Corticotropin-releasing hormone signaling from prefrontal cortex to lateral septum suppresses interaction with familiar mice.

Social preference, the decision to interact with one member of the same species over another, is critical to optimize social interactions. Thus, adult rodents favor interacting with novel conspecifics over familiar ones, but whether this social preference stems from neural circuits facilitating interactions with novel individuals or suppressing interactions with familiar ones remains unknown. Here, we identify neurons in the infra-limbic area (ILA) of the mouse prefrontal cortex that express the neuropeptide corticotropin-releasing hormone (CRH) and project to the dorsal region of the rostral lateral septum (rLS). We show how release of CRH during familiar encounters disinhibits rLS neurons, thereby suppressing social interactions with familiar mice and contributing to social novelty preference. We further demonstrate how the maturation of CRH expression in ILA during the first 2 post-natal weeks enables the developmental shift from a preference for littermates in juveniles to a preference for novel mice in adults.

An Amygdala Circuit Mediates Experience-Dependent Momentary Arrests during Exploration.

Exploration of novel environments ensures survival and evolutionary fitness. It is expressed through exploratory bouts and arrests that change dynamically based on experience. Neural circuits mediating exploratory behavior should therefore integrate experience and use it to select the proper behavioral output. Using a spatial exploration assay, we uncovered an experience-dependent increase in momentary arrests in locations where animals arrested previously. Calcium imaging in freely exploring mice revealed a genetically and projection-defined neuronal ensemble in the basolateral amygdala that is active during self-paced behavioral arrests. This ensemble was recruited in an experience-dependent manner, and closed-loop optogenetic manipulation of these neurons revealed that they are sufficient and necessary to drive experience-dependent arrests during exploration. Projection-specific imaging and optogenetic experiments revealed that these arrests are effected by basolateral amygdala neurons projecting to the central amygdala, uncovering an amygdala circuit that mediates momentary arrests in familiar places but not avoidance or anxiety/fear-like behaviors.

Representations of Novelty and Familiarity in a Mushroom Body Compartment.

Animals exhibit a behavioral response to novel sensory stimuli about which they have no prior knowledge. We have examined the neural and behavioral correlates of novelty and familiarity in the olfactory system of Drosophila. Novel odors elicit strong activity in output neurons (MBONs) of the α'3 compartment of the mushroom body that is rapidly suppressed upon repeated exposure to the same odor. This transition in neural activity upon familiarization requires odor-evoked activity in the dopaminergic neuron innervating this compartment. Moreover, exposure of a fly to novel odors evokes an alerting response that can also be elicited by optogenetic activation of α'3 MBONs. Silencing these MBONs eliminates the alerting behavior. These data suggest that the α'3 compartment plays a causal role in the behavioral response to novel and familiar stimuli as a consequence of dopamine-mediated plasticity at the Kenyon cell-MBONα'3 synapse.

The TrkC-PTPσ complex governs synapse maturation and anxiogenic avoidance via synaptic protein phosphorylation.

The precise organization of pre- and postsynaptic terminals is crucial for normal synaptic function in the brain. In addition to its canonical role as a neurotrophin-3 receptor tyrosine kinase, postsynaptic TrkC promotes excitatory synapse organization through interaction with presynaptic receptor-type tyrosine phosphatase PTPσ. To isolate the synaptic organizer function of TrkC from its role as a neurotrophin-3 receptor, we generated mice carrying TrkC point mutations that selectively abolish PTPσ binding. The excitatory synapses in mutant mice had abnormal synaptic vesicle clustering and postsynaptic density elongation, more silent synapses, and fewer active synapses, which additionally exhibited enhanced basal transmission with impaired release probability. Alongside these phenotypes, we observed aberrant synaptic protein phosphorylation, but no differences in the neurotrophin signaling pathway. Consistent with reports linking these aberrantly phosphorylated proteins to neuropsychiatric disorders, mutant TrkC knock-in mice displayed impaired social responses and increased avoidance behavior. Thus, through its regulation of synaptic protein phosphorylation, the TrkC-PTPσ complex is crucial for the maturation, but not formation, of excitatory synapses in vivo.

CA2: A Highly Connected Intrahippocampal Relay.

Although Lorente de No' recognized the anatomical distinction of the hippocampal Cornu Ammonis (CA) 2 region, it had, until recently, been assigned no unique function. Its location between the key players of the circuit, CA3 and CA1, which along with the entorhinal cortex and dentate gyrus compose the classic trisynaptic circuit, further distracted research interest. However, the connectivity of CA2 pyramidal cells, together with unique patterns of gene expression, hints at a much larger contribution to hippocampal information processing than has been ascribed. Here we review recent advances that have identified new roles for CA2 in hippocampal centric processing, together with specialized functions in social memory and, potentially, as a broadcaster of novelty. These new data, together with CA2's role in disease, justify a closer look at how this small region exerts its influence and how it might best be exploited to understand and treat disease-related circuit dysfunctions.

