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© 2014 Nature America, Inc. All rights reserved.
Throughout life, new neurons are generated in the hippocampus, where they form a structure that supports memory creation. When new neurons are integrated into the hippocampus, they compete with e xisting cells, forging new synaptic connections that may weaken or replace older ones. As a result, high rates of h ippocampal n eurogenesis may drive the loss of information stored in existing circuits—i.e., forgetting. In many species, including mice and humans, rates of hippocampal neurogenesis are high d uring infancy and decline markedly over time. Consistent with the idea that hippocampal neurogenesis and f orgetting are p ositively correlated, infancy in these species is also characterized by the absence of longterm memory formation. The c orrelation piqued the interest of Sheena Josselyn and Paul Frankland, n euroscientists at the University of Toronto and Hospital for Sick Children (both in Toronto, Canada): “This inverse relationship between the l evels of neurogenesis and the ability to form a longterm memory got us thinking that maybe one is due to the other,” Josselyn told The Scientist. Josselyn and Frankland’s team carried out experiments to assess whether hippocampal
Emilia Stasiak/Hemera/Thinkstock
Eternal sunshine of the rodent mind
neurogenesis regulates f orgetting. Rodents were placed in a distinctive box where they received electric shocks and hence learned to fear the box. The team then manipulated neurogenesis in the rodents either p harmacologically or by p roviding access to running wheels (running e nhances n eurogenesis). The rodents were later returned to the box, and their reactions were observed (Science 344, 598–602; 2014). Freezing, considered a fear response, is a common reaction and indicates that the
rodents remembered their previous n egative experience with the box. Providing access to a running wheel and pharmacologically increasing neurogenesis both curtailed freezing behavior in mice, suggesting that the mice had forgotten their previous negative experience. Furthermore, pharmacological inhibition of neurogenesis in mice with running wheels and in infant mice increased freezing behavior, s uggesting that limiting neurogenesis improved memory retention. The researchers also studied guinea pigs and degus, which have lower rates of neurogenesis during infancy than do mice or humans. Guinea pigs and degus remembered the box for much longer than did mice, but boosting neurogenesis (either pharmacologically or by providing access to a running wheel) induced them to forget. The results show that neurogenesis can disrupt established memories and that increasing neurogenesis can induce forgetting. The findings support the idea that there is a trade-off between formation of new memories and retention of existing ones. As Josselyn points out, “forgetting is an important part of healthy memory.” Monica Harrington
The heart of an endurance athlete Physical activity has many positive effects on the cardiovascular system, but intense endurance training can also be detrimental. Athletes, especially those with a long training history, are more likely to develop arrhythmias. Sinus bradycardia (a slow resting heart rate) is the most common training-associated arrhythmia. Although it is often a benign physiological adaptation to maintain normal cardiac output and blood pressure by compensating for training-induced increases in stroke volume, bradycardia can become pathological and lead to the need for electronic pacemaker implantation. High incidences of pacemaker implantation to control bradyarrhythmias have been reported among former professional cyclists and among elderly marathon runners. Training-induced bradycardia has been attributed to changes in the autonomic nervous system, such as an increase in vagal tone. But bradycardia is observed in athletes even when the autonomic nervous system is blocked. Instead, some data suggest that long-term endurance training may induce pathological remodeling of the heart that manifests in arrhythmia. A study recently published by Mark Boyett (University of Manchester, UK) and colleagues supports this explanation. Boyett’s work shows that training-induced bradycardia is caused by electrophysiological changes in the sinus node, the pacemaker of the heart, and, more specifically, by a remodeling of the ion channels that control pacemaking (Nat. Commun. 5, 3775; 2014). In Boyett’s study, rats and mice underwent exercise training (running or swimming), and their cardiovascular function was compared with that of sedentary controls. Trained animals developed sinus bradycardia that persisted after blockade of the autonomous nervous system. Exercise training also induced a widespread remodeling of pacemaker ion channels, decreasing expression of the HCN4 channel and activity of its corresponding ionic current. ‘Detraining’ the mice reversed these changes. The results indicate that heart rate adaption to endurance training does not result from changes in autonomic tone but is primarily caused by remodeling of the sinus node. The higher incidence of sinus node disease and pacemaker implantation among veteran endurance athletes is likely a consequence of this remodeling. Sinus-node remodeling may also help explain syncope in young athletes, and analogous remodeling of other parts of the heart may explain other training-associated arrhythmias (e.g., atrial fibrillation, heart block and bundle branch block). Although sinus-node remodeling and its consequences were reversible after short-term endurance training, it is unclear whether they remain reversible after long-term training. The findings provide a molecular explanation for potentially pathological heart rate adaptations to endurance training and may help inform lifestyle choices in athletes. Monica Harrington
LAB ANIMAL
Volume 43, No. 7 | JULY 2014 223
npg
© 2014 Nature America, Inc. All rights reserved.
