We studied a mouse model of the haploinsufficiency form of Rubinstein-Taybi syndrome (RTS), an inheritable disorder caused by mutations in the gene encoding the CREB binding protein (CBP) and characterized by mental retardation and skeletal abnormalities. In these mice, chromatin acetylation, some forms of long-term memory, and the late phase of hippocampal long-term potentiation (L-LTP) were impaired. We ameliorated the L-LTP deficit in two ways: (1) by enhancing the expression of CREB-dependent genes, and (2) by inhibiting histone deacetyltransferase activity (HDAC), the molecular counterpart of the histone acetylation function of CBP. Inhibition of HDAC also reversed the memory defect observed in fear conditioning. These findings suggest that some of the cognitive and physiological deficits observed on RTS are not simply due to the reduction of CBP during development but may also result from the continued requirement throughout life for both the CREB co-activation and the histone acetylation function of CBP.

Whereas significant insight exists as to how LTP-related changes can contribute to the formation of long-term memory, little is known about the role of hippocampal LTD-like changes in learning and memory storage. We describe a mouse lacking the transcription factor SRF in the adult forebrain. This mouse could not acquire a hippocampus-based immediate memory for a novel context even across a few minute timespan, which led to a profound but selective deficit in explicit spatial memory. These animals were also impaired in the induction of LTD, including LTD triggered by a cholinergic agonist. Moreover, genes regulating two processes essential for LTD-calcium release from intracellular stores and phosphatase activation-were abnormally expressed in knockouts. These findings suggest that for the hippocampus to form associative spatial memories through LTP-like processes, it must first undergo learning of the context per se through exploration and the learning of familiarity, which requires LTD-like processes.

The present study investigated the role of dopamine neurotransmission within the nucleus accumbens (NAc) in flavor preference learning induced by the postoral consequences of carbohydrates. In Experiment 1, rats fitted with a gastric catheter were trained with a flavor (CS+) paired with intragastric (IG) infusions of 8% glucose and a different flavor (CS-) paired with IG water infusions. The CS+ preference was then evaluated in two-bottle preference tests following bilateral injection of the dopamine D1-like receptor antagonist SCH23390 into the NAc shell at total doses of 0, 12, 24 and 48 nmol. SCH23390 produced dose-related reductions in CS+ intake but did not block the CS+ preference except at the highest dose, which also greatly suppressed the CS intakes. In Experiment 2, new rats were injected daily in the NAc shell with either saline or SCH23390 (12 nmol), 10 min prior to training sessions with CS+ with IG glucose and CS- with IG water. In the two-bottle preference tests, the drug-treated rats, unlike the control rats, did not significantly prefer the CS+ (61 vs. 83% preference). In Experiment 3, new rats were trained with the same procedures as Experiment 2, except that brain injections were in the NAc core. In contrast to control rats, SCH-treated rats failed to prefer the CS+ to the CS- in two-bottle tests (55% vs. 89% preference). These results demonstrate that D1-like receptors in the NAc shell and core are greatly involved in the acquisition, but less so in the expression, of a flavor preference conditioned by postingestive effects of glucose.

An early study performed in Bart Hoebel’s laboratory suggested that dopamine (DA) signaling in the nucleus accumbens was involved in learned flavor preferences produced by post-oral nutritive feedback. This paper summarizes our studies investigating the role of DA in flavor preferences conditioning using selective DA receptor antagonists. Food-restricted rats were trained to prefer a flavored saccharin solution (CS+) paired with intragastric (IG) sugar infusions over a flavored saccharin solution (CS−) paired with water infusions. Systemic injections of a D1-like receptor antagonist (SCH23390), but not a D2-like receptor antagonist (raclopride) during training blocked flavor preference learning. Neither drug prevented the expression of an already learned preference except at high doses that greatly suppressed total intakes. Central sites of action were examined by local microinjections of SCH23390 (12 nmol) during flavor training or testing. Drug infusions in the nucleus accumbens, amygdala, medial prefrontal cortex, or lateral hypothalamus during training blocked or attenuated CS+ flavor conditioning by IG glucose infusions. The same drug dose did not suppress the expression of a learned CS+ preference. The findings suggest that DA signaling within different components of a distributed brain network is involved in sugar-based flavor preferences. A possible role of DA in conditioned increases in flavor acceptance is discussed.

