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bioRxiv2026

Divergent excitatory and inhibitory signaling in a head direction circuit

Neural cell types are often clustered into inhibitory, excitatory, or neuromodulatory populations. However, the signaling mechanism between two neurons ultimately depends on their neurotransmitter-receptor pairings. Here, we demonstrate an example of a glutamatergic population of neurons that appears to either excite or inhibit their downstream partners depending on the type of glutamate receptor expressed in the downstream cell type. The upstream population encodes a sinusoidal head direction signal. The downstream partners that are excited by glutamate encode the same signal while the downstream partners that are inhibited by glutamate encode a 180{degrees} phase-shifted copy. The upstream population therefore appears to pass on two different phases of the same signal by making either excitatory or inhibitory connections to different downstream partners.

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bioRxiv2019

Nonlinear convergence preserves information

Neural circuits are structured with layers of converging and diverging connectivity, and selectivity-inducing nonlinearities at neurons and synapses. These components have the potential to hamper an accurate encoding of the circuit inputs. Past computational studies have optimized the nonlinearities of single neurons, or connection weights in networks, to maximize encoded information, but have not grappled with the simultaneous impact of convergent circuit structure and nonlinear response functions for efficient coding. Our approach is to compare model circuits with different combinations of convergence, divergence, and nonlinear neurons to discover how interactions between these components affect coding efficiency. We find that a convergent circuit with divergent parallel pathways can encode more information with nonlinear subunits than with linear subunits, despite the compressive loss induced by the convergence and the nonlinearities when considered individually. These results show that the combination of selective nonlinearities and a convergent architecture - both elements that reduce information when acting separately - can promote efficient coding. Significance StatementComputation in neural circuits relies on a common set of motifs, including divergence of common inputs to parallel pathways, convergence of multiple inputs to a single neuron, and nonlinearities that select some signals over others. Convergence and circuit nonlinearities, considered individually, can lead to a loss of information about inputs. Past work has detailed how optimized nonlinearities and circuit weights can maximize information, but here, we show that incorporating non-invertible nonlinearities into a circuit with divergence and convergence, can enhance encoded information despite the suboptimality of these components individually. This study extends a broad literature on efficient coding to convergent circuits. Our results suggest that neural circuits may preserve more information using suboptimal components than one might expect.

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bioRxiv2023

Hebbian priming of human spinal motor learning

Learning or relearning of motor skills requires plasticity in relevant neural circuits. Motor recovery following lesions to the corticospinal system can be augmented through neuromodulation techniques targeting the affected or compensatory neural circuits. By repeatedly pairing transcranial magnetic stimulation of the primary motor cortex (M1) and motoneuronal electrical stimulation (i.e., paired corticomotoneuronal stimulation, PCMS) timed to arrive at the corticomotoneuronal (CM) synapses in close temporal proximity, spike-timing-dependent bidirectional changes in CM transmission can be induced in humans (Taylor & Martin, 2009). PCMS-induced increases in CM transmission have been demonstrated to transiently improve motor control in patients with spinal cord injury (Bunday & Perez 2012), whereas effects on the malleability of neural circuits are entirely unexplored. We hypothesized that PCMS can prime mechanisms of subsequent motor learning exclusively when directed to the neural circuitry underpinning the motor behavior. In three experiments, we provide the first evidence ( Experiment I) and a double-blinded, sham-controlled replication ( Experiment II) that PCMS targeting the spinal CM synapses can prime subsequent learning of rapid finger movements relying on spinal neuroplasticity. Finally, we demonstrate that the effects of PCMS are circuit-specific and bidirectional. When PCMS was timed to arrive at a facilitatory interval in M1 but an inhibitory interval at the CM synapses subsequent learning was transiently impeded ( Experiment III). Taken together, our results provide proof-of-principle that non-invasively induced plasticity governed by Hebbian learning rules interacts with experience-dependent plasticity in the spinal cord with positive implications for motor learning. Our results offer a mechanistic rationale for priming sensorimotor training with individualized PCMS to enhance the effects of motor practice in neurorehabilitation. HighlightsO_LIPaired corticomotoneuronal stimulations (PCMS) promote ballistic motor learning and facilitate corticospinal excitability compared to rest and sham protocols. C_LIO_LIA double-blinded sham experiment replicates priming effects of PCMS on ballistic motor learning and demonstrates long-term benefits of combined PCMS and motor practice. C_LIO_LIThe facilitating effect of PCMS on ballistic motor learning is circuit-specific with superior effects on ballistic motor learning after facilitating PCMS compared to control protocols. C_LI

