Publications by authors named "Pico Caroni"

61 Publications

Long-Lasting Rescue of Network and Cognitive Dysfunction in a Genetic Schizophrenia Model.

Cell 2019 09 29;178(6):1387-1402.e14. Epub 2019 Aug 29.

Friedrich Miescher Institute, 4058 Basel, Switzerland. Electronic address:

Although sensitizing processes occur earlier, schizophrenia is diagnosed in young adulthood, which suggests that it might involve a pathological transition during late brain development in predisposed individuals. Parvalbumin (PV) interneuron alterations have been noticed, but their role in the disease is unclear. Here we demonstrate that adult LgDel mice, a genetic model of schizophrenia, exhibit PV neuron hypo-recruitment and associated chronic PV neuron plasticity together with network and cognitive deficits. All these deficits can be permanently rescued by chemogenetic activation of PV neurons or D2R antagonist treatments, specifically in the ventral hippocampus (vH) or medial-prefrontal cortex during a late-adolescence-sensitive time window. PV neuron alterations were initially restricted to the hippocampal CA1/subiculum, where they became responsive to treatment in late adolescence. Therefore, progression to disease in schizophrenia-model mice can be prevented by treatments supporting vH-mPFC PV network function during a sensitive time window late in adolescence, suggesting therapeutic strategies to prevent the outbreak of schizophrenia.
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http://dx.doi.org/10.1016/j.cell.2019.07.023DOI Listing
September 2019

[Formula: see text] Long-term verbal memory deficit and associated hippocampal alterations in 22q11.2 deletion syndrome.

Child Neuropsychol 2020 04 28;26(3):289-311. Epub 2019 Aug 28.

Developmental Imaging and Psychopathology Lab, Department of Psychiatry, University of Geneva School of Medicine, Geneva, Switzerland.

Chromosome 22q11.2 deletion syndrome (22q11.2DS) is a genetic disease associated with an increased risk for schizophrenia and a specific cognitive profile. In this paper, we challenge the current view of spared verbal memory in 22q11.2DS by investigating verbal memory consolidation processes over an extended time span to further qualify the neuropsychological profile. Our hypotheses are based on brain anomalies of the medial temporal lobes consistently reported in this syndrome.Eighty-four participants (45 with 22q11.2DS), aged 8-24 years old, completed a verbal episodic memory task to investigate long-term memory on four different time delays. We compared trajectories of forgetting between groups (22q11.2DS vs. controls) and analyzed performance inside the 22q11.2DS sample through cluster analyses. Potential links between memory performance and volume of the hippocampal subfields were examined.We showed accelerated long-term forgetting (ALF) in the 22q11.2DS group, visible after a delay of one day. Using mixed models, we showed significant differences in the shape of memory trajectories between subgroups of participants with 22q11.2DS. These sub-groups differed in terms of memory recognition, intellectual functioning, positive psychotic symptoms and grey matter volume of hippocampal subfields but not in terms of age.In conclusion, by investigating memory processes on longer delays than standardized memory tasks, we identified deficits in long-term memory consolidation leading to ALF in 22q11.2DS. Nevertheless, we showed that a subgroup of patients had larger memory consolidation deficit associated with lower intellectual functioning, higher rates of positive psychotic symptoms and hippocampal alterations.
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http://dx.doi.org/10.1080/09297049.2019.1657392DOI Listing
April 2020

Author Correction: Infralimbic cortex is required for learning alternatives to prelimbic promoted associations through reciprocal connectivity.

Nat Commun 2019 Jul 12;10(1):3082. Epub 2019 Jul 12.

Friedrich Miescher Institut, Basel, CH-4058, Switzerland.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41467-019-11205-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6626027PMC
July 2019

Author Correction: Time units for learning involving maintenance of system-wide cFos expression in neuronal assemblies.

Nat Commun 2019 Jul 12;10(1):3083. Epub 2019 Jul 12.

Friedrich Miescher Institut, Maulbeerstrasse 66, CH-4058, Basel, Switzerland.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41467-019-11208-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6626039PMC
July 2019

Parvalbumin Interneuron Plasticity for Consolidation of Reinforced Learning.

