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The longevity-assurance activity of the tumor suppressor p53 depends on the levels of Δ40p53 (p44), a short and naturally occurring isoform of the p53 gene. As such, increased dosage of p44 in the mouse leads to accelerated aging and short lifespan. Here we show that mice homozygous for a transgene encoding p44 (p44+/+) display cognitive decline and synaptic impairment early in life. The synaptic deficits are attributed to hyperactivation of insulin-like growth factor 1 receptor (IGF-1R) signaling and altered metabolism of the microtubule-binding protein tau. In fact, they were rescued by either Igf1r or Mapt haploinsufficiency. When expressing a human or a ‘humanized’ form of the amyloid precursor protein (APP), p44+/+ animals developed a selective degeneration of memory-forming and -retrieving areas of the brain, and died prematurely. Mechanistically, the neurodegeneration was caused by both paraptosis- and autophagy-like cell deaths. These results indicate that altered longevity-assurance activity of p53:p44 causes memory loss and neurodegeneration by affecting IGF-1R signaling. Importantly, Igf1r haploinsufficiency was also able to correct the synaptic deficits of APP695/swe mice, a model of Alzheimer’s disease.

Fetal alcohol spectrum disorders (FASD) are the leading non-genetic cause of neurodevelopmental disability in children. Although alcohol is clearly teratogenic, environmental factors such as gravidity and socioeconomic status significantly modify individual FASD risk despite equivalent alcohol intake. An explanation for this variability could inform FASD prevention. Here we show that the most common nutritional deficiency of pregnancy, iron deficiency without anemia (ID), is a potent and synergistic modifier of FASD risk. Using an established rat model of third trimester-equivalent binge drinking, we show that ID significantly interacts with alcohol to impair postnatal somatic growth, associative learning, and white matter formation, as compared with either insult separately. For the associative learning and myelination deficits, the ID-alcohol interaction was synergistic and the deficits persisted even after the offsprings’ iron status had normalized. Importantly, the observed deficits in the ID-alcohol animals comprise key diagnostic criteria of FASD. Other neurobehaviors were normal, showing the ID-alcohol interaction was selective and did not reflect a generalized malnutrition. Importantly ID worsened FASD outcome even though the mothers lacked overt anemia; thus diagnostics that emphasize hematological markers will not identify pregnancies at-risk. This is the first direct demonstration that, as suggested by clinical studies, maternal iron status has a unique influence upon FASD outcome. While alcohol is unquestionably teratogenic, this ID-alcohol interaction likely represents a significant portion of FASD diagnoses because ID is more common in alcohol-abusing pregnancies than generally appreciated. Iron status may also underlie the associations between FASD and parity or socioeconomic status. We propose that increased attention to normalizing maternal iron status will substantially improve FASD outcome, even if maternal alcohol abuse continues. These findings offer novel insights into how alcohol damages the developing brain.

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Poor self-control, lack of inhibition, and impulsivity contribute to the propensity of adolescents to engage in risky or dangerous behaviors. Brain regions (e.g., prefrontal cortex) involved in impulse-control, reward-processing, and decision-making continue to develop during adolescence, raising the possibility that an immature brain contributes to dangerous behavior during adolescence. However, very few validated animal behavioral models are available for behavioral neuroscientists to explore the relationship between brain development and behavior. To that end, a valid model must be conducted in the relatively brief window of adolescence and not use manipulations that potentially compromise development. The present experiments used three operant arrangements to assess whether adolescent rats differ from adults in measures of learning, behavioral inhibition, and impulsivity, within the aforementioned time frame without substantial food restriction. In Experiment 1, separate squads of rats were trained to lever-press and then transitioned to two types of extinction. Relative to their baselines, adolescent rats responded more during extinction than adults, suggesting that they were less sensitive to the abolishment of the reinforcement contingency. Experiment 2 demonstrated similar age-related differences during exposure to a differential reinforcement of low rates schedule, a test of behavioral inhibition. Lastly, in Experiment 3, adolescent's responding decreased more slowly than adults during exposure to a resetting delay of reinforcement schedule, suggesting impaired self-control. Results from these experiments suggest that adolescents exhibit impaired learning, behavioral inhibition and self-control, and in concert with recent reports, provide researchers with three behavioral models to more fully explore neurobiology of risk-taking behavior in adolescence.

