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Review
. 2011 Nov;96(4):507-16.
doi: 10.1016/j.nlm.2011.01.004. Epub 2011 Jan 12.

Bidirectional metabolic regulation of neurocognitive function

Alexis M Stranahan  1 , Mark P Mattson
Affiliations
Review

Bidirectional metabolic regulation of neurocognitive function

Alexis M Stranahan et al. Neurobiol Learn Mem. 2011 Nov.

Abstract

The efficiency of somatic energy metabolism is correlated with cognitive change over the lifespan. This relationship is bidirectional, with improved overall fitness associated with enhanced synaptic function and neuroprotection, and synaptic endangerment occurring in the context of impaired energy metabolism. In this review, we discuss recent advancements in the fields of exercise, dietary energy intake and diabetes, as they relate to neuronal function in the hippocampus. Because hippocampal neurons have energy requirements that are relatively higher than those of other brain regions, they are uniquely poised to benefit from exercise, and to be harmed by diabetes. We view exercise and dietary energy restriction as being associated with enhanced hippocampal plasticity at one end of a continuum, with obesity and diabetes accompanied by cognitive impairment at the other end of the continuum. Understanding the mechanisms for this continuum may yield novel therapeutic targets for the prevention and treatment of cognitive decline following aging, disease, or injury.

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Figures

Figure 1
Figure 1. The metabolic continuum confers resistance or vulnerability to neuronal mechanisms underlying cognitive impairment and AD
Exercise and dietary energy restrictions induce adaptive cellular stress responses that are associated with neuroprotection, neurogenesis, and synaptic plasticity. These mechanisms both promote neuronal function and suppress deleterious changes that lead to cognitive impairment and AD. On the other hand, sedentary lifestyles, obesity, and diabetes reduce adaptive cellular stress responses and promote negative outcomes such as oxidative stress and inflammation. These factors contribute to impaired synaptic plasticity and neurogenesis, rendering neurons more susceptible to changes that lead to cognitive impairment and AD. Abbreviations: BDNF, brain-derived neurotrophic factor; IGF-1, insulin-like growth factor 1; HSP-70, heat shock protein 70; GRP-78, 78kDa glucose-regulated protein; UCPs, uncoupling proteins; Mn-SOD, manganese superoxide dismutase; HO-1, heme-oxygenase 1.
Figure 2
Figure 2. Insulin signaling counterbalances glucocorticoid signaling to maintain neuroplasticity, and impairment of insulin signaling increases neuronal vulnerability to stress
(A), Under normal physiological circumstances, hippocampal insulin signaling protects against the negative effects of exposure to moderately elevated glucocorticoid hormones. Glucocorticoids act via the hippocampal glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), facilitating HPA axis shutoff. While activation of GR in particular leads to transcription of genes that attenuate plasticity (Morsink et al., 2006), concurrent insulin receptor (IR) activation would counteract this effect by promoting survival signaling. Similarly, neuronal utilization of glucose and lactate would suppress the energetic stress associated with glucocorticoid receptor activation. (B), In the diabetic hippocampus, GR expression is compromised (Campbell et al., in press), leading to impairment of HPA axis shutoff. Moreover, insulin receptor signaling is impaired, and neuronal access to energy substrates is diminished. This creates a scenario in which the effects of exposure to elevated corticosterone levels, in the context of reduced insulin signaling and impaired metabolism, lead to neuronal endangerment. This model is a reductionist view of how insulin signaling and the availability of energy substrates might interact with the stress response. In the interests of space, other factors such as 11β-hydroxysteroid dehydrogenase 1, which locally modulates glucocorticoid actions in the hippocampus, and feeding-related peptides such as ghrelin and leptin, are not included in the diagram but could potentially contribute to the relationship between metabolism and stress.
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