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bioRxiv2017

Drosophila Fezf coordinates laminar-specific connectivity through cell-intrinsic and cell-extrinsic mechanisms

Laminar arrangement of neural connections is a fundamental feature of neural circuit organization. Identifying mechanisms that coordinate neural connections within correct layers is thus vital for understanding how neural circuits are assembled. In the medulla of the Drosophila visual system neurons form connections within ten parallel layers. The M3 layer receives input from two neuron types that sequentially innervate M3 during development. Here we show that M3-specific innervation by both neurons is coordinated by Drosophila Fezf (dFezf), a conserved transcription factor that is selectively expressed by the earlier targeting input neuron. In this cell, dFezf instructs layer specificity and activates the expression of a secreted molecule (Netrin) that regulates the layer specificity of the other input neuron. We propose that employment of transcriptional modules that cell-intrinsically target neurons to specific layers, and cell-extrinsically recruit other neurons is a general mechanism for building layered networks of neural connections.

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bioRxiv2024

Electrical Synapse Rectification Enables Dual-Network Activity in the crab Cancer borealis

Flexibility of rhythmic networks includes neuromodulator-elicited changes in neuronal participation between networks. We are examining the role of rectifying electrical synapses in this neuronal switching. Electrical synapses can have complex, non-intuitive effects on network output. However, it is often difficult to measure and manipulate rectification across conditions to determine their functional contributions. Here, we use the Jonah crab Cancer borealis to investigate rectification in well-described rhythmic networks. In an established modulatory state, stimulating the projection neuron MCN5 or bath applying its neuropeptide Gly1-SIFamide causes the two LPG neurons to switch from pyloric rhythm-only (food filtering, [~]1 Hz) activity to dual pyloric and gastric mill rhythm (chewing, [~]0.1 Hz) activity. Typically, LPG is co-active with the two PD and single AB pyloric pacemaker neurons due to rectifying electrical coupling. In Gly1-SIFamide, LPG continues to burst in pyloric time with AB/PD but periodically "escapes" and generates intrinsic longer-duration gastric mill-timed bursts, decreasing its overall synchrony with AB/PD, while AB/PD retain their synchronous pyloric timing. Using two-electrode voltage clamp recordings, we find that Gly1-SIFamide does not alter electrical coupling strength or the rectification between LPG and AB/PD. However, in a computational model, rectification is necessary for LPG to escape AB/PD electrical coupling and generate longer, gastric mill-timed bursts. This was confirmed in the biological system by adding a dynamic clamp non-rectifying electrical synapse between LPG and PD, which decreased LPGs escape from AB/PD and its gastric mill-timed activity. Thus, rectification between electrically coupled oscillators can underlie modulator-elicited changes in their synchrony. Significance statementBehavioral adaptability includes rapid changes in neural circuit composition. Unlike chemical synapses, little is known about electrical synapse contributions to circuit flexibility. Here, we identify an important role for electrical coupling rectification (asymmetrical current flow between coupled neurons) in regulating neuronal participation between neural circuits. A neuromodulator causes the activity of two sets of electrically-coupled neurons participating in an oscillatory neural circuit to diverge, allowing one set to additionally participate in a second oscillatory circuit at a distinct frequency. Using mathematical modeling and the dynamic clamp technique, we show that this transition depends on rectification. This newly-identified function of electrical synapse rectification may have implications for oscillatory networks underlying a range of functions, due to the prevalence of electrical coupling.

