Publications by authors named "Sadegh Nabavi"

14 Publications

  • Page 1 of 1

Fear Memory Relapse: The Importance of Input Associativity.

Trends Neurosci 2021 May 9;44(5):337-339. Epub 2021 Mar 9.

DANDRITE, The Danish Research Institute of Translational Neuroscience, Aarhus University, Aarhus, Denmark; Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark; Center for Proteins in Memory - PROMEMO, Danish National Research Foundation, Aarhus University, Aarhus, Denmark.

An inherent property of extinguished fear memories is that the fear may return. A recent study in mice by Li et al. provides novel insights into the mechanisms underlying the relapse of an extinguished memory through converging sensory and contextual cues from the auditory cortex (ACx) and ventral hippocampus (vHPC) to the lateral amygdala (LA).
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http://dx.doi.org/10.1016/j.tins.2021.02.006DOI Listing
May 2021

Rapid generation of regionally specified CNS neurons by sequential patterning and conversion of human induced pluripotent stem cells.

Stem Cell Res 2020 10 3;48:101945. Epub 2020 Aug 3.

Danish Research Institute of Translational Neuroscience (DANDRITE), Nordic EMBL Partnership for Molecular Medicine, Aarhus University, Denmark; Department of Biomedicine, Aarhus University, Denmark. Electronic address:

The differentiation of patient-specific induced pluripotent stem cells (iPSCs) into specific neuronal subtypes has been exploited as an approach for modeling a variety of neurological disorders. However, achieving a highly pure population of neurons is challenging when using directed differentiation methods, especially for neuronal subtypes generated by complex and protracted protocols. In this study, we efficiently produced highly pure populations of regionally specified CNS neurons by using a modified NGN2-Puromycin direct conversion protocol. The protocol is amenable across a range of iPSC lines, with more than 95% of cells at day 21 positive for the neuronal marker MAP2. We found that conversion from pluripotent stem cells resulted in neurons from the central and peripheral nervous system; however, by incorporating a short CNS patterning step, we eliminated these peripheral neurons. Furthermore, we used the patterning step to control the rostral-caudal identity. This approach of sequential patterning and conversion produced pure populations of forebrain neurons, when patterned with SMAD inhibitors. Additionally, when SMAD inhibitors and WNT agonists were applied, the approach produced anterior hindbrain excitatory neurons and resulted in a neuronal population containing VSX2/SHOX2 V2a interneurons. Overall, this sequential patterning and conversion protocol can be used for the production of a variety of CNS excitatory neurons from patient-derived iPSCs, and is a highly versatile system for investigating early disease events for a range of neurological disorders including Alzheimer's disease, motor neurons disease and spinal cord injury.
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http://dx.doi.org/10.1016/j.scr.2020.101945DOI Listing
October 2020

TRACE: An Unbiased Method to Permanently Tag Transiently Activated Inputs.

Front Cell Neurosci 2020 12;14:114. Epub 2020 May 12.

Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.

A fundamental interest in circuit analysis is to parse out the synaptic inputs underlying a behavioral experience. Toward this aim, we have devised an unbiased strategy that specifically labels the afferent inputs that are activated by a defined stimulus in an activity-dependent manner. We validated this strategy in four brain circuits receiving known sensory inputs. This strategy, as demonstrated here, accurately identifies these inputs.
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http://dx.doi.org/10.3389/fncel.2020.00114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243865PMC
May 2020

Organotypic slice culture model demonstrates inter-neuronal spreading of alpha-synuclein aggregates.

Acta Neuropathol Commun 2019 12 19;7(1):213. Epub 2019 Dec 19.

Danish Research Institute of Translational Neuroscience - DANDRITE, Aarhus University, Aarhus, Denmark.

