Neuroscience
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In brain glycogen, formed from glucose, is degraded (glycogenolysis) in astrocytes but not in neurons. Although most of the degradation follows the same pathway as glucose, its breakdown product, l-lactate, is released from astrocytes in larger amounts than glucose when glycogenolysis is activated by noradrenaline. However, this is not the case when glycogenolysis is activated by high potassium ion (K+) concentrations - possibly because noradrenaline in contrast to high K+ stimulates glycogenolysis by an increase not only in free cytosolic Ca2+ concentration ([Ca2+]i) but also in cyclic AMP (c-AMP), which may increase the expression of the monocarboxylate transporter through which it is released. ⋯ In addition the released l-lactate has effects on neurons which are essential for learning and for learning-related long-term potentiation (LTP), including induction of the neuronal gene Arc/Arg3.1 and activation of gene cascades mediated by CREB and cofilin. Inhibition of glycogenolysis blocks learning, LTP and all related molecular events, but all changes can be reversed by injection of l-lactate. The effect of extracellular l-lactate is due to both astrocyte-mediated signaling which activates noradrenergic activity on all brain cells and to a minor uptake, possibly into dendritic spines.
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The hippocampus enables a range of behaviors through its intrinsic circuits and concerted actions with other brain regions. One such important function is the retrieval of episodic memories. How hippocampal cells support retrieval of contextual fear memory remains largely unclear. ⋯ Moreover, retrieval preferentially re-activated Erk1/2 in the same set of CA1 neurons previously activated during conditioning in a context-specific manner. By confining drug inhibition within dorsal CA1, we established the crucial role for Erk1/2 activity in retrieval of long-term memory, as well as in amygdala activation associated with fear expression. These data provide functional evidence that Erk1/2 signaling in CA1 encodes a specific neural representation of contextual memory with emotional value.
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Potocki-Shaffer Syndrome is a rare neurodevelopmental syndrome associated with microdeletion of a region of Chromosome 11p11.2. Genetic evidence has implicated haploinsufficiency of PHF21A, a gene that encodes a histone-binding protein, as the likely cause of intellectual disability and craniofacial abnormalities in Potocki-Shaffer Syndrome. However, the molecular consequences of reduced PHF21A expression remain elusive. ⋯ Finally, PHF21A-deficient patient-derived cells exhibited a delayed induction of immediate early genes following forskolin stimulation. These results suggest that an impaired response to cAMP signaling might be involved in the pathology of PHF21A deficiency. This article is part of a Special Issue entitled: [SI: Molecules & Cognition].
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Nuclear receptors (NR) are emerging as key players in the central nervous system (CNS) with reported implications in physiological and pathophysiological conditions. While a number of NR has been studied, it is unknown whether invalidation of the pregnane xenobiotic receptor (PXR, NR1I2) corresponds to neurological modifications in the adult brain. PXR-/- C57BL/6J and wild-type mice were used to investigate: (i) recognition memory, motor coordination, and anxiety-like behaviors; (ii) longitudinal video-electroencephalographic (EEG) recordings and frequency wave analysis; (iii) neurovascular structures by histological evaluation and expression of the cerebrovascular tight junctions ZO1 and CLDN5. ⋯ Neurophysiological changes did not correspond to significant structural changes in the adult brain, expect for a localized and minor increase in the fronto-parietal neurovascular density and reduced ZO1, but not CLDN5, expression in isolated brain capillaries. Our results converge with existing evidence supporting a link between NR expression and brain physiology. Although the exact modalities remain to be elucidated, the possibility that extra-physiological modulation of PXR may constitute a pathophysiological entry point or a molecular target for brain diseases is proposed.
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The cognitive impairment characterizing the phenotype of older adults has been related to the efficiency of the antioxidant system. This study aimed at investigating the effect of memory training (MT) on memory, global cognitive functioning, and the oxidant and antioxidant capacity of plasma. We recruited 52 healthy subjects aged over 60. ⋯ When we considered the Δvalue (Δvariable = variable post-MT minus variable pre-MT) in EG, the ΔMMSE and ΔLTM scores were negatively associated to Δd-ROMs, and positively to ΔBAP and ΔBAP/dROM. In conclusion, our results suggest that MT improves memory and global cognitive functioning. These processes were significantly associated to increase in resistance against oxidative stress at the plasma level in healthy older adults.