Biology subjects

Tripodi, M.

Publications and source records attributed to Tripodi, M..

9 recordsLinked to original sources

bioRxiv2026

A collicular somatostatinergic circuit gates sensory access to action

Animals are exposed to far more sensory information than can be converted into action and must prioritise behaviourally salient events. Although salience is commonly studied as modulation of sensory representations, stimulus prioritisation may also arise at premotor stages, through mechanisms that regulate the readiness of action-generating circuits to be recruited by sensory input. The superior colliculus links visual signals to spatially directed orienting and contains Pitx2-expressing spatial-motor modules that coordinate spatially targeted actions, providing a substrate for premotor regulation of sensory access to action. However, the circuit elements that regulate this access remain unknown. Here we identify an intersectionally targeted population of somatostatin-expressing inhibitory neurons in the mouse superior colliculus that is, at the population level, suppressed during orienting movements and visual stimulation. These neurons provide input to Pitx2-expressing spatial-motor modules, and their optogenetic silencing increased retinally evoked firing in Pitx2 neurons, showing that somatostatinergic inhibition constrains the visual recruitment of collicular motor output. Increasing somatostatinergic tone reduced interception of low- and intermediate-contrast visual targets while sparing responses to high-contrast targets, consistent with graded control of sensory access to action. Cholecystokinin-expressing inhibitory neurons and multiple cortical and subcortical regions provide anatomical input to the somatostatinergic population, identifying candidate routes for local and context-dependent regulation. Together, these findings establish somatostatinergic inhibition as a premotor control point that regulates the readiness of spatial-motor circuits for sensory recruitment and identify a circuit architecture through which the behavioural impact of salient sensory events could be regulated downstream of sensory encoding.

neuroscience↗

bioRxiv2026

Reward expectation signals in the superior colliculus during associative learning

Predicting future rewards allows neutral sensory cues to acquire motivational significance and guide goal-directed actions that maximise reward acquisition. These reward predictions are updated when outcomes differ from expectations resulting in an error in prediction. Midbrain dopamine neurons provide a canonical neural correlate of reward prediction error signal that are broadcast to multiple brain areas. These learned reward predictions ultimately influence neural processes that enable animals to select, prepare and execute actions towards expected rewards. Reward expectation signals have been observed across sensory and motor circuits where they can modulate sensory processing and action selection and vigor. This raises the question of how integrative sensorimotor circuits represent information about reward expectation alongside sensory and motor variables that drive reward-seeking actions. The superior colliculus (SC), a sensorimotor area in the midbrain traditionally associated with orienting and action selection, is strongly influenced by reward context. Expected reward modulates visual and premotor activity, learned object values shape sensory responses, and recent reward alters visual processing in the mouse SC. The SC also provides input to midbrain dopamine neurons and can relay or acquire conditioned sensory responses that influence dopaminergic activity. However, SC projections can also drive orienting movements without supporting reinforcement, raising the possibility that cue-related activity reflects salience or motor preparation rather than reward prediction itself. Here, using an associative-learning task in which auditory cues predicted distinct reward probabilities, together with longitudinal monitoring of intermediate SC population activity across learning, we asked whether the SC acquires signals related to reward probability, whether these signals can be dissociated from anticipatory licking, and whether outcome responses exhibit the hallmarks of reward-prediction errors. We found that cue-evoked SC activity progressively differentiated reward probabilities across learning, and that cue-associated reward probability explained neural activity beyond anticipatory licking. Thus, the intermediate SC carries a learned reward-expectation signal that is multiplexed with, but not reducible to, motor preparation. By contrast, outcome responses did not exhibit a consistent population-level signature of reward-prediction errors. Together, these findings identify the SC as a site where predicted reward is integrated with anticipatory action during associative learning.

neuroscience↗

bioRxiv2025

Absence of Local Retinotopy in the Mouse Optic Tract

Retinotopy is a fundamental organizational principle of the visual system, where neighboring neurons represent adjacent points in visual space. This spatial relationship is established by precise anatomical wiring across successive areas, e.g., from the retina to the lateral geniculate nucleus (LGN) to the visual cortex. To examine the precision of this topographic arrangement within the long-range projection axons themselves, we recorded retinal ganglion cell (RGC) axons in the mouse optic tract (OT) and mapped their receptive fields (RFs). As expected for a retinotopically organized area, we found that nearby LGN cell pairs had significantly smaller RF distances than distant pairs. In contrast, no such relationship was observed among RGC axons in the OT. Modelling analyses further confirmed that the observed RF distances in the OT were incompatible with any locally retinotopic arrangement. Instead, the OT retained only coarse topography, with [~]18{degrees} RF deviations or [~]40 {micro}m axonal displacements from an ideal retinotopic organization. These results demonstrate that the mouse OT lacks fine-scale retinotopy and maintains only broad topographic structure.

