Biomedical subjects
Publications and source records attributed to Michael A Sutton.
Considerable evidence suggests that the formation of long-term memories requires a critical period of new protein synthesis. Recently, the notion that some of these newly synthesized proteins originate through local translation in neuronal dendrites has gained some traction. Here, we review the experimental support for this idea and highlight some of the key questions outstanding in this area.
Activity deprivation in neurons induces a slow compensatory scaling up of synaptic strength, reflecting a homeostatic mechanism for stabilizing neuronal activity. Prior studies have focused on the loss of action potential (AP) driven neurotransmission in synaptic homeostasis. Here, we show that the miniature synaptic transmission that persists during AP blockade profoundly shapes the time course and mechanism of homeostatic scaling. A brief blockade of NMDA receptor (NMDAR) mediated miniature synaptic events ("minis") rapidly scales up synaptic strength, over an order of magnitude faster than with AP blockade alone. The rapid scaling induced by NMDAR mini blockade is mediated by increased synaptic expression of surface GluR1 and the transient incorporation of Ca2+-permeable AMPA receptors at synapses; both of these changes are implemented locally within dendrites and require dendritic protein synthesis. These results indicate that NMDAR signaling during miniature synaptic transmission serves to stabilize synaptic function through active suppression of dendritic protein synthesis.
Local protein synthesis in dendrites has emerged as a key mechanism contributing to enduring forms of synaptic plasticity. Although the translational capability of dendrites has been appreciated for over 20 years, it is only recently that significant progress has been made in elucidating mechanisms that contribute to its regulation. It is clear from work over the last few years that the control of translation in dendrites is complex, involving a host of unique (and often surprising) mechanisms that can operate together or in parallel to tightly control gene expression in time and space. Here, we discuss the strategies used by neurons to regulate translation in dendrites and how these are implemented in the service of long-term information storage.
From the basic light microscope through high-end imaging systems such as multiphoton confocal microscopy and electron microscopes, microscopy has been and will continue to be an essential tool in developing an understanding of cardiovascular development, function, and disease. In this review we briefly touch on a number of studies that illustrate the importance of these forms of microscopy in studying cardiovascular biology. We also briefly review a number of imaging modalities such as computed tomography (CT), magnetic resonance imaging (MRI), ultrasound, and positron emission tomography (PET) that, although they do not fall under the realm of microscopy, are imaging modalities that greatly complement microscopy. Finally we examine the role of proper imaging system calibration and the potential importance of calibration in understanding biological tissues, such as the cardiovascular system, that continually undergo deformation in response to strain.
We examined dendritic protein synthesis after a prolonged blockade of action potentials alone and after a blockade of both action potentials and miniature excitatory synaptic events (minis). Relative to controls, dendrites exposed to a prolonged blockade of action potentials showed diminished protein synthesis. Dendrites in which both action potentials and minis were blocked showed enhanced protein synthesis, suggesting that minis inhibit dendritic translation. When minis were acutely blocked or stimulated, an immediate increase or decrease, respectively, in dendritic translation was observed. Taken together, these results reveal a role for miniature synaptic events in the acute regulation of dendritic protein synthesis in neurons.
Recent studies of long-term synaptic plasticity and long-term memory have demonstrated that the same functional endpoint, such as long-term potentiation, can be induced through distinct signaling pathways engaged by different patterns of stimulation. A critical question raised by these studies is whether different induction pathways either converge onto a common molecular mechanism or engage different molecular cascades for the maintenance of long-term plasticity. We directly examined this issue in the context of memory for sensitization in the marine mollusk Aplysia. In this system, training with a single tail shock normally induces short-term memory (<30 min) for sensitization of tail-elicited siphon withdrawal, whereas repeated spaced shocks induce both intermediate-term memory (ITM) (>90 min) and long-term memory (>24 hr). We now show that a single tail shock can also induce ITM that is expressed selectively at the trained site (site-specific ITM). Although phenotypically similar to the form of ITM induced by repeated trials, the mechanisms by which site-specific ITM is induced and maintained are distinct. Unlike repeated-trial ITM, site-specific ITM requires neither protein synthesis nor PKA activity for induction or maintenance. Rather, the induction of site-specific ITM requires calpain-dependent proteolysis of activated PKC, yielding a persistently active PKC catalytic fragment (PKM) that also serves to maintain the memory in the intermediateterm temporal domain. Thus, two unique forms of ITM that have different induction requirements also use distinct molecular mechanisms for their maintenance.
The tail-elicited siphon withdrawal reflex (TSW) has been a useful preparation in which to study learning and memory in Aplysia. However, comparatively little is known about the neural circuitry that translates tail sensory input (via the P9 nerves to the pleural ganglion) to final reflex output by siphon motor neurons (MNs) in the abdominal ganglion. To address this question, we examined the functional architecture of the TSW circuit by selectively severing nerves of semi-intact preparations and recording either tail-evoked responses in the siphon MNs or measuring siphon withdrawal responses directly. We found that the neural circuit underlying TSW is functionally lateralized. We next tested whether the expression of learning in the TSW reflects the underlying circuit architecture and shows side-specificity. We tested behavioral and physiological correlates of three forms of learning: sensitization, habituation, and dishabituation. Consistent with the circuit architecture, we found that sensitization and habituation of TSW are expressed in a side-specific manner. Unexpectedly, we found that dishabituation was expressed bilaterally, suggesting that a modulatory pathway bridges the two (ipsilateral) input pathways of the circuit, but this path is only revealed for a specific form of learning, dishabituation. These results suggest that the effects of a descending modulatory signal are differentially "gated" during sensitization and dishabituation.
