Sensory History Drives Adaptive Neural Geometry in LP/Pulvinar-Prefrontal Cortex Circuits.

Prior expectations guide attention and support perceptual filtering for efficient processing during decision-making. Here we show that during a visual discrimination task, mice adaptively use prior stimulus history to guide ongoing choices by estimating differences in evidence between consecutive trials (| Δ Dir |). The thalamic lateral posterior (LP)/pulvinar nucleus provides robust inputs to the Anterior Cingulate Cortex (ACC), which has been implicated in selective attention and predictive processing, but the function of the LP-ACC projection is unknown.

Astrocytic modulation of population encoding in mouse visual cortex via GABA transporter 3 revealed by multiplexed CRISPR/Cas9 gene editing.

Astrocytes, which are increasingly recognized as pivotal constituents of brain circuits governing a wide range of functions, express GABA transporter 3 (Gat3), an astrocyte-specific GABA transporter responsible for maintenance of extra-synaptic GABA levels. Here, we examined the functional role of Gat3 in astrocyte-mediated modulation of neuronal activity and information encoding. First, we developed a multiplexed CRISPR construct applicable for effective genetic ablation of Gat3 in the visual cortex of adult mice.

Cortical norepinephrine-astrocyte signaling critically mediates learned behavior.

Updating behavior based on feedback from the environment is a crucial means by which organisms learn and develop optimal behavioral strategies. Norepinephrine (NE) release from the locus coeruleus (LC) has been shown to mediate learned behaviors such that in a task with graded stimulus uncertainty and performance, a high level of NE released after an unexpected outcome causes improvement in subsequent behavior. Yet, how the transient activity of LC-NE neurons, lasting tens of milliseconds, influences behavior several seconds later, is unclear.

Diversity of ancestral brainstem noradrenergic neurons across species and multiple biological factors.

The brainstem region, locus coeruleus (LC), has been remarkably conserved across vertebrates. Evolution has woven the LC into wide-ranging neural circuits that influence functions as broad as autonomic systems, the stress response, nociception, sleep, and high-level cognition among others. Given this conservation, there is a strong possibility that LC activity is inherently similar across species, and furthermore that age, sex, and brain state influence LC activity similarly across species.

miR126-mediated impaired vascular integrity in Rett syndrome.

Rett syndrome (RTT) is a neurodevelopmental disorder that is caused by mutations in melty-CpG binding protein 2 (MeCP2). MeCP2 is a non-cell type-specific DNA binding protein, and its mutation influences not only neural cells but also non-neural cells in the brain, including vasculature associated with endothelial cells. Vascular integrity is crucial for maintaining brain homeostasis, and its alteration may be linked to the pathology of neurodegenerative disease, but a non-neurogenic effect, especially the relationship between vascular alternation and Rett syndrome pathogenesis, has not been shown.

In Vivo Optical Clearing of Mammalian Brain.

Established methods for imaging the living mammalian brain have, to date, taken optical properties of the tissue as fixed; we here demonstrate that it is possible to modify the optical properties of the brain itself to significantly enhance at-depth imaging while preserving native physiology. Using a small amount of any of several biocompatible materials to raise the refractive index of solutions superfusing the brain prior to imaging, we could increase several-fold the signals from the deepest cells normally visible and, under both one-photon and two-photon imaging, visualize cells previously too dim to see. The enhancement was observed for both anatomical and functional fluorescent reporters across a broad range of emission wavelengths.

Early differential impact of MeCP2 mutations on functional networks in Rett syndrome patient-derived human cerebral organoids.

Human cerebral organoids derived from induced pluripotent stem cells can recapture early developmental processes and reveal changes involving neurodevelopmental disorders. Mutations in the X-linked methyl-CpG binding protein 2 (MECP2) gene are associated with Rett syndrome, and disease severity varies depending on the location and type of mutation. Here, we focused on neuronal activity in Rett syndrome patient-derived organoids, analyzing two types of MeCP2 mutations - a missense mutation (R306C) and a truncating mutation (V247X) - using calcium imaging with three-photon microscopy.