Cold Spring Harb Symp Quant Biol 2018 9;83:25-35. Epub 2019 Jul 9.

Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland.

Parvalbumin (PV) basket cells are widespread local interneurons that inhibit principal neurons and each other through perisomatic boutons. They enhance network function and regulate local ensemble activities, particularly in the γ range. Organized network activity is critically important for long-term memory consolidation during a late time window 11-15 h after acquisition. Here, we discuss the role of learning-related plasticity in PV neurons for long-term memory consolidation. The plasticity can lead to enhanced (high-PV) or reduced (low-PV) expression of PV/GAD67. High-PV plasticity is induced upon definite reinforced learning in early-born PV basket cells, whereas low-PV plasticity is induced upon provisional reinforced learning in late-born PV basket cells. The plasticity is first detectable 6 h after acquisition, at the end of a time window for memory specification through experience, and is critically important 11-15 h after acquisition for enhanced network activity and long-term memory consolidation. High- and low-PV plasticity appear to regulate activity in distinct local networks of principal neurons and PV basket cells. These findings suggest how flexibility and stability in learning and memory might be implemented through parallel circuits and networks.
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http://dx.doi.org/10.1101/sqb.2018.83.037630DOI Listing
July 2019

Managing Neuronal Ensembles: Somatostatin Interneuron Subpopulations Shape and Protect Cortical Neuronal Ensembles for Learning.

Neuron 2019 04;102(1):6-8

Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland. Electronic address:

Learning is accompanied by temporal compression and sharpening of neuronal firing sequences. In this issue of Neuron, Adler et al. (2019), using a motor skill paradigm and its variant, uncover a dual role for somatostatin interneuron regulation to support ensemble compaction and protection in learning.
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http://dx.doi.org/10.1016/j.neuron.2019.03.016DOI Listing
April 2019

mA-epitranscriptome modulates memory strength.

Cell Res 2019 01;29(1):4-5

Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.

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http://dx.doi.org/10.1038/s41422-018-0121-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6318321PMC
January 2019

Time units for learning involving maintenance of system-wide cFos expression in neuronal assemblies.

Nat Commun 2018 10 8;9(1):4122. Epub 2018 Oct 8.

Friedrich Miescher Institut, Maulbeerstrasse 66, CH-4058, Basel, Switzerland.

Repeated experiences may be integrated in succession during a learning process, or they may be combined as a whole within dedicated time windows to possibly promote quality control. Here we show that in Pavlovian, incremental and incidental learning, related information acquired within time windows of 5 h is combined to determine what mice learn. Trials required for learning had to occur within 5 h, when learning-related shared cues could produce association and interference. Upon acquisition, cFos expression was elevated during 5 h throughout specific system-wide neuronal assemblies. Time window function depended on network activity and cFos expression. Local cFos activity was required for distant assembly recruitment through network activity and distant BDNF. Activation of learning-related cFos assemblies was sufficient and necessary for time window function. Therefore, learning processes consist of dedicated 5 h time windows (time units for learning), involving maintenance of system-wide neuronal assemblies through network activity and cFos expression.
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http://dx.doi.org/10.1038/s41467-018-06516-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175937PMC
October 2018

Author Correction: PV plasticity sustained through D1/5 dopamine signaling required for long-term memory consolidation.

Nat Neurosci 2018 Sep;21(9):1290

Friedrich Miescher Institut, Basel, Switzerland.

In the version of this article initially published, the right panel in Fig. 2b was duplicated from the corresponding panel in Fig. 2c, and some data points in Fig. 3b were duplicated from Fig. 3a. None of the conclusions in the paper are affected. The errors have been corrected in the HTML and PDF versions of the article, and source data have been posted for the revised panels. The original and corrected figures are shown in the accompanying Author Correction.
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http://dx.doi.org/10.1038/s41593-018-0179-0DOI Listing
September 2018

Infralimbic cortex is required for learning alternatives to prelimbic promoted associations through reciprocal connectivity.

