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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VGF is a neurotrophin-inducible, activity-regulated gene product that is expressed in CNS and PNS neurons, in which it is processed into peptides and secreted. VGF synthesis is stimulated by BDNF, a critical regulator of hippocampal development and function, and two VGF C-terminal peptides increase synaptic activity in cultured hippocampal neurons. To assess VGF function in the hippocampus, we tested heterozygous and homozygous VGF knock-out mice in two different learning tasks, assessed long-term potentiation (LTP) and depression (LTD) in hippocampal slices from VGF mutant mice, and investigated how VGF C-terminal peptides modulate synaptic plasticity. Treatment of rat hippocampal slices with the VGF-derived peptide TLQP62 resulted in transient potentiation through a mechanism that was selectively blocked by the BDNF scavenger TrkB-Fc, the Trk tyrosine kinase inhibitor K252a (100 nM), and tPA STOP, an inhibitor of tissue plasminogen activator (tPA), an enzyme involved in pro-BDNF cleavage to BDNF, but was not blocked by the NMDA receptor antagonist APV, anti-p75 NTR function-blocking antiserum, or previous tetanic stimulation. Although LTP was normal in slices from VGF knock-out mice, LTD could not be induced, and VGF mutant mice were impaired in hippocampal-dependent spatial learning and contextual fear conditioning tasks. Our studies indicate that the VGF C-terminal peptide TLQP62 modulates hippocampal synaptic transmission through a BDNF-dependent mechanism and that VGF deficiency in mice impacts synaptic plasticity and memory in addition to depressive behavior.

High-gamma signals mirror the tuning and temporal profiles of neurons near a recording electrode in sensory and motor areas. These frequencies appear to aggregate local neuronal activity, but it is unclear how this relationship affects information encoding in high-gamma activity (HGA) in cortical areas where neurons are heterogeneous in selectivity and temporal responses, and are not functionally clustered. Here we report that populations of neurons and HGA recorded from the orbitofrontal cortex (OFC) encode similar information, although there is little correspondence between signals recorded by the same electrode. HGA appears to aggregate heterogeneous neuron activity, such that the spiking of a single cell corresponds to only small increases in HGA. Interestingly, large-scale spatiotemporal dynamics are revealed in HGA, but less apparent in the population of single neurons. Overall, HGA is closely related to neuron activity in OFC, and provides a unique means of studying large-scale spatiotemporal dynamics of information processing.

Optimal decision-making requires that stimulus-value associations are kept up to date by constantly comparing the expected value of a stimulus with its experienced outcome. To do this, value information must be held in mind when a stimulus and outcome are separated in time. However, little is known about the neural mechanisms of working memory (WM) for value. Contradicting theories have suggested WM requires either persistent or transient neuronal activity, with stable or dynamic representations respectively. To test these hypotheses, we recorded neuronal activity in the orbitofrontal and anterior cingulate cortex of two monkeys performing a valuation task. We found that features of all hypotheses were simultaneously present in prefrontal activity, and no single hypothesis was exclusively supported. Instead, mixed dynamics supported robust, time invariant value representations while also encoding the information in a temporally specific manner. We suggest that this hybrid coding is a critical mechanism supporting flexible cognitive abilities.