Hippocampal neurons with stable excitatory connectivity become part of neuronal representations.

Experiences are represented in the brain by patterns of neuronal activity. Ensembles of neurons representing experience undergo activity-dependent plasticity and are important for learning and recall. They are thus considered cellular engrams of memory. Yet, the cellular events that bias neurons to become part of a neuronal representation are largely unknown. In rodents, turnover of structural connectivity has been proposed to underlie the turnover of neuronal representations and also to be a cellular mechanism defining the time duration for which memories are stored in the hippocampus. If these hypotheses are true, structural dynamics of connectivity should be involved in the formation of neuronal representations and concurrently important for learning and recall. To tackle these questions, we used deep-brain 2-photon (2P) time-lapse imaging in transgenic mice in which neurons expressing the Immediate Early Gene (IEG) Arc (activity-regulated cytoskeleton-associated protein) could be permanently labeled during a specific time window. This enabled us to investigate the dynamics of excitatory synaptic connectivity-using dendritic spines as proxies-of hippocampal CA1 (cornu ammonis 1) pyramidal neurons (PNs) becoming part of neuronal representations exploiting Arc as an indicator of being part of neuronal representations. We discovered that neurons that will prospectively express Arc have slower turnover of synaptic connectivity, thus suggesting that synaptic stability prior to experience can bias neurons to become part of representations or possibly engrams. We also found a negative correlation between stability of structural synaptic connectivity and the ability to recall features of a hippocampal-dependent memory, which suggests that faster structural turnover in hippocampal CA1 might be functional for memory.

Subregion-specific rules govern the distribution of neuronal immediate-early gene induction.

The induction of immediate-early gene (IEG) expression in brain nuclei in response to an experience is necessary for the formation of long-term memories. Additionally, the rapid dynamics of IEG induction and decay motivates the common use of IEG expression as markers for identification of neuronal assemblies ("ensembles") encoding recent experience. However, major gaps remain in understanding the rules governing the distribution of IEGs within neuronal assemblies. Thus, the extent of correlation between coexpressed IEGs, the cell specificity of IEG expression, and the spatial distribution of IEG expression have not been comprehensively studied. To address these gaps, we utilized quantitative multiplexed single-molecule fluorescence in situ hybridization (smFISH) and measured the expression of IEGs (Arc, Egr2, and Nr4a1) within spiny projection neurons (SPNs) in the dorsal striatum of mice following acute exposure to cocaine. Exploring the relevance of our observations to other brain structures and stimuli, we also analyzed data from a study of single-cell RNA sequencing of mouse cortical neurons. We found that while IEG expression is graded, the expression of multiple IEGs is tightly correlated at the level of individual neurons. Interestingly, we observed that region-specific rules govern the induction of IEGs in SPN subtypes within striatal subdomains. We further observed that IEG-expressing assemblies form spatially defined clusters within which the extent of IEG expression correlates with cluster size. Together, our results suggest the existence of IEG-expressing neuronal "superensembles," which are associated in spatial clusters and characterized by coherent and robust expression of multiple IEGs.

Sex-specific declines in cholinergic-targeting tRNA fragments in the nucleus accumbens in Alzheimer's disease.

INTRODUCTION: Females with Alzheimer's disease (AD) suffer accelerated dementia and loss of cholinergic neurons compared to males, but the underlying mechanisms are unknown. Seeking causal contributors to both these phenomena, we pursued changes in transfer RNS (tRNA) fragments (tRFs) targeting cholinergic transcripts (CholinotRFs). METHODS: We analyzed small RNA-sequencing (RNA-Seq) data from the nucleus accumbens (NAc) brain region which is enriched in cholinergic neurons, compared to hypothalamic or cortical tissues from AD brains; and explored small RNA expression in neuronal cell lines undergoing cholinergic differentiation. RESULTS: NAc CholinotRFs of mitochondrial genome origin showed reduced levels that correlated with elevations in their predicted cholinergic-associated mRNA targets. Single-cell RNA seq from AD temporal cortices showed altered sex-specific levels of cholinergic transcripts in diverse cell types; inversely, human-originated neuroblastoma cells under cholinergic differentiation presented sex-specific CholinotRF elevations. DISCUSSION: Our findings support CholinotRFs contributions to cholinergic regulation, predicting their involvement in AD sex-specific cholinergic loss and dementia.

