Linking Genetically Defined Neurons to Behavior through a Broadly Applicable Silencing Allele

Kim, Jun Chul; Cook, Melloni N.; Carey, Megan R.; Shen, Chung‐Wei; Regehr, Wade G.; Dymecki, Susan M.

doi:10.1016/j.neuron.2009.07.010

Cited by 125 publications

(133 citation statements)

References 49 publications

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“…45 Platelet-specific VAMP2/3 2/2 mice were generated by PF4-Cre-mediated 46 expression of tetanus neurotoxin endopeptidase, which cleaves both VAMP2 and VAMP3. 47 VAMP2/3/8 2/2 mice were generated from VAMP2/3 2/2 and VAMP8 2/2 mice and will be described else-…”

Section: Methods Mouse Strainsmentioning

confidence: 99%

Autophagy is induced upon platelet activation and is essential for hemostasis and thrombosis

Ouseph

Huang

Banerjee

et al. 2015

Blood

123

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Key Points• Autophagy, an essential degradation pathway, is constitutively active in resting platelets and is induced upon platelet activation.• Platelet autophagy is indispensable for hemostasis and thrombus formation.Autophagy is important for maintaining cellular homeostasis, and thus its deficiency is implicated in a broad spectrum of human diseases. Its role in platelet function has only recently been examined. Our biochemical and imaging studies demonstrate that the core autophagy machinery exists in platelets, and that autophagy is constitutively active in resting platelets. Moreover, autophagy is induced upon platelet activation, as indicated by agonist-induced loss of the autophagy marker LC3II. Additional experiments, using inhibitors of platelet activation, proteases, and lysosomal acidification, as well as platelets from knockout mouse strains, show that agonist-induced LC3II loss is a consequence of platelet signaling cascades and requires proteases, acidic compartments, and membrane fusion. To assess the physiological role of platelet autophagy, we generated a mouse strain with a megakaryocyte-and platelet-specific deletion of Atg7, an enzyme required for LC3II production. Ex vivo analysis of platelets from these mice shows modest defects in aggregation and granule cargo packaging. Although these mice have normal platelet numbers and size distributions, they exhibit a robust bleeding diathesis in the tail-bleeding assay and a prolonged occlusion time in the FeCl 3 -induced carotid injury model. Our results demonstrate that autophagy occurs in platelets and is important for hemostasis and thrombosis. (Blood. 2015;126(10):1224-1233 Introduction Autophagy, one of the major degradation pathways in eukaryotes, is important for cellular homeostasis and is implicated in a broad spectrum of human diseases including cancer, neurodegeneration, and cardiovascular diseases.1 There are 3 main types: chaperone-mediated autophagy, 2 microautophagy, 3,4 and the primary form, macroautophagy (referred to hereafter as autophagy).5 Autophagy involves de novo synthesis of double-membraned organelles called autophagosomes that contain cytosolic constituents including damaged organelles (eg, mitochondria) and protein aggregates. Autophagosomes fuse with multivesicular bodies, late endosomes, and lysosomes to form autolysosomes, 6 in which waste elimination, energy production, and recycling of cellular components take place.Autophagosome biogenesis and maturation use several protein complexes. [7][8][9][10] In mammals, cellular signals (eg, starvation) activate the Ulk1 complex (Ulk1, FIP200, Atg13, and Atg101), 11-14 which together with syntaxin 17, 15 localizes Atg14/Atg14L [16][17][18][19] to the endoplasmic reticulum. 15,20 This recruits the Beclin 1-Vps34 core complex (Beclin 1, Vps34, and Vps15) to autophagosome initiation sites and promotes phosphatidylinositol 3-phosphate production for recruitment of additional autophagy pathway components.20,21 Two ubiquitin-like conjugation systems are also important for autoph...

