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.

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.

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).

Experienced entropy drives choice behavior in a boring decision-making task.

Boredom has been defined as an aversive mental state that is induced by the disability to engage in satisfying activity, most often experienced in monotonous environments. However, current understanding of the situational factors inducing boredom and driving subsequent behavior remains incomplete. Here, we introduce a two-alternative forced-choice task coupled with sensory stimulation of different degrees of monotony. We find that human subjects develop a bias in decision-making, avoiding the more monotonous alternative that is correlated with self-reported state boredom. This finding was replicated in independent laboratory and online experiments and proved to be specific for the induction of boredom rather than curiosity. Furthermore, using theoretical modeling we show that the entropy in the sequence of individually experienced stimuli, a measure of information gain, serves as a major determinant to predict choice behavior in the task. With this, we underline the relevance of boredom for driving behavioral responses that ensure a lasting stream of information to the brain.

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.

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.

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.

The 'creatures' of the human cortical somatosensory system.

Penfield's description of the 'homunculus', a 'grotesque creature' with large lips and hands and small trunk and legs depicting the representation of body-parts within the primary somatosensory cortex (S1), is one of the most prominent contributions to the neurosciences. Since then, numerous studies have identified additional body-parts representations outside of S1. Nevertheless, it has been implicitly assumed that S1's homunculus is representative of the entire somatosensory cortex. Therefore, the distribution of body-parts representations in other brain regions, the property that gave Penfield's homunculus its famous 'grotesque' appearance, has been overlooked. We used whole-body somatosensory stimulation, functional MRI and a new cortical parcellation to quantify the organization of the cortical somatosensory representation. Our analysis showed first, an extensive somatosensory response over the cortex; and second, that the proportional representation of body parts differs substantially between major neuroanatomical regions and from S1, with, for instance, much larger trunk representation at higher brain regions, potentially in relation to the regions' functional specialization. These results extend Penfield's initial findings to the higher level of somatosensory processing and suggest a major role for somatosensation in human cognition.

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.

Logical negation mapped onto the brain.

High-level cognitive capacities that serve communication, reasoning, and calculation are essential for finding our way in the world. But whether and to what extent these complex behaviors share the same neuronal substrate are still unresolved questions. The present study separated the aspects of logic from language and numerosity-mental faculties whose distinctness has been debated for centuries-and identified a new cytoarchitectonic area as correlate for an operation involving logical negation. A novel experimental paradigm that was implemented here in an RT/fMRI study showed a single cluster of activity that pertains to logical negation. It was distinct from clusters that were activated by numerical comparison and from the traditional language regions. The localization of this cluster was described by a newly identified cytoarchitectonic area in the left anterior insula, ventro-medial to Broca's region. We provide evidence for the congruence between the histologically and functionally defined regions on multiple measures. Its position in the left anterior insula suggests that it functions as a mediator between language and reasoning areas.

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.

Publisher Correction: Idiosyncratic choice bias naturally emerges from intrinsic stochasticity in neuronal dynamics.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Author Correction: Inhibitory connectivity defines the realm of excitatory plasticity.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Idiosyncratic choice bias naturally emerges from intrinsic stochasticity in neuronal dynamics.

Idiosyncratic tendency to choose one alternative over others in the absence of an identified reason is a common observation in two-alternative forced-choice experiments. Here we quantify idiosyncratic choice biases in a perceptual discrimination task and a motor task. We report substantial and significant biases in both cases that cannot be accounted for by the experimental context. Then, we present theoretical evidence that even in an idealized experiment, in which the settings are symmetric, idiosyncratic choice bias is expected to emerge from the dynamics of competing neuronal networks. We thus argue that idiosyncratic choice bias reflects the microscopic dynamics of choice and therefore is virtually inevitable in any comparison or decision task.

Deviation from the matching law reflects an optimal strategy involving learning over multiple timescales.

Behavior deviating from our normative expectations often appears irrational. For example, even though behavior following the so-called matching law can maximize reward in a stationary foraging task, actual behavior commonly deviates from matching. Such behavioral deviations are interpreted as a failure of the subject; however, here we instead suggest that they reflect an adaptive strategy, suitable for uncertain, non-stationary environments. To prove it, we analyzed the behavior of primates that perform a dynamic foraging task. In such nonstationary environment, learning on both fast and slow timescales is beneficial: fast learning allows the animal to react to sudden changes, at the price of large fluctuations (variance) in the estimates of task relevant variables. Slow learning reduces the fluctuations but costs a bias that causes systematic behavioral deviations. Our behavioral analysis shows that the animals solved this bias-variance tradeoff by combining learning on both fast and slow timescales, suggesting that learning on multiple timescales can be a biologically plausible mechanism for optimizing decisions under uncertainty.

Inhibitory connectivity defines the realm of excitatory plasticity.

Recent experiments demonstrate substantial volatility of excitatory connectivity in the absence of any learning. This challenges the hypothesis that stable synaptic connections are necessary for long-term maintenance of acquired information. Here we measure ongoing synaptic volatility and use theoretical modeling to study its consequences on cortical dynamics. We show that in the balanced cortex, patterns of neural activity are primarily determined by inhibitory connectivity, despite the fact that most synapses and neurons are excitatory. Similarly, we show that the inhibitory network is more effective in storing memory patterns than the excitatory one. As a result, network activity is robust to ongoing volatility of excitatory synapses, as long as this volatility does not disrupt the balance between excitation and inhibition. We thus hypothesize that inhibitory connectivity, rather than excitatory, controls the maintenance and loss of information over long periods of time in the volatile cortex.

Striatal action-value neurons reconsidered.

It is generally believed that during economic decisions, striatal neurons represent the values associated with different actions. This hypothesis is based on studies, in which the activity of striatal neurons was measured while the subject was learning to prefer the more rewarding action. Here we show that these publications are subject to at least one of two critical confounds. First, we show that even weak temporal correlations in the neuronal data may result in an erroneous identification of action-value representations. Second, we show that experiments and analyses designed to dissociate action-value representation from the representation of other decision variables cannot do so. We suggest solutions to identifying action-value representation that are not subject to these confounds. Applying one solution to previously identified action-value neurons in the basal ganglia we fail to detect action-value representations. We conclude that the claim that striatal neurons encode action-values must await new experiments and analyses.