Nat Commun 2018 07 13;9(1):2727. Epub 2018 Jul 13.

Friedrich Miescher Institut, Basel, CH-4058, Switzerland.

Prefrontal cortical areas mediate flexible adaptive control of behavior, but the specific contributions of individual areas and the circuit mechanisms through which they interact to modulate learning have remained poorly understood. Using viral tracing and pharmacogenetic techniques, we show that prelimbic (PreL) and infralimbic cortex (IL) exhibit reciprocal PreL↔IL layer 5/6 connectivity. In set-shifting tasks and in fear/extinction learning, activity in PreL is required during new learning to apply previously learned associations, whereas activity in IL is required to learn associations alternative to previous ones. IL→PreL connectivity is specifically required during IL-dependent learning, whereas reciprocal PreL↔IL connectivity is required during a time window of 12-14 h after association learning, to set up the role of IL in subsequent learning. Our results define specific and opposing roles of PreL and IL to together flexibly support new learning, and provide circuit evidence that IL-mediated learning of alternative associations depends on direct reciprocal PreL↔IL connectivity.
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http://dx.doi.org/10.1038/s41467-018-05318-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6045592PMC
July 2018

Functional and structural underpinnings of neuronal assembly formation in learning.

Nat Neurosci 2016 12 17;19(12):1553-1562. Epub 2016 Oct 17.

Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.

Learning and memory are associated with the formation and modification of neuronal assemblies: populations of neurons that encode what has been learned and mediate memory retrieval upon recall. Functional studies of neuronal assemblies have progressed dramatically thanks to recent technological advances. Here we discuss how a focus on assembly formation and consolidation has provided a powerful conceptual framework to relate mechanistic studies of synaptic and circuit plasticity to behaviorally relevant aspects of learning and memory. Neurons are likely recruited to particular learning-related assemblies as a function of their relative excitabilities and synaptic activation, followed by selective strengthening of pre-existing synapses, formation of new connections and elimination of outcompeted synapses to ensure memory formation. Mechanistically, these processes involve linking transcription to circuit modification. They include the expression of immediate early genes and specific molecular and cellular events, supported by network-wide activities that are shaped and modulated by local inhibitory microcircuits.
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http://dx.doi.org/10.1038/nn.4418DOI Listing
December 2016

CLK2 inhibition ameliorates autistic features associated with SHANK3 deficiency.

Science 2016 Mar 4;351(6278):1199-203. Epub 2016 Feb 4.

Developmental Molecular Pathways, Novartis Institutes for Biomedical Research, Basel, Switzerland.

SH3 and multiple ankyrin repeat domains 3 (SHANK3) haploinsufficiency is causative for the neurological features of Phelan-McDermid syndrome (PMDS), including a high risk of autism spectrum disorder (ASD). We used unbiased, quantitative proteomics to identify changes in the phosphoproteome of Shank3-deficient neurons. Down-regulation of protein kinase B (PKB/Akt)-mammalian target of rapamycin complex 1 (mTORC1) signaling resulted from enhanced phosphorylation and activation of serine/threonine protein phosphatase 2A (PP2A) regulatory subunit, B56β, due to increased steady-state levels of its kinase, Cdc2-like kinase 2 (CLK2). Pharmacological and genetic activation of Akt or inhibition of CLK2 relieved synaptic deficits in Shank3-deficient and PMDS patient-derived neurons. CLK2 inhibition also restored normal sociability in a Shank3-deficient mouse model. Our study thereby provides a novel mechanistic and potentially therapeutic understanding of deregulated signaling downstream of Shank3 deficiency.
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http://dx.doi.org/10.1126/science.aad5487DOI Listing
March 2016

PV plasticity sustained through D1/5 dopamine signaling required for long-term memory consolidation.

Nat Neurosci 2016 Mar 25;19(3):454-64. Epub 2016 Jan 25.

Friedrich Miescher Institut, Basel, Switzerland.

