Publications by authors named "Maya Groysman"

14 Publications

  • Page 1 of 1

Features of hippocampal astrocytic domains and their spatial relation to excitatory and inhibitory neurons.

Glia 2021 Jun 12. Epub 2021 Jun 12.

Edmond and Lily Safra Center for Brain Sciences (ELSC), The Hebrew University of Jerusalem, Jerusalem, Israel.

The mounting evidence for the involvement of astrocytes in neuronal circuits function and behavior stands in stark contrast to the lack of detailed anatomical description of these cells and the neurons in their domains. To fill this void, we imaged >30,000 astrocytes in hippocampi made transparent by CLARITY, and determined the elaborate structure, distribution, and neuronal content of astrocytic domains. First, we characterized the spatial distribution of >19,000 astrocytes across CA1 lamina, and analyzed the morphology of thousands of reconstructed domains. We then determined the excitatory somatic content of CA1 astrocytes, and measured the distance between inhibitory neuronal somata to the nearest astrocyte soma. We find that on average, there are almost 14 pyramidal neurons per domain in the CA1, increasing toward the pyramidal layer midline, compared to only five excitatory neurons per domain in the amygdala. Finally, we discovered that somatostatin neurons are found in close proximity to astrocytes, compared to parvalbumin and VIP inhibitory neurons. This work provides a comprehensive large-scale quantitative foundation for studying neuron-astrocyte interactions. MAIN POINTS: Large scale detection of 3D astrocytic domains following CLARITY. Different distributions of neuronal content in CA1 and BLA astrocytic domains. SST neurons are located in close proximity to neighboring astrocytes, relative to PV, and VIP neurons.
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http://dx.doi.org/10.1002/glia.24044DOI Listing
June 2021

Egr2 induction in spiny projection neurons of the ventrolateral striatum contributes to cocaine place preference in mice.

Elife 2021 Mar 16;10. Epub 2021 Mar 16.

The Edmond and Lily Safra Center for Brain Sciences, Jerusalem, Israel.

Drug addiction develops due to brain-wide plasticity within neuronal ensembles, mediated by dynamic gene expression. Though the most common approach to identify such ensembles relies on immediate early gene expression, little is known of how the activity of these genes is linked to modified behavior observed following repeated drug exposure. To address this gap, we present a broad-to-specific approach, beginning with a comprehensive investigation of brain-wide cocaine-driven gene expression, through the description of dynamic spatial patterns of gene induction in subregions of the striatum, and finally address functionality of region-specific gene induction in the development of cocaine preference. Our findings reveal differential cell-type specific dynamic transcriptional recruitment patterns within two subdomains of the dorsal striatum following repeated cocaine exposure. Furthermore, we demonstrate that induction of the IEG in the ventrolateral striatum, as well as the cells within which it is expressed, are required for the development of cocaine seeking.
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http://dx.doi.org/10.7554/eLife.65228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8057818PMC
March 2021

Astrocytes contribute to remote memory formation by modulating hippocampal-cortical communication during learning.

Nat Neurosci 2020 10 3;23(10):1229-1239. Epub 2020 Aug 3.

Edmond and Lily Safra Center for Brain Sciences (ELSC), The Hebrew University of Jerusalem, Jerusalem, Israel.

Remote memories depend on coordinated activity in the hippocampus and frontal cortices, but the timeline of these interactions is debated. Astrocytes sense and modify neuronal activity, but their role in remote memory is scarcely explored. We expressed the G-coupled designer receptor hM4Di in CA1 astrocytes and discovered that astrocytic manipulation during learning specifically impaired remote, but not recent, memory recall and decreased activity in the anterior cingulate cortex (ACC) during retrieval. We revealed massive recruitment of ACC-projecting CA1 neurons during memory acquisition, which was accompanied by the activation of ACC neurons. Astrocytic G activation disrupted CA3 to CA1 communication in vivo and reduced the downstream response in the ACC. In behaving mice, it induced a projection-specific inhibition of CA1-to-ACC neurons during learning, which consequently prevented ACC recruitment. Finally, direct inhibition of CA1-to-ACC-projecting neurons spared recent and impaired remote memory. Our findings suggest that remote memory acquisition involves projection-specific functions of astrocytes in regulating CA1-to-ACC neuronal communication.
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http://dx.doi.org/10.1038/s41593-020-0679-6DOI Listing
October 2020

Claustral Neurons Projecting to Frontal Cortex Mediate Contextual Association of Reward.