Dissecting the Roles of Supervised and Unsupervised Learning in Perceptual Discrimination Judgments.

Our ability to compare sensory stimuli is a fundamental cognitive function, which is known to be affected by two biases: choice bias, which reflects a preference for a given response, and contraction bias, which reflects a tendency to perceive stimuli as similar to previous ones. To test whether both reflect supervised processes, we designed feedback protocols aimed to modify them and tested them in human participants. Choice bias was readily modifiable. However, contraction bias was not. To compare these results to those predicted from an optimal supervised process, we studied a noise-matched optimal linear discriminator (Perceptron). In this model, both biases were substantially modified, indicating that the "resilience" of contraction bias to feedback does not maximize performance. These results suggest that perceptual discrimination is a hierarchical, two-stage process. In the first, stimulus statistics are learned and integrated with representations in an unsupervised process that is impenetrable to external feedback. In the second, a binary judgment, learned in a supervised way, is applied to the combined percept.SIGNIFICANCE STATEMENT The seemingly effortless process of inferring physical reality from the sensory input is highly influenced by previous knowledge, leading to perceptual biases. Two common ones are contraction bias (the tendency to perceive stimuli as similar to previous ones) and choice bias (the tendency to prefer a specific response). Combining human psychophysical experiments with computational modeling we show that they reflect two different learning processes. Contraction bias reflects unsupervised learning of stimuli statistics, whereas choice bias results from supervised or reinforcement learning. This dissociation reveals a hierarchical, two-stage process. The first, where stimuli statistics are learned and integrated with representations, is unsupervised. The second, where a binary judgment is applied to the combined percept, is learned in a supervised way.

Paradoxical relationship between speed and accuracy in olfactory figure-background segregation.

In natural settings, many stimuli impinge on our sensory organs simultaneously. Parsing these sensory stimuli into perceptual objects is a fundamental task faced by all sensory systems. Similar to other sensory modalities, increased odor backgrounds decrease the detectability of target odors by the olfactory system. The mechanisms by which background odors interfere with the detection and identification of target odors are unknown. Here we utilized the framework of the Drift Diffusion Model (DDM) to consider possible interference mechanisms in an odor detection task. We first considered pure effects of background odors on either signal or noise in the decision-making dynamics and showed that these produce different predictions about decision accuracy and speed. To test these predictions, we trained mice to detect target odors that are embedded in random background mixtures in a two-alternative choice task. In this task, the inter-trial interval was independent of behavioral reaction times to avoid motivating rapid responses. We found that increased backgrounds reduce mouse performance but paradoxically also decrease reaction times, suggesting that noise in the decision making process is increased by backgrounds. We further assessed the contributions of background effects on both noise and signal by fitting the DDM to the behavioral data. The models showed that background odors affect both the signal and the noise, but that the paradoxical relationship between trial difficulty and reaction time is caused by the added noise.

Features of hippocampal astrocytic domains and their spatial relation to excitatory and inhibitory neurons.

The mounting evidence for the involvement of astrocytes in neuronal circuits function and behavior stands in stark contrast to the lack of detailed anatomical description of these cells and the neurons in their domains. To fill this void, we imaged >30,000 astrocytes in hippocampi made transparent by CLARITY, and determined the elaborate structure, distribution, and neuronal content of astrocytic domains. First, we characterized the spatial distribution of >19,000 astrocytes across CA1 lamina, and analyzed the morphology of thousands of reconstructed domains. We then determined the excitatory somatic content of CA1 astrocytes, and measured the distance between inhibitory neuronal somata to the nearest astrocyte soma. We find that on average, there are almost 14 pyramidal neurons per domain in the CA1, increasing toward the pyramidal layer midline, compared to only five excitatory neurons per domain in the amygdala. Finally, we discovered that somatostatin neurons are found in close proximity to astrocytes, compared to parvalbumin and VIP inhibitory neurons. This work provides a comprehensive large-scale quantitative foundation for studying neuron-astrocyte interactions.

Hierarchical cortical gradients in somatosensory processing.