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bioRxiv2024

Endophilin A1 facilitates organization of the GABAergic postsynaptic machinery to maintain excitation-inhibition balance

The assembly and operation of neural circuits in the brain rely on the coordination and balance of excitatory and inhibitory activities. Inhibitory synapses are key regulators of the functional balance of neural circuits. However, due to the diversity of inhibitory presynaptic neurons, the complex composition of postsynaptic receptor subunits and the lack of typical postsynaptic dense structure, there are relatively few studies on the regulatory mechanisms for inhibitory synaptic structure and function, and insufficient understanding of the cellular and molecular abnormalities of inhibitory synapses in neurological and neuropsychiatric disorders. Here, we report a crucial role for endophilin A1 in inhibitory synapses. We show that endophilin A1 directly interacts with the inhibitory postsynaptic scaffold protein gephyrin in excitatory neurons, and promotes organization of the inhibitory postsynaptic density and synaptic recruitment/stabilization of the {gamma}-aminobutyric acid type A receptors via its plasma membrane association and actin polymerization promoting activities. Loss of endophilin A1 by gene knockout in mouse hippocampal CA1 pyramidal cells weakens inhibitory synaptic transmission and causes imbalance in the excitatory/inhibitory function of neural circuits, leading to increased susceptibility to epilepsy. Our findings identify endophilin A1 as an iPSD component and provide new insights into the organization and stabilization of inhibitory postsynapses to maintain E/I balance as well as the pathogenesis of epilepsy.

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bioRxiv2026

Precursor Cells in the Parenchyma Act in Concert with Ventricular Neural Progenitors to Facilitate Dramatic Astrocyte Turnover and Recovery Following Natural Neuronal Death

Seasonal environmental variation represents one of the most pervasive and recurring forces shaping the vertebrate brain through cycles of neural circuit plasticity and remodeling that ultimately serves to maintain adaptive behavior. Although the contribution of adult neurogenesis to such remodeling is well-characterized across vertebrates, the role of astrocytes in supporting or enabling this process remains almost entirely unknown. Here, using the robust and natural seasonal loss of neurons within the sensorimotor nucleus HVC of the songbird, we identify a rapid astrocytic turnover event following neuronal loss and reveal a previously undescribed cellular mechanism supporting neural circuit recovery. Using lineage-specific and proliferation labeling, we establish the presence of a previously undescribed SOX2-positive neural progenitor-like population residing within the vertebrate parenchyma, outside the canonical ventricular zone niche. These parenchymal astrocyte precursor cells (pAPCs) maintain quantifiable, steady-state proliferation under homeostatic conditions, yet expand in pool size following seasonally-driven neuronal loss. The coordinated response of canonical neural progenitor cells and pAPCs produces new astrocytes that persist throughout the re-establishment of homeostasis. These findings reveal extensive astrocyte plasticity in the adult vertebrate brain, operating across both canonical and non-canonical progenitor niches, and challenge the prevailing view that parenchymal astrocytes are largely post-mitotic outside of injury contexts. More broadly, our findings establish a framework for understanding how glial populations contribute to neural circuit resilience both to the physiological and neural changes that recurring seasonal transitions drive, and to the accelerating environmental changes that increasingly challenge the adaptive capacity of animal brains worldwide.

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bioRxiv2025

Developmental synaptic pruning in the olivo-cerebellar circuit sculpts predictive processing

Developmental synaptic pruning is thought to refine neural circuits by eliminating excess connectivity, but whether this process changes the computations performed by developing circuits remains poorly understood. Here, we show that synaptic pruning sharpens neural representations in the developing zebrafish cerebellum. Climbing fiber (CF) inputs to Purkinje neurons (PNs) progressively transition from poly- to predominantly mono-innervation during the first two weeks of life. In vivo whole-cell recordings reveal that individual CFs convey distinct sensorimotor information, and that convergence of differently tuned CFs degrades the precision of PN representations. As this convergence is reduced during development, PN responses become more selective and temporally precise. Later-stage PNs also exhibit stronger predictive responses to expected sensory events and enhanced responses to violations of those expectations, accompanied by improved behavioral adaptation. These findings suggest that developmental synaptic pruning is not simply a process of reducing excess connectivity, but can contribute to the functional specialization of neural circuits by sharpening neuronal representations and enabling increasingly precise predictive sensorimotor computations.

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bioRxiv2024

Establishment of an optimized and automated workflow for whole brain probing of neuronal activity.