On the evolutionary developmental biology of the cell.

Organisms are complex assemblages of cells, cells that produce light, shoot harpoons, and secrete glue. Therefore, identifying the mechanisms that generate novelty at the level of the individual cell is essential for understanding how multicellular life evolves. For decades, the field of evolutionary developmental biology (Evo-Devo) has been developing a framework for connecting genetic variation that arises during embryonic development to the emergence of diverse adult forms. With increasing access to new single cell 'omics technologies and an array of techniques for manipulating gene expression, we can now extend these inquiries inward to the level of the individual cell. In this opinion, I argue that applying an Evo-Devo framework to single cells makes it possible to explore the natural history of cells, where this was once only possible at the organismal level.

Does the use of unusual combinations of datasets contribute to greater scientific impact?

Scientific datasets play a crucial role in contemporary data-driven research, as they allow for the progress of science by facilitating the discovery of new patterns and phenomena. This mounting demand for empirical research raises important questions on how strategic data utilization in research projects can stimulate scientific advancement. In this study, we examine the hypothesis inspired by the recombination theory, which suggests that innovative combinations of existing knowledge, including the use of unusual combinations of datasets, can lead to high-impact discoveries. Focusing on social science, we investigate the scientific outcomes of such atypical data combinations in more than 30,000 publications that leverage over 5,000 datasets curated within one of the largest social science databases, Interuniversity Consortium for Political and Social Research. This study offers four important insights. First, combining datasets, particularly those infrequently paired, significantly contributes to both scientific and broader impacts (e.g., dissemination to the general public). Second, infrequently paired datasets maintain a strong association with citation even after controlling for the atypicality of dataset topics. In contrast, the atypicality of dataset topics has a much smaller positive impact on citation counts. Third, smaller and less experienced research teams tend to use atypical combinations of datasets in research more frequently than their larger and more experienced counterparts. Last, despite the benefits of data combination, papers that amalgamate data remain infrequent. This finding suggests that the unconventional combination of datasets is an underutilized but powerful strategy correlated with the scientific impact and broader dissemination of scientific discoveries.

Efr3b is essential for social recognition by modulating the excitability of CA2 pyramidal neurons.

CA2 pyramidal neurons (PNs) are associated with social behaviors. The mechanisms, however, remain to be fully investigated. Here, we report that Efr3b, a protein essential for phospholipid metabolism at the plasma membrane, is widely expressed in the brain, especially in the hippocampal CA2/CA3 areas. To assess the functional significance of Efr3b in the brain, we generated Efr3bf/f mice and crossed them with Nestin-cre mice to delete Efr3b specifically in the brain. We find that Efr3b deficiency in the brain leads to deficits of social novelty recognition and hypoexcitability of CA2 PNs. We then knocked down the expression of Efr3b specifically in CA2 PNs of C57BL/6J mice, and our results showed that reducing Efr3b in CA2 PNs also resulted in deficits of social novelty recognition and hypoexcitability of CA2 PNs. More interestingly, restoring the expression of Efr3b in CA2 PNs enhances their excitability and improves social novelty recognition in Efr3b-deficient mice. Furthermore, direct activation of CA2 PNs with chemogenetics improves social behaviors in Efr3b-deficient mice. Together, our data suggest that Efr3b is essential for social novelty by modulating the excitability of CA2 PNs.

The axial skeleton of Tiktaalik roseae.

The axial columns of the earliest limbed vertebrates show distinct patterns of regionalization as compared to early tetrapodomorphs. Included among their novel features are sacral ribs, which provide linkage between the vertebral column and pelvis, contributing to body support and propulsion by the hindlimb. Data on the axial skeletons of the closest relatives of limbed vertebrates are sparce, with key features of specimens potentially covered by matrix. Therefore, it is unclear in what sequence and under what functional context specializations in the axial skeletons of tetrapods arose. Here, we describe the axial skeleton of the elpistostegalian Tiktaalik roseae and show that transformations to the axial column for head mobility, body support, and pelvic fin buttressing evolved in finned vertebrates prior to the origin of limbs. No atlas-axis complex is observed; however, an independent basioccipital-exoccipital complex suggests increased mobility at the occipital vertebral junction. While the construction of vertebrae in Tiktaalik is similar to early tetrapodomorphs, its ribs possess a specialized sacral domain. Sacral ribs are expanded and ventrally curved, indicating likely attachment to the expanded iliac blade of the pelvis by ligamentous connection. Thus, the origin of novel rib types preceded major alterations to trunk vertebrae, and linkage between pelvic fins and axial column preceded the origin of limbs. These data reveal an unexpected combination of post-cranial skeletal characters, informing hypotheses of body posture and movement in the closest relatives of limbed vertebrates.

