It has been 70 years since Donald Hebb published his formalized theory of synaptic adaptation during learning. Hebb's seminal work foreshadowed some of the great neuroscientific discoveries of the ...following decades, including the discovery of long-term potentiation and other lasting forms of synaptic plasticity, and more recently the residence of memories in synaptically connected neuronal assemblies. Our understanding of the processes underlying learning and memory has been dominated by the view that synapses are the principal site of information storage in the brain. This view has received substantial support from research in several model systems, with the vast majority of studies on the topic corroborating a role for synapses in memory storage. Yet, despite the neuroscience community's best efforts, we are still without conclusive proof that memories reside at synapses. Furthermore, an increasing number of non-synaptic mechanisms have emerged that are also capable of acting as memory substrates. In this review, we address the key findings from the synaptic plasticity literature that make these phenomena such attractive memory mechanisms. We then turn our attention to evidence that questions the reliance of memory exclusively on changes at the synapse and attempt to integrate these opposing views.
Highlights • A framework for potential roles of metaplasticity in vivo is presented. • Metaplasticity can prepare synapses and networks for learning. • Metaplasticity can homeostatically keep ...synaptic plasticity within a dynamic range. • Metaplasticity mechanisms may play roles in disease and treatment.
Synapses undergo significant structural and functional reorganization in response to varying patterns of stimulation. These forms of plasticity are considered fundamental to cognition and neuronal ...homeostasis. An increasing number of reports highlight the importance of activity-dependent synaptic strengthening (long term potentiation: LTP) for learning. However, the functional significance of activity-dependent weakening of synapses (long term depression: LTD) remains relatively poorly understood. One form of synaptic weakening, induced by group I metabotropic glutamate receptors (mGluRs), has received significant attention from a mechanistic point of view and because of its augmentation in a murine model of Fragile X Syndrome. Yet, studies of this form of plasticity often yield confusing, contradictory results. These conflicting findings are likely attributable to the bulk stimulation and recording techniques often used to study synaptic plasticity (typically involving evoked extracellular recordings, which represent the summed activity of many synapses). Such studies inherently blur the identity of the synapses undergoing change, thus giving the illusion that synapses per se are being modified when in fact this may only be true of a specific subset of synapses. Indeed, studies employing minimal synaptic activation paint a fundamentally different picture of what is commonly called "mGluR-LTD". Here, I review the evidence in favour of group I mGluRs as mediators of various forms of synaptic downregulation and attempt to explain discrepancies in the literature. I argue that, while multiple forms of synaptic weakening may be triggered by these receptors, the canonical form of group I mGluR-mediated depression, mGluR-LTD, is in fact not a depression of basal synaptic responses. Rather, it is a reversal of established LTP and thus a form of depotentiation. Far from being arbitrary, this distinction has significant implications for the role of group I mGluRs in cognition, both in the healthy brain and in pathological conditions. Further, the differential actions of group I mGluRs at naïve and potentiated synapses suggest these receptors signal in a state-dependent manner to regulate various stages of the learning process.
Long-term potentiation (LTP) is regulated in part by metaplasticity, the activity-dependent alterations in neural state that coordinate the direction, amplitude, and persistence of future synaptic ...plasticity. Previously, we documented a heterodendritic metaplasticity effect whereby high-frequency priming stimulation in stratum oriens (SO) of hippocampal CA1 suppressed subsequent LTP in the stratum radiatum (SR). The cytokine tumor necrosis factor (TNF) mediated this heterodendritic metaplasticity in wild-type rodents and in a mouse model of Alzheimer's disease. Here, we investigated whether LTP at other afferent synapses to CA1 pyramidal cells were similarly affected by priming stimulation. We found that priming stimulation in SO inhibited LTP only in SR and not in a second independent pathway in SO, nor in stratum lacunosum moleculare (SLM). Synapses in SR were also more sensitive than SO or SLM to the LTP-inhibiting effects of pharmacological TNF priming. Neither form of priming was sex-specific, while the metaplasticity effects were absent in TNFR1 knock-out mice. Our findings demonstrate an unexpected pathway specificity for the heterodendritic metaplasticity in CA1. That Schaffer collateral/commissural synapses in SR are particularly susceptible to such metaplasticity may reflect an important control of information processing in this pathway in addition to its sensitivity to neuroinflammation under disease conditions.
