The nucleus accumbens, a site within the ventral striatum, is best known for its prominent role in mediating the reinforcing effects of drugs of abuse such as cocaine, alcohol, and nicotine. Indeed, it is generally believed that this structure subserves motivated behaviors, such as feeding, drinking, sexual behavior, and exploratory locomotion, which are elicited by natural rewards or incentive stimuli. A basic rule of positive reinforcement is that motor responses will increase in magnitude and vigor if followed by a rewarding event. It is likely, therefore, that the nucleus accumbens may serve as a substrate for reinforcement learning. However, there is surprisingly little information concerning the neural mechanisms by which appetitive responses are learned. In the present study, we report that treatment of the nucleus accumbens core with the selective competitive N-methyl-D-aspartate (NMDA) antagonist 2-amino-5-phosphonopentanoic acid (A P-5; 5 nmol͞0.5 l bilaterally) impairs responsereinforcement learning in the acquisition of a simple leverpress task to obtain food. Once the rats learned the task, AP-5 had no effect, demonstrating the requirement of NMDA receptor-dependent plasticity in the early stages of learning. Infusion of AP-5 into the accumbens shell produced a much smaller impairment of learning. Additional experiments showed that AP-5 core-treated rats had normal feeding and locomotor responses and were capable of acquiring stimulusreward associations. We hypothesize that stimulation of NMDA receptors within the accumbens core is a key process through which motor responses become established in response to reinforcing stimuli. Further, this mechanism, may also play a critical role in the motivational and addictive properties of drugs of abuse.The basal ganglia constitute a group of structures in the mammalian forebrain that have traditionally been considered as motor control regions. Indeed, one of the most prominent signs of basal ganglia disorders is motor disturbance or impairment (1). However, in more recent years empirical work has implicated the striatum (a major component of the basal ganglia) in cognition, reinforcement mechanisms, and sensorimotor integration (2, 3). Although the outflow of the striatum indeed reaches major extrapyramidal motor centers such as globus pallidus, substantia nigra, and subthalamic nucleus, the input to this structure, arising from the neocortex, limbic system, and midbrain, suggests that it plays a complex integrative role in adaptive motor actions (4, 5).One region of the striatum that has received considerable attention in this regard is the nucleus accumbens. The nucleus accumbens is best known for its role in mediating the reinforcing and rewarding properties of drugs of abuse (6). Drugs such as cocaine, heroin, alcohol, and even nicotine are hypothesized to produce their rewarding effects via activation of accumbens dopamine (7), and it has been recently postulated that chronic neuroadaptations in this system may underlie the addiction process (8...

In a number of animal species, the growth-associated protein (GAP), GAP-43 (aka: F1, neuromodulin, B-50, G50, pp46), has been implicated in the regulation of presynaptic vesicular function and axonal growth and plasticity via its own biochemical properties and interactions with a number of other presynaptic proteins. Changes in the expression of GAP-43 mRNA or distribution of the protein coincide with axonal outgrowth as a consequence of neuronal damage and presynaptic rearrangement that would occur following instances of elevated patterned neural activity including memory formation and development. While functional enhancement in GAP-43 mRNA and/or protein activity has historically been hypothesized as a central mediator of axonal neuroplastic and regenerative responses in the central nervous system, it does not appear to be the crucial substrate sufficient for driving these responses. This review explores the historical discovery of GAP-43 (and associated monikers), its transcriptional, post-transcriptional and post-translational regulation and current understanding of protein interactions and regulation with respect to its role in axonal function. While GAP-43 itself appears to have moved from a pivotal to a supporting factor, there is no doubt that investigations into its functions have provided a clearer understanding of the biochemical underpinnings of axonal plasticity.

