Biology subjects

Hirth, F.

Publications and source records attributed to Hirth, F..

12 recordsLinked to original sources

bioRxiv2026

Cerebral Organization in the trilobite Yunnanocephalus yunnanensis

The clade Trilobita is recognized for its extraordinary morphological diversifications amidst a highly constrained body plan. This raises the question of whether trilobite nervous systems were conservative or comparably diverse. However, despite the identification of thousands of trilobite species and increasing evidence for neural preservation in other Paleozoic euarthropods, the recognition of a fossilized trilobite brain has remained elusive. Here we describe the identification of a trilobite brain and its spatially constrained position within its cranidium. An unusually preserved specimen of the lower Cambrian trilobite Yunnanocephalus yunnanensis reveals a bilaterally organized organ connected to its lateral eyes. Comparisons to the brain of a trilobitomorph xandarellid support the interpretation of this organ as a modest cerebrum comprising prosocerebral, protocerebral, and deutocerebral domains, an organization typifying the euarthropod cerebral ground pattern. These findings suggest that the cerebrum of Yunnanocephalus could have supported the multimodal sensory processing and behavioral repertoires of trilobites, while retaining the deep evolutionary conservation of brain organization across euarthropod lineages

evolutionary biology↗

bioRxiv2026

Cambrian Artiopoda Reveals a Constraint in Euarthropod Brain Evolution

Cambrian stem mandibulates and chelicerates have provided robust evidence of brains that conform to a cerebral ground pattern also defining extant euarthopods. But information about the brains of trilobites or their immediate relatives remains a mystery. Here we describe the detailed organization of the specialized brain of Xandarella spectaculum, a member of the subphylum Trilobitomorpha which went extinct at the end Permian. While retaining the pre-Cambrian cephalic ground pattern as three seriate domains, empirical evidence indicates clade-specific accentuation of some and loss of other neural arrangements typifying extant mandibulates. The trilobitomorph deutocerebral organization is dominated by exaggerated glomerular centers whereas its prominent lateral eyes supply minute visual centers. Paired ocelli are associated with the prominent prosocerebral bridge of the forebrain, an essential center for path integration. Together these modifications indicate neural organization typifying some extant benthic crustaceans and even hexapods that engage in foraging behaviors. With reference to existing neurological attributes of living pancrustaceans major divergences of the trilobitomorph brain from the ancestral cerebral ground pattern may have weakened its resilience to geo-ecological disruptions and hence the final extinction of the clade to which trilobitomorphs belong.

evolutionary biology↗

bioRxiv2025

Overexpression of α-Synuclein Alters The Nanoscopic Organisation of Presynaptic Proteins

Parkinsons Disease (PD) is characterised by accumulation of -synuclein (-Syn), but how elevated -Syn alters presynaptic architecture during prodromal phases of the disease remains unclear. We investigated presynaptic morphology and two key presynaptic proteins: MYCBP2; and the Active Zone (AZ) protein ELKS. Primary rat cortical neurons were transfected with wildtype -Syn, or the familial A30P mutant, and nanoscopic changes to bouton morphology and protein localisation were investigated using super-resolution microscopy. Variant specific accumulation patterns for overexpressed -Syn were observed without changes to bouton structure. Additionally, increases of both -Syn variants affected presynaptic proteins, decreasing MYCBP2 puncta count and intensity, and reducing ELKS protein density. Since MYCBP2 potentially regulates ELKS, these findings suggest that elevated -Syn perturbs AZ components whilst presynaptic structure is preserved. Our study supports growing evidence that increased -Syn disturbs presynaptic function potentially through a MYCBP2-ELKS axis, a mechanism which may provide a valuable target for PD therapeutics.

neuroscience↗

bioRxiv2025

Synaptotoxic forms of amyloid-b and a-synuclein act through a common pathway.

