A role for synapsin tetramerization in synaptic vesicle clustering.

Although synapsins have long been proposed to be key regulators of synaptic vesicle (SV) clustering, their mechanism of action has remained mysterious and somewhat controversial. Here, we review synapsins and their associations with each other and with SVs. We highlight the recent hypothesis that synapsin tetramerization is a mechanism for SV clustering. This hypothesis, which aligns with numerous experimental results, suggests that the larger size of synapsin tetramers, in comparison to dimers, allows tetramers to form optimal bridges between SVs that overcome the repulsive force associated with the negatively charged membrane of SVs and allow synapsins to form a reserve pool of SVs within presynaptic terminals.

Protocol to study dam-pup social transmission using a modified paradigm for transmission of food preference.

The social transmission of food preference, a rudimentary form of social learning, has primarily been studied in pairs of adult rodents. Here, we present a protocol to explore the parent-offspring context in social learning using an adaptation of this classic paradigm for rodent dam-pup dyads. We describe steps for studying weanling mice from the same mother and present a worked example using weight-based (food consumption) and time-based (exploration) indices of social learning.

Optogenetic stimulation of neurons in the anterior cingulate cortex induces changes in intravesical bladder pressure and the micturition reflex.

Lower urinary tract (LUT) function is controlled by the central nervous system, including higher-order cognitive brain regions. The anterior cingulate cortex (ACC) is one of these regions, but the role of its activity in LUT function remains poorly understood. In the present study, we conducted optogenetic experiments to manipulate neural activity in mouse ACC while monitoring bladder pressure to elucidate how the activity of ACC regulates LUT function. Selective optogenetic stimulation of excitatory neurons in ACC induced a sharp increase in bladder pressure, whereas activation of inhibitory neurons in ACC prolonged the interval between bladder contractions. Pharmacological manipulation of ACC also altered bladder contractions, consistent with those observed in optogenetic experiments. Optogenetic mapping of the cortical area responsible for eliciting the increase in bladder pressure revealed that stimulation to ACC showed more potent effects than the neighboring motor cortical areas. These results suggest that ACC plays a crucial role in initiating the bladder pressure change and the micturition reflex. Thus, the balance between excitation and inhibition in ACC may regulate the reflex bidirectionally.

Synapsin 2a tetramerisation selectively controls the presynaptic nanoscale organisation of reserve synaptic vesicles.

Neurotransmitter release relies on the regulated fusion of synaptic vesicles (SVs) that are tightly packed within the presynaptic bouton of neurons. The mechanism by which SVs are clustered at the presynapse, while preserving their ability to dynamically recycle to support neuronal communication, remains unknown. Synapsin 2a (Syn2a) tetramerization has been suggested as a potential clustering mechanism. Here, we used Dual-pulse sub-diffractional Tracking of Internalised Molecules (DsdTIM) to simultaneously track single SVs from the recycling and the reserve pools, in live hippocampal neurons. The reserve pool displays a lower presynaptic mobility compared to the recycling pool and is also present in the axons. Triple knockout of Synapsin 1-3 genes (SynTKO) increased the mobility of reserve pool SVs. Re-expression of wild-type Syn2a (Syn2aWT), but not the tetramerization-deficient mutant K337Q (Syn2aK337Q), fully rescued these effects. Single-particle tracking revealed that Syn2aK337QmEos3.1 exhibited altered activity-dependent presynaptic translocation and nanoclustering. Therefore, Syn2a tetramerization controls its own presynaptic nanoclustering and thereby contributes to the dynamic immobilisation of the SV reserve pool.

The claustrum and consciousness: An update

The seminal paper of Crick and Koch (2005) proposed that the claustrum, an enigmatic and thin grey matter structure that lies beside the insular cortex, may be involved in the processing of consciousness. As a result, this otherwise obscure structure has received ever-increasing interest in the search for neural correlates of consciousness. Here we review theories of consciousness and discuss the possible relationship between the claustrum and consciousness. We review relevant experimental evidence collected since the Crick and Koch (2005) paper and consider whether these findings support or contradict their hypothesis. We also explore how future experimental work can be designed to clarify how consciousness emerges from neural activity and to understand the role of the claustrum in consciousness. (AU)

The claustrum and consciousness: An update.

The seminal paper of Crick and Koch (2005) proposed that the claustrum, an enigmatic and thin grey matter structure that lies beside the insular cortex, may be involved in the processing of consciousness. As a result, this otherwise obscure structure has received ever-increasing interest in the search for neural correlates of consciousness. Here we review theories of consciousness and discuss the possible relationship between the claustrum and consciousness. We review relevant experimental evidence collected since the Crick and Koch (2005) paper and consider whether these findings support or contradict their hypothesis. We also explore how future experimental work can be designed to clarify how consciousness emerges from neural activity and to understand the role of the claustrum in consciousness.

