bioRxiv Subject Collection: Neuroscience's Journal

Medial prefrontal dopamine dynamics reflect allocation of selective attention
The mesocortical dopamine system is comprised of midbrain dopamine neurons that predominantly innervate the medial prefrontal cortex (mPFC) and exert a powerful neuromodulatory influence over this region1,2. mPFC dopamine activity is thought to be critical for fundamental neurobiological processes including valence coding and decision-making3,4. Despite enduring interest in this pathway, the stimuli and conditions that engage mPFC dopamine release have remained enigmatic due to inherent limitations in conventional methods for dopamine monitoring which have prevented real-time in vivo observation5. Here, using a fluorescent dopamine sensor enabling time-resolved recordings of cortical dopamine activity in freely behaving mice, we reveal the coding properties of this system and demonstrate that mPFC dopamine dynamics conform to a selective attention signal. Contrary to the long-standing theory that mPFC dopamine release preferentially encodes aversive and stressful events6-8, we observed robust dopamine responses to both appetitive and aversive stimuli which dissipated with increasing familiarity irrespective of stimulus intensity. We found that mPFC dopamine does not evolve as a function of learning but displays striking temporal precedence with second-to-second changes in behavioral engagement, suggesting a role in allocation of attentional resources. Systematic manipulation of attentional demand revealed that quieting of mPFC dopamine signals the allocation of attentional resources towards an expected event which, upon detection triggers a sharp dopamine transient marking the transition from decision-making to action. The proposed role of mPFC dopamine as a selective attention signal is the first model based on direct observation of time-resolved dopamine dynamics and reconciles decades of competing theories.

Loss of Esr1 Does Not Affect Hearing and Balance
Although estrogen affects the structure and function of the nervous system and brain and has a number of effects on cognition, its roles in the auditory and vestibular systems remain unclear. The actions of estrogen are mediated predominately through two classical nuclear estrogen receptors, estrogen receptor 1 (ESR1) and estrogen receptor 2 (ESR2). In the current study, we investigated the roles of ESR1 in normal auditory function and balance performance using 3-month-old wild-type (WT) and Esr1 knockout (KO) mice on a CBA/CaJ background, a normal-hearing strain. As expected, body weight of Esr1 KO females was lower than that of Esr1 KO males. Body weight of Esr1 KO females was higher than that of WT females, while there was no difference in body weight between WT and Esr1 KO males. Similarly, head diameter was higher in Esr1 KO vs. WT females. Contrary to our expectations, there were no differences in auditory brainstem response (ABR) thresholds, ABR waves I-V amplitudes and ABR waves I-V latencies at 8, 16, 32, and 48 kHz, distortion product otoacoustic emission (DPOAE) thresholds and amplitudes at 8, 16, and 32 kHz, and rotarod balance performance (latency to fall) between WT and Esr1 KO mice. Furthermore, there were no sex differences in ABRs, DPOAEs, and rotarod balance performance in Esr1 KO mice. Taken together, our findings show that Esr1 deficiency does not affect auditory function or balance performance in normal hearing mice, and suggest that loss of Esr1 is likely compensated by ESR2 or other estrogen receptors to maintain the structure and function of the auditory and vestibular systems under normal physiological conditions.

Feature-independent Encoding of Visual Salience inthe Mouse Superior Colliculus
Detecting conspicuous stimuli in a visual scene is crucial for animal survival, yet it remains debated how the brain encodes visual salience. Here we investigate how visual salience is represented in the superficial superior collicular (sSC) of awake mice using two-photon calcium imaging. We report on a feature-independent salience map in the sSC. Specifically, conspicuous stimuli evoke stronger responses in both excitatory and inhibitory neurons compared to uniform stimuli, with similar encoding patterns observed in both neuron types. The largest response occurs when a salient stimulus is positioned at the receptive field center, with contextual effects extending about 40 degrees away from the center. The response amplitude correlates well with the salience strength of stimuli and is not influenced by the orientation or motion direction preferences of neurons. Furthermore, visual salience is encoded in a feature-independent manner, and neurons involved in salience encoding are less likely to exhibit orientation or direction selectivity.

