Publications by authors named "Joseph Bedont"

15 Publications

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Short and long sleeping mutants reveal links between sleep and macroautophagy.

Elife 2021 Jun 4;10. Epub 2021 Jun 4.

Chronobiology and Sleep Institute, Perelman Medical School of University of Pennsylvania, Philadelphia, United States.

Sleep is a conserved and essential behavior, but its mechanistic and functional underpinnings remain poorly defined. Through unbiased genetic screening in , we discovered a novel short-sleep mutant we named . Positional cloning and subsequent complementation, CRISPR/Cas9 knock-out, and RNAi studies identified Argus as a transmembrane protein that acts in adult peptidergic neurons to regulate sleep. mutants accumulate undigested Atg8a(+) autophagosomes, and genetic manipulations impeding autophagosome formation suppress sleep phenotypes, indicating that autophagosome accumulation drives short-sleep. Conversely, a neurodegenerative mutant that impairs autophagosome formation was identified independently as a gain-of-sleep mutant, and targeted RNAi screens identified additional genes involved in autophagosome formation whose knockdown increases sleep. Finally, autophagosomes normally accumulate during the daytime and nighttime sleep deprivation extends this accumulation into the following morning, while daytime gaboxadol feeding promotes sleep and reduces autophagosome accumulation at nightfall. In sum, our results paradoxically demonstrate that wakefulness increases and sleep decreases autophagosome levels under unperturbed conditions, yet strong and sustained upregulation of autophagosomes decreases sleep, whereas strong and sustained downregulation of autophagosomes increases sleep. The complex relationship between sleep and autophagy suggested by our findings may have implications for pathological states including chronic sleep disorders and neurodegeneration, as well as for integration of sleep need with other homeostats, such as under conditions of starvation.
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http://dx.doi.org/10.7554/eLife.64140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8177895PMC
June 2021

The Lineage Before Time: Circadian and Nonclassical Clock Influences on Development.

Annu Rev Cell Dev Biol 2020 10;36:469-509

Chronobiology and Sleep Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; email:

Diverse factors including metabolism, chromatin remodeling, and mitotic kinetics influence development at the cellular level. These factors are well known to interact with the circadian transcriptional-translational feedback loop (TTFL) after its emergence. What is only recently becoming clear, however, is how metabolism, mitosis, and epigenetics may become organized in a coordinated cyclical precursor signaling module in pluripotent cells prior to the onset of TTFL cycling. We propose that both the precursor module and the TTFL module constrain cellular identity when they are active during development, and that the emergence of these modules themselves is a key lineage marker. Here we review the component pathways underlying these ideas; how proliferation, specification, and differentiation decisions in both developmental and adult stem cell populations are or are not regulated by the classical TTFL; and emerging evidence that we propose implies a primordial clock that precedes the classical TTFL and influences early developmental decisions.
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http://dx.doi.org/10.1146/annurev-cellbio-100818-125454DOI Listing
October 2020

G1/S cell cycle regulators mediate effects of circadian dysregulation on tumor growth and provide targets for timed anticancer treatment.

PLoS Biol 2019 04 30;17(4):e3000228. Epub 2019 Apr 30.

Penn Chronobiology, Howard Hughes Medical Institute, Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

Circadian disruption has multiple pathological consequences, but the underlying mechanisms are largely unknown. To address such mechanisms, we subjected transformed cultured cells to chronic circadian desynchrony (CCD), mimicking a chronic jet-lag scheme, and assayed a range of cellular functions. The results indicated a specific circadian clock-dependent increase in cell proliferation. Transcriptome analysis revealed up-regulation of G1/S phase transition genes (myelocytomatosis oncogene cellular homolog [Myc], cyclin D1/3, chromatin licensing and DNA replication factor 1 [Cdt1]), concomitant with increased phosphorylation of the retinoblastoma (RB) protein by cyclin-dependent kinase (CDK) 4/6 and increased G1-S progression. Phospho-RB (Ser807/811) was found to oscillate in a circadian fashion and exhibit phase-shifted rhythms in circadian desynchronized cells. Consistent with circadian regulation, a CDK4/6 inhibitor approved for cancer treatment reduced growth of cultured cells and mouse tumors in a time-of-day-specific manner. Our study identifies a mechanism that underlies effects of circadian disruption on tumor growth and underscores the use of treatment timed to endogenous circadian rhythms.
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http://dx.doi.org/10.1371/journal.pbio.3000228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6490878PMC
April 2019

Asymmetric vasopressin signaling spatially organizes the master circadian clock.