Mechanisms of heterosynaptic metaplasticity Hulme, Sarah R.; Jones, Owen D.; Raymond, Clarke R. ...
Philosophical transactions of the Royal Society of London. Series B. Biological sciences,
01/2014, Letnik:
369, Številka:
1633
Journal Article
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Synaptic plasticity is fundamental to the neural processes underlying learning and memory. Interestingly, synaptic plasticity itself can be dynamically regulated by prior activity, in a process ...termed ‘metaplasticity’, which can be expressed both homosynaptically and heterosynaptically. Here, we focus on heterosynaptic metaplasticity, particularly long-range interactions between synapses spread across dendritic compartments, and review evidence for intracellular versus intercellular signalling pathways leading to this effect. Of particular interest is our previously reported finding that priming stimulation in stratum oriens of area CA1 in the hippocampal slice heterosynaptically inhibits subsequent long-term potentiation and facilitates long-term depression in stratum radiatum. As we have excluded the most likely intracellular signalling pathways that might mediate this long-range heterosynaptic effect, we consider the hypothesis that intercellular communication may be critically involved. This hypothesis is supported by the finding that extracellular ATP hydrolysis, and activation of adenosine A2 receptors are required to induce the metaplastic state. Moreover, delivery of the priming stimulation in stratum oriens elicited astrocytic calcium responses in stratum radiatum. Both the astrocytic responses and the metaplasticity were blocked by gap junction inhibitors. Taken together, these findings support a novel intercellular communication system, possibly involving astrocytes, being required for this type of heterosynaptic metaplasticity.
Legal decision-making in criminal contexts includes two essential functions performed by impartial “third parties:” assessing responsibility and determining an appropriate punishment. To explore the ...neural underpinnings of these processes, we scanned subjects with fMRI while they determined the appropriate punishment for crimes that varied in perpetrator responsibility and crime severity. Activity within regions linked to affective processing (amygdala, medial prefrontal and posterior cingulate cortex) predicted punishment magnitude for a range of criminal scenarios. By contrast, activity in right dorsolateral prefrontal cortex distinguished between scenarios on the basis of criminal responsibility, suggesting that it plays a key role in third-party punishment. The same prefrontal region has previously been shown to be involved in punishing unfair economic behavior in two-party interactions, raising the possibility that the cognitive processes supporting third-party legal decision-making and second-party economic norm enforcement may be supported by a common neural mechanism in human prefrontal cortex.
DETECTING MENS REA IN THE BRAIN Jones, Owen D.; Montague, Read; Yaffe, Gideon
University of Pennsylvania law review,
12/2020, Letnik:
169, Številka:
1
Journal Article
Recenzirano
Mental states matter. Consequently, we and colleagues designed and executed a brain-imaging experiment attempting to detect - for the first time - differences between mental states relevant to ...criminal law. With a grant from the MacArthur Foundation Research Network on Law and Neuroscience, we as part of a larger interdisciplinary team set out to investigate the knowing-reckless distinction in the brain, and the boundary that may separate them. Specifically, we aimed to see if we could use brain activity alone to detect the difference between those who the law would classify as "knowing" and as "reckless." By combining the relatively new technical achievements of functional magnetic resonance imaging (fMRI) with new advances in the analytic abilities of machine-learning algorithms (a form of artificial intelligence) our team conducted the first assault on this thorny legal problem. This essay reports and describes, for a legal audience, the results and implications of our experiment. We found evidence strongly supporting the existence of a brain-based distinction between knowing and reckless mental states., Mental states matter. Consequently, we and colleagues designed and executed a brain-imaging experiment attempting to detect - for the first time - differences between mental states relevant to criminal law. With a grant from the MacArthur Foundation Research Network on Law and Neuroscience, we — as part of a larger interdisciplinary team — set out to investigate the knowing-reckless distinction in the brain, and the boundary that may separate them. Specifically, we aimed to see if we could use brain activity alone to detect the difference between those who the law would classify as “knowing” and as “reckless.” By combining the relatively new technical achievements of functional magnetic resonance imaging (fMRI) with new advances in the analytic abilities of machine-learning algorithms (a form of artificial intelligence) our team conducted the first assault on this thorny legal problem. This essay reports and describes, for a legal audience, the results and implications of our experiment. We found evidence strongly supporting the existence of a brain-based distinction between knowing and reckless mental states.