Distinct prelimbic cortex neuronal responses to emotional states of others drive emotion recognition in adult male mice
The ability to perceive the emotional states of others, termed emotion recognition, allows individuals to adapt their conduct to the social environment. The brain mechanisms underlying this capacity, known to be impaired in individuals with autism spectrum disorder (ASD), remain, however, elusive. Using the emotional state preference paradigm, we show that adult mice can discern emotional states of conspecifics in a sex-specific manner, behavior impaired in an ASD mouse model. Fiber photometry revealed inhibition of pyramidal neurons in the prelimbic medial prefrontal cortex (PrL) during investigation of aroused individuals, as opposed to transient excitation towards non-aroused conspecifics. Augmenting this differential neuronal response enhanced emotion recognition, while abolishing this response eliminated such behavior, as demonstrated via optogenetic stimulation. Chronic electrophysiological recordings at the single-cell level indicated social stimulus-specific responses in PrL neurons at the onset and conclusion of social investigation bouts, potentially regulating the initiation and termination of social interactions. The dysregulated activity of these neurons may thus contribute to deficits in social behavior observed in ASD.

Lateral olivocochlear neurons modulate cochlear responses to noise exposure
The sense of hearing originates in the cochlea, which detects sounds across dynamic sensory environments. Like other peripheral organs, the cochlea is subjected to environmental insults, including loud, damage-inducing sounds. In response to internal and external stimuli, the central nervous system directly modulates cochlear function through olivocochlear neurons (OCNs), which are located in the brainstem and innervate the cochlear sensory epithelium. One population of OCNs, the lateral olivocochlear (LOC) neurons, target spiral ganglion neurons (SGNs), the primary sensory neurons of the ear. LOCs alter their transmitter expression for days to weeks in response to noise exposure (NE), suggesting that they are well-positioned to tune SGN excitability over long time periods in response to auditory experience. To examine how LOCs affect auditory function after NE, we characterized the transcriptional profiles of OCNs and found that LOCs exhibit transient changes in gene expression after NE, including upregulation of multiple neuropeptide-encoding genes. Next, by generating intersectional mouse lines that selectively target LOCs, we chemogenetically ablated LOC neurons and assayed auditory responses at baseline and after NE. Compared to controls, mice lacking LOCs showed stronger NE-induced functional deficits one day later and had worse auditory function after a two-week recovery period. The number of remaining presynaptic puncta at the SGN synapse with inner hair cells did not differ between control and LOC-ablated animals, suggesting that the primary role of LOCs after NE is likely not one of protection, but one of compensation, ensuring that SGN function is enhanced during periods of need.

Task interference as a neuronal basis for the cost of cognitive flexibility
Humans and animals have an impressive ability to juggle multiple tasks in a constantly changing environment. This flexibility, however, leads to decreased performance under uncertain task conditions. Here, we combined monkey electrophysiology, human psychophysics, and artificial neural network modeling to investigate the neuronal mechanisms of this performance cost. We developed a behavioural paradigm to measure and influence participants' decision-making and perception in two distinct perceptual tasks. Our data revealed that both humans and monkeys, unlike an artificial neural network trained for the same tasks, make less accurate perceptual decisions when the task is uncertain. We generated a mechanistic hypothesis by comparing this neural network trained to produce correct choices with another network trained to replicate the participants' choices. We hypothesized, and confirmed with further behavioural, physiological, and causal experiments, that the cost of task flexibility comes from what we term task interference. Under uncertain conditions, interference between different tasks causes errors because it results in a stronger representation of irrelevant task features and entangled neuronal representations of different features. Our results suggest a tantalizing, general hypothesis: that cognitive capacity limitations, both in health and disease, stem from interference between neural representations of different stimuli, tasks, or memories.