Throughout life, new neurons are generated in the hippocampus, where they form a structure that supports memory creation. When new neurons are integrated into the hippocampus, they compete with e xisting cells, forging new synaptic connections that may weaken or replace older ones. As a result, high rates of h ippocampal n eurogenesis may drive the loss of information stored in existing circuits—i.e., forgetting. In many species, including mice and humans, rates of hippocampal neurogenesis are high d uring infancy and decline markedly over time. Consistent with the idea that hippocampal neurogenesis and f orgetting are p ositively correlated, infancy in these species is also characterized by the absence of longterm memory formation. The c orrelation piqued the interest of Sheena Josselyn and Paul Frankland, n euroscientists at the University of Toronto and Hospital for Sick Children (both in Toronto, Canada): “This inverse relationship between the l evels of neurogenesis and the ability to form a longterm memory got us thinking that maybe one is due to the other,” Josselyn told The Scientist. Josselyn and Frankland’s team carried out experiments to assess whether hippocampal
Emilia Stasiak/Hemera/Thinkstock
Eternal sunshine of the rodent mind
neurogenesis regulates f orgetting. Rodents were placed in a distinctive box where they received electric shocks and hence learned to fear the box. The team then manipulated neurogenesis in the rodents either p harmacologically or by p roviding access to running wheels (running e nhances n eurogenesis). The rodents were later returned to the box, and their reactions were observed (Science 344, 598–602; 2014). Freezing, considered a fear response, is a common reaction and indicates that the
rodents remembered their previous n egative experience with the box. Providing access to a running wheel and pharmacologically increasing neurogenesis both curtailed freezing behavior in mice, suggesting that the mice had forgotten their previous negative experience. Furthermore, pharmacological inhibition of neurogenesis in mice with running wheels and in infant mice increased freezing behavior, s uggesting that limiting neurogenesis improved memory retention. The researchers also studied guinea pigs and degus, which have lower rates of neurogenesis during infancy than do mice or humans. Guinea pigs and degus remembered the box for much longer than did mice, but boosting neurogenesis (either pharmacologically or by providing access to a running wheel) induced them to forget. The results show that neurogenesis can disrupt established memories and that increasing neurogenesis can induce forgetting. The findings support the idea that there is a trade-off between formation of new memories and retention of existing ones. As Josselyn points out, “forgetting is an important part of healthy memory.” Monica Harrington
The heart of an endurance athlete Physical activity has many positive effects on the cardiovascular system, but intense endurance training can also be detrimental. Athletes, especially those with a long training history, are more likely to develop arrhythmias. Sinus bradycardia (a slow resting heart rate) is the most common training-associated arrhythmia. Although it is often a benign physiological adaptation to maintain normal cardiac output and blood pressure by compensating for training-induced increases in stroke volume, bradycardia can become pathological and lead to the need for electronic pacemaker implantation. High incidences of pacemaker implantation to control bradyarrhythmias have been reported among former professional cyclists and among elderly marathon runners. Training-induced bradycardia has been attributed to changes in the autonomic nervous system, such as an increase in vagal tone. But bradycardia is observed in athletes even when the autonomic nervous system is blocked. Instead, some data suggest that long-term endurance training may induce pathological remodeling of the heart that manifests in arrhythmia. A study recently published by Mark Boyett (University of Manchester, UK) and colleagues supports this explanation. Boyett’s work shows that training-induced bradycardia is caused by electrophysiological changes in the sinus node, the pacemaker of the heart, and, more specifically, by a remodeling of the ion channels that control pacemaking (Nat. Commun. 5, 3775; 2014). In Boyett’s study, rats and mice underwent exercise training (running or swimming), and their cardiovascular function was compared with that of sedentary controls. Trained animals developed sinus bradycardia that persisted after blockade of the autonomous nervous system. Exercise training also induced a widespread remodeling of pacemaker ion channels, decreasing expression of the HCN4 channel and activity of its corresponding ionic current. ‘Detraining’ the mice reversed these changes. The results indicate that heart rate adaption to endurance training does not result from changes in autonomic tone but is primarily caused by remodeling of the sinus node. The higher incidence of sinus node disease and pacemaker implantation among veteran endurance athletes is likely a consequence of this remodeling. Sinus-node remodeling may also help explain syncope in young athletes, and analogous remodeling of other parts of the heart may explain other training-associated arrhythmias (e.g., atrial fibrillation, heart block and bundle branch block). Although sinus-node remodeling and its consequences were reversible after short-term endurance training, it is unclear whether they remain reversible after long-term training. The findings provide a molecular explanation for potentially pathological heart rate adaptations to endurance training and may help inform lifestyle choices in athletes. Monica Harrington
LAB ANIMAL
Volume 43, No. 7 | JULY 2014 223