Neuroscientists in court Jones, Owen D; Wagner, Anthony D; Faigman, David L ...
Nature reviews. Neuroscience,
10/2013, Letnik:
14, Številka:
10
Journal Article
Recenzirano
Neuroscientific evidence is increasingly being offered in court cases. Consequently, the legal system needs neuroscientists to act as expert witnesses who can explain the limitations and ...interpretations of neuroscientific findings so that judges and jurors can make informed and appropriate inferences. The growing role of neuroscientists in court means that neuroscientists should be aware of important differences between the scientific and legal fields, and, especially, how scientific facts can be easily misunderstood by non-scientists, including judges and jurors.
LTP, a fundamental mechanism of learning and memory, is a highly regulated process. One form of regulation is metaplasticity (i.e., the activity-dependent and long-lasting changes in neuronal state ...that orchestrate the direction, magnitude, and persistence of future synaptic plasticity). We have previously described a heterodendritic metaplasticity effect, whereby strong high-frequency priming stimulation in stratum oriens inhibits subsequent LTP in the stratum radiatum of hippocampal area CA1, potentially by engagement of the enmeshed astrocytic network. This effect may occur due to neuron-glia interactions in response to priming stimulation that leads to the release of gliotransmitters. Here we found in male rats that TNFα and associated signal transduction enzymes, but not interleukin-1β (IL-1β), were responsible for mediating the metaplasticity effect. Replacing priming stimulation with TNFα incubation reproduced these effects. As TNFα levels are elevated in Alzheimer's disease, we examined whether heterodendritic metaplasticity is dysregulated in a transgenic mouse model of the disease, either before or after amyloid plaque formation. We showed that TNFα and IL-1β levels were significantly increased in aged but not young transgenic mice. Although control LTP was impaired in the young transgenic mice, it was not TNFα-dependent. In the older transgenic mice, however, LTP was impaired in a way that occluded further reduction by heterosynaptic metaplasticity, whereas LTP was entirely rescued by incubation with a TNFα antibody, but not an IL-1β antibody. Thus, TNFα mediates a heterodendritic metaplasticity in healthy rodents that becomes constitutively and selectively engaged in a mouse model of Alzheimer's disease.
The proinflammatory cytokine TNFα is known to be capable of inhibiting LTP and is upregulated several-fold in brain tissue, serum, and CSF of Alzheimer's disease (AD) patients. However, the mechanistic roles played by TNFα in plasticity and AD remain poorly understood. Here we show that TNFα and its downstream signaling molecules p38 MAPK, ERK, and JNK contribute fundamentally to a long-range metaplastic inhibition of LTP in rats. Moreover, the impaired LTP in aged
mice is rescued by incubation with a TNFα antibody. Thus, there is an endogenous engagement of the metaplasticity mechanism in this mouse model of AD, supporting the idea that blocking TNFα might be of therapeutic benefit in the disease.
Law, responsibility, and the brain Mobbs, Dean; Lau, Hakwan C; Jones, Owen D ...
PLoS biology,
04/2007, Letnik:
5, Številka:
4
Journal Article
Recenzirano
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A similar pattern emerges for the amygdala, where damage can result in increased or decreased aggression 23,56. ...in court proceedings, many experts have argued against the use of ambitious ...speculations concerning the brain (e.g., State of Tennessee v. Paul Dennis Reid Jr., 2002, No. 38887), particularly where the link between the criminal act and the neurological damage is based solely on brain-imaging data. ...important legal questions such as moral blameworthiness, culpability, responsibility, and the likelihood of recidivism depend to some degree on improved understandings of human behaviour. ...biological advances in understanding human brain architecture and function may overlap in important ways with legal inquiries.
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