Role of cyclic nucleotides and their downstream signaling cascades in memory function:Being at the right time at the right spot

A plethora of studies indicate the important role of cAMP and cGMP cascades in neuronal plasticity and memory function. As a result, altered cyclic nucleotide signaling has been implicated in the pathophysiology of mnemonic dysfunction encountered in several diseases. In the present review we provide a wide overview of studies regarding the involvement of cyclic nucleotides, as well as their upstream and downstream molecules, in physiological and pathological mnemonic processes. Next, we discuss the regulation of the intracellular concentration of cyclic nucleotides via phosphodiesterases, the enzymes that degrade cAMP and/or cGMP, and via A-kinase-anchoring proteins that refine signal compartmentalization of cAMP signaling. We also provide an overview of the available data pointing to the existence of specific time windows in cyclic nucleotide signaling during neuroplasticity and memory formation and the significance to target these specific time phases for improving memory formation. Finally, we highlight the importance of emerging imaging tools like Förster resonance energy transfer imaging and optogenetics in detecting, measuring and manipulating the action of cyclic nucleotide signaling cascades

Electrical stimulation alleviates depressive-like behaviors of rats: investigation of brain targets and potential mechanisms

Deep brain stimulation (DBS) is a promising therapy for patients with refractory depression. However, key questions remain with regard to which brain target(s) should be used for stimulation, and which mechanisms underlie the therapeutic effects. Here, we investigated the effect of DBS, with low- and high-frequency stimulation (LFS, HFS), in different brain regions (ventromedial prefrontal cortex, vmPFC; cingulate cortex, Cg; nucleus accumbens (NAc) core or shell; lateral habenula, LHb; and ventral tegmental area) on a variety of depressive-like behaviors using rat models. In the naive animal study, we found that HFS of the Cg, vmPFC, NAc core and LHb reduced anxiety levels and increased motivation for food. In the chronic unpredictable stress model, there was a robust depressive-like behavioral phenotype. Moreover, vmPFC HFS, in a comparison of all stimulated targets, produced the most profound antidepressant effects with enhanced hedonia, reduced anxiety and decreased forced-swim immobility. In the following set of electrophysiological and histochemical experiments designed to unravel some of the underlying mechanisms, we found that vmPFC HFS evoked a specific modulation of the serotonergic neurons in the dorsal raphe nucleus (DRN), which have long been linked to mood. Finally, using a neuronal mapping approach by means of c-Fos expression, we found that vmPFC HFS modulated a brain circuit linked to the DRN and known to be involved in affect. In conclusion, HFS of the vmPFC produced the most potent antidepressant effects in naive rats and rats subjected to stress by mechanisms also including the DRN.postprin

Possible overlapping time frames of acquisition and consolidation phases in object memory processes: a pharmacological approach

In previous studies, we have shown that acetylcholinesterase inhibitors and phosphodiesterase inhibitors (PDE-Is) are able to improve object memory by enhancing acquisition processes. On the other hand, only PDE-Is improve consolidation processes. Here we show that the cholinesterase inhibitor donepezil also improves memory performance when administered within 2 min after the acquisition trial. Likewise, both PDE5-I and PDE4-I reversed the scopolamine deficit model when administered within 2 min after the learning trial. PDE5-I was effective up to 45 min after the acquisition trial and PDE4-I was effective when administered between 3 and 5.5 h after the acquisition trial. Taken together, our study suggests that acetylcholine, cGMP, and cAMP are all involved in acquisition processes and that cGMP and cAMP are also involved in early and late consolidation processes, respectively. Most important, these pharmacological studies suggest that acquisition processes continue for some time after the learning trial where they share a short common time frame with early consolidation processes. Additional brain concentration measurements of the drugs suggest that these acquisition processes can continue up to 4–6 min after learning

Acute effects of acetyl-L-carnitine on sodium cyanide-induced behavioral and biochemical deficits

In the present study we investigated the effects of acute treatment with acetyl-L-carnitine (50 mg/kg, i.v. 90 min before the sodium cyanide injection) on a sodium cyanide-induced behavioral deficit in the Morris water escape task. In a first experiment the spatial discrimination performance of the rats was found to be dose-dependently impaired after an i.c.v. injection of sodium cyanide (2.5 and 5.0 mu g). Acute treatment with acetyl-L-carnitine was found to increase the behavioral deficit after sodium cyanide, these findings were replicated in a second experiment. Based on these results it can be argued that an acute administration of acetyl-L-carnitine appears to potentiate a sodium cyanide-induced behavioral deficit. An additional in vitro experiment with rat brain synaptosomes showed clear effects of administered sodium cyanide on the energy-dependent incorporation of inositol into phosphoinositides and on the ATP concentration. In vitro acetyl-L-carnitine administration had no effect on the sodium cyanide-induced energy depletion. The negative behavioral findings are in contrast with our previously found protective effect of chronic treatment with acetyl-L-carnitine (via drinking water) on the sodium cyanide-induced behavioral deficit. Since chronic acetyl-L-carnitine treatment has no effect on the phosphoinositide metabolism it was suggested that acetyl-L-carnitine may act via the formation of an ATP-independent reservoir of activated acyl groups. Thus, fatty acids as acylated derivatives can be used for reacylation processes during an acute period of energy depletion. However, we have no clear explanation for the discrepancy in behavioral results between the chronic vs acute treatment of acetyl-L-carnitine at present. Further research is needed to characterize the mechanism of action of acetyl-L-carnitine in relation to sodium cyanide. (C) 1998 Elsevier Science Ltd. All rights reserved

Phosphodiesterase inhibitors roflumilast and vardenafil prevent sleep deprivation-induced deficits in spatial pattern separation

Sleep deprivation (SD) is known to impair hippocampus-dependent memory processes, in part by stimulating the phosphodiesterase (PDE) activity. In the present study, we assessed in mice whether SD also affects spatial pattern separation, a cognitive process that specifically requires the dentate gyrus (DG) subregion of the hippocampus. Adult male mice were trained in an object pattern separation (OPS) task in the middle of the light phase and then tested 24 hr thereafter. In total, we conducted three studies using the OPS task. In the first study, we validated the occurrence of pattern separation and tested the effects of SD. We found that 6 hr of SD during the first half of the light phase directly preceding the test trial impaired the spatial pattern separation performance. As a next step, we assessed in two consecutive studies whether the observed SD-induced performance deficits could be prevented by the systemic application of two different PDE inhibitors that are approved for human use. Both the PDE4 inhibitor roflumilast and PDE5 inhibitor vardenafil successfully prevented SD-induced deficits in spatial pattern separation. As a result, these PDE inhibitors have clinical potential for the prevention of memory deficits associated with loss of sleep