The noncoding circular RNA regulates developmental experience-dependent plasticity in mouse visual cortex.

Circular RNAs (circRNAs) are noncoding RNAs abundant in brain tissue, and many are derived from activity-dependent, linear mRNAs encoding for synaptic proteins, suggesting that circRNAs may directly or indirectly play a role in regulating synaptic development, plasticity, and function. However, it is unclear if the circular forms of these RNAs are similarly regulated by activity and what role these circRNAs play in developmental plasticity. Here, we employed transcriptome-wide analysis comparing differential expression of both mRNAs and circRNAs in juvenile mouse primary visual cortex (V1) following monocular deprivation (MD), a model of developmental plasticity.

The A53T Mutation in α-Synuclein Enhances Proinflammatory Activation in Human Microglia Upon Inflammatory Stimulus.

Background: Parkinson's disease (PD) is the second most common neurodegenerative disease, following Alzheimer's. It is characterized by the aggregation of α-synuclein into Lewy bodies and Lewy neurites in the brain. Microglia-driven neuroinflammation may contribute to neuronal death in PD; however, the exact role of microglia remains unclear and has been understudied.

Long-term labeling and imaging of synaptically connected neuronal networks in vivo using double-deletion-mutant rabies viruses.

Rabies-virus-based monosynaptic tracing is a widely used technique for mapping neural circuitry, but its cytotoxicity has confined it primarily to anatomical applications. Here we present a second-generation system for labeling direct inputs to targeted neuronal populations with minimal toxicity, using double-deletion-mutant rabies viruses. Viral spread requires expression of both deleted viral genes in trans in postsynaptic source cells.

Mixtures of strategies underlie rodent behavior during reversal learning.

In reversal learning tasks, the behavior of humans and animals is often assumed to be uniform within single experimental sessions to facilitate data analysis and model fitting. However, behavior of agents can display substantial variability in single experimental sessions, as they execute different blocks of trials with different transition dynamics. Here, we observed that in a deterministic reversal learning task, mice display noisy and sub-optimal choice transitions even at the expert stages of learning.

The A53T mutation in α-synuclein enhances pro-inflammatory activation in human microglia.

Parkinson's disease (PD) is characterized by the aggregation of α-synuclein into Lewy bodies and Lewy neurites in the brain. Microglia-driven neuroinflammation may contribute to neuronal death in PD, however the exact role of microglia remains unclear and has been understudied. The A53T mutation in the gene coding for α-synuclein has been linked to early-onset PD, and exposure to A53T-mutant human α-synuclein increases the potential for inflammation of murine microglia.

Effective and efficient neural networks for spike inference from calcium imaging.

Calcium imaging provides advantages in monitoring large populations of neuronal activities simultaneously. However, it lacks the signal quality provided by neural spike recording in traditional electrophysiology. To address this issue, we developed a supervised data-driven approach to extract spike information from calcium signals.

Differential Effects of Astrocyte Manipulations on Learned Motor Behavior and Neuronal Ensembles in the Motor Cortex.

Although motor cortex is crucial for learning precise and reliable movements, whether and how astrocytes contribute to its plasticity and function during motor learning is unknown. Here, we report that astrocyte-specific manipulations in primary motor cortex (M1) during a lever push task alter motor learning and execution, as well as the underlying neuronal population coding. Mice that express decreased levels of the astrocyte glutamate transporter 1 (GLT1) show impaired and variable movement trajectories, whereas mice with increased astrocyte Gq signaling show decreased performance rates, delayed response times, and impaired trajectories.

Algebraic approach for subspace decomposition and clustering of neural activity.

We developed an approach to decompose neuronal signals into disjoint components, corresponding to task- or event-based epochs. This protocol describes how to project behavioral templates onto a low-dimensional subspace of neuronal responses to derive neuronal templates, then how to decompose and cluster neuronal responses using these derived templates. We outline these steps on complementary datasets of calcium imaging and spiking activity.