neuroscience↗

bioRxiv2024

Negative regulation of miRNAs sorting in EVs: the RNA-binding protein PCBP2 impairs SYNCRIP-mediated miRNAs EVs loading

While it is accepted that Extracellular Vesicles (EVs)-mediated transfer of microRNAs contributes to intercellular communication, the knowledge about molecular mechanisms controlling the selective and dynamic miRNA-loading in EVs is still limited to few specific RNA-binding proteins interacting with sequence determinants. Moreover, although mutagenesis analysis demonstrated the presence/function of specific intracellular retention motifs, the interacting protein/s remained unknown. Here, PCBP2 was identified as a direct interactor of an intracellular retention motif: CLIP coupled to RNA pull down and proteomic analysis demonstrated that it binds to miRNAs embedding this motif and mutagenesis proved the binding specificity. Notably, PCBP2 binding requires SYNCRIP, a previously characterized miRNA EV-loader as indicated by SYNCRIP knock-down. SYNCRIP and PCBP2 may contemporarily bind to miRNAs as demonstrated by EMSA assays and PCBP2 knock-down causes EV-loading of intracellular microRNAs. This evidence highlights that multiple proteins/miRNA interactions govern miRNA compartmentalization and identifies PCBP2 as a dominant inhibitor of SYNCRIP function.

molecular biology↗

bioRxiv2024

Histamine interferes with the early visual processing in mice

Sensory processing is dynamically modulated by an animals behavior and internal states. Growing evidence suggests that such modulation starts from early stages, already at the retina, but the underlying mechanisms remain elusive. Combining pharmacological and chemogenetic tools with single-unit extracellular recordings in awake head-fixed mice, here we identified that the visual responses of retinal ganglion cells and the lateral geniculate nucleus were both made weaker and slower by histaminergic projections from the tuberomammillary nucleus of the posterior hypothalamus. The observed changes in the visual responses were, however, not directly linked with histaminergic modulation of pupil dynamics or locomotion behavior. Instead, our computational modelling analysis suggests that the temporal response modulations arise from changes in the intrinsic properties of the circuit, such as gain modulation via the histamine H1 receptors in the retina. Facilitation of visual processing at low histamine levels may offer an ethological advantage, enabling animals to respond rapidly to visual threats during periods of reduced activity.

neuroscience↗

bioRxiv2022

Awake responses suggest inefficient dense coding in the mouse retina

The structure and function of the vertebrate retina have been extensively studied across species with an isolated, ex vivo preparation. Retinal function in vivo, however, remains elusive, especially in awake animals. Here we performed single-unit extracellular recordings in the optic tract of head-fixed mice to compare the output of awake, anesthetized, and ex vivo retinas. While the visual response properties were overall similar across conditions, we found that awake retinal output had in general 1) faster kinetics with less variability in the response latencies; 2) a larger dynamic range; and 3) higher firing activity, by [~]20 Hz on average, for both baseline and visually evoked responses. Our modeling analyses further showed that such awake response patterns convey comparable total information but less efficiently, and allow for a linear population decoder to perform significantly better than the anesthetized or ex vivo responses. These results highlight distinct retinal behavior in awake states, in particular suggesting that the retina employs dense coding in vivo, rather than sparse efficient coding as has been often assumed from ex vivo studies.

neuroscience↗

bioRxiv2021

Relaxin/insulin-like family peptide receptor 4 (Rxfp4) expressing hypothalamic neurons modulate food intake and preference in mice