Forskolin reverses the O-GlcNAcylation dependent decrease in GABAAR current amplitude at hippocampal synapses possibly at a neurosteroid site on GABAARs.
GABAergic transmission is influenced by post-translational modifications, like phosphorylation, impacting channel conductance, allosteric modulator sensitivity, and membrane trafficking. O-GlcNAcylation is a post-translational modification involving the O-linked attachment of {beta}-N-acetylglucosamine on serine/threonine residues. Previously we reported an acute increase in O-GlcNAcylation elicits a long-term depression of evoked GABAAR inhibitory post synaptic currents (eIPSCs) onto hippocampal principal cells. Importantly O-GlcNAcylation and phosphorylation can co-occur or compete for the same residue; whether they interact in modulating GABAergic IPSCs is unknown. We tested this by recording IPSCs from hippocampal principal cells and pharmacologically increased O-GlcNAcylation, before or after increasing serine phosphorylation using the adenylate cyclase activator, forskolin. Although forskolin had no significant effect on baseline eIPSC amplitude, we found that a prior increase in O-GlcNAcylation unmasks a forskolin-dependent increase in eIPSC amplitude, reversing the O-GlcNAc-induced eIPSC depression. Inhibition of adenylate cyclase or protein kinase A did not prevent the potentiating effect of forskolin, indicating serine phosphorylation is not the mechanism. Surprisingly, increasing O-GlcNAcylation also unmasked a potentiating effect of the neurosteroids 5-pregnane-3,21-diol-20-one (THDOC) and progesterone on eIPSC amplitude, mimicking forskolin. Our findings show under conditions of heightened O-GlcNAcylation, the neurosteroid site on synaptic GABAARs is accessible to agonists, permitting strengthening of synaptic inhibition.

Domain general frontoparietal regions show modality-dependent coding of auditory and visual rules
A defining feature of human cognition is our ability to respond flexibly to what we see and hear, changing how we respond depending on our current goals. In fact, we can rapidly associate almost any input stimulus with any arbitrary behavioural response. This remarkable ability is thought to depend on a frontoparietal 'multiple demand' circuit which is engaged by many types of cognitive demand and widely referred to as domain general. However, it is not clear how responses to multiple input modalities are structured within this system. Domain generality could be achieved by holding information in an abstract form that generalises over input modality, or in a modality-tagged form, which uses similar resources but produces unique codes to represent the information in each modality. We used a stimulus-response task, with conceptually identical rules in two sensory modalities (visual and auditory), to distinguish between these possibilities. Multivariate decoding of functional magnetic resonance imaging data showed that representations of visual and auditory rules recruited overlapping neural resources but were expressed in modality-tagged non-generalisable neural codes. Our data suggest that this frontoparietal system may draw on the same or similar resources to solve multiple tasks, but does not create modality-general representations of task rules, even when those rules are conceptually identical between domains.

MYT1L deficiency impairs excitatory neuron trajectory during cortical development
Mutations that reduce the function of MYT1L, a neuron-specific transcription factor, are associated with a syndromic neurodevelopmental disorder. Furthermore, MYT1L is routinely used as a proneural factor in fibroblast-to-neuron transdifferentiation. MYT1L has been hypothesized to play a role in the trajectory of neuronal specification and subtype specific maturation, but this hypothesis has not been directly tested, nor is it clear which neuron types are most impacted by MYT1L loss. In this study, we profiled 313,335 nuclei from the forebrains of wild-type and MYT1L-deficient mice at two developmental stages: E14 at the peak of neurogenesis and P21, when neurogenesis is complete, to examine the role of MYT1L levels in the trajectory of neuronal development. We found that MYT1L deficiency significantly disrupted the relative proportion of cortical excitatory neurons at E14 and P21. Significant changes in gene expression were largely concentrated in excitatory neurons, suggesting that transcriptional effects of MYT1L deficiency are largely due to disruption of neuronal maturation programs. Most effects on gene expression were cell autonomous and persistent through development. In addition, while MYT1L can both activate and repress gene expression, the repressive effects were most sensitive to haploinsufficiency, and thus more likely mediate MYT1L syndrome. These findings illuminate the intricate role of MYT1L in orchestrating gene expression dynamics during neuronal development, providing insights into the molecular underpinnings of MYT1L syndrome.