Fragile X Syndrome Patient-Derived Neurons Developing in the Mouse Brain Show FMR1-Dependent Phenotypes.

Background: Fragile X syndrome (FXS) is characterized by physical abnormalities, anxiety, intellectual disability, hyperactivity, autistic behaviors, and seizures. Abnormal neuronal development in FXS is poorly understood. Data on patients with FXS remain scarce, and FXS animal models have failed to yield successful therapies.

Dynamic control of visually guided locomotion through corticosubthalamic projections.

Goal-directed locomotion requires control signals that propagate from higher order areas to regulate spinal mechanisms. The corticosubthalamic hyperdirect pathway offers a short route for cortical information to reach locomotor centers in the brainstem. We developed a task in which head-fixed mice run to a visual landmark and then stop and wait to collect the reward and examined the role of secondary motor cortex (M2) projections to the subthalamic nucleus (STN) in controlling locomotion.

Label-free three-photon imaging of intact human cerebral organoids for tracking early events in brain development and deficits in Rett syndrome.

Human cerebral organoids are unique in their development of progenitor-rich zones akin to ventricular zones from which neuronal progenitors differentiate and migrate radially. Analyses of cerebral organoids thus far have been performed in sectioned tissue or in superficial layers due to their high scattering properties. Here, we demonstrate label-free three-photon imaging of whole, uncleared intact organoids (~2 mm depth) to assess early events of early human brain development.

Cortical-subcortical interactions in goal-directed behavior.

Flexibly selecting appropriate actions in response to complex, ever-changing environments requires both cortical and subcortical regions, which are typically described as participating in a strict hierarchy. In this traditional view, highly specialized subcortical circuits allow for efficient responses to salient stimuli, at the cost of adaptability and context specificity, which are attributed to the neocortex. Their interactions are often described as the cortex providing top-down command signals for subcortical structures to implement; however, as available technologies develop, studies increasingly demonstrate that behavior is represented by brainwide activity and that even subcortical structures contain early signals of choice, suggesting that behavioral functions emerge as a result of different regions interacting as truly collaborative networks.

Molecular Signatures of Response to Mecasermin in Children With Rett Syndrome.

Rett syndrome (RTT) is a devastating neurodevelopmental disorder without effective treatments. Attempts at developing targetted therapies have been relatively unsuccessful, at least in part, because the genotypical and phenotypical variability of the disorder. Therefore, identification of biomarkers of response and patients' stratification are high priorities.

Spatiotemporal dynamics of noradrenaline during learned behaviour.

Noradrenaline released from the locus coeruleus (LC) is a ubiquitous neuromodulator that has been linked to multiple functions including arousal, action and sensory gain, and learning. Whether and how activation of noradrenaline-expressing neurons in the LC (LC-NA) facilitates different components of specific behaviours is unknown. Here we show that LC-NA activity displays distinct spatiotemporal dynamics to enable two functions during learned behaviour: facilitating task execution and encoding reinforcement to improve performance accuracy.

Brain-wide mapping of inputs to the mouse lateral posterior (LP/Pulvinar) thalamus-anterior cingulate cortex network.

The rodent homolog of the primate pulvinar, the lateral posterior (LP) thalamus, is extensively interconnected with multiple cortical areas. While these cortical interactions can span the entire LP, subdivisions of the LP are characterized by differential connections with specific cortical regions. In particular, the medial LP has reciprocal connections with frontoparietal cortical areas, including the anterior cingulate cortex (ACC).

Multiplexed action-outcome representation by striatal striosome-matrix compartments detected with a mouse cost-benefit foraging task.

Learning about positive and negative outcomes of actions is crucial for survival and underpinned by conserved circuits including the striatum. How associations between actions and outcomes are formed is not fully understood, particularly when the outcomes have mixed positive and negative features. We developed a novel foraging ('bandit') task requiring mice to maximize rewards while minimizing punishments.