The origin of blinking in both mudskippers and tetrapods is linked to life on land.

Blinking, the transient occlusion of the eye by one or more membranes, serves several functions including wetting, protecting, and cleaning the eye. This behavior is seen in nearly all living tetrapods and absent in other extant sarcopterygian lineages suggesting that it might have arisen during the water-to-land transition. Unfortunately, our understanding of the origin of blinking has been limited by a lack of known anatomical correlates of the behavior in the fossil record and a paucity of comparative functional studies. To understand how and why blinking originates, we leverage mudskippers (Oxudercinae), a clade of amphibious fishes that have convergently evolved blinking. Using microcomputed tomography and histology, we analyzed two mudskipper species, Periophthalmus barbarus and Periophthalmodon septemradiatus, and compared them to the fully aquatic round goby, Neogobius melanostomus. Study of gross anatomy and epithelial microstructure shows that mudskippers have not evolved novel musculature or glands to blink. Behavioral analyses show the blinks of mudskippers are functionally convergent with those of tetrapods: P. barbarus blinks more often under high-evaporation conditions to wet the eye, a blink reflex protects the eye from physical insult, and a single blink can fully clean the cornea of particulates. Thus, eye retraction in concert with a passive occlusal membrane can achieve functions associated with life on land. Osteological correlates of eye retraction are present in the earliest limbed vertebrates, suggesting blinking capability. In both mudskippers and tetrapods, therefore, the origin of this multifunctional innovation is likely explained by selection for increasingly terrestrial lifestyles.

Superhuman artificial intelligence can improve human decision-making by increasing novelty.

How will superhuman artificial intelligence (AI) affect human decision-making? And what will be the mechanisms behind this effect? We address these questions in a domain where AI already exceeds human performance, analyzing more than 5.8 million move decisions made by professional Go players over the past 71 y (1950 to 2021). To address the first question, we use a superhuman AI program to estimate the quality of human decisions across time, generating 58 billion counterfactual game patterns and comparing the win rates of actual human decisions with those of counterfactual AI decisions. We find that humans began to make significantly better decisions following the advent of superhuman AI. We then examine human players' strategies across time and find that novel decisions (i.e., previously unobserved moves) occurred more frequently and became associated with higher decision quality after the advent of superhuman AI. Our findings suggest that the development of superhuman AI programs may have prompted human players to break away from traditional strategies and induced them to explore novel moves, which in turn may have improved their decision-making.

Neural Activity Differentiates Novel and Learned Event Boundaries.

People parse continuous experiences at natural breakpoints called event boundaries, which is important for understanding an environment's causal structure and for responding to uncertainty within it. However, it remains unclear how different forms of uncertainty affect the parsing of continuous experiences and how such uncertainty influences the brain's processing of ongoing events. We exposed human participants of both sexes (N = 34) to a continuous sequence of semantically meaningless images. We generated sequences from random walks through a graph that grouped images into temporal communities. After learning, we asked participants to segment another sequence at natural breakpoints (event boundaries). Participants segmented the sequence at learned transitions between communities, as well as at novel transitions, suggesting that people can segment temporally extended experiences into events based on learned structure as well as prediction error. Greater segmentation at novel boundaries was associated with enhanced parietal scalp electroencephalography (EEG) activity between 250 and 450 ms after the stimulus onset. Multivariate classification of EEG activity showed that novel and learned boundaries evoked distinct patterns of neural activity, particularly theta band power in posterior electrodes. Learning also led to distinct neural representations for stimuli within the temporal communities, while neural activity at learned boundary nodes showed predictive evidence for the adjacent community. The data show that people segment experiences at both learned and novel boundaries and suggest that learned event boundaries trigger retrieval of information about the upcoming community that could underlie anticipation of the next event in a sequence.

Reframing research on evolutionary novelty and co-option: Character identity mechanisms versus deep homology.

