Over the past century, psychologists have discussed whether forgetting might arise from active mechanisms that promote memory loss to achieve various functions, such as minimizing errors, ...facilitating learning, or regulating one's emotional state. The past decade has witnessed a great expansion in knowledge about the brain mechanisms underlying active forgetting in its varying forms. A core discovery concerns the role of the prefrontal cortex in exerting top-down control over mnemonic activity in the hippocampus and other brain structures, often via inhibitory control. New findings reveal that such processes not only induce forgetting of specific memories but also can suppress the operation of mnemonic processes more broadly, triggering windows of anterograde and retrograde amnesia in healthy people. Recent work extends active forgetting to nonhuman animals, presaging the development of a multilevel mechanistic account that spans the cognitive, systems, network, and even cellular levels. This work reveals how organisms adapt their memories to their cognitive and emotional goals and has implications for understanding vulnerability to psychiatric disorders.
Highlights • Motivated forgetting of unwanted memories shapes what we retain of our personal past. • Motivated forgetting is achieved in part by inhibitory control over encoding or retrieval. • ...Prefrontal cortex reduces hippocampal and cortical activity to suppress memories. • Electrophysiological activity during motivated forgetting implicates active inhibition. • A neurobiological model of memory control can inform disordered control over memory.
Intrusive memories often take the form of distressing images that emerge into a person's awareness, unbidden. A fundamental goal of clinical neuroscience is to understand the mechanisms allowing ...people to control these memory intrusions and reduce their emotional impact. Mnemonic control engages a right frontoparietal network that interrupts episodic retrieval by modulating hippocampal activity; less is known, however, about how this mechanism contributes to affect regulation. Here we report evidence in humans (males and females) that stopping episodic retrieval to suppress an unpleasant image triggers parallel inhibition of mnemonic and emotional content. Using fMRI, we found that regulation of both mnemonic and emotional content was driven by a shared frontoparietal inhibitory network and was predicted by a common profile of medial temporal lobe downregulation involving the anterior hippocampus and the amygdala. Critically, effective connectivity analysis confirmed that reduced amygdala activity was not merely an indirect consequence of hippocampal suppression; rather, both the hippocampus and the amygdala were targeted by a top-down inhibitory control signal originating from the dorsolateral prefrontal cortex. This negative coupling was greater when unwanted memories intruded into awareness and needed to be purged. Together, these findings support the broad principle that retrieval suppression is achieved by regulating hippocampal processes in tandem with domain-specific brain regions involved in reinstating specific content, in an activity-dependent fashion.
Upsetting events sometimes trigger intrusive images that cause distress and that may contribute to psychiatric disorders. People often respond to intrusions by suppressing their retrieval, excluding them from awareness. Here we examined whether suppressing aversive images might also alter emotional responses to them, and the mechanisms underlying such changes. We found that the better people were at suppressing intrusions, the more it reduced their emotional responses to suppressed images. These dual effects on memory and emotion originated from a common right prefrontal cortical mechanism that downregulated the hippocampus and amygdala in parallel. Thus, suppressing intrusions affected emotional content. Importantly, participants who did not suppress intrusions well showed increased negative affect, suggesting that suppression deficits render people vulnerable to psychiatric disorders.
Neuroimaging has revealed robust interactions between the prefrontal cortex and the hippocampus when people stop memory retrieval. Efforts to stop retrieval can arise when people encounter reminders ...to unpleasant thoughts they prefer not to think about. Retrieval stopping suppresses hippocampal and amygdala activity, especially when cues elicit aversive memory intrusions, via a broad inhibitory control capacity enabling prepotent response suppression. Repeated retrieval stopping reduces intrusions of unpleasant memories and diminishes their affective tone, outcomes resembling those achieved by the extinction of conditioned emotional responses. Despite this resemblance, the role of inhibitory fronto-hippocampal interactions and retrieval stopping broadly in extinction has received little attention. Here we integrate human and animal research on extinction and retrieval stopping. We argue that reconceptualising extinction to integrate mnemonic inhibitory control with learning would yield a greater understanding of extinction's relevance to mental health. We hypothesize that fear extinction spontaneously engages retrieval stopping across species, and that controlled suppression of hippocampal and amygdala activity by the prefrontal cortex reduces fearful thoughts. Moreover, we argue that retrieval stopping recruits extinction circuitry to achieve affect regulation, linking extinction to how humans cope with intrusive thoughts. We discuss novel hypotheses derived from this theoretical synthesis.
