The mechanism of differential signaling of multiple FGF ligands through a single FGF receptor is poorly understood. Here, we use biophysical tools to quantify multiple aspects of FGFR1 signaling in response to FGF4, FGF8 and FGF9: potency, efficacy, bias, ligand-induced oligomerization and downregulation, and conformation of the active FGFR1 dimers. We find that the three ligands exhibit distinctly different potencies and efficacies for inducing responses in cells. We further discover qualitative differences in the actions of the three FGFs through FGFR1, as FGF8 preferentially activates some of the probed downstream responses (FRS2 phosphorylation and extracellular matrix loss), while FGF4 and FGF9 preferentially activate different probed responses (FGFR1 phosphorylation and cell growth arrest). Thus, FGF8 is a biased ligand, when compared to FGF4 and FGF9. Förster resonance energy transfer experiments reveal a correlation between biased signaling and the conformation of the FGFR1 tra

Almost all early cognitive development takes place in social contexts. At the moment, however, we know little about the neural and cognitive mechanisms that drive infant attention during social interactions. Recording EEG during naturalistic caregiver-infant interactions (N=66), we compare two different accounts. Attentional scaffolding perspectives emphasise the role of the caregiver in structuring the child’s behaviour, whilst active learning models focus on motivational factors, endogenous to the infant, that guide their attention. Our results show that, already by 12-months, intrinsic cognitive processes control infants’ attention: fluctuations in endogenous oscillatory neural activity associated with changes in infant attentiveness, and predicted the length of infant attention episodes towards objects. In comparison, infant attention was not forwards-predicted by caregiver gaze, or modulations in the spectral and temporal properties of their caregiver’s speech. Instead, caregivers

This study explores the relationship between the anatomy of the auditory cortex and multilingual experience, shedding light on the complex mechanisms of auditory processing in humans. Integrating previous research on auditory information processing and the impact of bi- and multilingualism on brain structure, we investigate how the morphology of auditory brain regions reflects individuals’ language experience and, more specifically, their phonological repertoire. Leveraging two distinct samples comprising over 200 participants, each exposed to between 1 and 7 languages encompassing 36 different languages, we explore whether the morphological variability of auditory brain regions reflects individual language experience, specifically focusing on the phonological repertoire. Additionally, we examine the potential influence of typological distances between languages spoken by multilingual individuals on the neural signatures of multilingualism within the auditory cortex. Our findings revea

Absence seizures are characterized by regular and generalized spike-and-wave electrical patterns in the brain, resulting in unresponsiveness to environmental stimuli. In patients suffering absence epilepsy, recurring seizures can significantly decrease their quality of life and lead to yet untreatable comorbidities. The mechanism underlying the reduced responsiveness to external stimulus remains unknown. This study aimed to investigate whole-brain responsiveness to visual and somatosensory whisker stimulation in GAERS, a well-established rat model for absence epilepsy. Animals were imaged continuously using a quiet zero-echo-time functional magnetic resonance imaging (fMRI) sequence while in a non-curarized awake state, allowing for naturally occurring seizures to be produced inside the 9.4T magnet. Sensory stimulations were applied in 28 fMRI sessions during interictal and ictal periods, as assessed by concurrent EEG recordings, and whole brain responsiveness and hemodynamic responses

The SNARE proteins are central in membrane fusion and, at the synapse, neurotransmitter release. However, their involvement in the dual regulation of the synchronous release while maintaining a pool of readily releasable vesicles remains unclear. Using a chimeric approach, we performed a systematic analysis of the SNARE domain of STX1A by exchanging the whole SNARE domain or its N- or C-terminus subdomains with those of STX2. We expressed these chimeric constructs in STX1-null hippocampal mouse neurons. Exchanging the C-terminal half of STX1’s SNARE domain with that of STX2 resulted in a reduced RRP accompanied by an increased release rate, while inserting the C-terminal half of STX1’s SNARE domain into STX2 lead to an enhanced priming and decreased release rate. Additionally, we found that the mechanisms for clamping spontaneous, but not for Ca2+- evoked release, are particularly susceptible to changes in specific residues on the outer surface of the C-terminus of the SNARE domain of