Behaviors are encoded by widespread neural circuits within the brain that change with age and experience. Immunodetection of the immediate early gene c-Fos has been successfully used for decades to reveal neural circuits active during specific tasks or conditions. Our objectives here were to develop and benchmark a workflow that circumvents classical temporal and spatial limitations associated with c-Fos quantification. We combined c-Fos immunohistochemistry with c-Fos driven Cre-dependent tdTomato expression in the TRAP2 mice, to visualize and perform a direct comparison of neural circuits activated at different times or during different tasks. By using open-source software (QuPath and ABBA), we established a workflow that optimize and automate cell detection, cell classification (e.g. c-Fos vs. c-Fos/tdTomato) and whole brain registration. We demonstrate that this workflow, based on fully automatic scripts, allows accurate cell number quantification with minimal interindividual variability. Further, interrogation of brain atlases at different scales (from simplified to detailed) allows gradually zooming on brain regions to explore spatial distribution of activated cells. We illustrate the potential of this approach by comparing patterns of neuronal activation in various contexts (two vigilance states, complex behavioral tasks...), in separate groups of mice or at two time points in the same animals. Finally, we explore software (BrainRender) for intuitive representation of the results. Altogether, this automated workflow accessible to all labs with some expertise in histology, allows an unbiased, fast and accurate analysis of the whole brain activity pattern at the cellular level, in various contexts.

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bioRxiv2024

Inference technique for the synaptic conductances in rhythmically active networks and application to respiratory central pattern generation circuits

Unraveling synaptic interactions between excitatory and inhibitory interneurons within rhythmic neural circuits, such as central pattern generation (CPG) circuits for rhythmic motor behaviors, is critical for deciphering circuit interactions and functional architecture, which is a major problem for understanding how neural circuits operate. Here we present a general method for extracting and separating patterns of inhibitory and excitatory synaptic conductances at high temporal resolution from single neuronal intracellular recordings in rhythmically active networks. These post-synaptic conductances reflect the combined synaptic inputs from the key interacting neuronal populations and can reveal the functional connectome of the active circuits. To illustrate the applicability of our analytic technique, we employ our method to infer the synaptic conductance profiles in identified rhythmically active interneurons within key microcircuits of the mammalian (mature rat) brainstem respiratory CPG and provide a perspective on how our approach can resolve the functional interactions and circuit organization of these interneuron populations. We demonstrate the versatility of our approach, which can be applied to any other rhythmic circuits where conditions allow for neuronal intracellular recordings.

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bioRxiv2023

Optical resolution is not the limiting factor for spatial precision of two-photon optogenetic photostimulation

Two-photon optogenetics combines nonlinear excitation with noninvasive activation of neurons to enable manipulation of neural circuits with a high degree of spatial precision. Combined with two-photon population calcium imaging, these approaches comprise a flexible platform for all-optical interrogation of neural circuits. However, a multitude of optical and biological factors dictate the exact precision of this approach in vivo, where it is most usefully applied. Here, we carefully assessed how the optical factors determine the spatial precision of activation. We found that optical resolution is not the limiting factor of the spatial precision of two-photon optogenetic photostimulation, and by doing so, reveal the key factors to improve to achieve maximal precision. Our results enable future work to focus on the optimal factors by providing key insight from controlled experiments in a manner not previously reported. This research can be applied to advance the state-of-the-art of all-optical interrogation, extending the toolkit for neuroscience research to achieve spatiotemporal precision at the crucial levels at which neural circuits operate.

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bioRxiv2019

LSO:Ce Inorganic Scintillators are Biocompatible with Neuronal and Circuit Function