J Comp Neurol 2018 09 22;526(13):2048-2067. Epub 2018 Aug 22.

Department of Biomedical Sciences, Marquette University, Milwaukee, WI, 53233.

The suprachiasmatic nucleus (SCN) is the neural network that drives daily rhythms in behavior and physiology. The SCN encodes environmental changes through the phasing of cellular rhythms across its anteroposterior axis, but it remains unknown what signaling mechanisms regulate clock function along this axis. Here we demonstrate that arginine vasopressin (AVP) signaling organizes the SCN into distinct anteroposterior domains. Spatial mapping of SCN gene expression using in situ hybridization delineated anterior and posterior domains for AVP signaling components, including complementary patterns of V1a and V1b expression that suggest different roles for these two AVP receptors. Similarly, anteroposterior patterning of transcripts involved in Vasoactive Intestinal Polypeptide- and Prokineticin2 signaling was evident across the SCN. Using bioluminescence imaging, we then revealed that inhibiting V1A and V1B signaling alters period and phase differentially along the anteroposterior SCN. V1 antagonism lengthened period the most in the anterior SCN, whereas changes in phase were largest in the posterior SCN. Further, separately antagonizing V1A and V1B signaling modulated SCN function in a manner that mapped onto anteroposterior expression patterns. Lastly, V1 antagonism influenced SCN period and phase along the dorsoventral axis, complementing effects on the anteroposterior axis. Together, these results indicate that AVP signaling modulates SCN period and phase in a spatially specific manner, which is expected to influence how the master clock interacts with downstream tissues and responds to environmental changes. More generally, we reveal anteroposterior asymmetry in neuropeptide signaling as a recurrent organizational motif that likely influences neural computations in the SCN clock network.
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http://dx.doi.org/10.1002/cne.24478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6158041PMC
September 2018

Beyond the Classic VTA: Extended Amygdala Projections to DA-Striatal Paths in the Primate.

Neuropsychopharmacology 2017 Jul 21;42(8):1563-1576. Epub 2017 Feb 21.

Boston University School of Medicine, Boston, MA, USA.

The central extended amygdala (CEA) has been conceptualized as a 'macrosystem' that regulates various stress-induced behaviors. Consistent with this, the CEA highly expresses corticotropin-releasing factor (CRF), an important modulator of stress responses. Stress alters goal-directed responses associated with striatal paths, including maladaptive responses such as drug seeking, social withdrawal, and compulsive behavior. CEA inputs to the midbrain dopamine (DA) system are positioned to influence striatal functions through mesolimbic DA-striatal pathways. However, the structure of this amygdala-CEA-DA neuron path to the striatum has been poorly characterized in primates. In primates, we combined neuronal tracer injections into various arms of the circuit through specific DA subpopulations to assess: (1) whether the circuit connecting amygdala, CEA, and DA cells follows CEA intrinsic organization, or a more direct topography involving bed nucleus vs central nucleus divisions; (2) CRF content of the CEA-DA path; and (3) striatal subregions specifically involved in CEA-DA-striatal loops. We found that the amygdala-CEA-DA path follows macrostructural subdivisions, with the majority of input/outputs converging in the medial central nucleus, the sublenticular extended amygdala, and the posterior lateral bed nucleus of the stria terminalis. The proportion of CRF+ outputs is >50%, and mainly targets the A10 parabrachial pigmented nucleus (PBP) and A8 (retrorubal field, RRF) neuronal subpopulations, with additional inputs to the dorsal A9 neurons. CRF-enriched CEA-DA projections are positioned to influence outputs to the 'limbic-associative' striatum, which is distinct from striatal regions targeted by DA cells lacking CEA input. We conclude that the concept of the CEA is supported on connectional grounds, and that CEA termination over the PBP and RRF neuronal populations can influence striatal circuits involved in associative learning.
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http://dx.doi.org/10.1038/npp.2017.38DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5518904PMC
July 2017

An LHX1-Regulated Transcriptional Network Controls Sleep/Wake Coupling and Thermal Resistance of the Central Circadian Clockworks.

Curr Biol 2017 Jan 22;27(1):128-136. Epub 2016 Dec 22.

Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Center for Human Systems Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Electronic address:

The suprachiasmatic nucleus (SCN) is the central circadian clock in mammals. It is entrained by light but resistant to temperature shifts that entrain peripheral clocks [1-5]. The SCN expresses many functionally important neuropeptides, including vasoactive intestinal peptide (VIP), which drives light entrainment, synchrony, and amplitude of SCN cellular clocks and organizes circadian behavior [5-16]. The transcription factor LHX1 drives SCN Vip expression, and cellular desynchrony in Lhx1-deficient SCN largely results from Vip loss [17, 18]. LHX1 regulates many genes other than Vip, yet activity rhythms in Lhx1-deficient mice are similar to Vip mice under light-dark cycles and only somewhat worse in constant conditions. We suspected that LHX1 targets other than Vip have circadian functions overlooked in previous studies. In this study, we compared circadian sleep and temperature rhythms of Lhx1- and Vip-deficient mice and found loss of acute light control of sleep in Lhx1 but not Vip mutants. We also found loss of circadian resistance to fever in Lhx1 but not Vip mice, which was partially recapitulated by heat application to cultured Lhx1-deficient SCN. Having identified VIP-independent functions of LHX1, we mapped the VIP-independent transcriptional network downstream of LHX1 and a largely separable VIP-dependent transcriptional network. The VIP-independent network does not affect core clock amplitude and synchrony, unlike the VIP-dependent network. These studies identify Lhx1 as the first gene required for temperature resistance of the SCN clockworks and demonstrate that acute light control of sleep is routed through the SCN and its immediate output regions.
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http://dx.doi.org/10.1016/j.cub.2016.11.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5269403PMC
January 2017

EphA4 is Involved in Sleep Regulation but Not in the Electrophysiological Response to Sleep Deprivation.

Sleep 2016 Mar 1;39(3):613-24. Epub 2016 Mar 1.

Center for Advanced Research in Sleep Medicine and Research Center, Hôpital du Sacré-Coeur de Montréal, Montreal, QC, Canada.

Study Objectives: Optimal sleep is ensured by the interaction of circadian and homeostatic processes. Although synaptic plasticity seems to contribute to both processes, the specific players involved are not well understood. The EphA4 tyrosine kinase receptor is a cell adhesion protein regulating synaptic plasticity. We investigated the role of EphA4 in sleep regulation using electrocorticography in mice lacking EphA4 and gene expression measurements.

Methods: EphA4 knockout (KO) mice, Clock(Δ19/Δ19) mutant mice and littermates, C57BL/6J and CD-1 mice, and Sprague-Dawley rats were studied under a 12 h light: 12 h dark cycle, under undisturbed conditions or 6 h sleep deprivation (SLD), and submitted to a 48 h electrophysiological recording and/or brain sampling at different time of day.

Results: EphA4 KO mice showed less rapid eye movement sleep (REMS), enhanced duration of individual bouts of wakefulness and nonrapid eye movement sleep (NREMS) during the light period, and a blunted daily rhythm of NREMS sigma activity. The NREMS delta activity response to SLD was unchanged in EphA4 KO mice. However, SLD increased EphA4 expression in the thalamic/hypothalamic region in C57BL/6J mice. We further show the presence of E-boxes in the promoter region of EphA4, a lower expression of EphA4 in Clock mutant mice, a rhythmic expression of EphA4 ligands in several brain areas, expression of EphA4 in the suprachiasmatic nuclei of the hypothalamus (SCN), and finally an unchanged number of cells expressing Vip, Grp and Avp in the SCN of EphA4 KO mice.

Conclusions: Our results suggest that EphA4 is involved in circadian sleep regulation.
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http://dx.doi.org/10.5665/sleep.5538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4763357PMC
March 2016

Constructing the suprachiasmatic nucleus: a watchmaker's perspective on the central clockworks.

Front Syst Neurosci 2015 8;9:74. Epub 2015 May 8.

Department of Neuroscience, Johns Hopkins University School of Medicine Baltimore, MD, USA ; Department of Ophthalmology, Johns Hopkins University School of Medicine Baltimore, MD, USA ; Department of Physiology, Johns Hopkins University School of Medicine Baltimore, MD, USA ; Department of Neurology, Johns Hopkins University School of Medicine Baltimore, MD, USA ; Center for High-Throughput Biology, Johns Hopkins University School of Medicine Baltimore, MD, USA.

The circadian system constrains an organism's palette of behaviors to portions of the solar day appropriate to its ecological niche. The central light-entrained clock in the suprachiasmatic nucleus (SCN) of the mammalian circadian system has evolved a complex network of interdependent signaling mechanisms linking multiple distinct oscillators to serve this crucial function. However, studies of the mechanisms controlling SCN development have greatly lagged behind our understanding of its physiological functions. We review advances in the understanding of adult SCN function, what has been described about SCN development to date, and the potential of both current and future studies of SCN development to yield important insights into master clock function, dysfunction, and evolution.
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http://dx.doi.org/10.3389/fnsys.2015.00074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4424844PMC
May 2015

Patterning, specification, and differentiation in the developing hypothalamus.