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Section: Methods Mouse Strainsmentioning

confidence: 99%

Autophagy is induced upon platelet activation and is essential for hemostasis and thrombosis

Ouseph

Huang

Banerjee

et al. 2015

Blood

123

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“…These areas showed profound 5-HT depletion in Pet1 knock-out mice, which would explain the anxiolytic phenotype in conflict exploratory tests. Accordingly, other genetic models of 5-HT depletion have shown a similar anxiolytic-like phenotype in these tests (Dai et al, 2008;Kim et al, 2009). Conversely, 5-HT inhibits fear responses through the targeting of specific amygdala and PAG subnuclei.…”

Section: Consequences On Anxiety-related Behaviorsmentioning

confidence: 82%

A Genetically Defined Morphologically and Functionally Unique Subset of 5-HT Neurons in the Mouse Raphe Nuclei

Kiyasova¹,

Fernandez²,

Lainé³

et al. 2011

J. Neurosci.

125

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Heterogeneity of central serotonin (5-HT) raphe neurons is suggested by numerous lines of evidence, but its genetic basis remains elusive.The transcription factor Pet1 is required for the acquisition of serotonergic identity in a majority of neurons in the raphe nuclei. Nevertheless, a subset of 5-HT neurons differentiates in Pet1 knock-out mice. We show here that these residual 5-HT neurons outline a unique subpopulation of raphe neurons with highly selective anatomical targets and characteristic synaptic differentiations. In Pet1 knock-out mice, 5-HT innervation strikingly outlines the brain areas involved in stress responses with dense innervation to the basolateral amygdala, the paraventricular nucleus of the hypothalamus, and the intralaminar thalamic nuclei. In these regions, 5-HT terminals establish asymmetric synaptic junctions. This target selectivity could not be related to altered growth of the remaining 5-HT neurons, as indicated by axon tracing and cell culture analyses. The residual 5-HT axon terminals are functional with maintained release properties in vitro and in vivo. The functional consequence of this uneven distribution of 5-HT innervation on behavior was characterized. Pet1 knock-out mice showed decreased anxiety behavior in novelty exploration and increased fear responses to conditioned aversive cues. Overall, our findings lead us to propose the existence of Pet1-dependent and Pet1-resistant 5-HT neurons targeting different brain centers that might delineate the anatomical basis for a dual serotonergic control on stress responses.

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“…Impairment of the serotonin system is involved in diverse behavioral abnormalities including anxiety, impulsivity, behavioral inhibition, aggression, feeding, panic and sleep (Cools et al, 2008;Heisler et al, 2006;Jouvet, 1999;Miyazaki et al, 2012;Nelson and Trainor, 2007;Soubrié , 1986). This functional diversity might be linked to diversity in the serotonergic neuron populations in terms of neural connectivity and cell lineage (Bang et al, 2012;Kim et al, 2009;Paul and Lowry, 2013). In fact, the optogenetic activation of the dorsal raphe (DR) Pet-1-positive neurons reinforced mice to explore the stimulationcoupled spatial region, shifts sucrose preference, drove optical self-stimulation, and directed sensory discrimination learning, suggesting that the DR neurons encode reward rather than punishment as we suggested for MR (Liu et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

The Habenulo-Raphe Serotonergic Circuit Encodes an Aversive Expectation Value Essential for Adaptive Active Avoidance of Danger

Amo

Fredes

Kinoshita

et al. 2014

Neuron

185

260

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Anticipation of danger at first elicits panic in animals, but later it helps them to avoid the real threat adaptively. In zebrafish, as fish experience more and more danger, neurons in the ventral habenula (vHb) showed tonic increase in the activity to the presented cue and activated serotonergic neurons in the median raphe (MR). This neuronal activity could represent the expectation of a dangerous outcome and be used for comparison with a real outcome when the fish is learning how to escape from a dangerous to a safer environment. Indeed, inhibiting synaptic transmission from vHb to MR impaired adaptive avoidance learning, while panic behavior induced by classical fear conditioning remained intact. Furthermore, artificially triggering this negative outcome expectation signal by optogenetic stimulation of vHb neurons evoked place avoidance behavior. Thus, vHb-MR circuit is essential for representing the level of expected danger and behavioral programming to adaptively avoid potential hazard.

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Linking Genetically Defined Neurons to Behavior through a Broadly Applicable Silencing Allele

Cited by 125 publications

References 49 publications

Autophagy is induced upon platelet activation and is essential for hemostasis and thrombosis

Autophagy is induced upon platelet activation and is essential for hemostasis and thrombosis

A Genetically Defined Morphologically and Functionally Unique Subset of 5-HT Neurons in the Mouse Raphe Nuclei

The Habenulo-Raphe Serotonergic Circuit Encodes an Aversive Expectation Value Essential for Adaptive Active Avoidance of Danger

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