Activin A Is Essential for Neurogenesis Following Neurodegeneration

Abdipranoto-Cowley, Andrea; Park, Jin-Sung; Croucher, David R.; Daniel, James; Henshall, Susan M.; Galbraith, Sally; Mervin, Kyle; Vissel, Bryce

doi:10.1002/stem.80

Cited by 65 publications

(57 citation statements)

References 59 publications

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“…Previous reports have suggested that neurons are a large source of activin A in the CNS26. To determine if neurons were the source of increased activin A in the NAc following cocaine self-administration, we performed double staining for activin A and NeuN (neuron marker27, Fig.…”

Section: Resultsmentioning

confidence: 99%

Activin A is increased in the nucleus accumbens following a cocaine binge

Wang

Martin

Gancarz

et al. 2017

Sci Rep

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Drug addiction is a long-lasting disease characterized by compulsive drug intake mediated in part by neuronal and biological adaptations in key brain areas, such as the nucleus accumbens (NAc). While we previously demonstrated involvement of the activin 2a receptor in drug taking, the role of its ligand, activin A, in cocaine relapse is unknown. Activin A levels in the NAc were assessed via ELISA and immunohistochemistry (in neurons, astrocytes, and microglia) following a cocaine binge paradigm. Cocaine exposure significantly increased the levels of activin A in the NAc of animals that had self-administered cocaine prior to the 14-day withdrawal compared with levels in saline controls. This was accompanied by an increase in the proportion of IBA1+ microglia in the NAc that were immunopositive for activin A. In contrast, the proportions of NeuN+ neurons and GFAP+ astrocytes that were immunopositive for activin A remained unaltered. In conclusion, these data suggest that increased secretion of activin A, particularly from microglia, in the NAc represents a novel potential target for the treatment of cocaine relapse.

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Section: Resultsmentioning

confidence: 99%

Activin A is increased in the nucleus accumbens following a cocaine binge

Wang

Martin

Gancarz

et al. 2017

Sci Rep

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“…We demonstrate here that activin A, like BDNF, which is probably the most intensively studied neurotrophic factor when it comes to antidepressant action [56,57,69], represents a common target of behavioral and electroconvulsive strategies in the treatment of depression. In view of the known functions of activin A as enhancer of synaptic plasticity [5,70,71], neuronal survival [4,6,72], and adult neurogenesis [2,73], it seems plausible to assume that a boost in activin A signaling by ECS or EE may help to reset a potentially pathologic state to normal. With the epigenetic regulator Kdm6b emerging as a direct target of activin signaling, it is well conceivable that sustained effects of the dramatic, but transient increase in activin levels after ECS might be achieved by chromatin remodeling.…”

Section: Discussionmentioning

confidence: 98%

Kdm6b and Pmepa1 as Targets of Bioelectrically and Behaviorally Induced Activin A Signaling

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Kurinna²,

Havlicek

et al. 2015

Mol Neurobiol

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The transforming growth factor-β (TGF-β) family member activin A exerts multiple neurotrophic and protective effects in the brain. Activin also modulates cognitive functions and affective behavior and is a presumed target of antidepressant therapy. Despite its important role in the injured and intact brain, the mechanisms underlying activin effects in the CNS are still largely unknown. Our goal was to identify the first target genes of activin signaling in the hippocampus in vivo. Electroconvulsive seizures, a rodent model of electroconvulsive therapy in humans, were applied to C57BL/6J mice to elicit a strong increase in activin A signaling. Chromatin immunoprecipitation experiments with hippocampal lysates subsequently revealed that binding of SMAD2/3, the intracellular effectors of activin signaling, was significantly enriched at the Pmepa1 gene, which encodes a negative feedback regulator of TGF-β signaling in cancer cells, and at the Kdm6b gene, which encodes an epigenetic regulator promoting transcriptional plasticity. Underlining the significance of these findings, activin treatment also induced PMEPA1 and KDM6B expression in human forebrain neurons generated from embryonic stem cells suggesting interspecies conservation of activin effects in mammalian neurons. Importantly, physiological stimuli such as provided by environmental enrichment proved already sufficient to engender a rapid and significant induction of activin signaling concomitant with an upregulation of Pmepa1 and Kdm6b expression. Taken together, our study identified the first target genes of activin signaling in the brain. With the induction of Kdm6b expression, activin is likely to gain impact on a presumed epigenetic regulator of activity-dependent neuronal plasticity.