Sensory information is processed in the visual cortex in distinct streams of different anatomical and functional properties. A comparable organizational principle has also been proposed to underlie auditory processing. This raises the question of whether a similar principle characterize the somatosensory domain. One property of a cortical stream is a hierarchical organization of the neuronal response properties along an anatomically distinct pathway. Indeed, several hierarchies between specific somatosensory cortical regions have been identified, primarily using electrophysiology, in non-human primates. However, it has been unclear how these local hierarchies are organized throughout the cortex. Here we used phase-encoded bilateral full-body light touch stimulation in healthy humans under functional MRI to study the large-scale organization of hierarchies in the somatosensory domain. We quantified two measures of hierarchy of BOLD responses, selectivity and laterality. We measured how selectivity and laterality change as we move away from the central sulcus within four gross anatomically-distinct regions. We found that both selectivity and laterality decrease in three directions: parietal, posteriorly along the parietal lobe, frontal, anteriorly along the frontal lobe and medial, inferiorly-anteriorly along the medial wall. The decline of selectivity and laterality along these directions provides evidence for hierarchical gradients. In view of the anatomical segregation of these three directions, the multiplicity of body representations in each region and the hierarchical gradients in our findings, we propose that as in the visual and auditory domains, these directions are streams of somatosensory information processing.

Predicting the Dynamics of Network Connectivity in the Neocortex.

Dynamic remodeling of connectivity is a fundamental feature of neocortical circuits. Unraveling the principles underlying these dynamics is essential for the understanding of how neuronal circuits give rise to computations. Moreover, as complete descriptions of the wiring diagram in cortical tissues are becoming available, deciphering the dynamic elements in these diagrams is crucial for relating them to cortical function. Here, we used chronic in vivo two-photon imaging to longitudinally follow a few thousand dendritic spines in the mouse auditory cortex to study the determinants of these spines' lifetimes. We applied nonlinear regression to quantify the independent contribution of spine age and several morphological parameters to the prediction of the future survival of a spine. We show that spine age, size, and geometry are parameters that can provide independent contributions to the prediction of the longevity of a synaptic connection. In addition, we use this framework to emulate a serial sectioning electron microscopy experiment and demonstrate how incorporation of morphological information of dendritic spines from a single time-point allows estimation of future connectivity states. The distinction between predictable and nonpredictable connectivity changes may be used in the future to identify the specific adaptations of neuronal circuits to environmental changes. The full dataset is publicly available for further analysis. Significance statement: The neural architecture in the neocortex exhibits constant remodeling. The functional consequences of these modifications are poorly understood, in particular because the determinants of these changes are largely unknown. Here, we aimed to identify those modifications that are predictable from current network state. To that goal, we repeatedly imaged thousands of dendritic spines in the auditory cortex of mice to assess the morphology and lifetimes of synaptic connections. We developed models based on morphological features of dendritic spines that allow predicting future turnover of synaptic connections. The dynamic models presented in this paper provide a quantitative framework for adding putative temporal dynamics to the static description of a neuronal circuit from single time-point connectomics experiments.

A Computational Model of Implicit Memory Captures Dyslexics' Perceptual Deficits.

Dyslexics are diagnosed for their poor reading skills, yet they characteristically also suffer from poor verbal memory and often from poor auditory skills. To date, this combined profile has been accounted for in broad cognitive terms. Here we hypothesize that the perceptual deficits associated with dyslexia can be understood computationally as a deficit in integrating prior information with noisy observations. To test this hypothesis we analyzed the performance of human participants in an auditory discrimination task using a two-parameter computational model. One parameter captures the internal noise in representing the current event, and the other captures the impact of recently acquired prior information. Our findings show that dyslexics' perceptual deficit can be accounted for by inadequate adjustment of these components; namely, low weighting of their implicit memory of past trials relative to their internal noise. Underweighting the stimulus statistics decreased dyslexics' ability to compensate for noisy observations. ERP measurements (P2 component) while participants watched a silent movie indicated that dyslexics' perceptual deficiency may stem from poor automatic integration of stimulus statistics. This study provides the first description of a specific computational deficit associated with dyslexia. SIGNIFICANCE STATEMENT: This study presents the first attempt to specify the mechanisms underlying dyslexics' perceptual difficulties computationally by applying a specific model, inspired by the Bayesian framework. This model dissociates between the contribution of sensory noise and that of the prior statistics in an auditory perceptual decision task. We show that dyslexics cannot compensate for their perceptual noise by incorporating prior information. By contrast, adequately reading controls' usage of previous information is often close to optimal. We used ERP measurements to assess the neuronal stage of this deficit. We found that unlike their peers, dyslexics' ERP responses are not sensitive to the relations between the current observation and the prior observation, indicating that they cannot establish a reliable prior.