A central topic in research at the intersection of development and evolution is the origin of novel traits. Despite progress on understanding how developmental mechanisms underlie patterns of diversity in the history of life, the problem of novelty continues to challenge researchers. Here we argue that research on evolutionary novelty and the closely associated phenomenon of co-option can be reframed fruitfully by: (1) specifying a conceptual model of mechanisms that underwrite character identity, (2) providing a richer and more empirically precise notion of co-option that goes beyond common appeals to "deep homology", and (3) attending to the nature of experimental interventions that can determine whether and how the co-option of identity mechanisms can help to explain novel character origins. This reframing has the potential to channel future investigation to make substantive progress on the problem of evolutionary novelty. To illustrate this potential, we apply our reframing to two case studies: treehopper helmets and beetle horns.

Clade-specific genes and the evolutionary origin of novelty; new tools in the toolkit.

Clade-specific (a.k.a. lineage-specific) genes are very common and found at all taxonomic levels and in all clades examined. They can arise by duplication of previously existing genes, which can involve partial truncations or combinations with other protein domains or regulatory sequences. They can also evolve de novo from non-coding sequences, leading to potentially truly novel protein domains. Finally, since clade-specific genes are generally defined by lack of sequence homology with other proteins, they can also arise by sequence evolution that is rapid enough that previous sequence homology can no longer be detected. In such cases, where the rapid evolution is followed by constraint, we consider them to be ontologically non-novel but likely novel at a functional level. In general, clade-specific genes have received less attention from biologists but there are increasing numbers of fascinating examples of their roles in important traits. Here we review some selected recent examples, and argue that attention to clade-specific genes is an important corrective to the focus on the conserved developmental regulatory toolkit that has been the habit of evo-devo as a field. Finally, we discuss questions that arise about the evolution of clade-specific genes, and how these might be addressed by future studies. We highlight the hypothesis that clade-specific genes are more likely to be involved in synapomorphies that arose in the stem group where they appeared, compared to other genes.

Taking flight!

Understanding the origins of novel complex traits, the evolutionary transitions they enabled, and how those shaped the subsequent course of evolution, are all foundational objectives of evolutionary biology. Yet how developmental systems may transform to yield the first eye, limb, or placenta remains poorly understood. Seminal work by Courtney Clark-Hachtel, David Linz, and Yoshinori Tomoyasu published in the Proceedings of the National Academy of Sciences in 2013 used the origins of insect wings - one of the most impactful innovations of animal life on Earth - to provide both a case study and a new way of thinking of how novel complex traits may come into being. This paradigm-setting study not only transformed the way we view insect wings, their origins, and their affinities to other morphological structures; even more importantly, it created entryways to envision innovation as emerging gradually, not somehow divorced from ancestral homology, but through it via the differential modification, fusion, and elaboration of ancestral component parts. In a conceptual universe of descent with modification, where everything new must ultimately emerge from the old, this work thereby established a powerful bridge connecting ancestral homology and novelty through a gradual process of innovation, sparking much creative and groundbreaking work to follow since its publication just a little over a decade ago.

Viral Receptor-Binding Protein Evolves New Function through Mutations That Cause Trimer Instability and Functional Heterogeneity.

When proteins evolve new activity, a concomitant decrease in stability is often observed because the mutations that confer new activity can destabilize the native fold. In the conventional model of protein evolution, reduced stability is considered a purely deleterious cost of molecular innovation because unstable proteins are prone to aggregation and are sensitive to environmental stressors. However, recent work has revealed that nonnative, often unstable protein conformations play an important role in mediating evolutionary transitions, raising the question of whether instability can itself potentiate the evolution of new activity. We explored this question in a bacteriophage receptor-binding protein during host-range evolution. We studied the properties of the receptor-binding protein of bacteriophage λ before and after host-range evolution and demonstrated that the evolved protein is relatively unstable and may exist in multiple conformations with unique receptor preferences. Through a combination of structural modeling and in vitro oligomeric state analysis, we found that the instability arises from mutations that interfere with trimer formation. This study raises the intriguing possibility that protein instability might play a previously unrecognized role in mediating host-range expansions in viruses.

Single-value brain activity scores reflect both severity and risk across the Alzheimer's continuum.