Optogenetics is widely used in neuroscience to control neural circuits. However, non-invasive methods for light delivery in brain are needed to avoid physical damage caused by current methods. One potential strategy could employ x-ray activation of radioluminescent particles (RPLs), enabling localized light generation within the brain. RPLs composed of inorganic scintillators can emit light at various wavelengths depending upon composition. Cerium doped lutetium oxyorthosilicate (LSO:Ce), an inorganic scintillator that emits blue light in response to x-ray or UV stimulation, could potentially be used to control neural circuits through activation of channelrhodopsin-2 (ChR2), a light-gated cation channel. Whether inorganic scintillators themselves negatively impact neuronal processes and synaptic function is unknown, and was investigated here using cellular, molecular, and electrophysiological approaches. As proof of principle, we applied UV stimulation to 4 m LSO:Ce particles during whole-cell recording of CA1 pyramidal cells in acutely prepared hippocampal slices from mice that expressed ChR2 in glutamatergic neurons. We observed an increase in frequency and amplitude of spontaneous excitatory postsynaptic currents (EPSCs), indicating UV activation of ChR2 and excitation of neurons. Importantly, we found that LSO:Ce particles have no effect on survival of primary mouse cortical neurons, even after 24 hours of exposure. In extracellular dendritic field potential recordings, we observed no change in strength of basal glutamatergic transmission up to 3 hours of exposure to LSO:Ce microparticles. However, there was a slight decrease in the frequency of spontaneous EPSCs in whole-cell voltage-clamp recordings from CA1 pyramidal cells, with no change in current amplitudes. No changes in the amplitude or frequency of spontaneous inhibitory postsynaptic currents (IPSCs) were observed. Finally, long term potentiation (LTP), a synaptic modification believed to underlie learning and memory and a robust measure of synaptic integrity, was successfully induced, although the magnitude was slightly reduced. Together, these results show LSO:Ce particles are biocompatible even though there are modest effects on baseline synaptic function and long-term synaptic plasticity. Importantly, we show that light emitted from LSO:Ce particles is able to activate ChR2 and modify synaptic function. Therefore, LSO:Ce inorganic scintillators are potentially viable for use as a new light delivery system for optogenetics.

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bioRxiv2021

Long-term imaging of the ventral nerve cord in behaving adult Drosophila

The dynamics and connectivity of neural circuits continuously change during an animals lifetime on timescales ranging from milliseconds to days. Therefore, to investigate how biological networks accomplish remarkable cognitive and behavioral tasks, minimally invasive methods are needed to perform repeated measurements, or perturbations of neural circuits in behaving animals across time. Such tools have been developed to investigate the brain but similar approaches are lacking for comprehensively and repeatedly recording motor circuits in behaving animals. Here we describe a suite of microfabricated technologies that enable long-term, minimally invasive optical recordings of the adult Drosophila melanogaster ventral nerve cord (VNC)--neural tissues that are functionally equivalent to the vertebrate spinal cord. These tools consist of (i) a manipulator arm that permits the insertion of (ii) a compliant implant into the thorax to expose the imaging region of interest; (iii) a numbered, transparent polymer window that encloses and provides optical access to the inside of the thorax, and (iv) a hinged remounting stage that allows gentle and repeated tethering of an implanted animal for two-photon imaging. We validate and illustrate the utility of our toolkit in several ways. First, we show that the thoracic implant and window have minimal impact on animal behavior and survival while also enabling neural recordings from individual animals across at least one month. Second, we follow the degradation of chordotonal organ mechanosensory nerve terminals in the VNC over weeks after leg amputation. Third, because our tools allow recordings of the VNC with the gut intact, we discover waves of neural population activity following ingestion of a high-concentration caffeine solution. In summary, our microfabricated toolkit makes it possible to longitudinally monitor anatomical and functional changes in premotor and motor neural circuits, and more generally opens up the long-term investigation of thoracic tissues.

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bioRxiv2020

The formin Fmn2 is required for the development of an excitatory interneuron module in the zebrafish acoustic startle circuit

The formin family member, Fmn2, is a neuronally enriched cytoskeletal remodelling protein conserved across vertebrates. Recent studies have implicated Fmn2 in neurodevelopmental disorders, including sensory processing dysfunction and intellectual disability in humans. Cellular characterization of Fmn2 in primary neuronal cultures has identified its function in the regulation of cell-substrate adhesion and consequently growth cone translocation. However, the role of Fmn2 in the development of neural circuits in vivo, and its impact on associated behaviours have not been tested. Using automated analysis of behaviour and systematic investigation of the associated circuitry, we uncover the role of Fmn2 in zebrafish neural circuit development. As reported in other vertebrates, the zebrafish ortholog of Fmn2 is also enriched in the developing zebrafish nervous system. We find that Fmn2 is required for the development of an excitatory interneuron pathway, the spiral fiber neuron, which is an essential circuit component in the regulation of the Mauthner cell-mediated acoustic startle response. Consistent with the loss of the spiral fiber neurons tracts, high-speed video recording revealed a reduction in the short latency escape events while responsiveness to the stimuli was unaffected. Taken together, this study provides evidence for a circuit-specific requirement of Fmn2 in eliciting an essential behaviour in zebrafish. Our findings underscore the importance of Fmn2 in neural development across vertebrate lineages and highlight zebrafish models in understanding neurodevelopmental disorders. SIGNIFICANCE STATEMENTFmn2 is a neuronally enriched cytoskeletal remodelling protein linked to neurodevelopment and cognitive disorders in humans. Recent reports have characterized its function in growth cone motility and chemotaxis in cultured primary neurons. However, the role of Fmn2 in the development of neural circuits in vivo and its implications in associated behaviours remain unexplored. This study shows that Fmn2 is required for the development of neuronal processes in the acoustic startle circuit to ensure robust escape responses to aversive stimuli in zebrafish. Our study underscores the crucial role of the non-diaphanous formin, Fmn2, in establishing neuronal connectivity and related behaviour in zebrafish.