Here we describe the use of an organotypic hippocampal slice model for studying α-synuclein aggregation and inter-neuronal spreading initiated by microinjection of pre-formed α-synuclein fibrils (PFFs). PFF injection at dentate gyrus (DG) templates the formation of endogenous α-synuclein aggregates in axons and cell bodies of this region that spread to CA3 and CA1 regions. Aggregates are insoluble and phosphorylated at serine-129, recapitulating Lewy pathology features found in Parkinson's disease and other synucleinopathies. The model was found to favor anterograde spreading of the aggregates. Furthermore, it allowed development of slices expressing only serine-129 phosphorylation-deficient human α-synuclein (S129G) using an adeno-associated viral (AAV) vector in α-synuclein knockout slices. The processes of aggregation and spreading of α-synuclein were thereby shown to be independent of phosphorylation at serine-129. We provide methods and highlight crucial steps for PFF microinjection and characterization of aggregate formation and spreading. Slices derived from genetically engineered mice or manipulated using viral vectors allow testing of hypotheses on mechanisms involved in the formation of α-synuclein aggregates and their prion-like spreading.
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http://dx.doi.org/10.1186/s40478-019-0865-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6924077PMC
December 2019

High-potency ligands for DREADD imaging and activation in rodents and monkeys.

Nat Commun 2019 10 11;10(1):4627. Epub 2019 Oct 11.

Biobehavioral Imaging and Molecular Neuropsychopharmacology Unit, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, 21224, USA.

Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are a popular chemogenetic technology for manipulation of neuronal activity in uninstrumented awake animals with potential for human applications as well. The prototypical DREADD agonist clozapine N-oxide (CNO) lacks brain entry and converts to clozapine, making it difficult to apply in basic and translational applications. Here we report the development of two novel DREADD agonists, JHU37152 and JHU37160, and the first dedicated F positron emission tomography (PET) DREADD radiotracer, [F]JHU37107. We show that JHU37152 and JHU37160 exhibit high in vivo DREADD potency. [F]JHU37107 combined with PET allows for DREADD detection in locally-targeted neurons, and at their long-range projections, enabling noninvasive and longitudinal neuronal projection mapping.
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http://dx.doi.org/10.1038/s41467-019-12236-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6788984PMC
October 2019

Hebbian plasticity in vivo: relevance and induction.

Curr Opin Neurobiol 2017 08 3;45:188-192. Epub 2017 Jul 3.

DANDRITE - Danish Research Institute of Translational Neuroscience, Denmark; Department of Molecular Biology and Genetics, Aarhus University, Denmark. Electronic address:

Hebbian plasticity, as represented by long-term potentiation (LTP) and long-term depression (LTD) of synapses, has been the most influential hypothesis to account for encoding of memories. The evidence for the physiological relevance of LTP is indisputable. However, until recently the ways by which LTP physiologically is induced in its natural environment, the brain, was less clear. Nonetheless, current evidence points to neuromodulators as an indispensable element. The case for LTD in vivo is less certain. Even its relevance has been a matter of speculation and doubts. However, emerging evidence for a physiological role for LTD is promising, as the phenomenon has been observed at different brain regions. More needs to be done before LTD can claim an equal status alongside LTP.
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http://dx.doi.org/10.1016/j.conb.2017.06.001DOI Listing
August 2017

Synaptic Plasticity, Engrams, and Network Oscillations in Amygdala Circuits for Storage and Retrieval of Emotional Memories.

Neuron 2017 May;94(4):731-743

The Danish Research Institute of Translational Neuroscience - DANDRITE, Nordic EMBL Partnership for Molecular Medicine, Department of Biomedicine, Aarhus University, Ole Worms Allé 3, 8000 Aarhus C, Denmark; Department of Biomedicine, Aarhus University, Wilhelm Meyers Allé 3, 8000 Aarhus C, Denmark. Electronic address:

The neuronal circuits of the basolateral amygdala (BLA) are crucial for acquisition, consolidation, retrieval, and extinction of associative emotional memories. Synaptic plasticity in BLA neurons is essential for associative emotional learning and is a candidate mechanism through which subsets of BLA neurons (commonly termed "engram") are recruited during learning and reactivated during memory retrieval. In parallel, synchronous oscillations in the theta and gamma bands between the BLA and interconnected structures have been shown to occur during consolidation and retrieval of emotional memories. Understanding how these cellular and network phenomena interact is vital to decipher the roles of emotional memory formation and storage in the healthy and pathological brain. Here, we review data on synaptic plasticity, engrams, and network oscillations in the rodent BLA. We explore mechanisms through which synaptic plasticity, engrams, and long-range synchrony might be interconnected.
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http://dx.doi.org/10.1016/j.neuron.2017.03.022DOI Listing
May 2017

Engineering a memory with LTD and LTP.

Nature 2014 Jul 1;511(7509):348-52. Epub 2014 Jun 1.