Spatial generalization in operant learning: lessons from professional basketball.

In operant learning, behaviors are reinforced or inhibited in response to the consequences of similar actions taken in the past. However, because in natural environments the "same" situation never recurs, it is essential for the learner to decide what "similar" is so that he can generalize from experience in one state of the world to future actions in different states of the world. The computational principles underlying this generalization are poorly understood, in particular because natural environments are typically too complex to study quantitatively. In this paper we study the principles underlying generalization in operant learning of professional basketball players. In particular, we utilize detailed information about the spatial organization of shot locations to study how players adapt their attacking strategy in real time according to recent events in the game. To quantify this learning, we study how a make\miss from one location in the court affects the probabilities of shooting from different locations. We show that generalization is not a spatially-local process, nor is governed by the difficulty of the shot. Rather, to a first approximation, players use a simplified binary representation of the court into 2 pt and 3 pt zones. This result indicates that rather than using low-level features, generalization is determined by high-level cognitive processes that incorporate the abstract rules of the game.

Contradictory behavioral biases result from the influence of past stimuli on perception.

Biases such as the preference of a particular response for no obvious reason, are an integral part of psychophysics. Such biases have been reported in the common two-alternative forced choice (2AFC) experiments, where participants are instructed to compare two consecutively presented stimuli. However, the principles underlying these biases are largely unknown and previous studies have typically used ad-hoc explanations to account for them. Here we consider human performance in the 2AFC tone frequency discrimination task, utilizing two standard protocols. In both protocols, each trial contains a reference stimulus. In one (Reference-Lower protocol), the frequency of the reference stimulus is always lower than that of the comparison stimulus, whereas in the other (Reference protocol), the frequency of the reference stimulus is either lower or higher than that of the comparison stimulus. We find substantial interval biases. Namely, participants perform better when the reference is in a specific interval. Surprisingly, the biases in the two experiments are opposite: performance is better when the reference is in the first interval in the Reference protocol, but is better when the reference is second in the Reference-Lower protocol. This inconsistency refutes previous accounts of the interval bias, and is resolved when experiments statistics is considered. Viewing perception as incorporation of sensory input with prior knowledge accumulated during the experiment accounts for the seemingly contradictory biases both qualitatively and quantitatively. The success of this account implies that even simple discriminations reflect a combination of sensory limitations, memory limitations, and the ability to utilize stimuli statistics.

Covariance-based synaptic plasticity in an attractor network model accounts for fast adaptation in free operant learning.

In free operant experiments, subjects alternate at will between targets that yield rewards stochastically. Behavior in these experiments is typically characterized by (1) an exponential distribution of stay durations, (2) matching of the relative time spent at a target to its relative share of the total number of rewards, and (3) adaptation after a change in the reward rates that can be very fast. The neural mechanism underlying these regularities is largely unknown. Moreover, current decision-making neural network models typically aim at explaining behavior in discrete-time experiments in which a single decision is made once in every trial, making these models hard to extend to the more natural case of free operant decisions. Here we show that a model based on attractor dynamics, in which transitions are induced by noise and preference is formed via covariance-based synaptic plasticity, can account for the characteristics of behavior in free operant experiments. We compare a specific instance of such a model, in which two recurrently excited populations of neurons compete for higher activity, to the behavior of rats responding on two levers for rewarding brain stimulation on a concurrent variable interval reward schedule (Gallistel et al., 2001). We show that the model is consistent with the rats' behavior, and in particular, with the observed fast adaptation to matching behavior. Further, we show that the neural model can be reduced to a behavioral model, and we use this model to deduce a novel "conservation law," which is consistent with the behavior of the rats.

Stochasticity, bistability and the wisdom of crowds: a model for associative learning in genetic regulatory networks.

