Specific connectivity optimizes learning in thalamocortical loops.

Thalamocortical loops have a central role in cognition and motor control, but precisely how they contribute to these processes is unclear. Recent studies showing evidence of plasticity in thalamocortical synapses indicate a role for the thalamus in shaping cortical dynamics through learning. Since signals undergo a compression from the cortex to the thalamus, we hypothesized that the computational role of the thalamus depends critically on the structure of corticothalamic connectivity. To test this, we identified the optimal corticothalamic structure that promotes biologically plausible learning in thalamocortical synapses. We found that corticothalamic projections specialized to communicate an efference copy of the cortical output benefit motor control, while communicating the modes of highest variance is optimal for working memory tasks. We analyzed neural recordings from mice performing grasping and delayed discrimination tasks and found corticothalamic communication consistent with these predictions. These results suggest that the thalamus orchestrates cortical dynamics in a functionally precise manner through structured connectivity.

An emergent temporal basis set robustly supports cerebellar time-series learning.

The cerebellum is considered a "learning machine" essential for time interval estimation underlying motor coordination and other behaviors. Theoretical work has proposed that the cerebellum's input recipient structure, the granule cell layer (GCL), performs pattern separation of inputs that facilitates learning in Purkinje cells (P-cells). However, the relationship between input reformatting and learning has remained debated, with roles emphasized for pattern separation features from sparsification to decorrelation. We took a novel approach by training a minimalist model of the cerebellar cortex to learn complex time-series data from time-varying inputs, typical during movements. The model robustly produced temporal basis sets from these inputs, and the resultant GCL output supported better learning of temporally complex target functions than mossy fibers alone. Learning was optimized at intermediate threshold levels, supporting relatively dense granule cell activity, yet the key statistical features in GCL population activity that drove learning differed from those seen previously for classification tasks. These findings advance testable hypotheses for mechanisms of temporal basis set formation and predict that moderately dense population activity optimizes learning.NEW & NOTEWORTHY During movement, mossy fiber inputs to the cerebellum relay time-varying information with strong intrinsic relationships to ongoing movement. Are such mossy fibers signals sufficient to support Purkinje signals and learning? In a model, we show how the GCL greatly improves Purkinje learning of complex, temporally dynamic signals relative to mossy fibers alone. Learning-optimized GCL population activity was moderately dense, which retained intrinsic input variance while also performing pattern separation.

Disrupting cortico-cerebellar communication impairs dexterity.

To control reaching, the nervous system must generate large changes in muscle activation to drive the limb toward the target, and must also make smaller adjustments for precise and accurate behavior. Motor cortex controls the arm through projections to diverse targets across the central nervous system, but it has been challenging to identify the roles of cortical projections to specific targets. Here, we selectively disrupt cortico-cerebellar communication in the mouse by optogenetically stimulating the pontine nuclei in a cued reaching task. This perturbation did not typically block movement initiation, but degraded the precision, accuracy, duration, or success rate of the movement. Correspondingly, cerebellar and cortical activity during movement were largely preserved, but differences in hand velocity between control and stimulation conditions predicted from neural activity were correlated with observed velocity differences. These results suggest that while the total output of motor cortex drives reaching, the cortico-cerebellar loop makes small adjustments that contribute to the successful execution of this dexterous movement.

The Statistical Structure of the Hippocampal Code for Space as a Function of Time, Context, and Value.

Hippocampal activity represents many behaviorally important variables, including context, an animal's location within a given environmental context, time, and reward. Using longitudinal calcium imaging in mice, multiple large virtual environments, and differing reward contingencies, we derived a unified probabilistic model of CA1 representations centered on a single feature-the field propensity. Each cell's propensity governs how many place fields it has per unit space, predicts its reward-related activity, and is preserved across distinct environments and over months. Propensity is broadly distributed-with many low, and some very high, propensity cells-and thus strongly shapes hippocampal representations. This results in a range of spatial codes, from sparse to dense. Propensity varied ∼10-fold between adjacent cells in salt-and-pepper fashion, indicating substantial functional differences within a presumed cell type. Intracellular recordings linked propensity to cell excitability. The stability of each cell's propensity across conditions suggests this fundamental property has anatomical, transcriptional, and/or developmental origins.