Wiley Interdiscip Rev Dev Biol 2015 Sep-Oct;4(5):445-68. Epub 2015 Mar 27.

Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Owing to its complex structure and highly diverse cell populations, the study of hypothalamic development has historically lagged behind that of other brain regions. However, in recent years, a greatly expanded understanding of hypothalamic gene expression during development has opened up new avenues of investigation. In this review, we synthesize existing work to present a holistic picture of hypothalamic development from early induction and patterning through nuclear specification and differentiation, with a particular emphasis on determination of cell fate. We will also touch on special topics in the field including the prosomere model, adult neurogenesis, and integration of migratory cells originating outside the hypothalamic neuroepithelium, and how these topics relate to our broader theme.
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http://dx.doi.org/10.1002/wdev.187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5890958PMC
May 2016

The LIM homeodomain factor Lhx2 is required for hypothalamic tanycyte specification and differentiation.

J Neurosci 2014 Dec;34(50):16809-20

Department of Neuroscience, Department of Ophthalmology, Department of Neurology, Center for High-Throughput Biology, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287,

Hypothalamic tanycytes, a radial glial-like ependymal cell population that expresses numerous genes selectively enriched in embryonic hypothalamic progenitors and adult neural stem cells, have recently been observed to serve as a source of adult-born neurons in the mammalian brain. The genetic mechanisms that regulate the specification and maintenance of tanycyte identity are unknown, but are critical for understanding how these cells can act as adult neural progenitor cells. We observe that LIM (Lin-11, Isl-1, Mec-3)-homeodomain gene Lhx2 is selectively expressed in hypothalamic progenitor cells and tanycytes. To test the function of Lhx2 in tanycyte development, we used an intersectional genetic strategy to conditionally delete Lhx2 in posteroventral hypothalamic neuroepithelium, both embryonically and postnatally. We observed that tanycyte development was severely disrupted when Lhx2 function was ablated during embryonic development. Lhx2-deficient tanycytes lost expression of tanycyte-specific genes, such as Rax, while also displaying ectopic expression of genes specific to cuboid ependymal cells, such as Rarres2. Ultrastructural analysis revealed that mutant tanycytes exhibited a hybrid identity, retaining radial morphology while becoming multiciliated. In contrast, postnatal loss of function of Lhx2 resulted only in loss of expression of tanycyte-specific genes. Using chromatin immunoprecipitation, we further showed that Lhx2 directly regulated expression of Rax, an essential homeodomain factor for tanycyte development. This study identifies Lhx2 as a key intrinsic regulator of tanycyte differentiation, sustaining Rax-dependent activation of tanycyte-specific genes while also inhibiting expression of ependymal cell-specific genes. These findings provide key insights into the transcriptional regulatory network specifying this still poorly characterized cell type.
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http://dx.doi.org/10.1523/JNEUROSCI.1711-14.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4261103PMC
December 2014

Lhx1 controls terminal differentiation and circadian function of the suprachiasmatic nucleus.

Cell Rep 2014 May 24;7(3):609-22. Epub 2014 Apr 24.

Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Center for High-Throughput Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Electronic address:

Vertebrate circadian rhythms are organized by the hypothalamic suprachiasmatic nucleus (SCN). Despite its physiological importance, SCN development is poorly understood. Here, we show that Lim homeodomain transcription factor 1 (Lhx1) is essential for terminal differentiation and function of the SCN. Deletion of Lhx1 in the developing SCN results in loss of SCN-enriched neuropeptides involved in synchronization and coupling to downstream oscillators, among other aspects of circadian function. Intact, albeit damped, clock gene expression rhythms persist in Lhx1-deficient SCN; however, circadian activity rhythms are highly disorganized and susceptible to surprising changes in period, phase, and consolidation following neuropeptide infusion. Our results identify a factor required for SCN terminal differentiation. In addition, our in vivo study of combinatorial SCN neuropeptide disruption uncovered synergies among SCN-enriched neuropeptides in regulating normal circadian function. These animals provide a platform for studying the central oscillator's role in physiology and cognition.
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http://dx.doi.org/10.1016/j.celrep.2014.03.060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4254772PMC
May 2014

WIDE AWAKE mediates the circadian timing of sleep onset.

