Project description:Working memory-the brain's ability to internalize information and use it flexibly to guide behaviour-is an essential component of cognition. Although activity related to working memory has been observed in several brain regions1-3, how neural populations actually represent working memory4-7 and the mechanisms by which this activity is maintained8-12 remain unclear13-15. Here we describe the neural implementation of visual working memory in mice alternating between a delayed non-match-to-sample task and a simple discrimination task that does not require working memory but has identical stimulus, movement and reward statistics. Transient optogenetic inactivations revealed that distributed areas of the neocortex were required selectively for the maintenance of working memory. Population activity in visual area AM and premotor area M2 during the delay period was dominated by orderly low-dimensional dynamics16,17 that were, however, independent of working memory. Instead, working memory representations were embedded in high-dimensional population activity, present in both cortical areas, persisted throughout the inter-stimulus delay period, and predicted behavioural responses during the working memory task. To test whether the distributed nature of working memory was dependent on reciprocal interactions between cortical regions18-20, we silenced one cortical area (AM or M2) while recording the feedback it received from the other. Transient inactivation of either area led to the selective disruption of inter-areal communication of working memory. Therefore, reciprocally interconnected cortical areas maintain bound high-dimensional representations of working memory.
Project description:The Working Memory model of human memory, first introduced by Baddeley and Hitch (1974), has been one of the most influential psychological constructs in cognitive psychology and human neuroscience. However the neuronal correlates of core components of this model have yet to be fully elucidated. Here we present data from two studies where human temporal cortical single neuron activity was recorded during tasks differentially affecting the maintenance component of verbal working memory. In Study One we vary the presence or absence of distracting items for the entire period of memory storage. In Study Two we vary the duration of storage so that distractors filled all, or only one-third of the time the memory was stored. Extracellular single neuron recordings were obtained from 36 subjects undergoing awake temporal lobe resections for epilepsy, 25 in Study one, 11 in Study two. Recordings were obtained from a total of 166 lateral temporal cortex neurons during performance of one of these two tasks, 86 study one, 80 study two. Significant changes in activity with distractor manipulation were present in 74 of these neurons (45%), 38 Study one, 36 Study two. In 48 (65%) of those there was increased activity during the period when distracting items were absent, 26 Study One, 22 Study Two. The magnitude of this increase was greater for Study One, 47.6%, than Study Two, 8.1%, paralleling the reduction in memory errors in the absence of distracters, for Study One of 70.3%, Study Two 26.3% These findings establish that human lateral temporal cortex is part of the neural system for working memory, with activity during maintenance of that memory that parallels performance, suggesting it represents active rehearsal. In 31 of these neurons (65%) this activity was an extension of that during working memory encoding that differed significantly from the neural processes recorded during overt and silent language tasks without a recent memory component, 17 Study one, 14 Study two. Contrary to the Baddeley model, that activity during verbal working memory maintenance often represented activity specific to working memory rather than speech or language.
Project description:The online maintenance and manipulation of information in working memory (WM) is essential for guiding behavior based on our goals. Understanding how WM alters sensory processing in pursuit of different behavioral objectives is therefore crucial to establish the neural basis of our goal-directed behavior. Here we show that, in the middle temporal (MT) area of rhesus monkeys, the power of the local field potentials in the αβ band (8-25 Hz) increases, reflecting the remembered location and the animal's performance. Moreover, the content of WM determines how coherently MT sites oscillate and how synchronized spikes are relative to these oscillations. These changes in spike timing are not only sufficient to carry sensory and memory information, they can also account for WM-induced sensory enhancement. These results provide a mechanistic-level understanding of how WM alters sensory processing by coordinating the timing of spikes across the neuronal population, enhancing the sensory representation of WM targets.
