Neuronal immediate-early gene (IEG) expression is regulated by synaptic activity and plays an important role in the neuroplastic mechanisms critical to memory consolidation. IEGs can be divided into two functional classes: (1) regulatory transcription factors (RTFs), which can broadly influence cell function depending on the "downstream" genes they regulate, and (2) "effector" proteins, which may directly modulate specific cellular functions. The objective of the current study was to determine whether the expression of an effector IEG (Arc) was similar to, or different from, that of two well characterized RTF IEGs (c-fos and zif268) after learning. IEG RNA levels from rats trained in spatial and nonspatial water tasks were determined using RNase protection assays and in situ hybridization. Overall, the regulation of the three IEGs was similar in the hippocampus and the entorhinal and primary visual cortices. Consequently, IEG RNA levels were positively correlated within a structure. By contrast, Arc and zif268 RNA levels were not correlated or only weakly correlated across structures, although c-fos RNA levels were moderately correlated across structures. Arc RNA expression differed from that of zif268 and c-fos in two regards: (1) hippocampal Arc RNA levels were correlated with learning of the hippocampal-dependent spatial, but not hippocampal-independent cued response, water task, and (2) Arc RNA levels in the hippocampus and entorhinal cortex increased after spatial reversal learning relative to an asymptotic performance group. Thus, although the expression of Arc, zif268, and c-fos exhibited many similarities, Arc was most responsive to differences in behavioral task demands.

The orbitofrontal cortex (OFC) and basolateral amygdala (BLA) are critical for using learned representations of outcomes to guide behavior. Neurophysiological findings suggest complementary roles in which the BLA acquires associations between cues and outcomes and the OFC subsequently uses them to guide behavior. Here, we have used a reinforcer devaluation paradigm to test this hypothesis. In this paradigm, rats are first trained to associate a light conditioned stimulus (CS) with a food outcome, and then the food is devalued by pairing it with illness. After this devaluation procedure, responding to the CS is assessed in a single probe session. Previously, we have shown that BLA and OFC lesions made before training do not affect the acquisition of conditioned responding but do impair the sensitivity of that responding to reinforcer devaluation. Rats with such lesions fail to exhibit the spontaneous decrease in conditioned responding to the light cue observed in controls in the probe test. Here, we have extended those findings by showing that performance in the probe test is impaired by OFC lesions made after light-food conditioning but not by BLA lesions made after that training. These findings indicate that the OFC and BLA play different roles in mediating normal goal-directed performance in this, and likely other, settings. The BLA seems critical to forming representations linking cues to the incentive properties of outcomes but not for maintaining these representations in memory, updating them with new information, or for expressing them in behavior. In contrast, the OFC seems essential for one or more of these latter processes.

Organisms eat not only in a response to signals related to energy balance. Eating also occurs in response to "extrinsic," or environmental, signals, including learned cues. Such cues can modify feeding based on motivational value acquired through association with either rewarding or aversive events. We provide evidence that a specific brain system, involving connections between basolateral amygdala and the lateral hypothalamus, is crucial for allowing learned cues (signals that were paired with food delivery when the animal was hungry) to override satiety and promote eating in sated rats. In an assessment of second-order conditioning, we also found that disconnection of this circuitry had no effect on the ability of a conditioned cue to support new learning. Knowledge about neural systems through which food-associated cues specifically control feeding behavior provides a defined model for the study of learning that may be informative for understanding mechanisms that contribute to eating disorders and more moderate forms of overeating.Key words: amygdala; hypothalamus; eating; feeding behavior; learning; goal-directed behavior; motivation Mild to severe obesity, estimated to affect ϳ60% of the adult population in developed countries, is a risk factor for a range of diseases (United States Department of Health and Human Services, 1999). Despite adverse health consequences, difficulties in achieving and maintaining weight control are common. Overeating is attributable, at least in part, to the fact that food consumption is powerfully influenced by a variety of environmental factors that are unrelated to energy requirements (Rodin, 1981;Booth, 1989). Eating can be socially facilitated (De Castro, 1997), and cues that become associated with food when hunger prevails can increase eating in satiated states (Weingarten, 1983).Recent research is beginning to define the neural systems through which such psychological processes influence eating. Under conditions that strongly potentiate feeding, laboratory rats with neurotoxic lesions of the basolateral amygdalar area (BLA) [including basolateral ("basal"), basomedial ("accessory basal"), and lateral nuclei] fail to increase eating in the presence of a conditioned stimulus (CS) that was previously paired with food (Gallagher, 2000;Holland et al., 2002). The BLA has anatomical connections with neural circuits in the hypothalamus that control feeding behavior (Elmquist et al., 1999;Swanson, 2000;DeFalco et al., 2001;Petrovich et al., 2001). It sends substantial, topographically organized projections to the lateral hypothalamic area (LHA) (Petrovich et al., 2001), which forms part of the feeding circuit and historically has been linked to initiation of feeding (Elmquist et al., 1999).The current investigation examined potentiation of feeding by a CS in rats with a preparation that disconnects the BLA and the LHA. Here we report that the BLA-LHA system is crucial for allowing learned cues to override satiety signals and stimulate eating in sated states. We further show that t...

