Intermittent Fasting Reverses Age-Associated Neural Changes
Eunyoung Bang, Annette S. Fincher, Sophie Nader, David A. Murchison, and William H. Griffith
(see pages 1020–1034)
The aging process involves breakdown of cellular repair processes, disruption of mitochondrial function, accumulation of oxidative damage and protein degradation products, impaired calcium handling, and persistent inflammation. These affect all bodily tissues, including the nervous system, where they result in impaired sensory processing and cognitive decline. Importantly, these effects can be accelerated by high-fat diets and sedentary lifestyles, and they can be slowed by caloric restriction and exercise. Indeed, caloric restriction has been shown to prolong life and reduce disease in many species, including rodents and monkeys. Similar effects can be produced by intermittent fasting in the absence of enforced caloric restriction. How early in life restricted eating regimens must be started and how long they must be maintained to achieve benefit remains unclear, however. Therefore, Bang et al. asked whether a few weeks of intermittent fasting was sufficient to reverse age-associated changes in basal forebrain neurons in old mice.
Consistent with previous work, depolarization of dissociated basal forebrain neurons produced smaller increases in intracellular calcium levels in aged (18–25 months old) mice than in young mice. This enhanced calcium buffering was associated with a decrease in the frequency, but not the amplitude, of IPSCs in these neurons. Remarkably, 6 weeks of intermittent fasting (no food access and unlimited access given on alternating days) was sufficient to restore calcium buffering and IPSC frequency in aged mice to levels similar to those in young mice. In contrast, 4 weeks of intermittent fasting was insufficient to reverse deficits on a spatial learning task in aged mice.
These results suggest that at least some of the benefits of caloric restriction and intermittent fasting can accrue within a few weeks, even if started at a late age. Future work should determine how long a period of intermittent fasting is required to restore cognitive function and how long benefits persist if animals return to a normal feeding schedule. More importantly, studies in humans should determine the extent to which human health can benefit from intermittent fasting.
The activity patterns elicited in PrL by presentation of conditioned stimulus (CS) and unconditioned stimulus (US) are similar across blocks, as indicated by activity trajectories projected onto three principal components (top). Inhibition of the LEC (bottom) reduces the across-block similarity of ensemble trajectories. See Pilkiw et al. for details.
Entorhinal Cortex Stabilizes Ensembles in Prelimbic Cortex
Maryna Pilkiw, Justin Jarovi, and Kaori Takehara-Nishiuchi
(see pages 1104–1118)
Trace eyeblink conditioning is a form of hippocampus-dependent learning in which an animal learns that a conditioned stimulus—a brief auditory or visual cue—will be followed, after a brief stimulus-free period, by an unconditioned stimulus—a puff of air or electric shock to the eyelid. After learning the association, the conditioned stimulus elicits a conditioned response—an eyeblink—at the time when the unconditioned stimulus is expected. Performance of this task requires activity in the prelimbic area (PrL) of the prefrontal cortex, which contains neurons that represent the conditioned stimulus, the unconditioned stimulus, and the learned interval between these stimuli. Reactivation of these neurons in the appropriate sequence is thought to lead to an output signal from the PrL to the cerebellum, which initiates the conditioned response.
Reactivation of specific activity patterns in neuronal ensembles has been proposed to underlie many kinds of learning. But this model has been challenged by accumulating evidence that activity patterns evoked in a particular brain area by a given stimulus gradually change over time. How can such neural drift produce stable behaviors? One possibility is that interactions between brain areas prevent excessive drift that would disrupt behavior. In support of this hypothesis, Pilkiw et al. present evidence that the lateral entorhinal cortex (LEC) provides stabilizing input to the PrL.
Consistent with previous work, silencing LEC activity with a GABA receptor agonist reduced the number of trials on which conditioned stimuli evoked a conditioned eyeblink response. To determine how LEC inactivation affected ensemble activity in PrL, the authors recorded spiking of individual neurons and mapped the evolving activity trajectory in neural state space using principal components analysis. They also asked whether classifiers trained on population activity in one block of trials could decode task phases recorded in subsequent blocks. These analyses revealed that neural representations in PrL were fairly stable over sessions when LEC was active, but neural drift increased when LEC was inactivated. Notably, the pattern of ensemble activity during the period between the conditioned and unconditioned stimuli was most affected by this drift. The failure to reinstate the representation of this interval may explain why animals failed to blink in anticipation of the unconditioned stimulus when LEC was inactivated.
Footnotes
This Week in The Journal was written by Teresa Esch, Ph.D.