Predictive learning shapes the representational geometry of the human brain
Predictive coding theories propose that the brain constantly updates its internal models of the world to minimize prediction errors and optimize sensory processing. However, the neural mechanisms that link the encoding of prediction errors and optimization of sensory representations remain unclear. Here, we provide direct evidence how predictive learning shapes the representational geometry of the human brain. We recorded magnetoencephalography (MEG) in human participants listening to acoustic sequences with different levels of regularity. Representational similarity analysis revealed how, through learning, the brain aligned its representational geometry to match the statistical structure of the sensory inputs, by clustering the representations of temporally contiguous and predictable stimuli. Crucially, we found that in sensory areas the magnitude of the representational shift correlated with the encoding strength of prediction errors. Furthermore, using partial information decomposition we found that, prediction errors were processed by a synergistic network of high-level associative and sensory areas. Importantly, the strength of synergistic encoding of precition errors predicted the magnitude of representational alignment during learning. Our findings provide evidence that large-scale neural interactions engaged in predictive processing modulate the representational content of sensory areas, which may enhance the efficiency of perceptual processing in response to the statistical regularities of the environment.

Electrophysiological correlates of divergent projections in the avian superior olivary nucleus
The physiological diversity of inhibitory neurons provides ample opportunity to influence a wide range of computational roles through their varied activity patterns, especially via feedback loops. In the avian auditory brainstem, inhibition originates primarily from the superior olivary nucleus (SON) and so it is critical to understand the intrinsic physiological properties and processing capabilities of these neurons. Neurons in the SON receive ascending input via the cochlear nuclei: directly from the intensity-coding cochlear nucleus angularis (NA) and indirectly via the interaural timing nucleus laminaris (NL), which itself receives input from cochlear nucleus magnocellularis. Two distinct populations of SON neurons provide either inhibitory feedback to ipsilateral NA, NL, and the timing cochlear nucleus NM, or to the contralateral SON. To determine whether these populations correspond to distinct response types, we investigated their electrophysiology in brain stem slices using patch clamp electrophysiology. We identified three phenotypes: single-spiking, chattering tonic, and regular tonic neurons. The two tonic phenotypes displayed distinct firing patterns and different membrane properties. Additionally, fluctuating noisy currents were used to probe the capability of SON neurons to encode temporal features. Each of the three phenotypes had a distinct level of sensitivity to this temporally modulated input. By using cell fills and anatomical reconstructions, we could correlate the firing phenotypes with their axonal projection patterns. We found that SON axons exited via three fiber tracts with specific phenotypes comprising each tract. Two ipsilateral tracts exit the SON, with the laterally projecting tract composed entirely of regular tonic neurons and medially projecting tract composed of both regular and chattering tonic neurons. The contralateral projection was composed entirely of single spiking neurons. These results provide a basis for understanding the role of specific inhibitory cell types in auditory function and elucidate the organization of the SON outputs.

Temporal attention recruits fronto-cingulate cortex to amplify stimulus representations
The human brain receives a continuous stream of input, but it faces significant constraints in its ability to process every item in a sequence of stimuli. Voluntary temporal attention can alleviate these constraints by using information about upcoming stimulus timing to selectively prioritize a task-relevant item over others in a sequence. But the neural mechanisms underlying this ability remain unclear. Here, we manipulated temporal attention to successive stimuli in a two-target temporal cueing task, while controlling for temporal expectation by using fully predictable stimulus timing. We recorded magnetoencephalography (MEG) in human observers and measured the effects of temporal attention on orientation representations of each stimulus using time-resolved multivariate decoding in both sensor and source space. Voluntary temporal attention enhanced the orientation representation of the first target 235-300 milliseconds after target onset. Unlike previous studies that did not isolate temporal attention from temporal expectation, we found no evidence that temporal attention enhanced early visual evoked responses. Instead, and unexpectedly, the primary source of enhanced decoding for attended stimuli in the critical time window was a contiguous region spanning left frontal cortex and cingulate cortex. The results suggest that voluntary temporal attention recruits cortical regions beyond the ventral stream at an intermediate processing stage to amplify the representation of a target stimulus, which may serve to protect it from subsequent interference by a temporal competitor.