It has been suggested that -synuclein (Syn), a major player in Parkinsons disease (PD), plays a role in Alzheimers disease (AD). Several reports have also concluded that Syn and amyloid-{beta} (A{beta}) are mechanistically linked, although how is unclear. Synapse loss is an early feature in both PD and AD and held to be the driver of both diseases. We have previously uncovered a signalling pathway required for A{beta}-driven dendritic spine loss - a non-canonical branch of Wnt signalling known as the Wnt/Planar Cell Polarity (Wnt/PCP) pathway. We asked if a synaptotoxic form of Syn known to impact dendritic spines, the A53T autosomal dominant PD mutant form of Syn (A53T-Syn), might act on synapses through the same pathway. Here, by blocking all Wnt activity with the porcupine inhibitor IWP2, we show that A53T-Syn-driven spine loss is Wnt-dependent. By silencing Daam1, which is unique to Wnt/PCP, we show that A53T-Syn spine loss is Daam1-dependent. Finally, using the pan-ROCK inhibitor fasudil indicates the mechanism also involves ROCK1/2, which Daam1 signals to via RhoA to modulate actin cytoskeletal dynamics within dendritic spines. Together, these observations indicate that A53T-Syn-driven spine loss involves the Wnt/PCP pathway, the same pathway that mediates A{beta} synaptotoxicity. This indicates that A{beta} and Syn are mechanistically connected and that a common pathway is responsible for synapse loss in AD and PD. It also begins to explain why this group of neurodegenerative diseases have many features in common and suggests that drugs which target Wnt/PCP could be of benefit for both AD and PD.

neuroscience↗

bioRxiv2025

A pancrustacean brain and its visual systems define a Cambrian great appendage arthropod.

Early Cambrian fossils from the Chengjiang biota demonstrate that over half a billion years ago early stem euarthropods existed coevally with representatives of already recognizable crown groups. Prominent stem taxa were Fuxianhuia protensa and Alalcomenaeus whose cerebral and ganglionic traits identify them as, respectively, stem mandibulates and stem chelicerates. Here we report features of the visual systems and brain of the enigmatic lower Cambrian stem euarthropod Jianfengia multisegmentalis, which despite the absence of trunk tagmatization reveals neural traits that justify its inclusion within stem Pancrustacea also known as Tetraconata. The sutured eyestalks of Jianfengia, typifying crown Malacostraca, terminate as compound eyes populated by ommatidia that reveal tetradic structures indicative of cone-building Semper cells. Preserved neuropils and tracts in the eyestalks of Jianfengia resolve nested optic neuropils as occur in eucrustaceans. The nauplius-like eyes of Jianfengia and their associated nerves supply a discrete forebrain region, as they do in pancrustaceans. These attributes distinguish Pancrustacea from stem Chelicerata and extant Myriapoda as does the organization of the jianfengiid deutocerebrum and tritocerebrum. In the absence of external traits that differentiate identities amongst stem euarthropods, neuroanatomical traits provide a powerful tool for discerning characteristic distinctions and correspondences for elucidating euarthropod relationships. Here, we demonstrate that cerebral arrangements in Jianfengia correspond to those of pancrustaceans existing today.

evolutionary biology↗

bioRxiv2024

Marine Origin of the Arachnid Brain Reveals Early Divergence of Chelicerata

Fossils from the lower Cambrian provide crucial insights into the diversification of arthropod lineages: Mandibulata, exemplified by centipedes, insects, and crustaceans; and Chelicerata, represented by sea spiders, horseshoe crabs, and arachnids, the last including spiders, scorpions, and ticks1. Two mid-Cambrian genera claimed as stem chelicerates are Mollisonia and Sanctacaris, defined by a carapaced prosoma equipped with clustered limbs, followed by a segmented trunk opisthosoma equipped with appendages for swimming and respiration2-4. Up to the present, the phyletic status of Mollisoniidae and Sanctacariidae has been that of a basal chelicerate2, stemward of Leanchoiliidae, whose neuromorphology resembles that of extant Merostomata (horseshoe crabs)5. Here, we identify preserved traces of neuronal tissues in Mollisonia symmetrica that crucially depart from a merostome organization. Instead, a radiating organization of metameric neuropils occupying most of its prosoma is situated behind a pair of oval unsegmented neuropils directly connected to paired chelicerae extending from the front of the prosoma. The disposition and connections of these neuropils is the neuroanatomical signature that denotes a complete reversal of the three genetically distinct domains defining arthropod brains6. Thus, in Mollisonia the deutocerebrum is the most rostral domain with the proso-and protocerebral domains folded backwards such that tracts from the principal eyes extend caudally to reach their prosocerebral destination. These defining neuromorphological features illuminate a marine origin of Arachnida from which evolved the planets most successful arthropodan predators.

paleontology↗

bioRxiv2022

Optogenetic Miro cleavage reveals direct consequences of real-time loss of function in Drosophila.

