Disrupting astrocyte-neuron lactate transfer persistently reduces conditioned responses to cocaine.

A central problem in the treatment of drug addiction is the high risk of relapse often precipitated by drug-associated cues. The transfer of glycogen-derived lactate from astrocytes to neurons is required for long-term memory. Whereas blockade of drug memory reconsolidation represents a potential therapeutic strategy, the role of astrocyte-neuron lactate transport in long-term conditioning has received little attention. By infusing an inhibitor of glycogen phosphorylase into the basolateral amygdala of rats, we report that disruption of astrocyte-derived lactate not only transiently impaired the acquisition of a cocaine-induced conditioned place preference but also persistently disrupted an established conditioning. The drug memory was rescued by L-Lactate co-administration through a mechanism requiring the synaptic plasticity-related transcription factor Zif268 and extracellular signal-regulated kinase (ERK) signalling pathway but not the brain-derived neurotrophic factor (Bdnf). The long-term amnesia induced by glycogenolysis inhibition and the concomitant decreased expression of phospho-ERK were both restored with L-Lactate co-administration. These findings reveal a critical role for astrocyte-derived lactate in positive memory formation and highlight a novel amygdala-dependent reconsolidation process, whose disruption may offer a novel therapeutic target to reduce the long-lasting conditioned responses to cocaine

The airbag problem-a potential culprit for bench-to-bedside translational efforts: relevance for Alzheimer's disease

For the last 20 years, the "amyloid cascade hypothesis" has dominated research aimed at understanding, preventing, and curing Alzheimer's disease (AD). During that time researchers have acquired an enormous amount of data and have been successful, more than 300 times, in curing the disease in animal model systems by treatments aimed at clearing amyloid deposits. However, to date similar strategies have not been successful in human AD patients. Hence, before rushing into further clinical trials with compounds that aim at lowering amyloid-beta (Aβ) levels in increasingly younger people, it would be of highest priority to re-assess the initial assumption that accumulation of Aβ in the brain is the primary pathological event driving AD. Here we question this assumption by highlighting experimental evidence in support of the alternative hypothesis suggesting that APP and Aβ are part of a neuronal stress/injury system, which is up-regulated to counteract inflammation/oxidative stress-associated neurodegeneration that could be triggered by a brain injury, chronic infections, or a systemic disease. In AD, this protective program may be overridden by genetic and other risk factors, or its maintenance may become dysregulated during aging. Here, we provide a hypothetical example of a hypothesis-driven correlation between car accidents and airbag release in analogy to the evolution of the amyloid focus and as a way to offer a potential explanation for the failure of the AD field to translate the success of amyloid-related therapeutic strategies in experimental models to the clinic

Re-evaluation of medical findings in alleged shaken baby syndrome and abusive head trauma in Norwegian courts fails to support abuse diagnoses

Aim The criteria for diagnosing abusive head trauma (AHT) are not well defined and this condition might be diagnosed on failing premises. Our aim was to review criminal AHT cases in Norwegian courts by scrutinising the underlying medical documentation. Methods Cases were identified in the data registry for Norwegian courts from 2004 to 2015. Documentation was obtained from relevant health institutions. The medical co-authors first made independent evaluations of the documentation for each child, followed by a consensus evaluation. Results A total of 17 children (11 boys) were identified, all diagnosed as AHT by court appointed experts, 15 were infants (mean age 2.6 months). A high proportion (41.2%) was born to immigrant parents and 31.3% were premature. The medical findings could be explained by alternative diagnoses in 16 of the 17 children; 8 boys (7 infants – mean age 2.9 months) had clinical and radiological characteristics compatible with external hydrocephalus complicated by chronic subdural haematoma. Six children (five infants with mean age 2.1 months) had a female preponderance and findings compatible with hypoxic ischaemic insults. Conclusion The medical condition in most children had not necessarily been caused by shaking or direct impact, as was originally concluded by the court experts