Developmental trajectory of cortical somatostatin interneuron function
GABAergic inhibition is critical to the proper development of neocortical circuits. However, GABAergic interneurons are highly diverse and the developmental roles of distinct inhibitory subpopulations remain largely unclear. Dendrite-targeting, somatostatin-expressing interneurons (SST-INs) in the mature cortex regulate synaptic integration and plasticity in excitatory pyramidal neurons (PNs) and exhibit unique feature selectivity. Relatively little is known about early postnatal SST-IN activity or impact on surrounding local circuits. We examined juvenile SST-INs and PNs in mouse primary visual cortex. PNs exhibited stable visual responses and feature selectivity from eye opening onwards. In contrast, SST-INs developed visual responses and feature selectivity during the third postnatal week in parallel with a rapid increase in excitatory synaptic innervation. SST-INs largely exerted a multiplicative effect on nearby PN visual responses at all ages, but this impact increased over time. Our results identify a developmental window for the emergence of an inhibitory circuit mechanism for normalization.

Human Anterior Insular Cortex Encodes Multiple Electrophysiological Representations of Anxiety-Related Behaviors
Anxiety is a common symptom across psychiatric disorders, but the neurophysiological underpinnings of these symptoms remain unclear. This knowledge gap has prevented the development of circuit-based treatments that can target the neural substrates underlying anxiety. Here, we conducted an electrophysiological mapping study to identify neurophysiological activity associated with self-reported state anxiety in 17 subjects implanted with intracranial electrodes for seizure localization. Participants had baseline anxiety traits ranging from minimal to severe. Subjects volunteered to participate in an anxiety induction task in which they were temporarily exposed to the threat of unpredictable shock during intracranial recordings. We found that anterior insular beta oscillatory activity was selectively elevated during epochs when unpredictable aversive stimuli were being delivered, and this enhancement in insular beta was correlated with increases in self-reported anxiety. Beta oscillatory activity within the frontoinsular region was also evoked selectively by cues-predictive of threat, but not safety cues. Anterior insular gamma responses were less selective than gamma, strongly evoked by aversive stimuli and had weaker responses to salient threat and safety cues. On longer timescales, this gamma signal also correlated with increased skin conductance, a measure of autonomic state. Lastly, we found that direct electrical stimulation of the anterior insular cortex in a subset of subjects elicited self-reported increases in anxiety that were accompanied by enhanced frontoinsular beta oscillations. Together, these findings suggest that electrophysiologic representations of anxiety-related states and behaviors exist within anterior insular cortex. The findings also suggest the potential of reducing anterior insular beta activity as a therapeutic target for refractory anxiety-spectrum disorders.

Endocannabinoid biomarkers of vulnerability to the development of trauma-induced generalized fear responses
Traumatic experiences result in the development of posttraumatic stress disorder (PTSD) in 10-25% of exposed individuals. While human clinical studies suggest that vulnerability is potentially linked to endocannabinoid (eCB) signaling, neurobiological PTSD vulnerability factors are poorly understood. Employing a rat model of PTSD, we characterized distinct resilient and vulnerable subpopulations based on generalized fear, a core symptom of PTSD. Vulnerable subjects showed lower prelimbic and higher ventral hippocampal levels of eCB 2-arachidonoyl-glycerol (2-AG). Ventral hippocampal 2-AG content positively correlated with the strength of fear generalization. Furthermore, vulnerability was associated with downregulation of neuronal activity and neuroplasticity markers, and altered expression of eCB-related genes. Unsupervised and semi-supervised statistical approaches highlighted that hippocampal gene expression patterns possess strong predictive power regarding vulnerability. Taken together, the marked eCB and neuroplasticity changes in vulnerable individuals associated with abnormal activity patterns in the fear circuitry possibly contribute to context coding deficits, resulting in generalized fear.

Comparing the limbic-frontal connectome across the primate order: conservation of connections and implications for translational neuroscience
The interaction of the limbic system and frontal cortex of the primate brain is important in many affective behaviors. For this reason, it is heavily implicated in a number of psychiatric conditions. This system is often studied in the macaque monkey, the most largely-used non human primate model species. However, how evolutionary conserved this system is and how well results obtained in any model species translate to the human can only be understood by studying its organization across the primate order. Here, we present an investigation of the topology of limbic-frontal connections across seven species, representing all major branches of the primate family tree. We show that dichotomous organization of amydalofugal and uncinate connections with frontal cortex is conserved across all species. Subgenual connectivity of the cingulum bundle, however, seems less prominent in prosimian and New World monkey brains. These results inform both translational neuroscience and primate brain evolution.