Center for Neural Circuits and Behavior, Department of Neuroscience and Section of Neurobiology, University of California at San Diego, California 92093, USA.

It has been proposed that memories are encoded by modification of synaptic strengths through cellular mechanisms such as long-term potentiation (LTP) and long-term depression (LTD). However, the causal link between these synaptic processes and memory has been difficult to demonstrate. Here we show that fear conditioning, a type of associative memory, can be inactivated and reactivated by LTD and LTP, respectively. We began by conditioning an animal to associate a foot shock with optogenetic stimulation of auditory inputs targeting the amygdala, a brain region known to be essential for fear conditioning. Subsequent optogenetic delivery of LTD conditioning to the auditory input inactivates memory of the shock. Then subsequent optogenetic delivery of LTP conditioning to the auditory input reactivates memory of the shock. Thus, we have engineered inactivation and reactivation of a memory using LTD and LTP, supporting a causal link between these synaptic processes and memory.
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http://dx.doi.org/10.1038/nature13294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4210354PMC
July 2014

GluA1 trafficking and metabotropic NMDA: addressing results from other laboratories inconsistent with ours.

Philos Trans R Soc Lond B Biol Sci 2014 Jan 2;369(1633):20130145. Epub 2013 Dec 2.

Department of Neurosciences, University of California, San Diego, , La Jolla, CA 92093, USA.

We have previously shown that when over-expressed in neurons, green fluorescent protein (GFP) tagged GluA1 (GluA1-GFP) delivery into synapses is dependent on plasticity. A recent study suggests that GluA1 over-expression leads to its incorporation into the synapse, in the absence of additional long-term potentiation-like manipulations. It is possible that a GFP tag was responsible for the difference. Using rectification index as a measure of synaptic delivery of GluA1, we found no difference in the synaptic delivery of GluA1-GFP versus untagged GluA1. We recently published a study showing that while D-APV blocks NMDAr-dependent long-term depression (LTD), MK-801 and 7-chloro kynurenate (7CK) fail to block LTD. We propose a metabotropic function for the NMDA receptor in LTD induction. In contrast to our observations, recent unpublished data suggest that the above antagonists are equally effective in blocking LTD. We noticed different methodology in their study. Here, we show that their methodology has complex effects on synaptic transmission. Therefore, it is not possible to conclude that 7CK is effective in blocking LTD from their type of experiment.
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http://dx.doi.org/10.1098/rstb.2013.0145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3843877PMC
January 2014

Optogenetic inhibition of synaptic release with chromophore-assisted light inactivation (CALI).

Neuron 2013 Jul;79(2):241-53

Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093-0647, USA.

Optogenetic techniques provide effective ways of manipulating the functions of selected neurons with light. In the current study, we engineered an optogenetic technique that directly inhibits neurotransmitter release. We used a genetically encoded singlet oxygen generator, miniSOG, to conduct chromophore assisted light inactivation (CALI) of synaptic proteins. Fusions of miniSOG to VAMP2 and synaptophysin enabled disruption of presynaptic vesicular release upon illumination with blue light. In cultured neurons and hippocampal organotypic slices, synaptic release was reduced up to 100%. Such inhibition lasted >1 hr and had minimal effects on membrane electrical properties. When miniSOG-VAMP2 was expressed panneuronally in Caenorhabditis elegans, movement of the worms was reduced after illumination, and paralysis was often observed. The movement of the worms recovered overnight. We name this technique Inhibition of Synapses with CALI (InSynC). InSynC is a powerful way to silence genetically specified synapses with light in a spatially and temporally precise manner.
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http://dx.doi.org/10.1016/j.neuron.2013.05.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3804158PMC
July 2013

Metabotropic NMDA receptor function is required for β-amyloid-induced synaptic depression.

Proc Natl Acad Sci U S A 2013 Mar 19;110(10):4033-8. Epub 2013 Feb 19.

Center for Neural Circuits and Behavior, Department of Neuroscience, University of California at San Diego, La Jolla, CA 92093, USA.