Systemic administration of dopamine D1 (SCH23390) and less so D2 (raclopride) receptor antagonists significantly reduce acquisition and expression of fructoseconditioned flavor preferences (CFP). Because dopamine in the nucleus accumbens shell (NAcS) is implicated in food reward, the present study examined whether NAcS D1 or D2 antagonists altered acquisition and/or expression of fructose-CFP. In Experiment 1, food-restricted rats with bilateral NAcS cannulae were trained to drink a fructose (8%) + saccharin (0.2%) solution mixed with one flavor (CS+/Fs) and a less-preferred 0.2% saccharin solution with mixed another flavor (CS−/s). Unlimited two-bottle tests with the two flavors in saccharin (0.2%: CS+/s, CS−/s) occurred 10 min following total bilateral NAcS doses of 0, 12, 24 or 48 nmol of SCH23390 or raclopride. Preference for CS+/s over CS−/s following vehicle treatment (76%) was significantly reduced by SCH23390 (48 nmol, 62%) and raclopride (24 nmol, 63%). In Experiment 2, rats received bilateral NAcS injections (12 nmol) of SCH23390 or raclopride on one-bottle training (16 ml) days. Yoked control rats received vehicle and were limited to the CS intakes of the D1 and D2 groups, whereas untreated controls without injections received their CS ration during training. Subsequent unlimited two-bottle tests revealed initial preferences of CS+/s over CS−/s in all groups that remained stable in untreated and yoked controls, but were lost over the 6 tests sessions in D1 and D2 groups. These data indicate that NAcS D1 and D2 antagonists

The present study was built on the original report of Eichenbaum et al. [Eichenbaum, H., Fagan, A., Mathews, P. & Cohen, N.J. (1988), Behav. Neurosci., 102, 3531-3542] on the contrasting effects of fornix lesion in different versions of an odour-guided discrimination task in rats, and attempted to extend this into a mouse model for the preferential loss of declarative memory seen in human senescence. Each of the two experiments reported here consisted of a two-stage paradigm, with an initial learning phase followed by a test phase. The information acquired in the first stage was identical in both experiments, i.e. the valence or reward contingency associated with six (three positive and three negative) arms of a radial maze. The only parameter which was varied between Experiment A and B, and also between the two successive stages within each experiment, was the way of presenting the arms to the mice, i.e. either in pairs (simultaneous discriminations) or one at a time (successive go : no-go discrimination). Performance in the first stage demonstrated that our aged mice were impaired in learning concurrent simultaneous discriminations but not successive go/no-go discrimination, thereby resembling that reported in rats with hippocampal damage. Most importantly, our present set of data supports the conclusion that two forms of memory expression for the same piece of acquired experience can be assessed in the same subjects by manipulating the way of presenting two arms that were previously experienced separately. These two forms of memory expressions are differentially affected in aged mice, thereby demonstrating the highly selective and specific deleterious effect of ageing.

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The role of the amygdala (AMY) in learning to associate complex flavor (taste + odor cues) with the oral and post-oral properties of nutrients was examined. Rats with excitotoxic lesions of the basolateral AMY learned to prefer flavors paired with intragastric (IG) infusions of maltodextrin or corn oil (Experiment 1), although the preference was slightly attenuated. However, rats with large AMY lesions failed to develop a preference for flavors paired with IG infusions of the same nutrients (Experiments 2 and 4) but were able to learn a preference for a taste mixture paired with IG maltodextrin infusions (Experiment 3). The rats with large AMY lesions also did not acquire a preference for a flavor cue paired with the sweet taste of fructose (Experiment 5). Collectively, these data provide evidence that AMY is essential for flavor- but not taste-nutrient preference learning.