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Luthi, A.

Publications and source records attributed to Luthi, A..

13 recordsLinked to original sources

Nethobench: Forecasting design and conditioning shape the structural realism of generated neural dynamics

Forecasting models are increasingly used to model neural population activity, yet existing benchmarks typically evaluate them by pointwise predictive fidelity to held-out observations. In stochastic, partially observed systems, agreement with one sampled realization is distinct from preserving the statistical and dynamical structure of the process. We introduce Nethobench, a benchmark that evaluates structural agreement across five metric families: distributional, temporal--spectral, relational, geometric, and state-dynamical. We validate Nethobench using targeted perturbations and stochastic systems with known dynamics, and apply it to mouse calcium imaging, mouse Neuropixels recordings, and human intracranial recordings, using empirical references to calibrate interpretation. Nethobench detects targeted structural failures and assigns high scores to independent samples from the correct synthetic process despite trajectory mismatch. It tracks structural changes during training and under domain shift. Model comparisons reveal how forecasting formulation, architecture, training regime, and loss shape structural profiles, while OmniMouse input ablations improve all five family means when behavior is added to video in one held-out session. In Brain Treebank, analog retrieval passes more structural checks while a multistep GRU better predicts the observed realization. These results motivate reporting calibrated family-level structural metrics alongside pointwise accuracy, proper probabilistic scores, and task-specific endpoints when evaluating neural forecasts across species and recording modalities.

neuroscience↗

Deleting learning-induced dendritic spines disrupts the memory they encode

Long-term memory is widely thought to depend on activity-dependent synaptic plasticity and the structural remodeling that accompanies it, yet direct causal evidence that this remodeling is required for memory storage has been lacking. A case in point is the formation of dendritic spines: new spines appear following learning, but whether they constitute a physical substrate of memory remains unresolved. To address this, we developed the New Spine Elimination Tool (NSET), a chemical-genetic strategy, that ablates dendritic spines formed within a defined window of synaptic plasticity. NSET combines inducible expression of a degradable form of the actin-binding protein Drebrin with ligand-triggered proteasomal degradation. Because mainly nascent spines incorporate the degradable proteins into their cytoskeleton, ligand application eliminates them while sparing pre-existing ones. In hippocampal slice cultures, NSET eliminated recently formed spines without altering overall spine density or affecting pre-existing spines. Applied in vivo in the mouse basolateral amygdala, selective removal of learning-induced spines disrupted auditory fear memory, whereas consolidated memories and the capacity for new learning remained intact. These findings provide direct causal evidence that newly formed dendritic spines are required for long-term memory storage.

neuroscience↗

A Conserved Locus Coeruleus fMRI Signature of Brain-State Transitions across Sleep, Anesthesia, and Wakefulness

Neuromodulatory systems dynamically reconfigure large-scale brain networks to support adaptation across behavioral and cognitive states. The locus coeruleus (LC), which broadcasts noradrenaline throughout the forebrain, is a central regulator of arousal and state-dependent dynamics. However, how LC activity manifests in brain-wide organization across physiological contexts, and how it biases fMRI connectivity, remains poorly understood. Using an optogenetically informed cross-species framework, we identify a transient LC-derived spatiotemporal pattern of brain activity accompanying brain-state transitions under progressively naturalistic conditions: controlled LC stimulation and endogenous LC fluctuations in anesthetized mice, sleep-wake transitions in rodents and humans, and resting-state activity in awake humans. This LC-derived signature is conserved across species and contexts, leaving a robust and detectable imprint on the BOLD signal. Critically, the prevalence of LC events systematically biases functional connectivity metrics in human fMRI. These findings establish LC activity as a mechanistically interpretable source of variability in resting-state measurements, with direct implications for the interpretation of fMRI biomarkers in arousal-related disorders.

neuroscience↗

Vagal afferent activation induces a NREM-sleep-like state with brain-body cooling, but locus coeruleus activation

