Recent behavioral evidence implicates reward prediction errors (RPEs) as a key factor in the acquisition of episodic memory. Yet, important neural predictions related to the role of RPEs in episodic memory acquisition remain to be tested. Humans (both sexes) performed a novel variable-choice task where we experimentally manipulated RPEs and found support for key neural predictions with fMRI. Our results show that in line with previous behavioral observations, episodic memory accuracy increases with the magnitude of signed (i.e., better/worse-than-expected) RPEs (SRPEs). Neurally, we observe that SRPEs are encoded in the ventral striatum (VS). Crucially, we demonstrate through mediation analysis that activation in the VS mediates the experimental manipulation of SRPEs on episodic memory accuracy. In particular, SRPE-based responses in the VS (during learning) predict the strength of subsequent episodic memory (during recollection). Furthermore, functional connectivity between task-relevant processing areas ...

What happens in the brain when conscious awareness of the surrounding world fades? We manipulated consciousness in two experiments in a group of healthy males and measured brain activity with positron emission tomography. Measurements were made during wakefulness, escalating and constant levels of two anesthetic agents (experiment 1, n = 39), and during sleep-deprived wakefulness and non-rapid eye movement sleep (experiment 2, n = 37). In experiment 1, the subjects were randomized to receive either propofol or dexmedetomidine until unresponsiveness. In both experiments, forced awakenings were applied to achieve rapid recovery from an unresponsive to a responsive state, followed by immediate and detailed interviews of subjective experiences during the preceding unresponsive condition. Unresponsiveness rarely denoted unconsciousness, as the majority of the subjects had internally generated experiences. Unresponsive anesthetic states and verified sleep stages, where a subsequent report of mental content inclu...

In the article “The Hippocampal Film Editor: Sensitivity and Specificity to Event Boundaries in Continuous Experience,” by Aya Ben-Yakov and Richard N. Henson, which appeared on pages [10057–10068][1] of the November 21, 2018 issue, there was an error in the code used for analysis. Ben-Yakov

Growing animal data evince a critical role of the sensory cortex in the long-term storage of aversive conditioning, following acquisition and consolidation in the amygdala. Whether and how this function is conserved in the human sensory cortex is nonetheless unclear. We interrogated this question in a human aversive conditioning study employing multidimensional assessments of conditioning and long-term (15 days) retention. Conditioned stimuli (CS; Gabor patches) were calibrated to differentially activate the parvocellular (P) and magnocellular (M) visual pathways, further elucidating cortical versus subcortical mechanisms. Full-blown conditioning and long-term retention emerged for M-biased CS (vs. limited effects for P-biased CS), especially among anxious individuals, in all four dimensions assessed: threat appraisal (threat ratings), physiological arousal (skin conductance response), perceptual learning (discrimination sensitivity, d ’, and response speed), and cortical plasticity (visual evoked potentia...

Reversible modification of AMPARs with ubiquitin regulates receptor levels at synapses and controls synaptic strength. The conserved deubiquitinating enzyme (DUB) USP-46 removes ubiquitin from AMPARs and protects them from degradation in both C. elegans and mammals. Although DUBs are critical for diverse physiological processes, the mechanisms that regulate DUBs, especially in the nervous system, are not well understood. We and others previously showed that the WD40-repeat proteins WDR-48 and WDR-20 bind to and stimulate the catalytic activity of USP-46. Here, we identify an activity-dependent mechanism that regulates WDR-20 expression and show that WDR-20 works together with USP-46 and WDR-48 to promote surface levels of the C. elegans AMPAR GLR-1. usp-46 , wdr-48 and wdr-20 loss-of-function mutants exhibit reduced levels of GLR-1 at the neuronal surface and corresponding defects in GLR-1-mediated behavior. Increased expression of WDR-20, but not WDR-48, is sufficient to increase GLR-1 surface levels in a...