Hebb (1949) proposed that after learning both presynaptic and postsynaptic structural changes form the neural substrate of long-lasting memory. Despite this, there are few instances linking presynaptic remodeling with learning. Here the authors demonstrate in two different rat strains that learning the location of a hidden platform induces expansion of the presynaptic hippocampal mossy fiber terminal field (MFTF) from the stratum lucidum to the distal stratum oriens (dSO). Prior to any training, Long Evans rats (LER) showed an extensive endogenous MFTF innervation of DSO, in contrast to Wistar rats (WR) that showed minimal innervation. LER showed better recall than WR on the hidden platform water maze task and a visible reversal water maze task. In both strains, significant MFTF expansion to dSO, spanning approximately 200 mum, was detected 7 days after training on the hidden platform task, but only LER showed significant MFTF expansion 24 h after training. It is attractive to think that the MFTF expansion to dSO contributes both to long-lasting memory formation and to facilitating spatial navigation strategies. The present results establish learning-induced axonal remodeling of the hippocampal MF system in adult rats as an especially useful system for exploring presynaptic morphological adjustments consequent to learning.

The effect of microinfusion of the W-methyl-D-aspartate (NMDA) antagonist 2-amino-5phosphonopentanoic acid (AP-5) into the amygdala, medial prefrontal cortex, and dorsal and ventral subiculum on acquisition of a lever-pressing task for food in rats was examined. Serial transmission between the basolateral amygdala and nucleus accumbens core was also examined in an asymmetric infusion design. AP-5 administered bilaterally into either the amygdala or medial prefrontal cortex markedly impaired learning, whereas administration into the dorsal or ventral subiculum had no effect. Unilateral infusion of AP-5 into either the nucleus accumbens core or amygdala was also sufficient to impair learning. These data provide novel evidence for NMDA receptor-dependent plasticity within corticostriatal networks in the acquisition of appetitive instrumental learning.

Mild traumatic brain injuries (mTBI) have been associated with long-term cognitive deficits relating to trauma-induced neurodegeneration. These long-term deficits include impaired memory and attention, changes in executive function, emotional instability, and sensorimotor deficits. Furthermore, individuals with concussions show a high co-morbidity with a host of psychiatric illnesses (e.g., depression, anxiety, addiction) and dementia. The neurological damage seen in mTBI patients is the result of the impact forces and mechanical injury, followed by a delayed neuroimmune response that can last hours, days, and even months after the injury. As part of the neuroimmune response, a cascade of pro- and anti-inflammatory cytokines are released and can be detected at the site of injury as well as subcortical, and often contralateral, regions. It has been suggested that the delayed neuroinflammatory response to concussions is more damaging then the initial impact itself. However, evidence exists for favorable consequences of cytokine production following traumatic brain injuries as well. In some cases, treatments that reduce the inflammatory response will also hinder the brain's intrinsic repair mechanisms. At present, there is no evidence-based pharmacological treatment for concussions in humans. The ability to treat concussions with drug therapy requires an in-depth understanding of the pathophysiological and neuroinflammatory changes that accompany concussive injuries. The use of neurotrophic factors [e.g., nerve growth factor (NGF)] and anti-inflammatory agents as an adjunct for the management of post-concussion symptomology will be explored in this review.

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Recent evidence suggests that N-methyl-D-aspartate (NMDA)-receptor mediated plasticity in hippocampus has a more subtle role in memory-based behaviours than originally thought. One idea is that NMDA-based plasticity is essential for the consolidation of post-training memory but not for the initial encoding or for short-term memory. To further test this idea we used a three-phase variant of the hidden goal water maze task. In the first phase, rats were pre-trained to an initial location. Next, intense, massed training was done in a 2-h interval to teach the rats to go to a new location after either an injection of the NMDA receptor antagonist (6)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) or of vehicle. Finally, under drug-free conditions 24 h after new location training, a competition test was done between the original and new locations. We find that N-methyl-D-aspartate (NMDA)-receptor blockade has little or no effect on new location training. In contrast, when tested 24 h later, the strength of the trace for the new location learned during NMDA-receptor blockade was much weaker compared with the trace for the new location learned after saline injection. Further experiments showed similar effects when NMDA-receptors were blocked immediately after the new location training, suggesting that this is a memory consolidation effect. Our results therefore reinforce the notion that hippocampal NMDA-receptors participate in post-training memory consolidation but are not essential for the processes necessary to learn or retain navigational information in the short term.