The mitogen-activated protein kinase (MAPK) pathway has been implicated recently in synaptic plasticity and memory. Here we used tail shock-induced sensitization of the tail-elicited siphon withdrawal reflex in Aplysia to examine the role of MAPK in three different phases of memory. We show that a specific pattern of serotonin (5-HT) application that produces intermediate-term and long-term synaptic facilitation (ITF and LTF, respectively) of the sensory-motor (SN-MN) synapses in Aplysia leads to sustained activation of extracellular signal-regulated kinase in the ventrocaudal cluster sensory neurons (SNs), which include the tail SNs. Furthermore, repeated tail shocks that induce intermediate-term and long-term memory (ITM and LTM, respectively) for sensitization also lead to sustained MAPK activation in the SNs. Given these results, we next examined the requirement of MAPK activity in (1) SN-MN synaptic facilitation and (2) memory for sensitization in Aplysia, by inhibiting MEK, the upstream kinase that phosphorylates and activates MAPK. In cellular experiments, we show that MAPK activity is required for ITF of tail SN-tail MN synapses, and, in parallel behavioral experiments, we show that ITM requires MAPK activity for its induction but not its expression. In contrast, short-term memory for sensitization does not require MAPK activity. Finally, 5-HT-induced LTF has been shown previously to require MAPK activity. Here we show that LTM for sensitization also requires MAPK activity. These results provide evidence that MAPK plays important roles specifically in long-lasting phases of synaptic plasticity and memory.
The induction of both synaptic plasticity and memory is thought to depend on the balance between opposing molecular regulatory factors, such as protein kinases and phosphatases. Here we show that inhibition of protein phosphatase 2B (calcineurin, CaN) facilitates the induction of intermediate-term memory (ITM) and long-term memory (LTM) for tail shock-induced sensitization in Aplysia without any effect on short-term memory. To identify the molecular cascade underlying the improvement of memory by inhibition of CaN, we examined the role of extracellular signal-regulated kinase 1/2/mitogen-activated protein kinase (MAPK). Molecular experiments revealed that one pulse of serotonin, which by itself does not activate MAPK, leads to significant MAPK activation in the sensory neurons of the pleural ganglia when CaN is inhibited. Extending these observations, behavioral experiments showed that the facilitated induction of ITM and LTM produced by CaN inhibition depends on MAPK activity. These results demonstrate: (i) that CaN acts as an inhibitory constraint in the formation of long-lasting phases of memory, and (ii) that facilitated induction of ITM and LTM by CaN inhibition requires MAPK activity.
Tyrosine kinases have been implicated in cellular processes thought to underlie learning and memory. Here we show that tyrosine kinases play a direct role in long-term synaptic facilitation (LTF) and long-term memory (LTM) for sensitization in Aplysia. Tyrosine kinase activity is required for serotonin-induced LTF of sensorimotor (SN-MN) synapses, and enhancement of endogenous tyrosine kinase activity facilitates the induction of LTF. These effects are mediated, at least in part, through mitogen-activated protein kinase (MAPK) activation and are blocked by transcriptional and translational inhibitors. Moreover, brain-derived neurotrophic factor (BDNF) also enhances the induction of LTF in a MAPK-dependent fashion. Finally, activation of endogenous tyrosine kinases enhances the induction of long-term memory for sensitization, and this enhancement also requires MAPK activation. Thus, tyrosine kinases, acting through MAPK, play a pivotal role in LTF and LTM formation.
Cocaine addiction is thought to involve persistent neurobiological changes that facilitate relapse to drug use despite efforts to abstain. But the propensity for relapse may be reduced by extinction training--a form of inhibitory learning that progressively reduces cocaine-seeking behaviour in the absence of cocaine reward. Here we show that extinction training during withdrawal from chronic cocaine self-administration induces experience-dependent increases in the GluR1 and GluR2/3 subunits of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate) glutamate receptors in the nucleus accumbens shell, a brain region that is critically involved in cocaine reward. Increases in the GluR1 subunit are positively associated with the level of extinction achieved during training, suggesting that GluR1 may promote extinction of cocaine seeking. Indeed, viral-mediated overexpression of both GluR1 and GluR2 in nucleus accumbens shell neurons facilitates extinction of cocaine- but not sucrose-seeking responses. A single extinction training session, when conducted during GluR subunit overexpression, attenuates stress-induced relapse to cocaine seeking even after GluR overexpression declines. Our findings indicate that extinction-induced plasticity in AMPA receptors may facilitate control over cocaine seeking by restoring glutamatergic tone in the nucleus accumbens, and may reduce the propensity for relapse under stressful situations in prolonged abstinence.
In Aplysia, three distinct phases of memory for sensitization can be dissociated based on their temporal and molecular features. A single training trial induces short-term memory (STM, lasting <30 min), whereas five trials delivered at 15-min intervals induces both intermediate-term memory (ITM, lasting >90 min) and long-term memory (LTM, lasting >24 h). Here, we explore the interaction of amount and pattern of training in establishing ITM and LTM by examining memory for sensitization after different numbers of trials (each trial = one tail shock) and different patterns of training (massed vs. spaced). Under spaced training patterns, two trials produced STM exclusively, whereas four or five trials each produced both ITM and LTM. Three spaced trials failed to induce LTM but did produce an early decaying form of ITM (E-ITM) that was significantly shorter and weaker in magnitude than the late-decaying ITM (L-ITM) observed after four to five trials. In addition, E-ITM was induced after three trials with both massed and spaced patterns of training. However, L-ITM and LTM after four to five trials require spaced training: Four or five massed trials failed to induce LTM and produced only E-ITM. Collectively, our results indicate that in addition to three identified phases of memory for sensitization--STM, ITM, and LTM--a unique temporal profile of memory, E-ITM, is revealed by varying either the amount or pattern of training.