Long-term consolidation of memories depends on processes occurring many hours after acquisition. Whether this involves plasticity that is specifically required for long-term consolidation remains unclear. We found that learning-induced plasticity of local parvalbumin (PV) basket cells was specifically required for long-term, but not short/intermediate-term, memory consolidation in mice. PV plasticity, which involves changes in PV and GAD67 expression and connectivity onto PV neurons, was regulated by cAMP signaling in PV neurons. Following induction, PV plasticity depended on local D1/5 dopamine receptor signaling at 0-5 h to regulate its magnitude, and at 12-14 h for its continuance, ensuring memory consolidation. D1/5 dopamine receptor activation selectively induced DARPP-32 and ERK phosphorylation in PV neurons. At 12-14 h, PV plasticity was required for enhanced sharp-wave ripple densities and c-Fos expression in pyramidal neurons. Our results reveal general network mechanisms of long-term memory consolidation that requires plasticity of PV basket cells induced after acquisition and sustained subsequently through D1/5 receptor signaling.
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http://dx.doi.org/10.1038/nn.4231DOI Listing
March 2016

Inhibitory microcircuit modules in hippocampal learning.

Authors:
Pico Caroni

Curr Opin Neurobiol 2015 Dec 10;35:66-73. Epub 2015 Jul 10.

Friedrich Miescher Institut, Maulbeerstrasse 66, CH-4058 Basel, Switzerland. Electronic address:

It has recently become possible to investigate connectivities and roles of identified hippocampal GABAergic interneurons (INs) in behaving rodents. INs targeting distinct pyramidal neuron subcompartments are recruited dynamically at defined phases of behavior and learning. They include Parvalbumin Axo-axonic and perisomatic Basket cells, and Somatostatin radiatum-oriens and oriens-lacunosum moleculare cells. Each IN is in turn either activated or inhibited upon specific behavioral and network state requirements through specific inputs and neuromodulators. Subpopulations of these principal neurons and INs interconnect selectively, suggesting selective processing and routing of alternate information streams. First canonical functional modules have emerged, which will have to be further defined and linked to identified afferents and efferents towards a circuit understanding of how hippocampal networks support behavior.
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http://dx.doi.org/10.1016/j.conb.2015.06.010DOI Listing
December 2015

Regulation of Parvalbumin Basket cell plasticity in rule learning.

Authors:
Pico Caroni

Biochem Biophys Res Commun 2015 Apr;460(1):100-3

Friedrich Miescher Institut, Maulbeerstrasse 66, CH-4058 Basel, Switzerland. Electronic address:

Local inhibitory Parvalbumin (PV)-expressing Basket cell networks shift to one of two possible opposite configurations depending on whether behavioral learning involves acquisition of new information or consolidation of validated rules. This reflects the existence of PV Basket cell subpopulations with distinct schedules of neurogenesis, output target neurons and roles in learning. Plasticity of hippocampal early-born PV neurons is recruited in rule consolidation, whereas plasticity of late-born PV neurons is recruited in new information acquisition. This involves regulation of early-born PV neuron plasticity specifically through excitation, and of late-born PV neuron plasticity specifically through inhibition. Therefore, opposite learning requirements are implemented by distinct local networks involving PV Basket cell subpopulations specifically regulated through inhibition or excitation.
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http://dx.doi.org/10.1016/j.bbrc.2015.02.023DOI Listing
April 2015

From intrinsic firing properties to selective neuronal vulnerability in neurodegenerative diseases.

Neuron 2015 Mar;85(5):901-10

Friedrich Miescher Institut for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland. Electronic address:

Neurodegenerative diseases (NDDs) involve years of gradual preclinical progression. It is widely anticipated that in order to be effective, treatments should target early stages of disease, but we lack conceptual frameworks to identify and treat early manifestations relevant to disease progression. Here we discuss evidence that a focus on physiological features of neuronal subpopulations most vulnerable to NDDs, and how those features are affected in disease, points to signaling pathways controlling excitation in selectively vulnerable neurons, and to mechanisms regulating calcium and energy homeostasis. These hypotheses could be tested in neuronal stress tests involving animal models or patient-derived iPS cells.
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http://dx.doi.org/10.1016/j.neuron.2014.12.063DOI Listing
March 2015

Early- and late-born parvalbumin basket cell subpopulations exhibiting distinct regulation and roles in learning.

