When making a subjective choice, the brain must compute a value for each option and compare those values to make a decision. The orbitofrontal cortex (OFC) is critically involved in this process, but the neural mechanisms remain obscure, in part due to limitations in our ability to measure and control the internal deliberations that can alter the dynamics of the decision process. Here, we tracked the dynamics by recovering temporally precise neural states from multi-dimensional data in OFC. During individual choices, OFC alternated between states associated with the value of two available options, with dynamics that predicted whether a subject would decide quickly or vacillate between the two alternatives. Ensembles of value-encoding neurons contributed to these states, with individual neurons shifting activity patterns as the network evaluated each option. Thus, the mechanism of subjective decision-making involves the dynamic activation of OFC states associated with each choice alternative.

(Sturnus vulgaris) to test whether corticosterone responses differed in birds held under normal laboratory conditions or conditions of chronic stress. Surprisingly, both basal corticosterone concentrations and corticosterone responses to acute stress were significantly reduced when birds were chronically stressed. To determine the mechanism underlying this reduced response, animals under both conditions were injected with lactated Ringer's solution (control), adrenocorticotropin (ACTH), arginine vasotocin (AVT), or dexamethasone (DEX). ACTH increased corticosterone concentrations above stress-induced levels in both cases, although maximum responses were lower in chronically stressed birds. AVT did not augment the corticosterone response under nonchronically stressed conditions, but it did under chronically stressed conditions. DEX reduced maximal corticosterone concentrations in both cases. Neither ovine nor rat corticotropin-releasing factor (CRF) altered normal stress responses. These data indicate that changes in responsiveness of the hypothalamic-pituitary-adrenal axis to ACTH and AVT serve to downregulate corticosterone responses during chronic stress. Furthermore, these data lead to the following hypothesis: ACTH output from the pituitary limits maximum corticosterone concentrations under normal conditions, but reduced AVT release from the hypothalamus regulates lower corticosterone concentrations under chronic stress conditions. environmental stress; negative feedback; hypothalamic-pituitary-adrenal axis; conservation GLUCOCORTICOIDS ARE STEROID hormones released from adrenal tissue in response to stressful stimuli. Upon perception of stress, the avian hypothalamus is activated to secrete arginine vasotocin (AVT, a congener of the mammalian arginine vasopressin) and corticotropin-releasing factor (CRF), which stimulate the pituitary to release adrenocorticotropin (ACTH), in turn, causing the release of glucocorticoids from the adrenals (7,8). This pathway constitutes the hypothalamic-pituitaryadrenal (HPA) axis, and its activation is one component of the physiological stress response. This response is believed to be aimed at maintaining or restoring homeostasis, thereby helping the animal to survive a stressful episode (45, 50). The primary avian glucocorticoid is corticosterone (CORT) (22).The presumed benefits of an acute activation of the HPA axis contrast with chronic activation. Various deleterious effects of chronic CORT elevation have been documented in many species, including suppression of reproductive function and behavior, immune system suppression, muscle wasting, growth suppression, and neuronal cell death (45, 49). Chronic stress generally produces chronic elevations in baseline CORT concentrations. However, studies of chronically stressed rats indicate that facilitation of the HPA axis takes place to maintain responsiveness to acute stressors (11,13,25), perhaps by increasing the role of vasopressin over CRF in the release of ACTH (1, 16, 17). Therefore, animals must avoid chronic stress ...

Multiple memory systems are distinguished by different sets of neuronal circuits and operating principles optimized to solve different problems across mammalian species (Tulving and Schacter, 1994). When a rat selects an arm in a + maze, for example, the choice can be guided by distinct neural systems (White and Wise, 1999) that encode different relationships among perceived stimuli, actions, and reward. Thus, egocentric or stimulus-response associations require striatal circuits, whereas spatial or episodic learning requires hippocampal circuits (Packard et al., 1989). Though these memory systems function in parallel (Packard and McGaugh, 1996), they can also interact competitively or synergistically (Kim and Ragozzino, 2005). The neuronal mechanisms that coordinate these multiple memory systems are not fully known, but converging evidence suggests that the prefrontal cortex is central. The prefrontal cortex (PFC) is crucial for abstract, rule-guided behavior in primates, and for switching rapidly between memory strategies in rats. We now report that rat medial PFC (mPFC) neuronal activity predicts switching between hippocampus-and caudate-dependent memory strategies. Prelimbic (PL) and infralimbic (IL) neuronal activity changed as rats switched memory strategies even as the rats performed identical behaviors, but did not change when rats learned new contingencies using the same strategy. PL dynamics anticipated learning performance while IL lagged, suggesting that the two regions help initiate and establish new strategies, respectively. These neuronal dynamics suggest that the PFC contributes to the coordination of memory strategies by integrating the predictive relationships among stimuli, actions, and reward.

Behavioral flexibility, in the form of strategy switching or set shifting, helps animals cope with changing contingencies in familiar environments. The prelimbic (PL) and infralimbic (IL) regions of the rat prefrontal cortex (PFC) contribute to this ability so that rats trained to use one strategy have difficulty learning a new one if the PL/IL is inactivated. Thus, the PL/IL mediates learning new tasks in place of old ones, but it may also be required to switch between familiar tasks. To test this hypothesis, we trained rats to perform multiple task switches on a plus-shaped maze, alternating between two familiar tasks. Muscimol inactivation of the PL/IL never impaired switch acquisition, but did impair memory for the recently acquired switch 24 h later. Additional experiments determined that control rats continued to perform the new task 24 h after a switch, but rats with PL/IL inactivation had impaired memory and performed the same task that was learned before inactivation. This impairment was observed in multiple switches, demonstrating that PL/IL activity was required to remember which of two familiar tasks was most recently successful. After many switches, however, muscimol no longer impaired performance, and both saline-and muscimol-infused rats appeared to use immediate task contingencies rather than memory to select among familiar tasks. This strategy may account for the decreased effect of PL/IL inactivation observed after extensive training. Thus, although PL/IL activity contributed to memory for multiple task switches, it was not required for flexibly selecting among highly familiar tasks.

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