Single-value scores reflecting the deviation from (FADE score) or similarity with (SAME score) prototypical novelty-related and memory-related functional magnetic resonance imaging (fMRI) activation patterns in young adults have been proposed as imaging biomarkers of healthy neurocognitive aging. Here, we tested the utility of these scores as potential diagnostic and prognostic markers in Alzheimer's disease (AD) and risk states like mild cognitive impairment (MCI) or subjective cognitive decline (SCD). To this end, we analyzed subsequent memory fMRI data from individuals with SCD, MCI, and AD dementia as well as healthy controls (HC) and first-degree relatives of AD dementia patients (AD-rel) who participated in the multi-center DELCODE study (N = 468). Based on the individual participants' whole-brain fMRI novelty and subsequent memory responses, we calculated the FADE and SAME scores and assessed their association with AD risk stage, neuropsychological test scores, CSF amyloid positivity, and ApoE genotype. Memory-based FADE and SAME scores showed a considerably larger deviation from a reference sample of young adults in the MCI and AD dementia groups compared to HC, SCD and AD-rel. In addition, novelty-based scores significantly differed between the MCI and AD dementia groups. Across the entire sample, single-value scores correlated with neuropsychological test performance. The novelty-based SAME score further differed between Aß-positive and Aß-negative individuals in SCD and AD-rel, and between ApoE ε4 carriers and non-carriers in AD-rel. Hence, FADE and SAME scores are associated with both cognitive performance and individual risk factors for AD. Their potential utility as diagnostic and prognostic biomarkers warrants further exploration, particularly in individuals with SCD and healthy relatives of AD dementia patients.

Is novel research worth doing? Evidence from peer review at 49 journals.

There are long-standing concerns that peer review, which is foundational to scientific institutions like journals and funding agencies, favors conservative ideas over novel ones. We investigate the association between novelty and the acceptance of manuscripts submitted to a large sample of scientific journals. The data cover 20,538 manuscripts submitted between 2013 and 2018 to the journals Cell and Cell Reports and 6,785 manuscripts submitted in 2018 to 47 journals published by the Institute of Physics Publishing. Following previous work that found that a balance of novel and conventional ideas predicts citation impact, we measure the novelty and conventionality of manuscripts by the atypicality of combinations of journals in their reference lists, taking the 90th percentile most atypical combination as "novelty" and the 50th percentile as "conventionality." We find that higher novelty is consistently associated with higher acceptance; submissions in the top novelty quintile are 6.5 percentage points more likely than bottom quintile ones to get accepted. Higher conventionality is also associated with acceptance (+16.3% top-bottom quintile difference). Disagreement among peer reviewers was not systematically related to submission novelty or conventionality, and editors select strongly for novelty even conditional on reviewers' recommendations (+7.0% top-bottom quintile difference). Manuscripts exhibiting higher novelty were more highly cited. Overall, the findings suggest that journal peer review favors novel research that is well situated in the existing literature, incentivizing exploration in science and challenging the view that peer review is inherently antinovelty.

A novel regulatory gene promotes novel cell fate by suppressing ancestral fate in the sea anemone Nematostella vectensis.

Cnidocytes (i.e., stinging cells) are an unequivocally novel cell type used by cnidarians (i.e., corals, jellyfish, and their kin) to immobilize prey. Although they are known to share a common evolutionary origin with neurons, the developmental program that promoted the emergence of cnidocyte fate is not known. Using functional genomics in the sea anemone, Nematostella vectensis, we show that cnidocytes develop by suppression of neural fate in a subset of neurons expressing RFamide. We further show that a single regulatory gene, a C2H2-type zinc finger transcription factor (ZNF845), coordinates both the gain of novel (cnidocyte-specific) traits and the inhibition of ancestral (neural) traits during cnidocyte development and that this gene arose by domain shuffling in the stem cnidarian. Thus, we report a mechanism by which a truly novel regulatory gene (ZNF845) promotes the development of a truly novel cell type (cnidocyte) through duplication of an ancestral cell lineage (neuron) and inhibition of its ancestral identity (RFamide).

Local production of corticotropin-releasing hormone in prefrontal cortex modulates male-specific novelty exploration.

Neuromodulatory substances can be released from distal afferents for communication between brain structures or produced locally to modulate neighboring circuit elements. Corticotropin-releasing hormone (CRH) from long-range neurons in the hypothalamus projecting to the medial prefrontal cortex (mPFC) has been shown to induce anxiety-like behaviors. However, the role of CRH produced in the mPFC has not been investigated. Here we demonstrate that a specific class of mPFC interneurons that express CRH (CrhINs) releases CRH upon high-frequency stimulation to enhance excitability of layer 2/3 pyramidal cells (L2/3 PCs) expressing the CRH receptors. When stimulated at low frequency, CrhINs release GABA resulting in the inhibition of oxytocin receptor-expressing interneurons (OxtrINs) and L2/3 PCs. Conditional deletion of CRH in mPFC CrhINs and chemogenetic activation of CrhINs have opposite effects on novelty exploration in male but not in female mice, and do not affect anxiety-related behaviors in either males or females. Our data reveal that CRH produced by local interneurons in the mPFC is required for sex-specific novelty exploration and suggest that our understanding of complex behaviors may require knowledge of local and remote neuromodulatory action.