Nucleus accumbens (NAcc) is critical for encoding and using information regarding the learned significance of cues predictive of reward. However, its role in processing information about cues predictive of aversive outcomes is less well studied. Here, we examined the effects of NAcc lesions in an odor-guided discrimination task in which rats use odor cues predictive of either appetitive or aversive outcomes to guide responding. Rats with sham or neurotoxic lesions of NAcc were trained on a series of two-odor discrimination problems. Performance on each problem was assessed by monitoring accuracy of choice behavior and by measuring latency to respond for fluid reinforcement after odor sampling. After acquisition of four problems, rats were trained on serial reversals of the final problem. Rats with NAcc lesions exhibited normal choice performance relative to controls on both acquisition and reversal of the discrimination problems (indeed, lesioned rats exhibited a mild facilitation on the first discrimination problem). Despite normal choice performance, however, lesioned rats failed to show normal changes in response latency during discrimination learning, particularly on trials involving the aversive outcome. These findings are consistent with a deficit in processing cue-outcome associations. These results are compared with those obtained from studies of basolateral amygdala and orbitofrontal cortex lesions in this task and suggest that NAcc integrates the motivational value of both appetitive and aversive cues to bias or modulate the vigor of subsequent responding.

Systemic or intracerebral administration of glucocorticoids enhances memory consolidation in several tasks. Previously, we reported that these effects depend on an intact basolateral nucleus of the amygdala (BLA) and efferents from the BLA that run through the stria terminalis (ST). The BLA projects directly to the nucleus accumbens (NAc) via this ST pathway. The NAc also receives direct projections from the hippocampus and, therefore, may be a site of convergence of BLA and hippocampal influences in modulating memory consolidation. In support of this view, we found previously that lesions of either the NAc or the ST also block the memory-modulatory effect of systemically administered glucocorticoids. The present experiments examined the effects of lesions of the NAc or the ST on the memory-modulatory effects of intracerebral glucocorticoids on inhibitory avoidance training. Microinfusions of the specific glucocorticoid receptor agonist 11␤,17␤-dihydroxy-6,21-dimethyl-17␣-pregna-4,6-trien-20yn-3-one (RU 28362; 1.0 or 3.0 ng) into either the BLA or the hippocampus of male Sprague Dawley rats administered immediately after training enhanced the 48 hr retention performance in a dose-dependent manner. Bilateral lesions of the NAc or the ST alone did not affect retention performance but blocked the memory enhancement induced by intra-BLA or intrahippocampal glucocorticoid receptor agonist administration. These findings indicate that the BLA-NAc pathway plays an essential role in mediating glucocorticoid effects on memory consolidation and suggest that the BLA interacts with hippocampal effects on memory consolidation via this pathway.