Subtypes of brain change in aging and their associations with cognition and Alzheimer's disease biomarkers
Structural brain changes underly cognitive changes in older age and contribute to inter-individual variability in cognition. Here, we assessed how changes in cortical thickness, surface area, and subcortical volume, are related to cognitive change in cognitively unimpaired older adults using structural magnetic resonance imaging (MRI) data-driven clustering. Specifically, we tested (1) which brain structural changes over time predict cognitive change in older age (2) whether these are associated with core cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers phosphorylated tau (p-tau) and amyloid-{beta}(A{beta}42), and (3) the degree of overlap between clusters derived from different structural features. In total 1899 cognitively healthy older adults (50 - 93 years) were followed up to 16 years with neuropsychological and structural MRI assessments, a subsample of which (n = 612) had CSF p-tau and A{beta}42 measurements. We applied Monte-Carlo Reference-based Consensus clustering to identify subgroups of older adults based on structural brain change patterns over time. Four clusters for each brain feature were identified, representing the degree of longitudinal brain decline. Each brain feature provided a unique contribution to brain aging as clusters were largely independent across modalities. Cognitive change and baseline cognition were best predicted by cortical area change, whereas higher levels of p-tau and A{beta}42 were associated with changes in subcortical volume. These results provide insights into the link between changes in brain morphology and cognition, which may translate to a better understanding of different aging trajectories.

Task structure tailors the geometry of neural representations in human lateral prefrontal cortex
How do human brains represent tasks of varying structure? The lateral prefrontal cortex (lPFC) flexibly represents task information. However, principles that shape lPFC representational geometry remain unsettled. We use deep sampling fMRI and pattern analyses to reveal the detailed structure of lPFC representational geometries as humans perform two distinct categorization tasks, one with flat, conjunctive categories and another with hierarchical, context-dependent categories. We show that lPFC encodes task relevant information with task tailored geometries of intermediate dimensionality. These geometries preferentially enhance the separability of task relevant variables while encoding a subset in abstract form. Specifically, in the flat task, a global axis encodes response relevant categories abstractly, while category- specific local geometries are high dimensional. In the hierarchy task, a global axis abstractly encodes the higher level context, while low dimensional, context- specific local geometries compress irrelevant information and abstractly encode the relevant information. Comparing these task geometries exposes generalizable principles by which lPFC tailors representations to different tasks.

Glutamate signaling and neuroligin/neurexin adhesion play opposing roles that are mediated by major histocompatibility complex I molecules in cortical synapse formation
Although neurons release neurotransmitter before contact, the role for this release in synapse formation remains unclear. Cortical synapses do not require synaptic vesicle release for formation, yet glutamate clearly regulates glutamate receptor trafficking and induces spine formation. Using a culture system to dissect molecular mechanisms, we found that glutamate rapidly decreases synapse density specifically in young cortical neurons in a local and calcium-dependent manner through decreasing NMDAR transport and surface expression as well as co-transport with neuroligin (NL1). Adhesion between NL1 and neurexin 1 protects against this glutamate-induced synapse loss. Major histocompatibility I (MHCI) molecules are required for the effects of glutamate in causing synapse loss through negatively regulating NL1 levels. Thus, like acetylcholine at the NMJ, glutamate acts as a dispersal signal for NMDARs and causes rapid synapse loss unless opposed by NL1-mediated trans-synaptic adhesion. Together, glutamate, MHCI and NL1 mediate a novel form of homeostatic plasticity in young neurons that induces rapid changes in NMDARs to regulate when and where nascent glutamatergic synapses are formed.