Project description:Brain oscillations most often occur in bursts, called oscillation packets, which span a finite extent in time and frequency. Recent studies have shown that these packets portray a much more dynamic picture of synchronization and transient communication between sites than previously thought. To understand their nature and statistical properties, techniques are needed to objectively detect oscillation packets and to quantify their temporal and frequency extent, as well as their magnitude. There are various methods to detect bursts of oscillations. The simplest ones divide the signal into band limited sub-components, quantifying the strength of the resulting components. These methods cannot by themselves cope with broadband transients that look like genuine oscillations when restricted to a narrow band. The most successful detection methods rely on time-frequency representations, which can readily show broadband transients and harmonics. However, the performance of such methods is conditioned by the ability of the representation to localize packets simultaneously in time and frequency, and by the capabilities of packet detection techniques, whose current state of the art is limited to extraction of bounding boxes. Here, we focus on the second problem, introducing two detection methods that use concepts derived from clustering and topographic prominence. These methods are able to delineate the packets' precise contour in the time-frequency plane. We validate the new approaches using both synthetic and real data recorded in humans and animals and rely on a super-resolution time-frequency representation, namely the superlets, as input to the detection algorithms. In addition, we define robust tests for benchmarking and compare the new methods to previous techniques. Results indicate that the two methods we introduce shine in low signal-to-noise ratio conditions, where they only miss a fraction of packets undetected by previous methods. Finally, algorithms that delineate precisely the border of spectral features and their subcomponents offer far more valuable information than simple rectangular bounding boxes (time and frequency span) and can provide a solid foundation to investigate neural oscillations' dynamics.
Project description:Acetylcholine plays a critical role in the neocortex. Cholinergic agonists and acetylcholinesterase inhibitors can enhance cognitive functioning, as does intermittent electrical stimulation of the cortical source of acetylcholine, the nucleus basalis (NB) of Meynert. Here we show in two male monkeys how NB stimulation affects working memory and alters its neural code. NB stimulation increases dorsolateral prefrontal activity during the delay period of spatial working memory tasks and broadens selectivity for stimuli but does not strengthen phasic responses to each neuron's optimal visual stimulus. Paradoxically, despite this decrease in neuronal selectivity, performance improves in many task conditions, likely indicating increased delay period stability. Performance under NB stimulation does decline if distractors similar to the target are presented, consistent with reduced prefrontal selectivity. Our results indicate that stimulation of the cholinergic forebrain increases prefrontal neural activity, and this neuromodulatory tone can improve cognitive performance, subject to a stability-accuracy tradeoff.
Project description:We investigated whether the representations of different objects are maintained independently in working memory or interact with each other. Observers were shown two sequentially presented orientations and required to reproduce each orientation after a delay. The sequential presentation minimized perceptual interactions so that we could isolate interactions between memory representations per se. We found that similar orientations were repelled from each other whereas dissimilar orientations were attracted to each other. In addition, when one of the items was given greater attentional priority by means of a cue, the representation of the high-priority item was not influenced very much by the orientation of the low-priority item, but the representation of the low-priority item was strongly influenced by the orientation of the high-priority item. This indicates that attention modulates the interactions between working memory representations. In addition, errors in the reported orientations of the two objects were positively correlated under some conditions, suggesting that representations of distinct objects may become grouped together in memory. Together, these results demonstrate that working-memory representations are not independent but instead interact with each other in a manner that depends on attentional priority.
Project description:Sensory neurons often have variable responses to repeated presentations of the same stimulus, which can significantly degrade the stimulus information contained in those responses. This information can in principle be preserved if variability is shared across many neurons, but depends on the structure of the shared variability and its relationship to sensory encoding at the population level. The structure of this shared variability in neural activity can be characterized by latent variable models, although they have thus far typically been used under restrictive mathematical assumptions, such as assuming linear transformations between the latent variables and neural activity. Here we introduce two nonlinear latent variable models for analyzing large-scale neural recordings. We first present a general nonlinear latent variable model that is agnostic to the stimulus tuning properties of the individual neurons, and is hence well suited for exploring neural populations whose tuning properties are not well characterized. This motivates a second class of model, the Generalized Affine Model, which simultaneously determines each neuron's stimulus selectivity and a set of latent variables that modulate these stimulus-driven responses both additively and multiplicatively. While these approaches can detect very general nonlinear relationships in shared neural variability, we find that neural activity recorded in anesthetized primary visual cortex (V1) is best described by a single additive and single multiplicative latent variable, i.e., an "affine model". In contrast, application of the same models to recordings in awake macaque prefrontal cortex discover more general nonlinearities to compactly describe the population response variability. These results thus demonstrate how nonlinear latent variable models can be used to describe population variability, and suggest that a range of methods is necessary to study different brain regions under different experimental conditions.