Social memory deficit caused by dysregulation of the cerebellar vermis.

Social recognition memory (SRM) is a key determinant of social interactions. While the cerebellum emerges as an important region for social behavior, how cerebellar activity affects social functions remains unclear. We selectively increased the excitability of molecular layer interneurons (MLIs) to suppress Purkinje cell firing in the mouse cerebellar vermis. Chemogenetic perturbation of MLIs impaired SRM without affecting sociability, anxiety levels, motor coordination or object recognition. Optogenetic interference of MLIs during distinct phases of a social recognition test revealed the cerebellar engagement in the retrieval, but not encoding, of social information. c-Fos mapping after the social recognition test showed that cerebellar manipulation decreased brain-wide interregional correlations and altered network structure from medial prefrontal cortex and hippocampus-centered to amygdala-centered modules. Anatomical tracing demonstrated hierarchical projections from the central cerebellum to the social brain network integrating amygdalar connections. Our findings suggest that the cerebellum organizes the neural matrix necessary for SRM.

Different mechanisms of synapsin-induced vesicle clustering at inhibitory and excitatory synapses.

Synapsins cluster synaptic vesicles (SVs) to provide a reserve pool (RP) of SVs that maintains synaptic transmission during sustained activity. However, it is unclear how synapsins cluster SVs. Here we show that either liquid-liquid phase separation (LLPS) or tetramerization-dependent cross-linking can cluster SVs, depending on whether a synapse is excitatory or inhibitory. Cell-free reconstitution reveals that both mechanisms can cluster SVs, with tetramerization being more effective. At inhibitory synapses, perturbing synapsin-dependent LLPS impairs SV clustering and synchronization of gamma-aminobutyric acid (GABA) release, while preventing synapsin tetramerization does not. At glutamatergic synapses, the opposite is true: synapsin tetramerization enhances clustering of glutamatergic SVs and mobilization of these SVs from the RP, while synapsin LLPS does not. Comparison of inhibitory and excitatory transmission during prolonged synaptic activity reveals that synapsin LLPS serves as a brake to limit GABA release, while synapsin tetramerization enables rapid mobilization of SVs from the RP to sustain glutamate release.

A functional logic for neurotransmitter corelease in the cholinergic forebrain pathway.

The cholinergic system of the basal forebrain plays an integral part in behaviors ranging from attention to learning, partly by altering the impact of noise in neural populations. The circuit computations underlying cholinergic actions are confounded by recent findings that forebrain cholinergic neurons corelease both acetylcholine (ACh) and GABA. We have identified that corelease of ACh and GABA by cholinergic inputs to the claustrum, a structure implicated in the control of attention, has opposing effects on the electrical activity of claustrum neurons that project to cortical vs. subcortical targets. These actions differentially alter neuronal gain and dynamic range in the two types of neurons. In model networks, the differential effects of ACh and GABA toggle network efficiency and the impact of noise on population dynamics between two different projection subcircuits. Such cholinergic switching between subcircuits provides a potential logic for neurotransmitter corelease in implementing behaviorally relevant computations.

The cerebellum and anxiety.

Although the cerebellum is traditionally known for its role in motor functions, recent evidence points toward the additional involvement of the cerebellum in an array of non-motor functions. One such non-motor function is anxiety behavior: a series of recent studies now implicate the cerebellum in anxiety. Here, we review evidence regarding the possible role of the cerebellum in anxiety-ranging from clinical studies to experimental manipulation of neural activity-that collectively points toward a role for the cerebellum, and possibly a specific topographical locus within the cerebellum, as one of the orchestrators of anxiety responses.

Synchrony in parent-offspring social interactions across development: A cross-species review of rodents and humans.

In humans, parent-child neural synchrony has been shown to support early communication, social attunement and learning. Further, some animal species (including rodents and bats) are now known to share neural synchrony during certain forms of social behaviour. However, very little is known about the developmental origins and sequelae of neural synchrony, and whether this neural mechanism might play a causal role in the control of social and communicative behaviour across species. Rodent models are optimal for exploring such questions of causality, with a plethora of tools available for both disruption/induction (optogenetics) and even mechanistic dissection of synchrony-induction pathways (in vivo electrical or optical recording of neural activity). However, before the benefits of rodent models for advancing research on parent-infant synchrony can be realised, it is first important to address a gap in understanding the forms of parent-pup synchrony that occur during rodent development, and how these social relationships evolve over time. Accordingly, this review seeks to identify parent-pup social behaviours that could potentially drive or facilitate synchrony and to discuss key differences or limitations when comparing mouse to human models of parent-infant synchrony. Uniquely, our review will focus on parent-pup dyadic social behaviours that have particular analogies to the human context, including instrumental, social interactive and vocal communicative behaviours. This review is intended to serve as a primer on the study of neurobehavioral synchrony across human and rodent dyadic developmental models.