The mechanisms by which β-amyloid (Aβ), a peptide fragment believed to contribute to Alzheimer's disease, leads to synaptic deficits are not known. Here we find that elevated oligomeric Aβ requires ion flux-independent function of NMDA receptors (NMDARs) to produce synaptic depression. Aβ activates this metabotropic NMDAR function on GluN2B-containing NMDARs but not on those containing GluN2A. Furthermore, oligomeric Aβ leads to a selective loss of synaptic GluN2B responses, effecting a switch in subunit composition from GluN2B to GluN2A, a process normally observed during development. Our results suggest that conformational changes of the NMDAR, and not ion flow through its channel, are required for Aβ to produce synaptic depression and a switch in NMDAR composition. This Aβ-induced signaling mediated by alterations in GluN2B conformation may be a target for therapeutic intervention of Alzheimer's disease.
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http://dx.doi.org/10.1073/pnas.1219605110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3593880PMC
March 2013

Metabotropic NMDA receptor function is required for NMDA receptor-dependent long-term depression.

Proc Natl Acad Sci U S A 2013 Mar 19;110(10):4027-32. Epub 2013 Feb 19.

Center for Neural Circuits and Behavior, Division of Biology, Department of Neuroscience and Section of Neurobiology, University of California at San Diego, La Jolla, CA 92093, USA.

NMDA receptor (NMDAR) activation controls long-term potentiation (LTP) as well as long-term depression (LTD) of synaptic transmission, cellular models of learning and memory. A long-standing view proposes that a high level of Ca(2+) entry through NMDARs triggers LTP; lower Ca(2+) entry triggers LTD. Here we show that ligand binding to NMDARs is sufficient to induce LTD; neither ion flow through NMDARs nor Ca(2+) rise is required. However, basal levels of Ca(2+) are permissively required. Lowering, but not maintaining, basal Ca(2+) levels with Ca(2+) chelators blocks LTD and drives strong synaptic potentiation, indicating that basal Ca(2+) levels control NMDAR-dependent LTD and basal synaptic transmission. Our findings indicate that metabotropic actions of NMDARs can weaken active synapses without raising postsynaptic calcium, thereby revising and expanding the mechanisms controlling synaptic plasticity.
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http://dx.doi.org/10.1073/pnas.1219454110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3593861PMC
March 2013

Cellular pharmacology of protein kinase Mζ (PKMζ) contrasts with its in vitro profile: implications for PKMζ as a mediator of memory.

J Biol Chem 2012 Apr 29;287(16):12879-85. Epub 2012 Feb 29.

Department of Pharmacology, University of California San Diego, La Jolla, California 92093, USA.

A number of recent studies have used pharmacological inhibitors to establish a role for protein kinase Mζ (PKMζ) in synaptic plasticity and memory. These studies use zeta inhibitory peptide (ZIP) and chelerythrine as inhibitors of PKMζ to block long term potentiation and memory; staurosporine is used as a negative control to show that a nonspecific kinase inhibitor does not block long term potentiation and memory. Here, we show that neither ZIP nor chelerythrine inhibits PKMζ in cultured cells or brain slices. In contrast, staurosporine does block PKMζ activity in cells and brain slices by inhibiting its upstream phosphoinositide-dependent kinase-1. These studies demonstrate that the effectiveness of drugs against purified PKMζ may not be indicative of their specificity in the more complex environment of the cell and suggest that PKMζ is unlikely to be the mediator of synaptic plasticity or memory.
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http://dx.doi.org/10.1074/jbc.M112.357244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3339930PMC
April 2012

The prion protein as a receptor for amyloid-beta.

Nature 2010 Aug;466(7308):E3-4; discussion E4-5

Center for Neural Circuits and Behavior, 9500 Gilman Drive 0634, University of California at San Diego, La Jolla, California 92093, USA.

Increased levels of brain amyloid-beta, a secreted peptide cleavage product of amyloid precursor protein (APP), is believed to be critical in the aetiology of Alzheimer's disease. Increased amyloid-beta can cause synaptic depression, reduce the number of spine protrusions (that is, sites of synaptic contacts) and block long-term synaptic potentiation (LTP), a form of synaptic plasticity; however, the receptor through which amyloid-beta produces these synaptic perturbations has remained elusive. Laurén et al. suggested that binding between oligomeric amyloid-beta (a form of amyloid-beta thought to be most active) and the cellular prion protein (PrP(C)) is necessary for synaptic perturbations. Here we show that PrP(C) is not required for amyloid-beta-induced synaptic depression, reduction in spine density, or blockade of LTP; our results indicate that amyloid-beta-mediated synaptic defects do not require PrP(c).
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http://dx.doi.org/10.1038/nature09217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3057871PMC
August 2010