Miro GTPases control mitochondrial morphology, calcium homeostasis and regulate mitochondrial distribution by mediating their attachment to the kinesin and dynein motor complex. It is not clear, however, how Miro proteins spatially and temporally integrate their function as acute disruption of protein function has not been performed. To address this issue, we have developed an optogenetic loss of function Split-Miro allele for precise control of Miro-dependent mitochondrial functions in Drosophila. Rapid optogenetic cleavage of Split-Miro leads to a striking rearrangement of the mitochondrial network, which is mediated by mitochondrial interaction with the microtubules. Unexpectedly, this treatment did not impact the ability of mitochondria to buffer calcium or their association with the endoplasmic reticulum. While Split-Miro overexpression is sufficient to augment mitochondrial motility, sustained photocleavage shows Split-Miro is surprisingly dispensable to maintain elevated mitochondrial processivity. In adult fly neurons in vivo, Split-Miro photocleavage affects both mitochondrial trafficking and neuronal activity. Furthermore, functional replacement of endogenous Miro with Split-Miro identifies its essential role in the regulation of locomotor activity in adult flies, demonstrating the feasibility of tuning animal behaviour by real-time loss of protein function.

cell biology↗

bioRxiv2022

Yeast NDI1 expression prevents the unfolded protein response and reconfigures metabolism to restore neuronal function in mitochondrial complex I deficiency

Mutations in subunits of the mitochondrial NADH dehydrogenase cause mitochondrial complex I deficiency, a group of severe neurological diseases that can result in death in infancy. The pathogenesis of complex I deficiency remain poorly understood, and as a result there are currently no available treatments. To better understand the underlying mechanisms, we modelled complex I deficiency in Drosophila using knockdown of the mitochondrial complex I subunit ND-75 (NDUFS1) specifically in neurons. Neuronal complex I deficiency causes locomotor defects, seizures and reduced lifespan. At the cellular level, complex I deficiency leads to mitochondrial morphology defects, reduced endoplasmic reticulummitochondria contacts and activation of the endoplasmic reticulum unfolded protein response (UPR) in neurons. Multi-omic analysis shows that complex I deficiency dramatically perturbs mitochondrial metabolism in the brain. We find that expression of the yeast non-proton translocating NADH dehydrogenase NDI1, which reinstates mitochondrial NADH oxidation but not ATP production, restores levels of several key metabolites in the brain in complex I deficiency. Remarkably, NDI1 expression also reinstates endoplasmic reticulummitochondria contacts, prevents UPR activation and rescues the behavioural and lifespan phenotypes caused by complex I deficiency. Together, these data show that metabolic disruption due to loss of neuronal NADH dehydrogenase activity cause UPR activation and drive pathogenesis in complex I deficiency.

neuroscience↗

bioRxiv2020

Presynaptic accumulation of α-synuclein causes synaptopathy and progressive neurodegeneration

Alpha-synuclein (-syn) mislocalisation and accumulation in intracellular inclusions is the major pathological hallmark of degenerative synucleinopathies, including Parkinsons disease, Parkinsons disease with Dementia and Dementia with Lewy Bodies. Typical symptoms are behavioural abnormalities including motor deficits that mark disease progression, while non-motor symptoms and synaptic deficits are already apparent during the early stages of disease. Synucleinopathies have therefore been considered synaptopathies that exhibit synaptic dysfunction prior to neurodegeneration. However, the mechanisms and events underlying synaptopathy are largely unknown. Here we investigated the cascade of pathological events underlying -syn accumulation and toxicity in a Drosophila model of synucleinopathy by employing a combination of histological, biochemical, behavioural and electrophysiological assays. Our findings demonstrate that targeted expression of human -syn leads to its accumulation in presynaptic terminals that caused downregulation of synaptic proteins, Cysteine String Protein, Synapsin, and Syntaxin 1A, and a reduction in the number of Bruchpilot puncta, the core component of the presynaptic active zone essential for its structural integrity and function. These -syn-mediated presynaptic alterations resulted in impaired neuronal function, which triggered behavioural deficits in ageing Drosophila that occurred prior to progressive degeneration of dopaminergic neurons. Comparable alterations in presynaptic active zone protein were found in patient brain samples of Dementia with Lewy Bodies. Together, these findings demonstrate that presynaptic accumulation of -syn impairs the active zone and neuronal function, which together cause synaptopathy that results in behavioural deficits and the progressive loss of dopaminergic neurons. This sequence of events resembles the cytological and behavioural phenotypes that characterise the onset and progression of synucleinopathies, suggesting that -syn mediated synaptopathy is an initiating cause of age-related neurodegeneration.