Curr Biol 2020 09 23;30(18):3522-3532.e6. Epub 2020 Jul 23.

The Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram, Jerusalem 9190401, Israel; Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram, Jerusalem 9190401, Israel; Program in Child and Brain Development, Canadian Institute for Advanced Research, MaRS Centre, West Tower, 661 University Avenue, Suite 505, Toronto, ON M5G 1M1, Canada. Electronic address:

The claustrum is a small nucleus, exhibiting vast reciprocal connectivity with cortical, subcortical, and midbrain regions. Recent studies, including ours, implicate the claustrum in salience detection and attention. In the current study, we develop an iterative functional investigation of the claustrum, guided by quantitative spatial transcriptional analysis. Using this approach, we identify a circuit involving dopamine-receptor expressing claustral neurons projecting to frontal cortex necessary for context association of reward. We describe the recruitment of claustral neurons by cocaine and their role in drug sensitization. In order to characterize the circuit within which these neurons are embedded, we apply chemo- and opto-genetic manipulation of increasingly specified claustral subpopulations. This strategy resolves the role of a defined network of claustrum neurons expressing dopamine D1 receptors and projecting to frontal cortex in the acquisition of cocaine conditioned-place preference and real-time optogenetic conditioned-place preference. In sum, our results suggest a role for a claustrum-to-frontal cortex circuit in the attribution of incentive salience, allocating attention to reward-related contextual cues.
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http://dx.doi.org/10.1016/j.cub.2020.06.064DOI Listing
September 2020

The Temporal Association Cortex Plays a Key Role in Auditory-Driven Maternal Plasticity.

Neuron 2020 08 29;107(3):566-579.e7. Epub 2020 May 29.

Department of Neurobiology, The Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel. Electronic address:

Mother-infant bonding develops rapidly following parturition and is accompanied by changes in sensory perception and behavior. Here, we study how ultrasonic vocalizations (USVs) are represented in the brain of mothers. Using a mouse line that allows temporally controlled genetic access to active neurons, we find that the temporal association cortex (TeA) in mothers exhibits robust USV responses. Rabies tracing from USV-responsive neurons reveals extensive subcortical and cortical inputs into TeA. A particularly dominant cortical source of inputs is the primary auditory cortex (A1), suggesting strong A1-to-TeA connectivity. Chemogenetic silencing of USV-responsive neurons in TeA impairs auditory-driven maternal preference in a pup-retrieval assay. Furthermore, dense extracellular recordings from awake mice reveal changes of both single-neuron and population responses to USVs in TeA, improving discriminability of pup calls in mothers compared with naive females. These data indicate that TeA plays a key role in encoding and perceiving pup cries during motherhood.
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http://dx.doi.org/10.1016/j.neuron.2020.05.004DOI Listing
August 2020

The Claustrum Supports Resilience to Distraction.

Curr Biol 2018 09 16;28(17):2752-2762.e7. Epub 2018 Aug 16.

Edmond and Lily Safra Center for Brain Sciences, Jerusalem, Israel; Institute of Life Sciences, Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram, Jerusalem 91904, Israel; Program in Child and Brain Development, Canadian Institute for Advanced Research, MaRS Centre, West Tower, 661 University Avenue, Suite 505, Toronto, ON M5G 1M1, Canada. Electronic address:

A barrage of information constantly assaults our senses, of which only a fraction is relevant at any given point in time. However, the neural circuitry supporting the suppression of irrelevant sensory distractors is not completely understood. The claustrum, a circuit hub with vast cortical connectivity, is an intriguing brain structure, whose restrictive anatomy, thin and elongated, has precluded functional investigation. Here, we describe the use of Egr2-CRE mice to access genetically defined claustral neurons. Utilizing conditional viruses for anterograde axonal labeling and retrograde trans-synaptic tracing, we validated this transgenic model for accessing the claustrum and extended the known repertoire of claustral input/output connectivity. Addressing the function of the claustrum, we inactivated CL neurons, chronically as well as acutely, in mice performing an automated two-alternative forced-choice behavioral task. Strikingly, inhibition of CL neurons did not significantly impact task performance under varying delay times and cue durations, but revealed a selective role for the claustrum in supporting performance in the presence of an irrelevant auditory distractor. Further investigation of behavior, in the naturalistic maternal pup-retrieval task, replicated the result of sensitization to an auditory distractor following inhibition of CL neurons. Initiating investigation into the underlying mechanism, we found that activation of CL neurons modulated cortical sensory processing, suppressing tone representation in the auditory cortex. This functional study, utilizing selective genetic access, implicates the claustrum in supporting resilience to distraction, a fundamental aspect of attention.
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http://dx.doi.org/10.1016/j.cub.2018.06.068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485402PMC
September 2018

Astrocytic Activation Generates De Novo Neuronal Potentiation and Memory Enhancement.