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bioRxiv2024

Adeno-Associated Viral Tools to Trace Neural Development and Connectivity Across Amphibians

The development, evolution, and function of the vertebrate central nervous system (CNS) can be best studied using diverse model organisms. Amphibians, with their unique phylogenetic position at the transition between aquatic and terrestrial lifestyles, are valuable for understanding the origin and evolution of the tetrapod brain and spinal cord. Their metamorphic developmental transitions and unique regenerative abilities also facilitate the discovery of mechanisms for neural circuit remodeling and replacement. The genetic toolkit for amphibians, however, remains limited, with only a few species having sequenced genomes and a small number of transgenic lines available. In mammals, recombinant adeno-associated viral vectors (AAVs) have become a powerful alternative to genome modification for visualizing and perturbing the nervous system. AAVs are DNA viruses that enable neuronal transduction in both developing and adult animals with low toxicity and spatial, temporal, and cell-type specificity. However, AAVs have never been shown to transduce amphibian cells efficiently. To bridge this gap, we established a simple, scalable, and robust strategy to screen AAV serotypes in three distantly-related amphibian species: the frogs Xenopus laevis and Pelophylax bedriagae, and the salamander Pleurodeles waltl, in both developing larval tadpoles and post-metamorphic animals. For each species, we successfully identified at least two AAV serotypes capable of infecting the CNS; however, no pan-amphibian serotype was identified, indicating rapid evolution of AAV tropism. In addition, we developed an AAV-based strategy that targets isochronic cohorts of developing neurons - a critical tool for parsing neural circuit assembly. Finally, to enable visualization and manipulation of neural circuits, we identified AAV variants for retrograde tracing of neuronal projections in adult animals. Our findings expand the toolkit for amphibians to include AAVs, establish a generalizable workflow for AAV screening in non-canonical research organisms, generate testable hypotheses for the evolution of AAV tropism, and lay the foundation for modern cross-species comparisons of vertebrate CNS development, function, and evolution.

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bioRxiv2026

Modeling interregional propagation of α-synuclein in human striatal-midbrain assembloids

Parkinsons disease is characterized by the progressive degeneration of dopaminergic (DA) neurons in the substantia nigra that project to the striatum. Postmortem studies have found that -synuclein pathology spreads across brain regions in a prion-like manner. Human three-dimensional neural tissues provide experimentally tractable platforms for clarifying the molecular pathology of synucleinopathy that overcome the limitations of postmortem brain studies. In this study, we established a human striatal-midbrain assembloid model enabling spatially and temporally controlled -synuclein induction after formation of the nigrostriatal pathway within hStrMAs. Human induced pluripotent stem cells (hiPSCs) were differentiated into striatal spheroids and midbrain spheroids, which were fused to reconstruct the nigrostriatal pathway in vitro. Histological, electrophysiological, and single-cell RNA sequencing analyses confirmed the generation of region-specific neuronal populations, including striatal GABAergic neurons and midbrain DA neurons, and demonstrated that distinct forebrain and ventral midbrain identities were preserved within assembloids. To model synucleinopathy, we generated a doxycycline-inducible -synuclein hiPSC line, permitting selective induction of -synuclein expression in the striatal region after assembloid formation. Spatially restricted -synuclein induction resulted in the progressive accumulation of phosphorylated and fibrillar -synuclein in midbrain DA neurons, indicating interregional propagation through established neural circuits. Transcriptomic analysis of the midbrain region revealed significant downregulation of DA identity and synaptic function genes, suggesting functional impairment of DA neurons following -synuclein propagation. These findings demonstrate that the human neural circuit architecture contributes to the interregional propagation of -synuclein pathology. Our controllable human assembloid platform provides a powerful experimental framework for dissecting the mechanisms of pathological protein spread and developing therapeutic strategies targeting molecular pathology in neurodegenerative diseases. Significance statementOne pathological feature of Parkinsons disease is the progressive spread of -synuclein pathology across brain regions. However, the molecular mechanisms underlying this process remain poorly understood. In this study, we established a human striatal-midbrain assembloid model in which -synuclein expression can be spatially restricted and temporally induced after the nigrostriatal pathway is formed, thus enabling the experimental dissection of interregional -synuclein propagation across brain regions. We demonstrated that -synuclein pathology initiated in the striatal region propagated to midbrain dopaminergic neurons, leading to disease-relevant molecular and transcriptional alterations. These findings provide direct evidence that human neural circuits contribute to the spread of synucleinopathy and offer a controllable human model for studying disease progression and therapeutic strategies.

