On the diverse and common evolutionary constraints acting on mitochondria across the eukaryotic tree Eukaryotes likely originated from an endosymbiosis between an α-protobacterium and an Asgard archaeal host. Although endosymbiosis was followed by massive gene transfer from the mitochondrial DNA (mtDNA) to the nuclear genome, mtDNA was retained in most eukaryotes. Since the early 1980s, the genetic variation, species diversity and functional implications of mtDNA’s genetic content have been extensively studied. Here, we assemble articles that discuss recent advances and new insights into mitochondrial evolution. In this introductory article, we begin by discussing the origin of mtDNA and the mechanisms that maintain the integrity of the mitochondrial and nuclear genomes. We then discuss the importance of asymmetry in communication between the two genomic partners in the context of sequestration of the archaeal genome in a nuclear compartment. Given the putative initial biparental inheritance of the multi-copy mtDNA in the absence of mitosis and meiosis-like mechanisms that control mtDNA segregation, we next discuss selection against selfish mtDNA. When considering the selective advantage and time frame for the emergence of uniparental mtDNA transmission, we ask how the evolution of uniparental inheritance is associated with the evolution of sexes and early germline sequestration. Finally, we analyse the possible expansion of mtDNA genetic content and its impact on the functional and evolutionary dynamics of mitochondria. We conclude by considering mito-nuclear coevolution and interaction.
How do RNA molecules distinguish self from non-self? RNA molecules form homotypic clusters in a variety of contexts. mRNAs enriched in germ granules in Drosophila embryos are a canonical example, with polar granule component (pgc) mRNAs colocalized with other pgc mRNAs, and nanos mRNAs with other nanos mRNAs. The observation of homotypic clustering poses a conundrum: how can RNAs of a given sequence distinguish other RNAs of the same sequence from those with different sequences? Here we show in silico that RNAs can distinguish self from non-self through the presence of palindromic regions within RNA sequences, and that palindromes can mediate homotypic clustering. We further show that RNA–RNA interactions are unlikely to lead to homotypic clusters in the absence of palindromes due to a competition between intra- and intermolecular RNA structures. We explore the implications of the palindrome-based clustering hypothesis for nanos and pgc mRNAs, and suggest how it may clear up a surprising feature of nanos clusters. More broadly, our results indicate that the palindrome content of RNAs may be under evolutionary selection pressure across a range of contexts.
How does curriculum learning influence cognitive map formation? Representing relational knowledge in a mental map is useful for adaptive behaviour. Here, we studied how curriculum learning (the use of different training regimes) influences the way that mental (or ‘cognitive’) maps are formed. We investigated how the order in which people learned one-step transitions impacted their subsequent ability to perform multi-step inference using the cognitive maps they had formed. Participants learned one map with a curriculum that grouped information by rows and columns (‘grouped curriculum’) and another that selected transitions for training in a spatially disjoint way (‘disjoint curriculum’). Subsequent multi-step navigation was performed better after training using the disjoint curriculum. We hypothesise that learning under a grouped curriculum results in mental fragmentation of the learned maps, which impairs subsequent navigation across rows and columns. By contrast, learning one-step transitions in a pseudo-random order facilitates subsequent integration of learned information into a mental map to enable adaptive behaviour.
From hidden springs to endless oceans: exploring the complementary roles of the amygdala and hippocampus in phenomenal experience Current theories of consciousness often emphasize its ego-centric functions, highlighting the role of the insular cortex in interoceptive self-modeling and subcortical brain regions in qualitative experience and motivation, aptly described as the ‘hidden spring’ of consciousness. From ecological and pragmatic perspectives, conscious experience may facilitate the self-organization of complex organisms by optimizing goals that are typically parallel, multifaceted, and difficult to reconcile. However, the notion that all forms of conscious experience are ego-centric, or at least grounded in a minimal sense of self, is challenged by credible reports of minimal phenomenal experience (MPE), which occur without any self-referential content. I propose that this apparent duality in conscious experience can be explained by the dual-origin theory of cortical development. This theory suggests a gradual expansion of cortical cytoarchitecture from two distinct subcortical origins. The ‘Amygdala-System’ supports interoceptive self-modeling for habitual interactions with the body and the environment. It expands ventrally from the olfactory system and amygdala, enabling ego-centric processing. In contrast, the ‘Hippocampus-System’, centered on the hippocampus and expanding dorsally, supports allocentric cognition and experiences that are not constrained by self-referential processing. This complementary system allows for open-ended, selfless forms of experience, akin to an ‘endless ocean’. In this framework, MPE may represent a fragile form of consciousness, typically overshadowed by the self-related interoceptive and exteroceptive functions of the Amygdala-System. Finally, I discuss how real-time functional magnetic resonance imaging (fMRI) neurofeedback could be used to upregulate the Hippocampus-System, potentially enabling the controlled study of MPE in neuroscientific settings.