Cell 2018 06 24;174(1):59-71.e14. Epub 2018 May 24.

Edmond and Lily Safra Center for Brain Sciences (ELSC), The Hebrew University of Jerusalem, Jerusalem 91904, Israel. Electronic address:

Astrocytes respond to neuronal activity and were shown to be necessary for plasticity and memory. To test whether astrocytic activity is also sufficient to generate synaptic potentiation and enhance memory, we expressed the Gq-coupled receptor hM3Dq in CA1 astrocytes, allowing their activation by a designer drug. We discovered that astrocytic activation is not only necessary for synaptic plasticity, but also sufficient to induce NMDA-dependent de novo long-term potentiation in the hippocampus that persisted after astrocytic activation ceased. In vivo, astrocytic activation enhanced memory allocation; i.e., it increased neuronal activity in a task-specific way only when coupled with learning, but not in home-caged mice. Furthermore, astrocytic activation using either a chemogenetic or an optogenetic tool during acquisition resulted in memory recall enhancement on the following day. Conversely, directly increasing neuronal activity resulted in dramatic memory impairment. Our findings that astrocytes induce plasticity and enhance memory may have important clinical implications for cognitive augmentation treatments.
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http://dx.doi.org/10.1016/j.cell.2018.05.002DOI Listing
June 2018

Mapping synaptic cortico-claustral connectivity in the mouse.

J Comp Neurol 2017 Apr 28;525(6):1381-1402. Epub 2016 Mar 28.

Edmond and Lily Safra Center for Brain Sciences, Jerusalem, Israel.

The claustrum is an intriguing brain structure, featuring the highest connectivity per regional volume in the brain. It is a thin and elongated structure enclosed between the striatum and the insular cortex, with widespread reciprocal connections with the sensory modalities and prefrontal cortices. Retinotopic and somatotopic organizations have been described in the claustrum, and anatomical studies in cats, monkeys, and rats have demonstrated topographic organization of cortico-claustral connections. In this study we mapped the projections from cortical modalities (visual, auditory, somatosensory, motor, and olfactory), and prefrontal regions (anterior cingulate cortex and orbitofrontal cortex) to the claustrum in mice. Utilizing expression of a virally encoded synaptic anterograde tracer, AAV-SynaptoTag, followed by 3D reconstruction of the cortical projections, we performed a comprehensive study of the organization of these projections within the mouse claustrum. Our results clearly demonstrate a dorsoventral laminar organization of projections from the sensory cortices to the claustrum, whereas frontal inputs are more extensive and overlap with the inputs from the sensory cortices. In addition, we find evidence supporting a core/shell organization of the claustrum. We propose that the overlap between the frontal inputs and the inputs from the sensory modalities may underlie executive regulation of the communication between the claustrum and the cortical modalities. J. Comp. Neurol. 525:1381-1402, 2017. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/cne.23997DOI Listing
April 2017

Functional transformations of odor inputs in the mouse olfactory bulb.

Front Neural Circuits 2014 4;8:129. Epub 2014 Nov 4.

Department of Neurobiology, Institute of Life Sciences, The Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem Jerusalem, Israel.

Sensory inputs from the nasal epithelium to the olfactory bulb (OB) are organized as a discrete map in the glomerular layer (GL). This map is then modulated by distinct types of local neurons and transmitted to higher brain areas via mitral and tufted cells. Little is known about the functional organization of the circuits downstream of glomeruli. We used in vivo two-photon calcium imaging for large scale functional mapping of distinct neuronal populations in the mouse OB, at single cell resolution. Specifically, we imaged odor responses of mitral cells (MCs), tufted cells (TCs) and glomerular interneurons (GL-INs). Mitral cells population activity was heterogeneous and only mildly correlated with the olfactory receptor neuron (ORN) inputs, supporting the view that discrete input maps undergo significant transformations at the output level of the OB. In contrast, population activity profiles of TCs were dense, and highly correlated with the odor inputs in both space and time. Glomerular interneurons were also highly correlated with the ORN inputs, but showed higher activation thresholds suggesting that these neurons are driven by strongly activated glomeruli. Temporally, upon persistent odor exposure, TCs quickly adapted. In contrast, both MCs and GL-INs showed diverse temporal response patterns, suggesting that GL-INs could contribute to the transformations MCs undergo at slow time scales. Our data suggest that sensory odor maps are transformed by TCs and MCs in different ways forming two distinct and parallel information streams.
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http://dx.doi.org/10.3389/fncir.2014.00129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4219419PMC
July 2015

Enhanced synaptic integration of adult-born neurons in the olfactory bulb of lactating mothers.