Neuron 2014 Apr 13;82(1):151-66. Epub 2014 Mar 13.

Department of Neurology, Johns Hopkins University, Baltimore, MD 21287, USA; Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21287, USA. Electronic address:

How the circadian clock regulates the timing of sleep is poorly understood. Here, we identify a Drosophila mutant, wide awake (wake), that exhibits a marked delay in sleep onset at dusk. Loss of WAKE in a set of arousal-promoting clock neurons, the large ventrolateral neurons (l-LNvs), impairs sleep onset. WAKE levels cycle, peaking near dusk, and the expression of WAKE in l-LNvs is Clock dependent. Strikingly, Clock and cycle mutants also exhibit a profound delay in sleep onset, which can be rescued by restoring WAKE expression in LNvs. WAKE interacts with the GABAA receptor Resistant to Dieldrin (RDL), upregulating its levels and promoting its localization to the plasma membrane. In wake mutant l-LNvs, GABA sensitivity is decreased and excitability is increased at dusk. We propose that WAKE acts as a clock output molecule specifically for sleep, inhibiting LNvs at dusk to promote the transition from wake to sleep.
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http://dx.doi.org/10.1016/j.neuron.2014.01.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3982794PMC
April 2014

Tanycytes of the hypothalamic median eminence form a diet-responsive neurogenic niche.

Nat Neurosci 2012 Mar 25;15(5):700-2. Epub 2012 Mar 25.

Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Adult hypothalamic neurogenesis has recently been reported, but the cell of origin and the function of these newborn neurons are unknown. Using genetic fate mapping, we found that median eminence tanycytes generate newborn neurons. Blocking this neurogenesis altered the weight and metabolic activity of adult mice. These findings reveal a previously unreported neurogenic niche in the mammalian hypothalamus with important implications for metabolism.
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http://dx.doi.org/10.1038/nn.3079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3380241PMC
March 2012

Myelination transition zone astrocytes are constitutively phagocytic and have synuclein dependent reactivity in glaucoma.

Proc Natl Acad Sci U S A 2011 Jan 3;108(3):1176-81. Epub 2011 Jan 3.

The Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Optic nerve head (ONH) astrocytes have been proposed to play both protective and deleterious roles in glaucoma. We now show that, within the postlaminar ONH myelination transition zone (MTZ), there are astrocytes that normally express Mac-2 (also known as Lgals3 or galectin-3), a gene typically expressed only in phagocytic cells. Surprisingly, even in healthy mice, MTZ and other ONH astrocytes constitutive internalize large axonal evulsions that contain whole organelles. In mouse glaucoma models, MTZ astrocytes further up-regulate Mac-2 expression. During glaucomatous degeneration, there are dystrophic processes in the retina and optic nerve, including the MTZ, which contain protease resistant γ-synuclein. The increased Mac-2 expression by MTZ astrocytes during glaucoma likely depends on this γ-synuclein, as mice lacking γ-synuclein fail to up-regulate Mac-2 at the MTZ after elevation of intraocular pressure. These results suggest the possibility that a newly discovered normal degradative pathway for axons might contribute to glaucomatous neurodegeneration.
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http://dx.doi.org/10.1073/pnas.1013965108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3024691PMC
January 2011

Fear and safety learning differentially affect synapse size and dendritic translation in the lateral amygdala.

Proc Natl Acad Sci U S A 2010 May 3;107(20):9418-23. Epub 2010 May 3.

Center for Neural Science, New York University, New York, NY 10003, USA.

Fear learning is associated with changes in synapse strength in the lateral amygdala (LA). To examine changes in LA dendritic spine structure with learning, we used serial electron microscopy to re-construct dendrites after either fear or safety conditioning. The spine apparatus, a smooth endoplasmic reticulum (sER) specialization found in very large spines, appeared more frequently after fear conditioning. Fear conditioning was associated with larger synapses on spines that did not contain a spine apparatus, whereas safety conditioning resulted in smaller synapses on these spines. Synapses on spines with a spine apparatus were smaller after safety conditioning but unchanged with fear conditioning, suggesting a ceiling effect. There were more polyribosomes and multivesicular bodies throughout the dendrites from fear conditioned rats, indicating increases in both protein synthesis and degradation. Polyribosomes were associated with the spine apparatus under both training conditions. We conclude that LA synapse size changes bidirectionally with learning and that the spine apparatus has a central role in regulating synapse size and local translation.
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http://dx.doi.org/10.1073/pnas.0913384107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2889073PMC
May 2010
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