Dopamine D ₁ , dopamine D ₂ , and adenosine A _2A receptors are highly expressed in striatal medium-sized spiny neurons. We have examined, in vivo , the influence of these receptors on the state of phosphorylation of the dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32). DARPP-32 is a potent endogenous inhibitor of protein phosphatase-1, which plays an obligatory role in dopaminergic transmission. A dose-dependent increase in the state of phosphorylation of DARPP-32 occurred in mouse striatum after systemic administration of the D ₂ receptor antagonist eticlopride (0.1–2.0 mg/kg). This effect was abolished in mice in which the gene coding for the adenosine A _2A receptor was disrupted by homologous recombination. A reduction was also observed in mice that had been pretreated with the selective A _2A receptor antagonist SCH 58261 (10 mg/kg). The eticlopride-induced increase in DARPP-32 phosphorylation was also decreased by pretreatment with the D ₁ receptor antagonist SCH 23390 (0.125 and 0.25 mg/kg) and completely reversed by combined pretreatment with SCH 23390 (0.25 mg/kg) plus SCH 58261 (10 mg/kg). SCH 23390, but not SCH 58261, abolished the increase in DARPP-32 caused by cocaine (15 mg/kg). The results indicate that, in vivo , the state of phosphorylation of DARPP-32 and, by implication, the activity of protein phosphatase-1 are regulated by tonic activation of D ₁ , D ₂ , and A _2A receptors. The results also underscore the fact that the adenosine system plays a role in the generation of responses to dopamine D ₂ antagonists in vivo .

Hospitalization for major surgery or critical illness often associates with cognitive decline. Inflammation and dysregulation of the innate immune system can exert broad effects in the periphery and central nervous system (CNS), yet the mechanisms underlying memory impairment after surgery remain poorly understood and without effective therapy. Endogenous regulation of acute inflammation is providing novel approaches to treat several disease states including sepsis, pain, obesity and diabetes. Resolvins are potent endogenous lipid mediators biosynthesized during the resolution phase of acute inflammation that display immunoresolvent actions. Here, using a mouse model of surgery‐induced cognitive decline we report that orthopedic surgery affects hippocampal neuronal‐glial function, including synaptic transmission and plasticity. Systemic prophylaxis with aspirin‐triggered resolvin D1 (AT‐RvD1: 7 S ,8 R ,17 R ‐trihydroxy‐4 Z ,9 E ,11 E ,13 Z ,15 E ,19 Z ‐docosahexaenoic acid, as little as 100 ng dose per mouse) improved memory decline following surgery and abolished signs of synaptic dysfunction. Moreover, delayed administration 24 h after surgery also attenuated signs of neuronal dysfunction postoperatively. AT‐RvD1 also limited peripheral damage by modulating the release of systemic interleukin (IL)‐6 and improved other clinical markers of tissue injury. Collectively, these results demonstrate a novel role of AT‐RvD1 in modulating the proinflammatory milieu after aseptic injury and protecting the brain from neuroinflammation, synaptic dysfunction and cognitive decline. These findings provide novel and safer approaches to treat postoperative cognitive decline and potentially other forms of memory dysfunctions.—Terrando, N., Gómez‐Galán, M., Yang, T., Carlström, M., Gustavsson, D., Harding, R. E., Lindskog, M., Eriksson, L. I., Aspirin‐triggered resolvin D1 prevents surgery‐induced cognitive decline. FASEB J. 27, 3564–3571 (2013). www.fasebj.org

Reinforcement learning theorizes that strengthening of synaptic connections in medium spiny neurons of the striatum occurs when glutamatergic input (from cortex) and dopaminergic input (from substantia nigra) are received simultaneously. Subsequent to learning, medium spiny neurons with strengthened synapses are more likely to fire in response to cortical input alone. This synaptic plasticity is produced by phosphorylation of AMPA receptors, caused by phosphorylation of various signalling molecules. A key signalling molecule is the phosphoprotein DARPP-32, highly expressed in striatal medium spiny neurons. DARPP-32 is regulated by several neurotransmitters through a complex network of intracellular signalling pathways involving cAMP (increased through dopamine stimulation) and calcium (increased through glutamate stimulation). Since DARPP-32 controls several kinases and phosphatases involved in striatal synaptic plasticity, understanding the interactions between cAMP and calcium, in particular the effect of transient stimuli on DARPP-32 phosphorylation, has major implications for understanding reinforcement learning. We developed a computer model of the biochemical reaction pathways involved in the phosphorylation of DARPP-32 on Thr34 and Thr75. Ordinary differential equations describing the biochemical reactions were implemented in a single compartment model using the software XPPAUT. Reaction rate constants were obtained from the biochemical literature. The first set of simulations using sustained elevations of dopamine and calcium produced phosphorylation levels of DARPP-32 similar to that measured experimentally, thereby validating the model. The second set of simulations, using the validated model, showed that transient dopamine elevations increased the phosphorylation of Thr34 as expected, but transient calcium elevations also increased the phosphorylation of Thr34, contrary to what is believed. When transient calcium and dopamine stimuli were paired, PKA activation and Thr34 phosphorylation increased compared with dopamine alone. This result, which is robust to variation in model parameters, supports reinforcement learning theories in which activity-dependent long-term synaptic plasticity requires paired glutamate and dopamine inputs. Reinforcement learning, based on the association of a stimulus-triggered movement with a reward, involves changes in connection strength between neurons. Memory storage occurs in the striatum, the input stage of the basal ganglia, when a stimulus or movement signal originating from the cortex and a reward signal originating from the midbrain reach the target striatal cells together. Repetitive pairing of these two signals strengthens the connection between cortical and striatal cells. The strengthening of the connections is caused by activation of biochemical signalling pathways inside the striatal cells. These intracellular signalling pathways are explored in a quantitative computational model describing the biochemical pathways important for reinforcement learning. Lindskog et al.'s study shows that when brief reward and stimuli signals are paired, a stronger response in the intracellular signalling occurs compared with the situation when each signal is given alone. This result illustrates mechanisms whereby paired stimuli, but not unpaired stimuli, can cause learning. Furthermore, the model predicts that the biochemical responses are different after brief stimulation as compared with prolonged stimulation. This result highlights the difficulties in predicting the nonlinear interactions within signalling cascades based on prolonged stimulations, which often are used in biochemical experiments.