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bioRxiv2022

Direct neural perturbations reveal a dynamical mechanism for robust computation

The rich repertoire of skilled mammalian behavior is the product of neural circuits that generate robust and flexible patterns of activity distributed across populations of neurons. Decades of associative studies have linked many behaviors to specific patterns of population activity, but association alone cannot reveal the dynamical mechanisms that shape those patterns. Are local neural circuits high-dimensional dynamical reservoirs able to generate arbitrary superpositions of patterns with appropriate excitation? Or might circuit dynamics be shaped in response to behavioral context so as to generate only the low-dimensional patterns needed for the task at hand? Here, we address these questions within primate motor cortex by delivering optogenetic and electrical microstimulation perturbations during reaching behavior. We develop a novel analytic approach that relates measured activity to theoretically tractable, dynamical models of excitatory and inhibitory neurons. This computational model captures the dynamical effects of these perturbations and demonstrates that motor cortical activity during reaching is shaped by a self-contained, low-dimensional dynamical system. The subspace containing task-relevant dynamics proves to be oriented so as to be robust to strong non-normal amplification within cortical circuits. This task dynamics space exhibits a privileged causal relationship with behavior, in that stimulation in motor cortex perturb reach kinematics only to the extent that it alters neural states within this subspace. Our results resolve long-standing questions about the dynamical structure of cortical activity associated with movement, and illuminate the dynamical perturbation experiments needed to understand how neural circuits throughout the brain generate complex behavior.

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bioRxiv2022

Remembering the "When": Hebbian Memory Models for the Time of Past Events

Humans and animals can remember how long ago specific events happened. Little is known about the neural mechanisms that enable remembering the "when" of memories stored for long durations in the episodic memory system - in contrast to interval-timing on the order of seconds and minutes. Based on a systematic exploration of neural coding, association and retrieval schemes, we develop model classes that span the space of possible mechanisms for the reconstruction of the time of past events. In concrete examples we show how network architecture, Hebbian plasticity, synaptic pruning or systems consolidation allow the retrieval of the time of past events. In a simulation, we demonstrate how these mechanisms would enable food caching animals like corvids to remember what they cached, where, and how long ago. To dissociate different hypotheses, we propose three kinds of novel, non-verbal experiments, that can be run with humans and animals. Our simulations predict the experimental results for different classes of models. Our study shows that remembering the "when" can be implemented by many biologically plausible mechanisms and that carefully designed experiments are needed to pin down the actual neural implementation of the memory for the time of past events in different species. Author summaryWas it yesterday, a week ago, or perhaps even longer since I last ate pizza? Questions like these are typically easy to answer, because humans have a good sense of how long ago specific events happened. Research involving animals, such as food-caching birds, has revealed that they, too, can remember the "when" of past events. So far, little is known about the neuronal mechanisms that enable remembering the "when". In this study, we explore systematically concrete hypotheses of how neural circuits, synaptic plasticity and ongoing restructuring of neural circuits allow remembering the "when". We propose experiments, that could be done with humans or animals, to discriminate different biologically plausible mechanisms for remembering the "when".

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