Project description:Neuronal differentiation and maturation are extended developmental processes. To determine whether neurons at different developmental stages have divergent chemosensitivities, we screened differentiating and maturing neuronal populations using a small compound library comprising FDA-approved and investigational drugs. Using a neurotoxicity assay format, both respective neuronal population-based screening campaigns performed robustly (Z-factors = 0.7-0.8), although the hit rate for the differentiating neurons (2.8%) was slightly higher than for maturing neurons (1.9%). While the majority of hits were toxic to both neuronal populations, these hits predominantly represented promiscuous drugs. Other drugs were selectively neurotoxic, with receptor tyrosine kinase inhibitors disproportionally represented after confirmation. Ponatinib and amuvatinib were neuroinhibitory for differentiating and maturing neurons, respectively. Chemoinformatic analyses confirmed differences in potential drug targets that may be differentially expressed during neuronal development. Subsequent studies demonstrated neuronal expression of AXL, an amuvatinib target, in both neuronal populations. However, functional AXL activity was confirmed only in the maturing neuronal population as determined by AXL phosphorylation in response to GAS6, the cognate ligand of AXL, and concurrent STAT3Y705 phosphorylation. Differentiating neurons were unresponsive to the effects of GAS6 suggesting that the AXL-STAT3 signaling axis was nonfunctional. Amuvatinib treatment of maturing neuronal cultures significantly reduced pAXL levels. These studies indicate that neuronal developmental states may exhibit unique chemosensitivities and that drugs may have different neuro-inhibitory effects depending upon the developmental stage of the neuronal population.
Project description:Distressed western carpenter ants, Camponotus modoc, produce alarm pheromone and substrate-borne vibrations. The alarm pheromone attracts nestmates but the effects of vibratory signals, or of bimodal pheromonal and vibratory signals, are not known. Worker ants of two Camponotus congeners reportedly stand still ("freeze") or run fast in response to engineered drumming vibrations inputted on plastic, but many responses to ant-produced vibratory signals on wood have not yet been investigated. Generally, orientating toward signalers under vertebrate predator attack seems maladaptive and not beneficial to ant colonies. We tested the hypotheses (1) that vibratory alarm signals cause freezing, rapid running but not attraction of nestmates, and (2) that bimodal alarm signals modulate responses to monomodal alarm signals, thereby possibly reducing predation risk. Laser Doppler vibrometry recordings revealed that the ants' vibratory signals readily propagate through ant nest lamellae, and thus quickly inform nest mates of perceived threats. With a speaker modified to record and deliver vibratory signals, we obtained drumming signals of distressed ants on a Douglas fir veneer, and bioassayed signal effects on ants in an arena with a suspended veneer floor. In response playback of vibratory signals, ants ran rapidly, or froze, but did not approach the vibratory signals. Exposed to alarm pheromone, ants frequently visited the pheromone source. However, concurrently exposed to both alarm pheromone and vibratory signals, ants visited the pheromone source less often but spent more time "frozen." The ants' modulated responses to bimodal signals seem adaptive but the reproductive fitness benefits are still to be quantified.
Project description:Memories link information about specific experiences to more general knowledge that is abstracted from and contextualizes those experiences. Hippocampal-cortical activity patterns representing features of past experience are reinstated during awake memory reactivation events, but whether representations of both specific and general features of experience are simultaneously reinstated remains unknown. We examined hippocampal and prefrontal cortical firing patterns during memory reactivation in rats performing a well-learned foraging task with multiple spatial paths. We found that specific hippocampal place representations are preferentially reactivated with the subset of prefrontal cortical task representations that generalize across different paths. Our results suggest that hippocampal-cortical networks maintain links between stored representations for specific and general features of experience, which could support abstraction and task guidance in mammals.