Neural integration of glutamate-and dopamine-coded signals within the nucleus accumbens (NAc) is a fundamental process governing cellular plasticity underlying reward-related learning. Intra-NAc core blockade of NMDA or D1 receptors in rats impairs instrumental learning (lever-pressing for sugar pellets), but it is not known during which phase of learning (acquisition or consolidation) these receptors are recruited, nor is it known what role AMPA/kainate receptors have in these processes. Here we show that pre-trial intra-NAc core administration of the NMDA, AMPA/KA, and D1 receptor antagonists AP-5 (1 µg/0.5 µL), LY293558 (0.01 or 0.1 µg/0.5 µL), and SCH23390 (1 µg/0.5 µL), respectively, impaired acquisition of a lever-pressing response, whereas post-trial administration left memory consolidation unaffected. An analysis of the microstructure of behavior while rats were under the influence of these drugs revealed that glutamatergic and dopaminergic signals contribute differentially to critical aspects of the initial, randomly emitted behaviors that enable reinforcement learning. Thus, glutamate and dopamine receptors are activated in a time-limited fashion-only being required while the animals are actively engaged in the learning context.In order to survive in changing environments, animals must be able to acquire, consolidate, and retrieve pertinent information regarding a given stimulus situation. The ability to learn associations between various stimuli and events, including motor actions, is the basis of instrumental learning (Rescorla 1991;Dickinson and Balleine 1994). Appetitive instrumental learning occurs when an animal associates its behavior with a favorable outcome such as food, sex, or the avoidance of pain. For instance, in a common experimental model of instrumental learning, a hungry rat learns to press a lever to obtain a food reward.The nucleus accumbens (NAc) and its associated circuitry have been linked to the acquisition of adaptive motor responses and the control of behaviors related to natural reinforcers (Setlow 1997;Parkinson et al. 2000;Corbit et al. 2001). Because of the rich glutamatergic and dopaminergic innervation of the NAc from regions associated with motivational, cognitive, and sensory processes, many studies have focused on the role of these neurotransmitter systems with respect to instrumental and incentive learning (Berridge and Robinson 1998;Cardinal et al. 2002;Beninger and Gerdjikov 2004;Kelley 2004). For example, blockade of glutamate (N-methyl-D-aspartate, NMDA) or dopamine D1 receptors within the NAc core potently impairs instrumental learning, and coinfusion of low, individually ineffective doses of AP-5 and SCH23390 also prevents learning, suggesting that convergence of both systems on post-synaptic neurons is required In the aforementioned studies, pre-trial blockade of NMDA and D1 receptors appeared to prevent the encoding (or acquisition) of information; however, it is possible that disruption of the consolidation phase of learning or retrieval could have contribut...

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Substantial experimental evidence exists suggesting a critical role for dopamine in reinforcer-related processes, such as learning and drug addiction. Dopamine receptors, and in particular D1 receptors, are widely considered as modulators of synaptic plasticity. The amygdala contains both dopamine terminals and dopamine D1 receptors and is intimately involved in motivation and learning. However, little is known about the involvement of D1 receptor activation in two subnuclei of the mammalian amygdala, the central nucleus and basolateral complex in instrumental learning. Following recovery from surgery and preliminary training, rats with bilateral indwelling cannulae aimed at the central nucleus or basolateral complex were trained to lever-press for sucrose pellets over 12 sessions. Infusion of the selective D1 antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (0.3 nmol and 3.0 nmol) prior to the first five training sessions dose-dependently impaired instrumental learning when compared with vehicleinfused controls. All rats were then exposed to five sessions drug-free; lever-pressing quickly reached equal levels across groups. A drug infusion prior to an 11th session revealed no effect on performance. Control experiments indicated that basic motivational processes and general motor responses were intact, such as spontaneous feeding and locomotor activity. These results show an essential role for D1-receptor activation in both the central nucleus and basolateral complex on the acquisition of lever pressing for sucrose pellets in rats, but not the performance of the behavior once conditioned. We propose that instrumental learning is dependent on plasticity in the central nucleus and basolateral complex amygdala, and that D1 receptor activation participates in transcriptional processes that underlie this plasticity.Keywords instrumental learning; amygdala; dopamine; D1; plasticity; rats Biologically important events, such as procurement of food, escape from predation, and access to sexual partners, often require flexible patterns of behavior in order to produce themforaging, vigilance, and defense, for example. Important biological reinforcers (Reinf), in turn, change the behavior that produced them, illustrating a form of adaptability termed "instrumental learning." Many Reinf-related processes are mediated by the mesocorticolimbic dopamine (DA) system, consisting of DA neurons in the ventral tegmental area and their projections to the nucleus accumbens, medial prefrontal cortex, striatum, amygdala and other *Corresponding author. Tel: +1-608-262-9332. E-mail address: mandrzejewsk@wisc.edu (M. E. Andrzejewski). (Beninger and Miller, 1998;Cardinal et al., 2002;Kelley and Berridge, 2002). Specifically, studies have shown that D1 receptor activation throughout this corticolimbicstriatal network plays a critical role in learning (Beninger and Gerdjikov, 2004). Indeed, D1 receptor activation is thought to serve a crucial modulatory function in the induction o...