neuroscience↗

bioRxiv2019

Ancestral regulatory mechanisms specify conserved midbrain circuitry in arthropods and vertebrates

Corresponding attributes of neural development and function suggest arthropod and vertebrate brains may have an evolutionarily conserved organization. However, the underlying mechanisms have remained elusive. Here we identify a gene regulatory and character identity network defining the deutocerebral-tritocerebral boundary (DTB) in Drosophila. We show this network comprises genes homologous to those directing midbrain-hindbrain boundary (MHB) formation in vertebrates and their closest chordate relatives. Genetic tracing reveals that the embryonic DTB gives rise to adult midbrain circuits that in flies control auditory and vestibular information processing and motor coordination, as do MHB-derived circuits in vertebrates. DTB-specific gene expression and function is directed by cis-regulatory elements (CREs) of developmental control genes that include homologs of mammalian Zinc finger of the cerebellum and Purkinje cell protein 4. Moreover, Drosophila DTB-specific CREs correspond to regulatory sequences of human ENGRAILED-2, PAX-2 and DACHSHUND-1 that direct MHB-specific expression in the embryonic mouse brain. Together, these findings imply ancestral regulatory mechanisms mediating the genetic specification of midbrain-cerebellar circuitry for balance and motor control that may predated the radiation of cephalic nervous systems across the animal kingdom.

neuroscience↗

bioRxiv2018

Dopamine D1 receptor signalling differentially regulates action sequences and turning behaviour in freely moving Drosophila

Here, we introduce a novel behavioural paradigm to study neural circuits and mechanisms underlying action selection and decision-making in freely moving Drosophila. We first validate our approach by studying FoxP mutants and show that normally invariant patterns of motor activity and turning behaviour are altered in these flies, reminiscent of indecision. Then, focusing on central complex (CX) circuits known to integrate different sensory modalities and controlling premotor regions, we show that action sequences and turning behaviour are regulated by dopamine D1 (Dop1R1) receptor signalling. Dop1R1 inputs onto CX columnar wedge and ellipsoid body R2/R4m ring neuron circuits both negatively gate motor activity but inversely control turning behaviour. While flies deficient of D1 receptor signalling present normal turning behaviour despite decreased activity, restoring Dop1R1 level in R2/R4m-specific circuitry affects the temporal organisation of motor actions and turning. These findings suggest that columnar wedge and ring neuron circuits of the CX differentially modulate patterns of motor action sequences and turning behaviour by comparative Dop1R1 signalling for goal-directed locomotion.

neuroscience↗

bioRxiv2017

A lineage-related reciprocal inhibition circuitry for sensory-motor action selection

The insect central complex and vertebrate basal ganglia are forebrain centres involved in selection and maintenance of behavioural actions. However, little is known about the formation of the underlying circuits, or how they integrate sensory information for motor actions. Here, we show that paired embryonic neuroblasts generate central complex ring neurons that mediate sensory-motor transformation and action selection in Drosophila. Lineage analysis resolves four ring neuron subtypes, R1-R4, that form GABAergic inhibition circuitry among inhibitory sister cells. Genetic manipulations, together with functional imaging, demonstrate subtype-specific R neurons mediate the selection and maintenance of behavioural activity. A computational model substantiates genetic and behavioural observations suggesting that R neuron circuitry functions as salience detector using competitive inhibition to amplify, maintain or switch between activity states. The resultant gating mechanism translates facilitation, inhibition and disinhibition of behavioural activity as R neuron functions into selection of motor actions and their organisation into action sequences.

neuroscience↗