Neuron 2015 Feb;85(4):770-86

Friedrich Miescher Institut, Maulbeerstrasse 66, 4058 Basel, Switzerland. Electronic address:

Brain networks can support learning by promoting acquisition of task-relevant information or by adhering to validated rules, but the mechanisms involved are poorly understood. Upon learning, local inhibitory parvalbumin (PV)-expressing Basket cell networks can switch to opposite configurations that either favor or interfere with further learning, but how this opposite plasticity is induced and relates to distinct learning requirements has remained unclear. Here, we show that PV Basket cells consist of hitherto unrecognized subpopulations, with distinct schedules of neurogenesis, input connectivities, output target neurons, and roles in learning. Plasticity of hippocampal early-born PV neurons was recruited in rule consolidation, whereas plasticity of late-born PV neurons was recruited in new information acquisition. This involved regulation of early-born neuron plasticity specifically through excitation, and of late-born neuron plasticity specifically through inhibition. Therefore, opposite learning requirements are implemented by distinct local networks involving PV Basket cell subpopulations specifically regulated through inhibition or excitation.
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http://dx.doi.org/10.1016/j.neuron.2015.01.011DOI Listing
February 2015

Synapse rearrangements upon learning: from divergent-sparse connectivity to dedicated sub-circuits.

Trends Neurosci 2014 Oct 22;37(10):604-14. Epub 2014 Sep 22.

Friedrich Miescher Institut, Basel, Switzerland.

Learning can involve formation of new synapses and loss of synapses, providing memory traces of learned skills. Recent findings suggest that these synapse rearrangements reflect assembly of task-related sub-circuits from initially broadly distributed and sparse connectivity in the brain. These local circuit remodeling processes involve rapid emergence of synapses upon learning, followed by protracted validation involving strengthening of some new synapses, and selective elimination of others. The timing of these consolidation processes can vary. Here, we review these findings, focusing on how molecular/cellular mechanisms of synapse assembly, strengthening, and elimination might interface with circuit/system mechanisms of learning and memory consolidation. An integrated understanding of these learning-related processes should provide a better basis to elucidate how experience, genetic background, and disease influence brain function.
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http://dx.doi.org/10.1016/j.tins.2014.08.011DOI Listing
October 2014

Modeling neuronal vulnerability in ALS.

Neuron 2014 Aug;83(4):758-60

Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland. Electronic address:

Using computational models of motor neuron ion fluxes, firing properties, and energy requirements, Le Masson et al. (2014) reveal how local imbalances in energy homeostasis may self-amplify and contribute to neurodegeneration in ALS.
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http://dx.doi.org/10.1016/j.neuron.2014.08.010DOI Listing
August 2014

Parvalbumin-expressing basket-cell network plasticity induced by experience regulates adult learning.

Nature 2013 Dec;504(7479):272-6

Friedrich Miescher Institut, Maulbeerstrasse 66, CH-4058 Basel, Switzerland.

Learning and memory processes can be influenced by recent experience, but the mechanisms involved are poorly understood. Enhanced plasticity during critical periods of early life is linked to differentiating parvalbumin (PV)-interneuron networks, suggesting that recent experience may modulate learning by targeting the differentiation state of PV neurons in the adult. Here we show that environmental enrichment and Pavlovian contextual fear conditioning induce opposite, sustained and reversible hippocampal PV-network configurations in adult mice. Specifically, enrichment promotes the emergence of large fractions of low-differentiation (low PV and GAD67 expression) basket cells with low excitatory-to-inhibitory synaptic-density ratios, whereas fear conditioning leads to large fractions of high-differentiation (high PV and GAD67 expression) basket cells with high excitatory-to-inhibitory synaptic-density ratios. Pharmacogenetic inhibition or activation of PV neurons was sufficient to induce such opposite low-PV-network or high-PV-network configurations, respectively. The low-PV-network configuration enhanced structural synaptic plasticity, and memory consolidation and retrieval, whereas these were reduced by the high-PV-network configuration. We then show that maze navigation learning induces a hippocampal low-PV-network configuration paralleled by enhanced memory and structural synaptic plasticity throughout training, followed by a shift to a high-PV-network configuration after learning completion. The shift to a low-PV-network configuration specifically involved increased vasoactive intestinal polypeptide (VIP)-positive GABAergic boutons and synaptic transmission onto PV neurons. Closely comparable low- and high-PV-network configurations involving VIP boutons were specifically induced in primary motor cortex upon rotarod motor learning. These results uncover a network plasticity mechanism induced after learning through VIP-PV microcircuit modulation, and involving large, sustained and reversible shifts in the configuration of PV basket-cell networks in the adult. This novel form of experience-related plasticity in the adult modulates memory consolidation, retrieval and learning, and might be harnessed for therapeutic strategies to promote cognitive enhancement and neuroprotection.
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http://dx.doi.org/10.1038/nature12866DOI Listing
December 2013