Cancer genomics studies have identified thousands of putative cancer driver genes
. Development of high-throughput and accurate models to define the functions of these genes is a major challenge. ...Here we devised a scalable cancer-spheroid model and performed genome-wide CRISPR screens in 2D monolayers and 3D lung-cancer spheroids. CRISPR phenotypes in 3D more accurately recapitulated those of in vivo tumours, and genes with differential sensitivities between 2D and 3D conditions were highly enriched for genes that are mutated in lung cancers. These analyses also revealed drivers that are essential for cancer growth in 3D and in vivo, but not in 2D. Notably, we found that carboxypeptidase D is responsible for removal of a C-terminal RKRR motif
from the α-chain of the insulin-like growth factor 1 receptor that is critical for receptor activity. Carboxypeptidase D expression correlates with patient outcomes in patients with lung cancer, and loss of carboxypeptidase D reduced tumour growth. Our results reveal key differences between 2D and 3D cancer models, and establish a generalizable strategy for performing CRISPR screens in spheroids to reveal cancer vulnerabilities.
•Retrieval suppression is a model for understanding inhibitory control over thought.•Suppression engages dorsolateral prefrontal cortex (DLPFC), reducing hippocampal activity.•Anterior cingulate ...cortex (ACC) may mediate DLPFC’s influence on the hippocampus.•ACC pathways may gate entorhinal input to the hippocampus to prevent retrieval.•ACC may suppress hippocampal activity via nucleus reuniens, to stop retrieval.
A key function of the prefrontal cortex is to support inhibitory control over behavior. It is widely believed that this function extends to stopping cognitive processes as well. Consistent with this, mounting evidence establishes the role of the right lateral prefrontal cortex in a clear case of cognitive control: retrieval suppression. Retrieval suppression refers to the ability to intentionally stop the retrieval process that arises when a reminder to a memory appears. Functional imaging data indicate that retrieval suppression involves top-down modulation of hippocampal activity by the dorsolateral prefrontal cortex, but the anatomical pathways supporting this inhibitory modulation remain unclear. Here we bridge this gap by integrating key findings about retrieval suppression observed through functional imaging with a detailed consideration of relevant anatomical pathways observed in non-human primates. Focusing selectively on the potential role of the anterior cingulate cortex, we develop two hypotheses about the pathways mediating interactions between lateral prefrontal cortex and the medial temporal lobes during suppression, and their cellular targets: the entorhinal gating hypothesis, and thalamo-hippocampal modulation via the nucleus reuniens. We hypothesize that whereas entorhinal gating is well situated to stop retrieval proactively, thalamo-hippocampal modulation may interrupt an ongoing act of retrieval reactively. Isolating the pathways that underlie retrieval suppression holds the potential to advance our understanding of a range of psychiatric disorders characterized by persistent intrusive thoughts. More broadly, an anatomical account of retrieval suppression would provide a key model system for understanding inhibitory control over cognition.
Memories play a ubiquitous role in our emotional lives, both causing vivid emotional experiences in their own right and imbuing perception of the external world with emotional significance. ...Controlling the emotional impact of memories therefore poses a major emotion-regulation challenge, suggesting that there might be a hitherto unexplored link between the neurocognitive mechanisms underlying memory control (MC) and emotion regulation. We present here a theoretical account of how the mechanisms of MC constitute core component processes of cognitive emotion regulation (CER), and how this observation may help to understand its basic mechanisms and their disruption in psychiatric disorders.