Persistent Interruption in Parvalbumin Positive Inhibitory Interneurons: Biophysical and Mathematical Mechanisms
Persistent activity in principal cells is a putative mechanism for maintaining memory traces during working memory. We recently demonstrated persistent interruption of firing in fast-spiking parvalbumin-expressing interneurons (PV-INs), a phenomenon which could serve as a substrate for persistent activity in principal cells through disinhibition lasting hundreds of milliseconds. Here, we find that hippocampal CA1 PV-INs exhibit type 2 excitability, like striatal and neocortical PV-INs. Modelling and mathematical analysis showed that the slowly inactivating potassium current Kv1 contributes to type 2 excitability, enables the multiple firing regimes observed experimentally in PV-INs, and provides a mechanism for robust persistent interruption of firing. Using a fast/slow separation of times scales approach with the Kv1 inactivation variable as a bifurcation parameter shows that the initial inhibitory stimulus stops repetitive firing by moving the membrane potential trajectory onto a co-existing stable fixed point corresponding to a non-spiking quiescent state. As Kv1 inactivation decays, the trajectory follows the branch of stable fixed points until it crosses a subcritical Hopf bifurcation then spirals out into repetitive firing. In a model describing entorhinal cortical PV-INs without Kv1, interruption of firing could be achieved by taking advantage of the bistability inherent in type 2 excitability based on a subcritical Hopf bifurcation, but the interruption was not robust to noise. Persistent interruption of firing is therefore broadly applicable to PV-INs in different brain regions but is only made robust to noise in the presence of a slow variable.

Neurodevelopmental defects in Dravet syndrome Scn1a+/- mice: selective rescue of behavioral alterations but not seizures by targeting GABA-switch.
Dravet syndrome (DS) is a developmental and epileptic encephalopathy (DEE) caused by mutations of the SCN1A gene and characterized by seizures, motor disabilities and cognitive/behavioral deficits, including autistic traits. The relative role of seizures and neurodevelopmental defects in disease progression is not clear yet. A delayed switch of GABAergic transmission from excitatory to inhibitory (GABA-switch) has been reported in models of DS, but its effects on the phenotype have not been investigated. In the Scn1a+/- mouse model of DS, we studied GABA-switch and neurodevelopmental defects before the onset of spontaneous seizures, and assessed their impact on epileptic and behavioral phenotypes performing specific treatments. We evaluated in vivo features performing behavioral tests and cellular/network properties performing ex-vivo electrophysiological recordings. Rescue of GABA-switch with the drugs KU55933 (KU) or bumetanide improved cognitive/behavioral defects. However, the treatments had no effect on seizures or mortality rate. Moreover, we observed early behavioral defects and delayed neurodevelopmental milestones well before seizure onset. Thus, we disclosed neurodevelopmental components in DS that selectively underlie some cognitive/behavioral defects, but not seizures, and provide evidence to the hypothesis that seizures and neuropsychiatric dysfunctions can be uncoupled in DEEs. They could be treated separately with targeted pharmacological strategies.

The role of olivary phase-locking oscillations in cerebellar sensorimotor adaptation
The function of the olivary nucleus is key to cerebellar adaptation as it modulates long term synaptic plasticity between parallel fibres and Purkinje cells. Here, we posit that the neural dynamics of the inferior olive (IO) network, and in particular the phase of subthreshold oscillations with respect to afferent excitatory inputs, plays a role in cerebellar sensorimotor adaptation. To test this hypothesis, we first modelled a network of 200 multi-compartment Hodgkin-Huxley IO cells, electrically coupled via anisotropic gap junctions. The model IO neural dynamics captured the properties of real olivary activity in terms of subthreshold oscillations and spike burst responses to dendritic input currents. Then, we integrated the IO network into a large-scale olivo-cerebellar model to study vestibular ocular reflex (VOR) adaptation. VOR produces eye movements contralateral to head motion to stabilise the image on the retina. Hence, studying cerebellar-dependent VOR adaptation provided insights into the functional interplay between olivary subthreshold oscillations and responses to retinal slips (i.e., image movements triggering optokinetic adaptation). Our results showed that the phase-locking of IO subthreshold oscillations to retina slip signals is a necessary condition for cerebellar VOR learning. We also found that phase-locking makes the transmission of IO spike bursts to Purkinje cells more informative with respect to the variable amplitude of retina slip errors. Finally, our results showed that the joint action of IO phase-locking and cerebellar nuclei GABAergic modulation of IO cells' electrical coupling is crucial to increase the state variability of the IO network, which significantly improves cerebellar adaptation.