Neuroprotection through excitability and mTOR required in ALS motoneurons to delay disease and extend survival.

Neuron 2013 Oct 2;80(1):80-96. Epub 2013 Oct 2.

Friedrich Miescher Institut, Maulbeerstrasse 66, CH-4058 Basel, Switzerland; Institute of Cell Biology, University of Bern, Balzerstrasse 4, CH-3012 Bern, Switzerland.

Delaying clinical disease onset would greatly reduce neurodegenerative disease burden, but the mechanisms influencing early preclinical progression are poorly understood. Here, we show that in mouse models of familial motoneuron (MN) disease, SOD1 mutants specifically render vulnerable MNs dependent on endogenous neuroprotection signaling involving excitability and mammalian target of rapamycin (mTOR). The most vulnerable low-excitability FF MNs already exhibited evidence of pathology and endogenous neuroprotection recruitment early postnatally. Enhancing MN excitability promoted MN neuroprotection and reversed misfolded SOD1 (misfSOD1) accumulation and MN pathology, whereas reducing MN excitability augmented misfSOD1 accumulation and accelerated disease. Inhibiting metabotropic cholinergic signaling onto MNs reduced ER stress, but enhanced misfSOD1 accumulation and prevented mTOR activation in alpha-MNs. Modulating excitability and/or alpha-MN mTOR activity had comparable effects on the progression rates of motor dysfunction, denervation, and death. Therefore, excitability and mTOR are key endogenous neuroprotection mechanisms in motoneurons to counteract clinically important disease progression in ALS.
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http://dx.doi.org/10.1016/j.neuron.2013.07.027DOI Listing
October 2013

A circuit mechanism for neurodegeneration.

Cell 2012 Oct;151(2):250-2

Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland.

How deficiency in SMN1 selectively affects motoneurons in spinal muscular atrophy is poorly understood. Here, Imlach et al. and Lotti et al. show that aberrant splicing of Stasimon in cholinergic sensory neurons and interneurons leads to motoneuron degeneration, suggesting that altered circuit function may underlie the disorder.
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http://dx.doi.org/10.1016/j.cell.2012.09.030DOI Listing
October 2012

Goal-oriented searching mediated by ventral hippocampus early in trial-and-error learning.

Nat Neurosci 2012 Nov 23;15(11):1563-71. Epub 2012 Sep 23.

Friedrich Miescher Institute, Basel, Switzerland.

Most behavioral learning in biology is trial and error, but how these learning processes are influenced by individual brain systems is poorly understood. Here we show that ventral-to-dorsal hippocampal subdivisions have specific and sequential functions in trial-and-error maze navigation, with ventral hippocampus (vH) mediating early task-specific goal-oriented searching. Although performance and strategy deployment progressed continuously at the population level, individual mice showed discrete learning phases, each characterized by particular search habits. Transitions in learning phases reflected feedforward inhibitory connectivity (FFI) growth occurring sequentially in ventral, then intermediate, then dorsal hippocampal subdivisions. FFI growth at vH occurred abruptly upon behavioral learning of goal-task relationships. vH lesions or the absence of vH FFI growth delayed early learning and disrupted performance consistency. Intermediate hippocampus lesions impaired intermediate place learning, whereas dorsal hippocampus lesions specifically disrupted late spatial learning. Trial-and-error navigational learning processes in naive mice thus involve a stereotype sequence of increasingly precise subtasks learned through distinct hippocampal subdivisions. Because of its unique connectivity, vH may relate specific goals to internal states in learning under healthy and pathological conditions.
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http://dx.doi.org/10.1038/nn.3224DOI Listing
November 2012

Structural plasticity upon learning: regulation and functions.