The neural correlates of emotion regulation have been studied extensively over the past decade, but without consideration of the mechanistic role of memory control.
Knowledge of the neurocognitive mechanisms enabling the suppression of memories and thoughts from conscious awareness has grown increasingly specific.
Recent studies reveal an association between memory control deficits and affective psychopathologies such as depression and post-traumatic stress disorder, suggesting that controlling memory and affect are interrelated.
Successfully controlling the retrieval of intrusive memories reduces their later emotional impact via modulation of amygdala activity, indicating that controlling memories regulates affect.
Memory control processes may provide a mechanistic foundation for emotion regulation, thereby contributing to a unified account of the mechanisms underlying this process.
Marine fish stocks are an important part of the world food system and are particularly important for many of the poorest people of the world. Most existing analyses suggest overfishing is increasing, ...and there is widespread concern that fish stocks are decreasing throughout most of the world. We assembled trends in abundance and harvest rate of stocks that are scientifically assessed, constituting half of the reported global marine fish catch. For these stocks, on average, abundance is increasing and is at proposed target levels. Compared with regions that are intensively managed, regions with less-developed fisheries management have, on average, 3-fold greater harvest rates and half the abundance as assessed stocks. Available evidence suggests that the regions without assessments of abundance have little fisheries management, and stocks are in poor shape. Increased application of area-appropriate fisheries science recommendations and management tools are still needed for sustaining fisheries in places where they are lacking.
CD4 T cell activation leads to proliferation and differentiation into effector (Teff) or regulatory (Treg) cells that mediate or control immunity. While each subset prefers distinct glycolytic or ...oxidative metabolic programs in vitro, requirements and mechanisms that control T cell glucose uptake and metabolism in vivo are uncertain. Despite expression of multiple glucose transporters, Glut1 deficiency selectively impaired metabolism and function of thymocytes and Teff. Resting T cells were normal until activated, when Glut1 deficiency prevented increased glucose uptake and glycolysis, growth, proliferation, and decreased Teff survival and differentiation. Importantly, Glut1 deficiency decreased Teff expansion and the ability to induce inflammatory disease in vivo. Treg cells, in contrast, were enriched in vivo and appeared functionally unaffected and able to suppress Teff, irrespective of Glut1 expression. These data show a selective in vivo requirement for Glut1 in metabolic reprogramming of CD4 T cell activation and Teff expansion and survival.
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•CD4 T cells express multiple glucose transporters, including Gluts 1, 3, 6, and 8•Glut1 has nonredundant function in activated, but not resting, CD4 T cells•CD4 Th1 and Th17 selectively require Glut1 in vivo to regulate immunologic diseases•Targeting T cell glucose metabolism in vivo can selectively impact effector cells
T cells undergo distinct metabolic reprogramming events upon activation and differentiation to inflammatory effectors or regulatory cells. Macintyre et al. show that Glut1 is the only glucose transporter required to drive glycolysis for growth and expansion of effector, but not resting or regulatory, CD4 T cells and induce inflammatory diseases.
Remembering a past experience can, surprisingly, cause forgetting. Forgetting arises when other competing traces interfere with retrieval and inhibitory control mechanisms are engaged to suppress the ...distraction they cause. This form of forgetting is considered to be adaptive because it reduces future interference. The effect of this proposed inhibition process on competing memories has, however, never been observed, as behavioral methods are 'blind' to retrieval dynamics and neuroimaging methods have not isolated retrieval of individual memories. We developed a canonical template tracking method to quantify the activation state of individual target memories and competitors during retrieval. This method revealed that repeatedly retrieving target memories suppressed cortical patterns unique to competitors. Pattern suppression was related to engagement of prefrontal regions that have been implicated in resolving retrieval competition and, critically, predicted later forgetting. Thus, our findings demonstrate a cortical pattern suppression mechanism through which remembering adaptively shapes which aspects of our past remain accessible.
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