J Neurosci 2012 May;32(22):7519-27

Department of Neurobiology, Institute of Life Sciences, Israel.

One of the most dramatic events during the life of adult mammals is the transition into motherhood. This transition is accompanied by specific maternal behaviors, displayed by the mother, that ensure the survival and the well-being of her offspring. The execution of these behaviors is most likely accompanied by plastic changes in specific neuronal circuits, but these are still poorly defined. In this work, we studied the mammalian olfactory bulb (OB), which has been shown to be an essential brain region for maternal behaviors in mice. In the OB, we focused on adult-born neurons, which are continuously incorporated into the circuit during adulthood, thus providing a potential substrate for heightened plasticity after parturition. We analyzed the dynamics and morphological characteristics of adult-born granule cells (abGCs), innervating the OB of primiparous lactating mothers, shortly after parturition as well as in naive females. In vivo time-lapse imaging of abGCs revealed that dendritic spines were significantly more stable in lactating mothers compared with naive virgins. In contrast, spine stability of resident GCs remained unchanged after parturition. In addition, while spine size distribution of abGCs was approximately similar between mothers and naive virgins, the spine density of abGCs was lower in lactating mothers and the density of their presynaptic components was higher. These structural features are indicative of enhanced integration of adult-born neurons into the bulbar circuitry of lactating mothers. This enhanced integration may serve as a cellular mechanism, supporting changes in olfactory coding of new mothers during their first days following parturition.
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http://dx.doi.org/10.1523/JNEUROSCI.6354-11.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6703584PMC
May 2012

A negative modulatory role for rho and rho-associated kinase signaling in delamination of neural crest cells.

Neural Dev 2008 Oct 22;3:27. Epub 2008 Oct 22.

Department of Anatomy and Cell Biology, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.

Background: Neural crest progenitors arise as epithelial cells and then undergo a process of epithelial to mesenchymal transition that precedes the generation of cellular motility and subsequent migration. We aim at understanding the underlying molecular network. Along this line, possible roles of Rho GTPases that act as molecular switches to control a variety of signal transduction pathways remain virtually unexplored, as are putative interactions between Rho proteins and additional known components of this cascade.

Results: We investigated the role of Rho/Rock signaling in neural crest delamination. Active RhoA and RhoB are expressed in the membrane of epithelial progenitors and are downregulated upon delamination. In vivo loss-of-function of RhoA or RhoB or of overall Rho signaling by C3 transferase enhanced and/or triggered premature crest delamination yet had no effect on cell specification. Consistently, treatment of explanted neural primordia with membrane-permeable C3 or with the Rock inhibitor Y27632 both accelerated and enhanced crest emigration without affecting cell proliferation. These treatments altered neural crest morphology by reducing stress fibers, focal adhesions and downregulating membrane-bound N-cadherin. Reciprocally, activation of endogenous Rho by lysophosphatidic acid inhibited emigration while enhancing the above. Since delamination is triggered by BMP and requires G1/S transition, we examined their relationship with Rho. Blocking Rho/Rock function rescued crest emigration upon treatment with noggin or with the G1/S inhibitor mimosine. In the latter condition, cells emigrated while arrested at G1. Conversely, BMP4 was unable to rescue cell emigration when endogenous Rho activity was enhanced by lysophosphatidic acid.

Conclusion: Rho-GTPases, through Rock, act downstream of BMP and of G1/S transition to negatively regulate crest delamination by modifying cytoskeleton assembly and intercellular adhesion.
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http://dx.doi.org/10.1186/1749-8104-3-27DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2577655PMC
October 2008

The haematopoietic specific signal transducer Vav1 is expressed in a subset of human neuroblastomas.

J Pathol 2003 Apr;199(4):526-33

Hubert H Humphrey Centre for Experimental Medicine and Cancer Research, Hebrew University-Hadassah Medical School, Jerusalem, Israel.