Feedback inhibition underlies new computational functions of cerebellar interneurons.

The function of a feedback inhibitory circuit between cerebellar Purkinje cells and molecular layer interneurons (MLIs) was defined by combining optogenetics, neuronal activity recordings both in cerebellar slices and in vivo, and computational modeling. Purkinje cells inhibit a subset of MLIs in the inner third of the molecular layer. This inhibition is non-reciprocal, short-range (less than 200 µm) and is based on convergence of one to two Purkinje cells onto MLIs. During learning-related eyelid movements in vivo, the activity of a subset of MLIs progressively increases as Purkinje cell activity decreases, with Purkinje cells usually leading the MLIs. Computer simulations indicate that these relationships are best explained by the feedback circuit from Purkinje cells to MLIs and that this feedback circuit plays a central role in making cerebellar learning efficient.

Topologically Organized Networks in the Claustrum Reflect Functional Modularization.

Using genetic strategies and viral-based directional tracers, we investigated the topological location and output networks of claustrum (CLA) neuron populations projecting to either the retrosplenial cortex, primary motor cortex, or basolateral amygdala. We found that all three CLA neuron populations clearly reside in distinct topological locations within the CLA complex and project broadly to multiple downstream targets. Each neuron population projects to different targets, suggesting that each CLA subzone coordinates a unique set of brain-wide functions. Our findings establish that the claustrum complex encompasses at least three minimally overlapping networks that are compartmentalized into different topological subzones. Such modularity is likely to be important for CLA function.

A neural circuit for excessive feeding driven by environmental context in mice.

Despite notable genetic influences, obesity mainly results from the overconsumption of food, which arises from the interplay of physiological, cognitive and environmental factors. In patients with obesity, eating is determined more by external cues than by internal physiological needs. However, how environmental context drives non-homeostatic feeding is elusive. Here, we identify a population of somatostatin (TNSST) neurons in the mouse hypothalamic tuberal nucleus that are preferentially activated by palatable food. Activation of TNSST neurons enabled a context to drive non-homeostatic feeding in sated mice and required inputs from the subiculum. Pairing a context with palatable food greatly potentiated synaptic transmission between the subiculum and TNSST neurons and drove non-homeostatic feeding that could be selectively suppressed by inhibiting TNSST neurons or the subiculum but not other major orexigenic neurons. These results reveal how palatable food, through a specific hypothalamic circuit, empowers environmental context to drive non-homeostatic feeding.

Changing the Cortical Conductor's Tempo: Neuromodulation of the Claustrum.

The claustrum is a thin sheet of neurons that is densely connected to many cortical regions and has been implicated in numerous high-order brain functions. Such brain functions arise from brain states that are influenced by neuromodulatory pathways from the cholinergic basal forebrain, dopaminergic substantia nigra and ventral tegmental area, and serotonergic raphe. Recent revelations that the claustrum receives dense input from these structures have inspired investigation of state-dependent control of the claustrum. Here, we review neuromodulation in the claustrum-from anatomical connectivity to behavioral manipulations-to inform future analyses of claustral function.

Synapsins and the Synaptic Vesicle Reserve Pool: Floats or Anchors?

In presynaptic terminals, synaptic vesicles (SVs) are found in a discrete cluster that includes a reserve pool that is mobilized during synaptic activity. Synapsins serve as a key protein for maintaining SVs within this reserve pool, but the mechanism that allows synapsins to do this is unclear. This mechanism is likely to involve synapsins either cross-linking SVs, thereby anchoring SVs to each other, or creating a liquid phase that allows SVs to float within a synapsin droplet. Here, we summarize what is known about the role of synapsins in clustering of SVs and evaluate experimental evidence supporting these two models.

Molecular Layer Interneurons: Key Elements of Cerebellar Network Computation and Behavior.

Molecular layer interneurons (MLIs) play an important role in cerebellar information processing by controlling Purkinje cell (PC) activity via inhibitory synaptic transmission. A local MLI network, constructed from both chemical and electrical synapses, is organized into spatially structured clusters that amplify feedforward and lateral inhibition to shape the temporal and spatial patterns of PC activity. Several recent in vivo studies indicate that such MLI circuits contribute not only to sensorimotor information processing, but also to precise motor coordination and cognitive processes. Here, we review current understanding of the organization of MLI circuits and their roles in the function of the mammalian cerebellum.

Neuroscience: A Role for the Claustrum in Drug Reward.

The claustrum is a poorly understood but intriguing part of the brain: a new study has found that it plays an important role in drug reward by providing incentive salience to the location where the drug is administered.