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“…Brains were extracted and sections were processed for cfos. The total number of cells positive for cfos (cfos+) in the IL and PL cortex was quantified using rigorous unbiased stereological methods (34). Additional home cage (HC+) control rats were added to the cfos analyses to provide a baseline level of cfos expression in the IL and PL for each surgical condition (n = 8).…”

Section: Compensatory Context Fear Is Characterized By Changes In Mpfmentioning

confidence: 99%

Prefrontal microcircuit underlies contextual learning after hippocampal loss

Zelikowsky

Bissière

Hast³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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152

147

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Specific brain circuits have been classically linked to dedicated functions. However, compensation following brain damage suggests that these circuits are capable of dynamic adaptation. Such compensation is exemplified by Pavlovian fear conditioning following damage to the dorsal hippocampus (DH). Although the DH normally underlies contextual fear and fear renewal after extinction, both can be learned in the absence of the DH, although the mechanisms and nature of this compensation are currently unknown. Here, we report that recruitment of alternate structures, specifically the infralimbic and prelimbic prefrontal cortices, is required for compensation following damage to the hippocampus. Disconnection of these cortices in DH-compromised animals and immediate early gene induction profiles for amygdala-projecting prefrontal cells revealed that communication and dynamic rebalancing within this prefrontal microcircuit is critical. Additionally, the infralimbic cortex normally plays a role in limiting generalization of contextual fear. These discoveries reveal that plasticity through recruitment of alternate circuits allows the brain to compensate following damage, offering promise for targeted treatment of memory disorders.anxiety | recovery of function | amnesia | medial prefrontal cortex A widely accepted view is that the brain is comprised of multiple independent circuits dedicated to performing specific functions and encoding specific information. This view is exemplified in the field of learning and memory, where it is held that different circuits specialize in integrating and storing different classes of memories (1). However, studies looking at learning following brain damage clearly demonstrate that the brain can also behave dynamically. For example, in Pavlovian fear conditioning, contextual memories can be formed in the absence of circuits classically thought to underpin integration and storage of information about an animal's environment or context (2).In fear conditioning, contexts play two key roles in controlling fear learning and expression. First, a context can act as a conditional stimulus (CS), to which fear can be directly conditioned when an aversive experience, such as a foot shock [unconditional stimulus (US)] is signaled by the context. Second, contexts can modulate responding to a discrete cue, such as a tone-CS, which has acquired multiple meanings. For example, in extinction, a tone previously conditioned to elicit fear is presented in the absence of the aversive foot shock US, such that the conditional fear response begins to extinguish. However, because extinction is not an erasure of the original fear but rather new learning that interferes with retrieval of the original fear memory, an extinguished cue has multiple meanings (shock/no shock), which compete for behavioral expression (3). This competition is mediated by context, as fear renewal occurs when an extinguished stimulus is presented outside of the extinction context (4).These context-sensitive effects provide excellent models t...

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Activin A Is Essential for Neurogenesis Following Neurodegeneration

Cited by 65 publications

References 59 publications

Activin A is increased in the nucleus accumbens following a cocaine binge

Activin A is increased in the nucleus accumbens following a cocaine binge

Kdm6b and Pmepa1 as Targets of Bioelectrically and Behaviorally Induced Activin A Signaling

Prefrontal microcircuit underlies contextual learning after hippocampal loss

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