Relaxin/insulin-like-family peptide receptor-4 (RXFP4), the cognate receptor for insulin-like peptide 5 (INSL5), has been implicated in feeding behaviour as Rxfp4 knockout mice display shorter meal durations and reduced high fat diet (HFD) intake. Here, we generated transgenic Rxfp4-Cre mice to explore Rxfp4 expression and physiology. Using this model, we identified Rxfp4 expression in the central nervous system, including in the ventromedial hypothalamus (VMH). Intra-VMH infusion of INSL5 increased HFD and highly palatable liquid meal intake (HPM) of ad libitum fed wildtype mice. Single-cell RNA-sequencing of VMH Rxfp4-expressing cells (RXFP4VMH) defined a cluster of Rxfp4-labelled neurons expressing Esr1, Tac1 and Oxtr, alongside known appetite-modulating neuropeptide receptors (Mc4r, Cckar and Nmur2). Viral tracing demonstrated RXFP4VMH neural projections to the bed nucleus of the stria terminalis, paraventricular hypothalamus, paraventricular thalamus and central nucleus of the amygdala. Utilising designer receptors exclusively activated by designer drugs (DREADDs), we found that whole body chemogenetic inhibition (Di) of Rxfp4-expressing cells, mimicking native INSL5-RXFP4 signalling, increased intake of HFD and HPM, whilst activation (Dq), either at whole body level or specifically within the VMH, reduced HFD and HPM intake and altered food preference. Ablating VMH Rxfp4-expressing cells recapitulated the lower HFD intake phenotype of Rxfp4 knockout mice, resulting in reduced body weight. These findings identify a discrete Rxfp4-expressing neuronal population as a key regulator of food intake and preference and reveal hypothalamic RXFP4 signalling as a target for feeding behaviour manipulation.

physiology↗

bioRxiv2020

Genomic stability of Self-inactivating Rabies

Transsynaptic viral vectors provide means to gain genetic access to neurons based on synaptic connectivity and are essential tools for the dissection of neural circuit function. Among them, the retrograde monosynaptic {Delta}G-Rabies has been widely used in neuroscience research. A recently developed engineered version of the {Delta}G-Rabies, the non-toxic self-inactivating (SiR) virus, represents the first tool for open-ended genetic manipulation of neural circuits. However, the high mutational rate of the rabies virus poses a risk that mutations targeting the key genetic regulatory element in the SiR genome could emerge and revert it to a canonical {Delta}G-Rabies. Such revertant mutations have recently been identified in a SiR batch. To address the origin, incidence and relevance of these mutations, we investigated the genomic stability of SiR in vitro and in vivo. We found that "revertant" mutations are rare and accumulate only when SiR is extensively amplified in vitro, particularly in suboptimal production cell lines that have insufficient levels of TEV protease activity. Moreover, we confirmed that SiR-CRE, unlike canonical {Delta}G-Rab-CRE or revertant-SiR-CRE, is non-toxic and that revertant mutations do not emerge in vivo during long-term experiments. HighlightsO_LIRevertant mutations are rare and do not accumulate when SiR is produced in high-TEVp expressing production cell lines C_LIO_LISiR is non-toxic in vivo C_LIO_LIRevertant SiR mutations do not accumulate during in vivo experiments C_LI

neuroscience↗

bioRxiv2018

Cerebral organoids at the air-liquid interface generate diverse nerve tracts with functional output

Three-dimensional neural organoids are emerging tools with the potential for improving our understanding of human brain development and neurological disorders. Recent advances in this field have demonstrated their capacity to model neurogenesis1,2, neuronal migration and positioning3,4, and even response to sensory input5. However, it remains to be seen whether these tissues can model axon guidance dynamics and the formation of complex connectivity with functional neuronal output. Here, we have established a longterm air-liquid interface culture paradigm that leads to improved neuronal survival and allows for imaging of axon guidance. Over time, these cultures spontaneously form thick axon tracts capable of projecting over long distances. Axon bundles display various morphological behaviors including intracortical projection within and across the organoid, growth cone turning, decussation, and projection away from the organoid. Single-cell RNA-sequencing reveals the full repertoire of cortical neuronal identities, and retrograde labelling demonstrates these tract morphologies match the appropriate molecular identities, namely callosal and corticofugal neuron types. We show that these neurons are functionally mature, generate active networks within the organoid, and that extracortical projecting tracts innervate and activate mouse spinal cord-muscle explants. Muscle contractions can be evoked by stimulation of the organoid, while axotomy of the innervating tracts abolishes the muscle contraction response, demonstrating dependence on connection with the organoid. Overall, these results reveal a remarkable selforganization of corticofugal and callosal tracts with a functional output, providing new opportunities to examine relevant aspects of human CNS development and response to injury.

neuroscience↗