Parasympathetic nervous system activity, vital for restorative sleep, is influenced by vagal sensory afferents, but how these shape brain-body correlates of sleep remains open. We investigated this by combining vagal sensory neuron (VSN) stimulation with EEG/EMG, heart rate, brain-body temperature, and noradrenergic locus coeruleus (LC) neuron population activity measures. Opto-/chemogenetic VSN manipulations in Vglut2-Cre mice were validated via in vitro synaptic physiology, cFos expression, and heart rate measures. Chemogenetic VSN stimulation during the resting phase induced a non-rapid-eye-movement sleep (NREMS)-like state with enriched, but homeostatically regulated, low-frequency (0.75-4 Hz) EEG activity, yet suppressed REMS. Simultaneously, brain-body temperatures dropped while LC activity increased. Recovery was gradual towards normal NREMS-REMS-cycles but accelerated by external warming, identifying cooling as key factor. We conclude that VSN activation can promote brain-body correlates as a continuum of normal NREM sleep while engaging forebrain neuromodulation, offering insights into mechanisms of sleep disruptions linked to autonomic dysregulation.

neuroscience↗

Neural mechanisms of adaptive value coding in the amygdala

To address their needs, animals must optimize behavior by integrating external cues with internal state signals, such as hunger or thirst, environmental conditions, and past experiences. Accordingly, the perceived value of a reward varies depending on an animals current needs. Updating the specific value of rewards predicted by external cues depends on the basolateral amygdala (BLA). However, neurophysiological investigations have centered around the assumption of stimulus-invariant value representations and have not been able to account for behavioral findings that support the BLAs ability to represent stimulus-specific value of distinct appetitive or aversive outcomes. To address how the BLA encodes and updates stimulus-specific value representations, we exposed head-fixed mice to distinct sets of gustatory rewards while tracking perceived value using lick microstructural analysis. Two-photon calcium imaging of BLA principal neurons revealed that the magnitude of the BLA population response scaled with perceived reward value and that the values of different rewards were encoded by distinct neuronal subpopulations. Moreover, reward representations rapidly re-scaled when mice were exposed to a reward that was larger than all previous rewards. Finally, value representations depended on an animals internal state as thirst selectively increased the responses to water rewards whereas aversive experiences strongly attenuated responses to sucrose. Our findings demonstrate that value representations in the BLA are stimulus-specific and highly adaptive to account for changes in relative reward value and to reflect an animals current affective and homeostatic state. This mechanism enables sensory-specific value updates necessary for state-adapted decision making and learning.

neuroscience↗

Locus coeruleus activity fluctuations set a non-reducible timeframe for mammalian NREM-REM sleep cycles

The noradrenergic locus coeruleus (LC) is vital for brain states underlying wakefulness, whereas its roles for sleep remain uncertain. Combining mouse sleep-wake monitoring, behavioral manipulations, LC fiber photometry and closed-loop optogenetics, we found that LC neuronal activity partitioned non-rapid-eye-movement sleep (NREMS) into alternating brain and autonomic states that rule the NREMS-REMS cycle. High LC activity levels generated an autonomic-subcortical arousal state that facilitated cortical microarousals, while low levels were obligatory for REMS entries. Timed optogenetic LC inhibition revealed that this functional alternation set the duration of the NREMS-REMS cycle by ruling REMS entries during undisturbed sleep and when pressure for REMS was high. A stimulus-enriched, stress-promoting wakefulness increased high LC activity levels at the expense of low ones in subsequent NREMS, fragmenting NREMS through microarousals and delaying REMS onset. We conclude that LC activity fluctuations gatekeep the NREM-REMS cycle over recurrent infraslow intervals, but they also convey vulnerability to adverse wake experiences.

neuroscience↗

Autophagy in parvalbumin interneurons is required for inhibitory transmission and memory via regulation of synaptic proteostasis