Nat Rev Neurosci 2012 Jun 20;13(7):478-90. Epub 2012 Jun 20.

Friedrich Miescher Institut, 4058 Basel, Switzerland.

Recent studies have provided long-sought evidence that behavioural learning involves specific synapse gain and elimination processes, which lead to memory traces that influence behaviour. The connectivity rearrangements are preceded by enhanced synapse turnover, which can be modulated through changes in inhibitory connectivity. Behaviourally related synapse rearrangement events tend to co-occur spatially within short stretches of dendrites, and involve signalling pathways partially overlapping with those controlling the functional plasticity of synapses. The new findings suggest that a mechanistic understanding of learning and memory processes will require monitoring ensembles of synapses in situ and the development of synaptic network models that combine changes in synaptic function and connectivity.
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http://dx.doi.org/10.1038/nrn3258DOI Listing
June 2012

Life-or-death decisions upon axonal damage.

Neuron 2012 Feb;73(3):405-7

Friedrich Miescher Institute, Maulbeerstrasse 66, Basel, Switzerland.

In this issue of Neuron, Hu et al. (2012) report that upon axonal damage, CHOP and XBP1 unfolded protein response pathways are not recruited equally and have opposite effects on neuronal survival. XBP1 pathway boosting may represent a valuable neuroprotective strategy.
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http://dx.doi.org/10.1016/j.neuron.2012.01.009DOI Listing
February 2012

Selective neuronal vulnerability in neurodegenerative diseases: from stressor thresholds to degeneration.

Neuron 2011 Jul;71(1):35-48

Friedrich Miescher Institut, Novartis Research Foundation, CH-4058 Basel, Switzerland.

Neurodegenerative diseases selectively target subpopulations of neurons, leading to the progressive failure of defined brain systems, but the basis of such selective neuronal vulnerability has remained elusive. Here, we discuss how a stressor-threshold model of how particular neurons and circuits are selectively vulnerable to disease may underly the etiology of familial and sporadic forms of diseases such as Alzheimer's, Parkinson's, Huntington's, and ALS. According to this model, the intrinsic vulnerabilities of neuronal subpopulations to stressors and specific disease-related misfolding proteins determine neuronal morbidity. Neurodegenerative diseases then involve specific combinations of genetic predispositions and environmental stressors, triggering increasing age-related stress and proteostasis dysfunction in affected vulnerable neurons. Damage to vasculature, immune system, and local glial cells mediates environmental stress, which could drive disease at all stages.
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http://dx.doi.org/10.1016/j.neuron.2011.06.031DOI Listing
July 2011

Learning-related feedforward inhibitory connectivity growth required for memory precision.

Nature 2011 May 1;473(7348):514-8. Epub 2011 May 1.

Friedrich Miescher Institute, Maulbeerstrasse 66, CH-4058 Basel, Switzerland.

