Computational design of enhanced learning protocols

Zhang, Yili; Liu, Rong‐Yu; Heberton, George A; Smolen, Paul; Baxter, Douglas A.; Cleary, Leonard J.; Byrne, John H.

doi:10.1038/nn.2990

Cited by 71 publications

(129 citation statements)

References 44 publications

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“…In Aplysia, however, maximal ERK1/2 activation occurred at ∼45 min after stimulation, which is much slower than our observations in rat sensory neurons. The synergistic activation of both kinases in Aplysia converges on transcriptional responses involving the cAMP response element-binding protein (CREB) (Zhang et al, 2012). Protocols that include properly timed stimuli have been developed to promote the interaction of PKA and ERK1/ 2, resulting in enhanced CREB phosphorylation and long-term potentiation (LTP) (Zhang et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

“…The synergistic activation of both kinases in Aplysia converges on transcriptional responses involving the cAMP response element-binding protein (CREB) (Zhang et al, 2012). Protocols that include properly timed stimuli have been developed to promote the interaction of PKA and ERK1/ 2, resulting in enhanced CREB phosphorylation and long-term potentiation (LTP) (Zhang et al, 2012). An age-dependent increase of crosstalk between these kinases, as observed here, may therefore also reflect enhanced 'learning' capabilities of adult sensory neurons.…”

Section: Discussionmentioning

confidence: 99%

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Crosstalk from cAMP to ERK1/2 emerges during postnatal maturation of nociceptive neurons and is maintained during aging

Isensee

Schild

Schwede

et al. 2017

Journal of Cell Science

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Maturation of nociceptive neurons depends on changes in transcription factors, ion channels and neuropeptides. Mature nociceptors initiate pain in part by drastically reducing the activation threshold via intracellular sensitization signaling. Whether sensitization signaling also changes during development and aging remains so far unknown. Using a novel automated microscopy approach, we quantified changes in intracellular signaling protein expression and in their signaling dynamics, as well as changes in intracellular signaling cascade wiring, in sensory neurons from newborn to senescent (24 months of age) rats. We found that nociceptive subgroups defined by the signaling components protein kinase A (PKA)-RIIβ (also known as PRKAR2B) and CaMKIIα (also known as CAMK2A) developed at around postnatal day 10, the time of nociceptor maturation. The integrative nociceptor marker, PKA-RIIβ, allowed subgroup segregation earlier than could be achieved by assessing the classical markers TRPV1 and Na v 1.8 (also known as SCN10A). Signaling kinetics remained constant over lifetime despite in part strong changes in the expression levels. Strikingly, we found a mechanism important for neuronal memory -i.e. the crosstalk from cAMP and PKA to ERK1 and ERK2 (ERK1/2, also known as MAPK3 and MAPK1, respectively) -to emerge postnatally. Thus, maturation of nociceptors is closely accompanied by altered expression, activation and connectivity of signaling pathways known to be central for pain sensitization and neuronal memory formation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Crosstalk from cAMP to ERK1/2 emerges during postnatal maturation of nociceptive neurons and is maintained during aging

Isensee

Schild

Schwede

et al. 2017

Journal of Cell Science

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“…Liu et al (2013) used small interfering RNA (siRNA) to reduce the basal level of CBP and impair LTF at sensory neuron-motor neuron (SN-MN) synapses of Aplysia. The mathematical model of Zhang et al (2012) was extended to include the cAMP/PKA and Raf/MEK/ERK pathways, as well as phosphorylation of CREB1, CREB2, and C/EBP. Simulations predicted training protocols that would compensate for the CBP deficit.…”

Section: Introductionmentioning

confidence: 99%

Rescue of Impaired Long-Term Facilitation at Sensorimotor Synapses ofAplysiafollowing siRNA Knockdown of CREB1