Chronic stress impairs the function of multiple brain regions and causes severe hedonic and motivational deficits. One brain region known to be susceptible to these effects is the prefrontal cortex. Neurons in this region, specifically neuronal projections from the prelimbic region (PL) to the nucleus accumbens core (NAcC), have a significant role in promoting motivated approach. However, little is known about how activity in this pathway changes during associative learning to encode cues that promote approach. Less is known about how activity in this pathway may be altered by stress. In this study, an intersectional fiber photometry approach was used in male Sprague Dawley rats engaged in a Pavlovian autoshaping design to characterize the involvement of the PL-NAcC pathway in the typical acquisition of learned approach (directed at both the predictive cue and the goal), and its potential alteration by stress. Specifically, the hypothesis that neural activity in PL-NAcC would encode a Pavlovian approach cu...

Perceptual decision-making is increasingly being understood to involve an interaction between bottom-up sensory-driven signals and top-down choice-driven signals, but how these signals interact to mediate perception is not well understood. The parieto-insular vestibular cortex (PIVC) is an area with prominent vestibular responsiveness, and previous work has shown that inactivating PIVC impairs vestibular heading judgments. To investigate the nature of PIVC’s contribution to heading perception, we recorded extracellularly from PIVC neurons in two male rhesus macaques during a heading discrimination task, and compared findings with data from previous studies of areas MSTd and VIP using identical stimuli. By computing partial correlations between neural responses, heading, and choice, we find that PIVC activity reflects a dynamically changing combination of sensory and choice signals. In addition, the sensory and choice signals are more balanced in PIVC, in contrast to the sensory dominance in MSTd and choice...

Dendritic spines act as the receptive contacts at most excitatory synapses. Spines are enriched in a network of actin filaments comprised of two kinetically distinct pools. The majority of spine actin is highly dynamic and regulates spine size, structural plasticity, and postsynaptic density organization. The remainder of the spine actin network is more stable, but the function of this minor actin population is not well understood, as tools to study it have not been available. Previous work has shown that disruption of the Abl2/Arg nonreceptor tyrosine kinase in mice compromises spine stability and size. Here, using cultured hippocampal neurons pooled from both sexes of mice, we provide evidence that binding to cortactin tethers Abl2 in spines, where Abl2 and cortactin maintain the small pool of stable actin required for dendritic spine stability. Using fluorescence recovery after photobleaching of GFP-actin, we find that disruption of Abl2:cortactin interactions eliminates stable actin filaments in dendri...

It is generally supposed that primary motor cortex (M1) receives somatosensory input predominantly via primary sensory cortex (S1). However, a growing body of evidence indicates that M1 also receives direct sensory input from the thalamus, independent of S1; such direct input is particularly evident at early ages before M1 contributes to motor control. Here, recording extracellularly from the forelimb regions of S1 and M1 in unanesthetized rats at postnatal day (P) 8 and P12, we compared S1 and M1 responses to self-generated (i.e., reafferent) forelimb movements during active sleep and wake, and to other-generated (i.e., exafferent) forelimb movements. At both ages, reafferent responses were processed in parallel by S1 and M1; in contrast, exafferent responses were processed in parallel at P8 but serially—from S1 to M1—at P12. To further assess this developmental difference in processing, we compared exafferent responses to proprioceptive and tactile stimulation. At both P8 and P12, proprioceptive stimulat...

Popular models of decision-making propose that noisy sensory evidence accumulates until reaching a bound. Behavioral evidence as well as trial-averaged ramping of neuronal activity in sensorimotor regions of the brain support this idea. However, averaging activity across trials can mask other processes, such as rapid shifts in decision commitment, calling into question the hypothesis that evidence accumulation is encoded by delay-period activity of individual neurons. We mined two sets of data from experiments in four monkeys in which we recorded from SC neurons during two different decision-making tasks and a delayed-saccade task. We applied second order statistical measures and spike train simulations to determine whether spiking statistics were similar or different in the different tasks and monkeys, despite similar trial-averaged activity across tasks and monkeys. During a motion direction discrimination task, single-trial delay-period activity behaved statistically consistent with accumulation. During...