In the adult brain, new synapses are formed and pre-existing ones are lost, but the function of this structural plasticity has remained unclear. Learning of new skills is correlated with formation of new synapses. These may directly encode new memories, but they may also have more general roles in memory encoding and retrieval processes. Here we investigated how mossy fibre terminal complexes at the entry of hippocampal and cerebellar circuits rearrange upon learning in mice, and what is the functional role of the rearrangements. We show that one-trial and incremental learning lead to robust, circuit-specific, long-lasting and reversible increases in the numbers of filopodial synapses onto fast-spiking interneurons that trigger feedforward inhibition. The increase in feedforward inhibition connectivity involved a majority of the presynaptic terminals, restricted the numbers of c-Fos-expressing postsynaptic neurons at memory retrieval, and correlated temporally with the quality of the memory. We then show that for contextual fear conditioning and Morris water maze learning, increased feedforward inhibition connectivity by hippocampal mossy fibres has a critical role for the precision of the memory and the learned behaviour. In the absence of mossy fibre long-term potentiation in Rab3a(-/-) mice, c-Fos ensemble reorganization and feedforward inhibition growth were both absent in CA3 upon learning, and the memory was imprecise. By contrast, in the absence of adducin 2 (Add2; also known as β-adducin) c-Fos reorganization was normal, but feedforward inhibition growth was abolished. In parallel, c-Fos ensembles in CA3 were greatly enlarged, and the memory was imprecise. Feedforward inhibition growth and memory precision were both rescued by re-expression of Add2 specifically in hippocampal mossy fibres. These results establish a causal relationship between learning-related increases in the numbers of defined synapses and the precision of learning and memory in the adult. The results further relate plasticity and feedforward inhibition growth at hippocampal mossy fibres to the precision of hippocampus-dependent memories.
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http://dx.doi.org/10.1038/nature09946DOI Listing
May 2011

β-Adducin is required for stable assembly of new synapses and improved memory upon environmental enrichment.

Neuron 2011 Mar;69(6):1132-46

Friedrich Miescher Institut, Maulbeerstrasse 66, CH-4058 Basel, Switzerland.

Learning is correlated with the assembly of new synapses, but the roles of synaptogenesis processes in memory are poorly understood. Here, we show that mice lacking β-Adducin fail to assemble new synapses upon enhanced plasticity and exhibit diminished long-term hippocampal memory upon environmental enrichment. Enrichment-enhanced the disassembly and assembly of dynamic subpopulations of synapses. Upon enrichment, stable assembly of new synapses depended on the presence of β-Adducin, disassembly involved β-Adducin phosphorylation through PKC, and both were required for augmented learning. In the absence of β-Adducin, enrichment still led to an increase in spine structures, but the assembly of synapses at those spines was compromised. Virus-mediated re-expression of β-Adducin in hippocampal granule cells of β-Adducin(-/-) mice rescued new synapse assembly and learning upon enrichment. Our results provide evidence that synapse disassembly and the establishment of new synapses are both critically important for augmented long-term learning and memory upon environmental enrichment.
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http://dx.doi.org/10.1016/j.neuron.2011.02.034DOI Listing
March 2011

Temporally matched subpopulations of selectively interconnected principal neurons in the hippocampus.

Nat Neurosci 2011 Apr 27;14(4):495-504. Epub 2011 Feb 27.

Friedrich Miescher Institute, Basel, Switzerland.

The extent to which individual neurons are interconnected selectively within brain circuits is an unresolved problem in neuroscience. Neurons can be organized into preferentially interconnected microcircuits, but whether this reflects genetically defined subpopulations is unclear. We found that the principal neurons in the main subdivisions of the hippocampus consist of distinct subpopulations that are generated during distinct time windows and that interconnect selectively across subdivisions. In two mouse lines in which transgene expression was driven by the neuron-specific Thy1 promoter, transgene expression allowed us to visualize distinct populations of principal neurons with unique and matched patterns of gene expression, shared distinct neurogenesis and synaptogenesis time windows, and selective connectivity at dentate gyrus-CA3 and CA3-CA1 synapses. Matched subpopulation marker genes and neuronal subtype markers mapped near clusters of olfactory receptor genes. The nonoverlapping matched timings of synaptogenesis accounted for the selective connectivities of these neurons in CA3. Therefore, the hippocampus contains parallel connectivity channels assembled from distinct principal neuron subpopulations through matched schedules of synaptogenesis.
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http://dx.doi.org/10.1038/nn.2768DOI Listing
April 2011

Signaling mechanisms.

Curr Opin Neurobiol 2010 Aug 22;20(4):397-9. Epub 2010 Aug 22.

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http://dx.doi.org/10.1016/j.conb.2010.08.003DOI Listing
August 2010