With the emerging role of the autophagic machinery in healthy brain development and aging, there is a pressing need to better characterize its functions in different neuronal populations, providing cellular insight into autophagy-related brain diseases. Here, we generated and characterized mice with conditional ablation of atg5 in GABAergic neurons expressing parvalbumin (PV-atg5KO), mostly comprising fast-spiking interneurons, as well as Purkinje cells in the cerebellum. Using light-sheet microscopy to image PV neurons throughout the brain, we reveal that autophagy is required for the sustenance of Purkinje cells but not of PV-interneurons. Yet, proteomic analysis showed that autophagy deficiency in cortical and hippocampal PV-interneurons alters the proteostasis of key synaptic proteins, as well as the surface expression of glutamate receptor subunits. Consistently, hippocampal autophagy-deficient PV-interneurons exhibit reduced inhibitory neurotransmission and PV-atg5KO mice display excitation-inhibition imbalance in the hippocampus and memory deficits. Our findings demonstrate a neuronal type-specific vulnerability to autophagy deficiency, while also identifying PV-interneurons as cellular substrates where autophagy is required for memory.

neuroscience↗

Region Selective Cortical Control Of The Thalamic Reticular Nucleus

Corticothalamic pathways, responsible for the top-down control of the thalamus display a classical, canonical organization in that every cortical region sends dual, layer 6 (L6) and layer 5 (L5) output to the thalamus. Here we demonstrate a qualitative, region-specific difference in the organization of corticothalamic pathways. We show that L5 pyramidal cells of the frontal, but not other cortical regions establish monosynaptic connection with the inhibitory thalamic reticular nucleus (TRN). The frontal L5-TRN pathway paralleled the L6-TRN projection but displayed distinct morphological and physiological features. The exact spike output of the L5 contacted TRN cells correlated with the level of cortical synchrony. Optogenetic perturbation of the L5-TRN connection disrupted the tight link between cortical and TRN activity. L5-driven TRN cells innervated all thalamic nuclei involved in the control of frontal cortical activity. Our data show that frontal cortical functions require a highly specialized cortical control over intrathalamic inhibitory processes.

neuroscience↗

Infraslow locus coeruleus activity coordinates spindle rhythms and heart rate to gate fluctuating non-REM sleep substates

One promising approach towards understanding what makes sleep vulnerable in disease is to look at how wake-promoting mechanisms affect healthy sleep. Wake-promoting neuronal activity is inhibited during non-REM sleep (NREMS). However, many mammalian species, including humans, show recurrent moments of sleep fragility during which sensory reactivity is elevated. Wake-related neuronal activity could thus remain active in NREMS, but its roles in dynamic variations of sensory reactivity remain unknown. Here, we demonstrate that mouse NREMS is a brain state with recurrent fluctuations of the wake-promoting neurotransmitter noradrenaline on the [~]50-seconds time-scale. These fluctuations occurred around mean noradrenaline levels greater than the ones of quiet wakefulness, while they declined steeply in REMS. They coincided with a clustering of sleep spindle rhythms in the forebrain and with heart rate variations. We addressed the origins of these fluctuations by using closed-loop optogenetic locus coeruleus (LC) activation or inhibition timed to moments of low and high spindle activity during NREMS. We could suppress, lock or entrain sleep spindle clustering or heart rate variations, demonstrating that both fore- and hindbrain-projecting LC neurons show synchronized infraslow activity variations in natural NREMS. Noradrenergic modulation of thalamic but not cortical circuits was required for sleep spindle clustering and involved noradrenaline release into primary sensory and reticular thalamic nuclei that activated both 1- and {beta}-adrenergic receptors to cause slowly decaying membrane depolarizations. Noradrenergic signaling by LC, primarily known for attention promotion in wakefulness, renders mammalian NREMS more wake-like on the close-to-minute-time scale through sustaining thalamocortical and autonomic sensory arousability.

neuroscience↗

Optogenetic silencing of neurotransmitter release with a naturally occurring invertebrate rhodopsin

Information is carried between brain regions through neurotransmitter release from axonal presynaptic terminals. Understanding the functional roles of defined neuronal projection pathways in cognitive and behavioral processes requires temporally precise manipulation of their activity in vivo. However, existing optogenetic tools have low efficacy and off-target effects when applied to presynaptic terminals, while chemogenetic tools are difficult to control in space and time. Here, we show that a targeting-enhanced mosquito homologue of the vertebrate encephalopsin (eOPN3) can effectively suppress synaptic transmission through the Gi/o signaling pathway. Brief illumination of presynaptic terminals expressing eOPN3 triggers a lasting suppression of synaptic output that recovers spontaneously within minutes in vitro as well as in vivo. In freely moving mice, eOPN3-mediated suppression of dopaminergic nigrostriatal afferents leads to an ipsiversive rotational bias. We conclude that eOPN3 can be used to selectively suppress neurotransmitter release at synaptic terminals with high spatiotemporal precision, opening new avenues for functional interrogation of long-range neuronal circuits in vivo.

