Endocannabinoids produced upon action potential firing evoke a Cl(-) current via type-2 cannabinoid receptors in the medial prefrontal cortex.

The functional presence of type-2 cannabinoid receptors (CB2Rs) in layer II/III pyramidal neurons of the rat medial prefrontal cortex (mPFC) was recently demonstrated. In the present study, we show that the application of the endocannabinoids (eCBs) 2-arachidonoylglycerol (2-AG) and methanandamide [a stable analog of the eCB anandamide (AEA)] can activate CB2Rs of mPFC layer II/III pyramidal neurons, which subsequently induces a Cl(-) current. In addition, we show that action potential (AP) firing evoked by 20-Hz current injections results in an eCB-mediated opening of Cl(-) channels via CB2R activation. This AP-evoked synthesis of eCBs is dependent on the Ca(2+) influx through N-type voltage-gated calcium channels. Our results indicate that 2-AG is the main eCB involved in this process. Finally, we demonstrate that under physiologically relevant intracellular Cl(-) conditions, 20-Hz AP firing leads to a CB2R-dependent reduction in neuronal excitability. Altogether, our data indicate that eCBs released upon action potential firing can modulate, through CB2R activation, neuronal activity in the mPFC. We discuss how this may be a mechanism to prevent excessive neuronal firing.

Early intake of long-chain polyunsaturated fatty acids preserves brain structure and function in diet-induced obesity.

Worldwide, the incidence of obesity is increasing at an alarming rate, and the number of children with obesity is especially worrisome. These developments raise concerns about the physical, psychosocial and cognitive consequences of obesity. It was shown that early dietary intake of arachidonic acid (ARA) and docosahexaenoic acid (DHA) can reduce the detrimental effects of later obesogenic feeding on lipid metabolism and adipogenesis in an animal model of mild obesity. In the present study, the effects of early dietary ARA and DHA on cognition and brain structure were examined in mildly obesogenic ApoE*3Leiden mouse model. We used cognitive tests and neuroimaging during early and later life. During their early development after weaning (4-13weeks of age), mice were fed a chow diet or ARA and DHA diet for 8 weeks and then switched to a high-fat and high-carbohydrate (HFHC) diet for 12weeks (14-26weeks of age). An HFHC-diet led to increased energy storage in white adipose tissue, increased cholesterol levels, decreased triglycerides levels, increased cerebral blood flow and decreased functional connectivity between brain regions as well as cerebrovascular and gray matter integrity. ARA and DHA intake reduced the HFHC-diet-induced increase in body weight, attenuated plasma triglycerides levels and improved cerebrovasculature, gray matter integrity and functional connectivity in later life. In conclusion, an HFHC diet causes adverse structural brain and metabolic adaptations, most of which can be averted by dietary ARA and DHA intake early in life supporting metabolic flexibility and cerebral integrity later in life.

How the Body Talks to the Brain; Peripheral Mediators of Physical Activity-Induced Proliferation in the Adult Hippocampus.

In the hippocampal dentate gyrus, stem cells maintain the capacity to produce new neurons into adulthood. These adult-generated neurons become fully functional and are incorporated into the existing hippocampal circuit. The process of adult neurogenesis contributes to hippocampal functioning and is influenced by various environmental, hormonal and disease-related factors. One of the most potent stimuli of neurogenesis is physical activity (PA). While the bodily and peripheral changes of PA are well known, e.g. in relation to diet or cardiovascular conditions, little is known about which of these also exert central effects on the brain. Here, we discuss PA-induced changes in peripheral mediators that can modify hippocampal proliferation, and address changes with age, sex or PA duration/intensity. Of the many peripheral factors known to be triggered by PA, serotonin, FGF-2, IGF-1, VEGF, ß-endorphin and adiponectin are best known for their stimulatory effects on hippocampal proliferation. Interestingly, while age negatively affects hippocampal proliferation per se, also the PA-induced response to most of these peripheral mediators is reduced and particularly the response to IGF-1 and NPY strongly declines with age. Sex differences per se have generally little effects on PA-induced neurogenesis. Compared to short term exercise, long term PA may negatively affect proliferation, due to a parallel decline in FGF-2 and the ß-endorphin receptor, and an activation of the stress system particularly during conditions of prolonged exercise but this depends on other variables as well and remains a matter of discussion. Taken together, of many possible mediators, serotonin, FGF-2, IGF-1, VEGF, ß-endorphin and adiponectin are the ones that most strongly contribute to the central effects of PA on the hippocampus. For a subgroup of these factors, brain sensitivity and responsivity is reduced with age.