholine and appears when animals are exposed to emotionally laden contexts such as a predator presence. Despite its involvement in emotions, type 2 theta has not been associated with the ventral hippocampus. Here, we show that optogenetic activation of oriens-lacunosum moleculare (OLM) interneurons in the ventral hippocampus drives type 2 theta. Moreover, we found that type 2 theta generation is associated with increased risk-taking behavior in response to predator odor. These results demonstrate that two theta oscillations subtypes originate in the two hippocampal regions that predominantly underlie either cognitive or emotion-related functions.

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Navegando por Autor "Mikulovic, Sanja"