neuroscience↗

Potassium channels, megapolarization, and water pore formation are key determinants for cationic cell-penetrating peptide translocation into cells

Cell-penetrating peptides (CPPs) allow intracellular delivery of cargo molecules. They provide efficient methodology to transfer bioactive molecules in cells, in particular in conditions when transcription or translation of cargo-encoding sequences is not desirable or achievable. The mechanisms allowing CPPs to enter cells are ill-defined. Using a CRISPR/Cas9-based screening, we discovered that KCNQ5, KCNN4, and KCNK5 potassium channels positively modulate cationic CPP direct translocation into cells by decreasing the transmembrane potential (Vm). These findings provide the first unbiased genetic validation of the role of Vm in CPP translocation in cells. In silico modeling and live cell experiments indicate that CPPs, by bringing positive charges on the outer surface of the plasma membrane, decrease the Vm to very low values (-150 mV or less), a situation we have coined megapolarization that then triggers formation of water pores used by CPPs to enter cells. Megapolarization lowers the free energy barrier associated with CPP membrane translocation. Using dyes of varying sizes, we assessed the diameter of the water pores in living cells and found that they readily accommodated the passage of 2 nm-wide molecules, in accordance with the structural characteristics of the pores predicted by in silico modeling. Pharmacological manipulation to lower transmembrane potential boosted CPPs cellular internalization in zebrafish and mouse models. Besides identifying the first proteins that regulate CPP translocation, this work characterized key mechanistic steps used by CPPs to cross cellular membrane. This opens the ground for strategies aimed at improving the ability of cells to capture CPP-linked cargos in vitro and in vivo.

cell biology↗

A thalamic reticular circuit for head direction cell tuning and spatial navigation

To navigate in space, an animal must refer to sensory cues to orient and move. Circuit and synaptic mechanisms that integrate cues with internal head-direction (HD) signals remain, however, unclear. We identify an excitatory synaptic projection from the presubiculum (PreS) and the multisensory-associative retrosplenial cortex (RSC) to the anterodorsal thalamic reticular nucleus (TRN), so far classically implied in gating sensory information flow. In vitro, projections to TRN involved AMPA/NMDA-type glutamate receptors that initiated TRN cell burst discharge and feedforward inhibition of anterior thalamic nuclei. In vivo, chemogenetic anterodorsal TRN inhibition modulated PreS/RSC-induced anterior thalamic firing dynamics, broadened the tuning of thalamic HD cells, and led to preferential use of allo-over egocentric search strategies in the Morris water maze. TRN-dependent thalamic inhibition is thus an integral part of limbic navigational circuits wherein it coordinates external sensory and internal HD signals to regulate the choice of search strategies during spatial navigation.

neuroscience↗

Adaptive disinhibitory gating by VIP interneurons permits associative learning

Learning drives behavioral adaptations necessary for survival. While plasticity of excitatory projection neurons during associative learning is studied extensively, little is known about the contributions of local interneurons. Using fear conditioning as a model for associative learning, we find that behaviorally relevant, salient stimuli cause learning by tapping into a local microcircuit consisting of precisely connected subtypes of inhibitory interneurons. By employing calcium imaging and optogenetics, we demonstrate that vasoactive intestinal peptide (VIP)-expressing interneurons in the basolateral amygdala are activated by aversive events and provide an instructive disinhibitory signal for associative learning. Notably, VIP interneuron responses are plastic and shift from the instructive to the predictive cue upon memory formation. We describe a novel form of adaptive disinhibitory gating by VIP interneurons that allows to discriminate unexpected, important from irrelevant information, and might be a general dynamic circuit motif to trigger stimulus-specific learning, thereby ensuring appropriate behavioral adaptations to salient events.

neuroscience↗