Focusing on color: How the eye chooses which wavelength to see best Humans can see in exquisite detail despite the fact that the eyes’ optics can only focus light at a single wavelength at a time. It remains an open question what wavelength is brought into best focus by the human eye. Here, we investigate this question. We used a custom optical apparatus to measure the eye’s focusing response (accommodation) to a range of stimuli with different wavelength compositions. We then developed a biologically informed model of the measured responses. Conventional wisdom holds that accommodation works to maximize visual acuity, but our findings suggest otherwise. Rather, our results support alternative lines of evidence that accommodation is guided by chromatic mechanisms that maximize signal quality in a color-opponent channel. Our results challenge prevailing views of oculomotor control and can inform therapeutic interventions for slowing the development and progression of myopia.
Research Articles, Behavioral/Cognitive Sparse spatial scaffolding for visual working memory When holding information ‘in mind’, it is vital to keep individual representations separated and selectively accessible for guiding behaviour. Space is known to serve as a foundational scaffold for mnemonic individuation, yet the format and flexibility of spatial scaffolding for working memory remain elusive. We hypothesised that information in working memory can be re-coded from its native format at encoding to organise and retain internal representations sparsely. To test this, we presented to-be-memorised visual items at distinct directions and distances and leveraged gaze biases during mnemonic selection as an implicit read-out of spatial scaffolding for working memory. We report how male and female humans abstract away over incidental item distance when direction alone suffices as a scaffold, but incorporate distance when it aids mnemonic individuation. This suggests the flexible use of a sparse spatial scaffold for working memory, resorting to the minimal spatial scaffold required for the individuation of internal representations.
Exploring the human brain: spatial transcriptomics challenges and approaches in post-mortem analysis Over the past century, studying the human brain has been one of the most complex and enduring biological challenges. Initial approaches, ranging from gross neural anatomy to cellular subtype organization, have significantly advanced our understanding of the intricate structure of the human brain. Recent innovations in spatial transcriptomic technologies offer high-resolution insights into mRNA expression at single-cell or even subcellular resolution. Developing a greater understanding of the spatial expression of genes in specific cell types in the human brain can provide additional insights into their functions and underlying mechanisms that influence neurological disease states. Although these tools have been highly successful in rodent and non-human primate brains, analysis of the human brain has several specific challenges. In this review, we initially provide a comparison of spatial transcriptomic tools, followed by a summary of studies using these tools in human brains, and finally, we discuss the associated challenges and opportunities. The guidelines should enable researchers to address the challenges of using new spatial transcriptomic technologies to analyse complex organs, such as the human brain.
Alzheimer’s disease pathology degrades an NMDA receptor-dependent spontaneous activity pattern in cortico-hippocampal circuits Memory-based cognition relies on the integrity of cortico-hippocampal circuits, which are compromised in Alzheimer’s disease (AD) as β-amyloid (Aβ) and tau accumulate. However, the mechanisms linking this pathology to circuit dysfunction remain unclear. In mouse models, using in vivo two-photon and Neuropixels recordings, we show that Aβ-tau pathology promotes both region- and layer-specific impairments, involving reduced burst firing in superficial cortical layers and CA1 and reduced mean firing of excitatory and inhibitory neurons in deep cortical layers and CA1. Exposure to Aβ primed the susceptibility of neuronal populations to tau-induced impairment. Combined Aβ-tau reduced synaptic NMDA receptor (NMDAR) density in both mouse and human tissue, while Aβ-tau co-reduction restored NMDARs and firing patterns and improved contextual memory. NMDAR antagonism in healthy mice phenocopied regional and laminar deficits. Our findings implicate synaptic NMDAR hypofunction as a reversible mechanism linking Aβ-tau synergy to cortico-hippocampal dysfunction in AD.
Synaptic Potentiation in Hippocampus by eEF2K Inhibitor A484954 An important mechanism controlling protein synthesis is through phosphorylation of the eukaryotic elongation factor 2 (eEF2) by its kinase eEF2K. Hyperphosphorylation of eEF2 is linked to many neuronal diseases characterized by cognitive impairments. Consistently, recent studies show that the inhibition of the eEF2K signaling via genetic or pharmacological approaches can alleviate synaptic failure and dementia syndromes in mouse models of Alzheimer’s disease (AD) and related dementias (ADRDs). One commonly used tool to study eEF2K signaling is A-484954 (or AG), a small molecule compound that is considered a highly selective and potent eEF2K antagonist. Here we reported that the AG compound (at three doses) can induce chemical long-term potentiation (LTP) in acute hippocampal slices from mice. Taking advantage of two transgenic mouse models with eEF2K knockout or overexpression, we further demonstrated that eEF2K-independent mechanisms contribute to chemical LTP induced by AG (dose-dependent). Our data suggest cautious interpretation of findings on neuronal effects of eEF2K inhibitors such as AG. Future investigations are warranted to elucidate the detailed molecular mechanisms underlying the effects of AG compound and other eEF2K inhibitors on synaptic and cognitive function.