The prevailing hierarchical view of the visual system consists of parallel circuits that begin in the retina, which then sum effects across sequential levels, increasing in complexity. Yet a separate type of interaction, whereby one visual pattern changes the influence of another, known as modulation, has received much less attention in terms of its circuit mechanisms. Retinal amacrine cells are a diverse class of inhibitory interneurons that are thought to have modulatory effects, but we lack a general understanding of their functional types. Using dynamic causal experiments in the salamander retina perturbing amacrine cells along with an unsupervised computational framework, we find that amacrine cell modulatory effects cluster into two distinct types. One type controls ganglion cell sensitivity to individual visual features, and a second type controls the ganglion cell’s output gain, acting to gate all features. These results establish three separate general roles of amacrine cells

When the eyes view separate and incompatible images, the brain suppresses one image and promotes the other into visual awareness. Periods of interocular suppression can be prolonged during continuous flash suppression (CFS) – when one eye views a static ‘target’ while the other views a complex dynamic stimulus. Measuring the time needed for a suppressed image to break CFS (bCFS) has been widely used to investigate unconscious processing, and the results have generated controversy regarding the scope of visual processing without awareness. Here, we address this controversy with a new ‘CFS tracking’ paradigm (tCFS) in which the suppressed monocular target steadily increases in contrast until breaking into awareness (as in bCFS) after which it decreases until it again disappears (reCFS), with this cycle continuing for many reversals. Unlike bCFS, tCFS provides a measure of suppression depth by quantifying the difference between breakthrough and suppression thresholds. tCFS confirms that:

The unexpected absence of danger constitutes a pleasurable event that is critical for the learning of safety. Accumulating evidence points to similarities between the processing of absent threat and the well-established reward prediction error (PE). However, clear-cut evidence for this analogy in humans is scarce. In line with recent animal data, we showed that the unexpected omission of (painful) electrical stimulation triggers reward-like activations within key regions of the canonical reward pathway and that these activations correlate with the pleasantness of the reported relief. Furthermore, by parametrically violating participants’ probability and intensity related expectations of the upcoming stimulation, we showed for the first time in humans that omission-related activations in the VTA/SN were stronger following omissions of more probable and intense stimulations, like a positive reward PE signal. Together, our findings provide additional support for an overlap in the neural p

Dopamine and orexins (hypocretins) play important roles in regulating reward-seeking behaviors. It is known that hypothalamic orexinergic neurons project to dopamine neurons in the ventral tegmental area (VTA), where they can stimulate dopaminergic neuronal activity. Although there are reciprocal connections between dopaminergic and orexinergic systems, whether and how dopamine regulates the activity of orexin neurons is currently not known. Here we implemented an opto-Pavlovian task in which mice learn to associate a sensory cue with optogenetic dopamine neuron stimulation to investigate the relationship between dopamine release and orexin neuron activity in the LH. We found that dopamine release can be evoked in LH upon optogenetic stimulation of VTA dopamine neurons, and is also naturally evoked by cue presentation after opto-Pavlovian learning. Furthermore, orexin neuron activity could also be upregulated by local stimulation of dopaminergic terminals in the LH in a way that is par

Targeting deep brain structures during electrophysiology and injections requires intensive training and expertise. Even with experience, researchers often can’t be certain that a probe is placed precisely in a target location and this complexity scales with the number of simultaneous probes used in an experiment. Here, we present Pinpoint , open-source software that allows for interactive exploration of stereotaxic insertion plans. Once an insertion plan is created, Pinpoint allows users to save these online and share them with collaborators. 3D modeling tools allow users to explore their insertions alongside rig and implant hardware and ensure plans are physically possible. Probes in Pinpoint can be linked to electronic micro-manipulators allowing real-time visualization of current brain region targets alongside neural data. In addition, Pinpoint can control manipulators to automate and parallelize the insertion process. Compared to previously available software, Pinpoint’s easy acces