Zhou¹,

Zhang²,

Liu³

et al. 2015

J. Neurosci.

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Memory impairment is often associated with disrupted regulation of gene induction. For example, deficits in cAMP response elementbinding protein (CREB) binding protein (CBP; an essential cofactor for activation of transcription by CREB) impair long-term synaptic plasticity and memory. Previously, we showed that small interfering RNA (siRNA)-induced knockdown of CBP in individual sensory neurons significantly reduced levels of CBP and impaired 5-HT-induced long-term facilitation (LTF) in sensorimotor cocultures from Aplysia. Moreover, computational simulations of the biochemical cascades underlying LTF successfully predicted training protocols that restored LTF following CBP knockdown. We examined whether simulations could also predict a training protocol that restores LTF impaired by siRNA-induced knockdown of the transcription factor CREB1. Simulations based on a previously described model predicted rescue protocols that were specific to CREB1 knockdown. Empirical studies demonstrated that one of these rescue protocols partially restored impaired LTF. In addition, the effectiveness of the rescue protocol was enhanced by pretreatment with rolipram, a selective cAMP phosphodiesterase inhibitor. These results provide further evidence that computational methods can help rescue disruptions in signaling cascades underlying memory formation. Moreover, the study demonstrates that the effectiveness of computationally designed training protocols can be enhanced with complementary pharmacological approaches.

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“…Recent studies have revealed aspects of the molecular and cellular mechanisms of LTM formation induced by repetitive training (8)(9)(10)(11), but how a single training induces a stable LTM is poorly understood (12).…”

mentioning

confidence: 99%

Distinct dopamine neurons mediate reward signals for short- and long-term memories

Yamagata

Ichinose

Aso

et al. 2014

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

238

287

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Drosophila melanogaster can acquire a stable appetitive olfactory memory when the presentation of a sugar reward and an odor are paired. However, the neuronal mechanisms by which a single training induces long-term memory are poorly understood. Here we show that two distinct subsets of dopamine neurons in the fly brain signal reward for short-term (STM) and long-term memories (LTM). One subset induces memory that decays within several hours, whereas the other induces memory that gradually develops after training. They convey reward signals to spatially segregated synaptic domains of the mushroom body (MB), a potential site for convergence. Furthermore, we identified a single type of dopamine neuron that conveys the reward signal to restricted subdomains of the mushroom body lobes and induces long-term memory. Constant appetitive memory retention after a single training session thus comprises two memory components triggered by distinct dopamine neurons.dopamine | learning and memory | Drosophila | mushroom body M emory of a momentous event persists for a long time.Whereas some forms of long-term memory (LTM) require repetitive training (1-3), a highly relevant stimulus such as food or poison is sufficient to induce LTM in a single training session (4-7). Recent studies have revealed aspects of the molecular and cellular mechanisms of LTM formation induced by repetitive training (8-11), but how a single training induces a stable LTM is poorly understood (12).Appetitive olfactory learning in fruit flies is suited to address the question, as a presentation of a sugar reward paired with odor induces robust short-term memory (STM) and LTM (6, 7). Odor is represented by a sparse ensemble of the 2,000 intrinsic neurons, the Kenyon cells (13). A current working model suggests that concomitant reward signals from sugar ingestion cause associative plasticity in Kenyon cells that might underlie memory formation (14-20). A single activation session of a specific cluster of dopamine neurons (PAM neurons) by sugar ingestion can induce appetitive memory that is stable over 24 h (19), underscoring the importance of sugar reward to the fly.The mushroom body (MB) is composed of the three different cell types, α/β, α′/β′, and γ, which have distinct roles in different phases of appetitive memories (11,(21)(22)(23)(24)(25). Similar to midbrain dopamine neurons in mammals (26,27), the structure and function of PAM cluster neurons are heterogeneous, and distinct dopamine neurons intersect unique segments of the MB lobes (19,(28)(29)(30)(31)(32)(33)(34). Further circuit dissection is thus crucial to identify candidate synapses that undergo associative modulation.By activating distinct subsets of PAM neurons for reward signaling, we found that short-and long-term memories are independently formed by two complementary subsets of PAM cluster dopamine neurons. Conditioning flies with nutritious and nonnutritious sugars revealed that the two subsets could represent different reinforcing properties: sweet taste and nutritional value of sugar....

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Computational design of enhanced learning protocols

Cited by 71 publications

References 44 publications

Crosstalk from cAMP to ERK1/2 emerges during postnatal maturation of nociceptive neurons and is maintained during aging

Crosstalk from cAMP to ERK1/2 emerges during postnatal maturation of nociceptive neurons and is maintained during aging

Rescue of Impaired Long-Term Facilitation at Sensorimotor Synapses ofAplysiafollowing siRNA Knockdown of CREB1

Distinct dopamine neurons mediate reward signals for short- and long-term memories

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