Cell-type specific contributions to theta-gamma coupled rhythms in the hippocampus
The distinct inhibitory cell types that participate in cognitively relevant nested brain rhythms require that model circuits reflect this diversity. The co-expression of theta and gamma rhythms may represent a general coding scheme and particular changes in these coupled rhythms occur in disease states. We develop a population rate model of the CA1 hippocampus that encompasses circuits of three inhibitory cell types (bistratified cells, parvalbumin (PV)-expressing and cholecystokinin (CCK)-expressing basket cells) and pyramidal cells to examine coupled rhythms. We constrain parameters and perform theoretical and numerical analyses of the model. We find that CCK-expressing basket cells initiate the coupled rhythms and regularize theta, and PV-expressing basket cells enhance both theta and gamma rhythms. Pyramidal and bistratified cells govern the generation of theta rhythms, PV-expressing basket and pyramidal cells play dominant roles in controlling theta frequencies. We predict circuit motifs for theta-gamma coupled rhythms which may be generally applicable.

The developing mouse dopaminergic system: Cortical-subcortical shift in D1/D2 receptor balance and increasing regional differentiation
The dopaminergic system of the brain is involved in complex cognitive functioning and undergoes extensive reorganization during development. Yet, these changes are poorly characterized. We have quantified the density of dopamine 1- and 2-receptor (D1 and D2) positive cells across the forebrain of male and female mice at five developmental stages. Our findings show a cortico-subcortical shift in D1/D2 balance, with increasing D1 dominance in cortical regions as a maturational pattern that occurs earlier in females. We describe postnatal trajectories of D1 and D2 cell densities across major brain regions and observe increasing regional differentiation of D1 densities through development. Our results provide the most comprehensive overview of the developing dopaminergic system to date, and an empirical foundation for further experimental and computational investigations of dopaminergic signaling.

External task switches activate default mode regions without enhanced processing of the surrounding scene
Default mode network (DMN) activity, measured with fMRI, typically increases during internally directed thought, and decreases during tasks that demand externally focused attention. However, Crittenden et al. (2015) and Smith et al. (2018) reported increased DMN activity during demanding external task switches between different cognitive domains, compared to within-domain switches and task repeats. This finding is hard to reconcile with many dominant views of DMN function. Here, we aimed to replicate this DMN task-switch effect in a similar paradigm and test whether it reflects increased representation of broader context, specifically of a scene presented behind the focal task. In Core DMN, we found significant activity for all task switches, compared to task repeats, and stronger activity for switches between rest and task. Although the content of the background scene was attended, recalled, and neurally decodable, there was no evidence that this differed by switch type. Therefore, external task switches activated DMN without enhanced processing of the surrounding scene. Surprisingly, DMN activity at within-domain switches was no less than at between-domain switches. We suggest that modulation of DMN activity by task switches reflects a shift in the current cognitive model and depends on the overall complexity of that model.

Entrainment Echoes in the Cerebellum
Historically, researchers have considered the cerebellum a coordinator of motor programs that ensures precise timing of movements and their adaptation to external events. However, it has become increasingly clear that this role is not restricted to the motor system. Rather, the cerebellum seems to play an important role in temporal prediction in general, as shown in its involvement in multiple functions that rely on precise event timing. Although previous work suggested that the cerebellum exclusively predicts the interval between two events, rather than tracking a global rhythm, it is also active when a rhythmic stimulus changes in rate. The latter finding is in line with a cerebellar role in speech processing that entails frequent rate changes. Neural mechanisms underlying the cerebellum's involvement in speech processing, however, remain poorly understood. Moreover, there is a lack of studies contrasting speech and non-speech stimuli to establish speech-specificity of the observed effects. In a re-analysis of magnetoencephalography (MEG) data, we found that activity in the cerebellum aligned to rhythmic sequences of noise-vocoded speech, irrespective of its intelligibility. We then tested whether these "entrained" responses persist, and how they interact with other brain regions, when the rhythmic stimulus stopped and temporal predictions had to be updated. We found that only intelligible speech produced rhythmic responses in the cerebellum that outlasted the stimulus. During this "entrainment echo", but not during rhythmic speech itself, cerebellar activity was coupled with that in the left inferior frontal gyrus (IFG), and specifically at rates corresponding to the preceding stimulus rhythm. This finding represents unprecedented evidence for specific cerebellum-driven temporal predictions in speech processing and their relay to cortical regions.