It is generally believed that associative memory in the brain depends on multistable synaptic dynamics, which enable the synapses to maintain their value for extended periods of time. However, multistable dynamics are not restricted to synapses. In particular, the dynamics of some genetic regulatory networks are multistable, raising the possibility that even single cells, in the absence of a nervous system, are capable of learning associations. Here we study a standard genetic regulatory network model with bistable elements and stochastic dynamics. We demonstrate that such a genetic regulatory network model is capable of learning multiple, general, overlapping associations. The capacity of the network, defined as the number of associations that can be simultaneously stored and retrieved, is proportional to the square root of the number of bistable elements in the genetic regulatory network. Moreover, we compute the capacity of a clonal population of cells, such as in a colony of bacteria or a tissue, to store associations. We show that even if the cells do not interact, the capacity of the population to store associations substantially exceeds that of a single cell and is proportional to the number of bistable elements. Thus, we show that even single cells are endowed with the computational power to learn associations, a power that is substantially enhanced when these cells form a population.

Spatiotemporal dynamics of locomotor decisions in Drosophila melanogaster.

Decision-making in animals often involves choosing actions while navigating the environment, a process markedly different from static decision paradigms commonly studied in laboratory settings. Even in decision-making assays in which animals can freely locomote, decision outcomes are often interpreted as happening at single points in space and single moments in time, a simplification that potentially glosses over important spatiotemporal dynamics. We investigated locomotor decision-making in Drosophila melanogaster in Y-shaped mazes, measuring the extent to which their future choices could be predicted through space and time. We demonstrate that turn-decisions can be reliably predicted from flies' locomotor dynamics, with distinct predictability phases emerging as flies progress through maze regions. We show that these predictability dynamics are not merely the result of maze geometry or wall-following tendencies, but instead reflect the capacity of flies to move in ways that depend on sustained locomotor signatures, suggesting an active, working memory-like process. Additionally, we demonstrate that fly mutants known to have sensory and information-processing deficits exhibit altered spatial predictability patterns, highlighting the role of visual, mechanosensory, and dopaminergic signaling in locomotor decision-making. Finally, highlighting the broad applicability of our analyses, we generalize our findings to other species and tasks. We show that human participants in a virtual Y-maze exhibited similar decision predictability dynamics as flies. This study advances our understanding of decision-making processes, emphasizing the importance of spatial and temporal dynamics of locomotor behavior in the lead-up to discrete choice outcomes.

How recent history affects perception: the normative approach and its heuristic approximation.

There is accumulating evidence that prior knowledge about expectations plays an important role in perception. The Bayesian framework is the standard computational approach to explain how prior knowledge about the distribution of expected stimuli is incorporated with noisy observations in order to improve performance. However, it is unclear what information about the prior distribution is acquired by the perceptual system over short periods of time and how this information is utilized in the process of perceptual decision making. Here we address this question using a simple two-tone discrimination task. We find that the "contraction bias", in which small magnitudes are overestimated and large magnitudes are underestimated, dominates the pattern of responses of human participants. This contraction bias is consistent with the Bayesian hypothesis in which the true prior information is available to the decision-maker. However, a trial-by-trial analysis of the pattern of responses reveals that the contribution of most recent trials to performance is overweighted compared with the predictions of a standard Bayesian model. Moreover, we study participants' performance in a-typical distributions of stimuli and demonstrate substantial deviations from the ideal Bayesian detector, suggesting that the brain utilizes a heuristic approximation of the Bayesian inference. We propose a biologically plausible model, in which decision in the two-tone discrimination task is based on a comparison between the second tone and an exponentially-decaying average of the first tone and past tones. We show that this model accounts for both the contraction bias and the deviations from the ideal Bayesian detector hypothesis. These findings demonstrate the power of Bayesian-like heuristics in the brain, as well as their limitations in their failure to fully adapt to novel environments.

Do Retinal Neurons Also Represent Somatosensory Inputs? On Why Neuronal Responses Are Not Sufficient to Determine What Neurons Do.

