Erin L. Rich

Rat Prefrontal Cortical Neurons Selectively Code Strategy Switches

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 plus 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). Although 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 (PFC) is central. The 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 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 whereas 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.

Prelimbic/Infralimbic Inactivation Impairs Memory for Multiple Task Switches, But Not Flexible Selection of Familiar Tasks

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.

The Neurotrophin-Inducible Gene Vgf Regulates Hippocampal Function and Behavior through a Brain-Derived Neurotrophic Factor-Dependent Mechanism

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-p75NTR 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.

Daily and photoperiod variations of basal and stress-induced corticosterone concentrations in house sparrows (Passer domesticus).

Abstract. Corticosterone concentrations were measured in captive house sparrows (Passer domesticus) and found to vary both daily and with different photoperiods. Basal corticosterone was highest during the dark hours of the daily cycle and lowest during the light hours. This trend remained constant when the birds were held on short-day and long-day light cycles, and while the birds were undergoing a prebasic molt. At all times, corticosterone concentrations significantly increased in response to the stress of handling and restraint. Stress-induced corticosterone concentrations, however, only reflected a daily rhythm when the birds were held on short-days. Furthermore, even though mean basal corticosterone concentrations were equivalent over the short-day, long-day, and molt, total corticosterone output in response to stress was lower in molting birds, especially at night. Therefore, these data indicate that captive house sparrows modulate corticosterone in daily cycles that change in response to photoperiod.

Decoding subjective decisions from orbitofrontal cortex

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 these dynamics by recovering temporally precise neural states from multidimensional 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.

Medial-lateral organization of the orbitofrontal cortex

Emerging evidence suggests that specific cognitive functions localize to different subregions of OFC, but the nature of these functional distinctions remains unclear. One prominent theory, derived from human neuroimaging, proposes that different stimulus valences are processed in separate orbital regions, with medial and lateral OFC processing positive and negative stimuli, respectively. Thus far, neurophysiology data have not supported this theory. We attempted to reconcile these accounts by recording neural activity from the full medial-lateral extent of the orbital surface in monkeys receiving rewards and punishments via gain or loss of secondary reinforcement. We found no convincing evidence for valence selectivity in any orbital region. Instead, we report differences between neurons in central OFC and those on the inferior-lateral orbital convexity, in that they encoded different sources of value information provided by the behavioral task. Neurons in inferior convexity encoded the value of external stimuli, whereas those in OFC encoded value information derived from the structure of the behavioral task. We interpret these results in light of recent theories of OFC function and propose that these distinctions, not valence selectivity, may shed light on a fundamental organizing principle for value processing in orbital cortex.

Striatal activity in borderline personality disorder with comorbid intermittent explosive disorder: sex differences.

Borderline Personality Disorder (BPD) is associated with behavioral and emotional dysregulation, particularly in social contexts; however, the underlying pathophysiology at the level of brain function is not well understood. Previous studies found abnormalities in frontal cortical and limbic areas suggestive of poor frontal regulation of downstream brain regions. However, the striatum, which is closely connected with the medial frontal cortices and plays an important role in motivated behaviors and processing of rewarding stimuli, has been understudied in BPD. Here we hypothesized that, in addition to frontal dysfunction, BPD patients may show abnormal striatal function. In this study, 38 BPD patients with intermittent explosive disorder (BPD-IED) and 36 healthy controls (HC) participated in the Point Subtraction Aggression Paradigm (PSAP), a computer game played with a fictitious other player. (18)Fluoro-deoxyglucose positron emission tomography (FDG-PET) measured relative glucose metabolism (rGMR) within caudate and putamen in response to aggression-provoking and non-provoking versions of the PSAP. Male BPD-IED patients had significantly lower striatal rGMR than all other groups during both conditions, although male and female BPD-IED patients did not differ in clinical or behavioral measures. These sex differences suggest differential involvement of frontal-striatal circuits in BPD-IED, and are discussed in relation to striatal involvement in affective learning and social decision-making.

Challenges of Interpreting Frontal Neurons during Value-Based Decision-Making

The frontal cortex is crucial to sound decision-making, and the activity of frontal neurons correlates with many aspects of a choice, including the reward value of options and outcomes. However, rewards are of high motivational significance and have widespread effects on neural activity. As such, many neural signals not directly involved in the decision process can correlate with reward value. With correlative techniques such as electrophysiological recording or functional neuroimaging, it can be challenging to distinguish neural signals underlying value-based decision-making from other perceptual, cognitive, and motor processes. In the first part of the paper, we examine how different value-related computations can potentially be confused. In particular, error-related signals in the anterior cingulate cortex, generated when one discovers the consequences of an action, might actually represent violations of outcome expectation, rather than errors per se. Also, signals generated at the time of choice are typically interpreted as reflecting predictions regarding the outcomes associated with the different choice alternatives. However, these signals could instead reflect comparisons between the presented choice options and previously presented choice alternatives. In the second part of the paper, we examine how value signals have been successfully dissociated from saliency-related signals, such as attention, arousal, and motor preparation in studies employing outcomes with both positive and negative valence. We hope that highlighting these issues will prove useful for future studies aimed at disambiguating the contribution of different neuronal populations to choice behavior.

What stays the same in orbitofrontal cortex

Researchers show that orbitofrontal neurons perform the same value-related computations across different decisions. Value computations are therefore a critical feature around which orbitofrontal representations are organized.

Linking dynamic patterns of neural activity in orbitofrontal cortex with decision making

Humans and animals demonstrate extraordinary flexibility in choice behavior, particularly when deciding based on subjective preferences. We evaluate options on different scales, deliberate, and often change our minds. Little is known about the neural mechanisms that underlie these dynamic aspects of decision-making, although neural activity in orbitofrontal cortex (OFC) likely plays a central role. Recent evidence from studies in macaques shows that attention modulates value responses in OFC, and that ensembles of OFC neurons dynamically signal different options during choices. When contexts change, these ensembles flexibly remap to encode the new task. Determining how these dynamic patterns emerge and relate to choices will inform models of decision-making and OFC function.