Vav1 is a signal transducer protein expressed exclusively in the haematopoietic system, where it plays a pivotal role in growth factor-induced differentiation and proliferation. Vav1 couples tyrosine kinase signals with the activation of the Rho/Rac GTPases, leading to cell differentiation and/or proliferation. Vav1 was originally detected as an oncogene, but its involvement in human malignancies has not been reported thus far. We report here that Vav1 is expressed in a neuroblastoma cell line, SK-N-MC. Molecular analysis indicated that there are no gross rearrangements or mutations in the Vav1 gene in SK-N-MC cells. Vav1 protein from SK-N-MC cells was similar to wild-type Vav1 in apparent molecular weight, phosphorylation state, and ability to associate with active EGFR. We also analysed the expression of Vav1 in 42 specimens of human neuroblastoma. Vav1 was expressed in the majority of these tumours. Our results suggest that Vav1 may play a role in the neoplastic process in a subset of neuroblastomas.
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http://dx.doi.org/10.1002/path.1314DOI Listing
April 2003

Vav1 and Ly-GDI two regulators of Rho GTPases, function cooperatively as signal transducers in T cell antigen receptor-induced pathways.

J Biol Chem 2002 Dec 16;277(51):50121-30. Epub 2002 Oct 16.

Hubert H. Humphrey Center for Experimental Medicine and Cancer Research, Hebrew University-Hadassah Medical School, Jerusalem, Israel.

The Rho family GTPases are pivotal for T cell signaling; however, the regulation of these proteins is not fully known. One well studied regulator of Rho GTPases is Vav1; a hematopoietic cell-specific guanine nucleotide exchange factor critical for signaling in T cells, including stimulation of the nuclear factor of activated T cells (NFAT). Surprisingly, Vav1 associates with Ly-GDI, a hematopoietic cell-specific guanine nucleotide dissociation inhibitor of Rac. Here, we studied the functional significance of the interaction between Vav1 and Ly-GDI in T cells. Upon organization of the immunological synapse, both Ly-GDI and Vav1 relocalize to T cell extensions in contact with the antigen-presenting cell. Ly-GDI is phosphorylated on tyrosine residues following T cell receptor stimulation, and it associates with the Src homology 2 region of an adapter protein, Shc. In addition, the interaction between Ly-GDI and Vav1 requires tyrosine phosphorylation. Overexpression of Ly-GDI alone is inhibitory to NFAT stimulation and calcium mobilization. However, when co-expressed with Vav1, Ly-GDI enhances Vav1 induction of NFAT activation, phospholipase Cgamma phosphorylation, and calcium mobilization. Moreover, Ly-GDI does not alter the regulation of these phenomena when coexpressed with oncogenic Vav1. Since oncogenic Vav1 does not bind Ly-GDI, this suggests that the functional cooperativity of Ly-GDI and Vav1 is dependent upon their association. Thus, our data suggest that the interaction of Vav1 and Ly-GDI creates a fine tuning mechanism for the regulation of intracellular signaling pathways leading to NFAT stimulation.
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http://dx.doi.org/10.1074/jbc.M204299200DOI Listing
December 2002

Signalling pathways induced by protease-activated receptors and integrins in T cells.

Immunology 2002 Jan;105(1):35-46

Department of Oncology, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.

Recent characterization of the thrombin receptor indicates that it plays a role in T-cell signalling pathways. However, little is known regarding the signalling events following stimulation of additional members of the protease-activated receptor (PAR) family, i.e. PAR2 and PAR3. Most of the postligand cascades are largely unknown. Here, we illustrate that in Jurkat T-leukaemic cells, activation of PAR1, PAR2 and PAR3 induce tyrosine phosphorylation of Vav1. This response was impaired in Jurkat T cells deficient in p56lck (JCaM1.6). Activation of PARs also led to an increase in tyrosine phosphorylation of ZAP-70 and SLP-76, two key proteins in T-cell receptor (TCR) signalling. We also demonstrated that p56lck is meaningful for integrin signalling. Thus, JCaM1.6 cells exhibited a marked reduction in their adherence to fibronectin-coated plates, as compared to the level of adherence of Jurkat T cells. While the phosphorylation of Vav1 in T cells is augmented following adhesion, no additional increase was noted following treatment of the adhered cells with PARs. Altogether, we have identified key components in the postligand-signalling cascade of PARs and integrins. Furthermore, we have identified Lck as a critical and possibly upstream component of PAR-induced Vav1 phosphorylation, as well as integrin activation, in Jurkat T cells.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1782632PMC
http://dx.doi.org/10.1046/j.0019-2805.2001.01351.xDOI Listing
January 2002
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