How does neuronal activity give rise to cognitive capacities? To address this question, neuroscientists hypothesize about what neurons "represent," "encode," or "compute," and test these hypotheses empirically. This process is similar to the assessment of hypotheses in other fields of science and as such is subject to the same limitations and difficulties that have been discussed at length by philosophers of science. In this paper, we highlight an additional difficulty in the process of empirical assessment of hypotheses that is unique to the cognitive sciences. We argue that, unlike in other scientific fields, comparing hypotheses according to the extent to which they explain or predict empirical data can lead to absurd results. Other considerations, which are perhaps more subjective, must be taken into account. We focus on one such consideration, which is the purposeful function of the neurons as part of a biological system. We believe that progress in neuroscience critically depends on properly addressing this difficulty.

Sex-specific declines in cholinergic-targeting tRNA fragments in the nucleus accumbens in Alzheimer's disease.

Introduction: Females with Alzheimer's disease (AD) suffer accelerated dementia and loss of cholinergic neurons compared to males, but the underlying mechanisms are unknown. Seeking causal contributors to both these phenomena, we pursued changes in tRNA fragments (tRFs) targeting cholinergic transcripts (CholinotRFs). Methods: We analyzed small RNA-sequencing data from the nucleus accumbens (NAc) brain region which is enriched in cholinergic neurons, compared to hypothalamic or cortical tissues from AD brains; and explored small RNA expression in neuronal cell lines undergoing cholinergic differentiation. Results: NAc CholinotRFs of mitochondrial genome origin showed reduced levels that correlated with elevations in their predicted cholinergic-associated mRNA targets. Single cell RNA seq from AD temporal cortices showed altered sex-specific levels of cholinergic transcripts in diverse cell types; inversely, human-originated neuroblastoma cells under cholinergic differentiation presented sex-specific CholinotRF elevations. Discussion: Our findings support CholinotRFs contributions to cholinergic regulation, predicting their involvement in AD sex-specific cholinergic loss and dementia.

Multiplicative dynamics underlie the emergence of the log-normal distribution of spine sizes in the neocortex in vivo.

What fundamental properties of synaptic connectivity in the neocortex stem from the ongoing dynamics of synaptic changes? In this study, we seek to find the rules shaping the stationary distribution of synaptic efficacies in the cortex. To address this question, we combined chronic imaging of hundreds of spines in the auditory cortex of mice in vivo over weeks with modeling techniques to quantitatively study the dynamics of spines, the morphological correlates of excitatory synapses in the neocortex. We found that the stationary distribution of spine sizes of individual neurons can be exceptionally well described by a log-normal function. We furthermore show that spines exhibit substantial volatility in their sizes at timescales that range from days to months. Interestingly, the magnitude of changes in spine sizes is proportional to the size of the spine. Such multiplicative dynamics are in contrast with conventional models of synaptic plasticity, learning, and memory, which typically assume additive dynamics. Moreover, we show that the ongoing dynamics of spine sizes can be captured by a simple phenomenological model that operates at two timescales of days and months. This model converges to a log-normal distribution, bridging the gap between synaptic dynamics and the stationary distribution of synaptic efficacies.

Learning reward timing in cortex through reward dependent expression of synaptic plasticity.

The ability to represent time is an essential component of cognition but its neural basis is unknown. Although extensively studied both behaviorally and electrophysiologically, a general theoretical framework describing the elementary neural mechanisms used by the brain to learn temporal representations is lacking. It is commonly believed that the underlying cellular mechanisms reside in high order cortical regions but recent studies show sustained neural activity in primary sensory cortices that can represent the timing of expected reward. Here, we show that local cortical networks can learn temporal representations through a simple framework predicated on reward dependent expression of synaptic plasticity. We assert that temporal representations are stored in the lateral synaptic connections between neurons and demonstrate that reward-modulated plasticity is sufficient to learn these representations. We implement our model numerically to explain reward-time learning in the primary visual cortex (V1), demonstrate experimental support, and suggest additional experimentally verifiable predictions.

Negative sentences exhibit a sustained effect in delayed verification tasks.

Negated sentences are known to be more cognitively taxing than positive ones (i.e., polarity effect). We present evidence that two factors contribute to the polarity effect in verification tasks: processing the sentence and verifying its truth value. To quantify the relative contribution of each, we used a delayed verification task. The results show that even when participants are given a considerable amount of time for processing the sentence prior to verification, the polarity effect is not entirely eliminated. We suggest that this sustained effect stems from a retained negation-containing representation in working memory. (PsycInfo Database Record (c) 2022 APA, all rights reserved).