Cortical pattern generation during dexterous movement is input-driven.

The motor cortex controls skilled arm movement by sending temporal patterns of activity to lower motor centres1. Local cortical dynamics are thought to shape these patterns throughout movement execution2-4. External inputs have been implicated in setting the initial state of the motor cortex5,6, but they may also have a pattern-generating role. Here we dissect the contribution of local dynamics and inputs to cortical pattern generation during a prehension task in mice. Perturbing cortex to an aberrant state prevented movement initiation, but after the perturbation was released, cortex either bypassed the normal initial state and immediately generated the pattern that controls reaching or failed to generate this pattern. The difference in these two outcomes was probably a result of external inputs. We directly investigated the role of inputs by inactivating the thalamus; this perturbed cortical activity and disrupted limb kinematics at any stage of the movement. Activation of thalamocortical axon terminals at different frequencies disrupted cortical activity and arm movement in a graded manner. Simultaneous recordings revealed that both thalamic activity and the current state of cortex predicted changes in cortical activity. Thus, the pattern generator for dexterous arm movement is distributed across multiple, strongly interacting brain regions.

Visually Guided Behavior and Optogenetically Induced Learning in Head-Fixed Flies Exploring a Virtual Landscape.

Studying the intertwined roles of sensation, experience, and directed action in navigation has been facilitated by the development of virtual reality (VR) environments for head-fixed animals, allowing for quantitative measurements of behavior in well-controlled conditions. VR has long featured in studies of Drosophila melanogaster, but these experiments have typically allowed the fly to change only its heading in a visual scene and not its position. Here we explore how flies move in two dimensions (2D) using a visual VR environment that more closely captures an animal's experience during free behavior. We show that flies' 2D interaction with landmarks cannot be automatically derived from their orienting behavior under simpler one-dimensional (1D) conditions. Using novel paradigms, we then demonstrate that flies in 2D VR adapt their behavior in response to optogenetically delivered appetitive and aversive stimuli. Much like free-walking flies after encounters with food, head-fixed flies exploring a 2D VR respond to optogenetic activation of sugar-sensing neurons by initiating a local search, which appears not to rely on visual landmarks. Visual landmarks can, however, help flies to avoid areas in VR where they experience an aversive, optogenetically generated heat stimulus. By coupling aversive virtual heat to the flies' presence near visual landmarks of specific shapes, we elicit selective learned avoidance of those landmarks. Thus, we demonstrate that head-fixed flies adaptively navigate in 2D virtual environments, but their reliance on visual landmarks is context dependent. These behavioral paradigms set the stage for interrogation of the fly brain circuitry underlying flexible navigation in complex multisensory environments.

Experience-dependent shaping of hippocampal CA1 intracellular activity in novel and familiar environments.

The hippocampus is critical for producing stable representations of familiar spaces. How these representations arise is poorly understood, largely because changes to hippocampal inputs have not been measured during spatial learning. Here, using intracellular recording, we monitored inputs and plasticity-inducing complex spikes (CSs) in CA1 neurons while mice explored novel and familiar virtual environments. Inputs driving place field spiking increased in amplitude - often suddenly - during novel environment exploration. However, these increases were not sustained in familiar environments. Rather, the spatial tuning of inputs became increasingly similar across repeated traversals of the environment with experience - both within fields and throughout the whole environment. In novel environments, CSs were not necessary for place field formation. Our findings support a model in which initial inhomogeneities in inputs are amplified to produce robust place field activity, then plasticity refines this representation into one with less strongly modulated, but more stable, inputs for long-term storage.

Mesoscale-duration activated states gate spiking in response to fast rises in membrane voltage in the awake brain.

Seconds-scale network states, affecting many neurons within a network, modulate neural activity by complementing fast integration of neuron-specific inputs that arrive in the milliseconds before spiking. Nonrhythmic subthreshold dynamics at intermediate timescales, however, are less well characterized. We found, using automated whole cell patch clamping in vivo, that spikes recorded in CA1 and barrel cortex in awake mice are often preceded not only by monotonic voltage rises lasting milliseconds but also by more gradual (lasting tens to hundreds of milliseconds) depolarizations. The latter exert a gating function on spiking, in a fashion that depends on the gradual rise duration: the probability of spiking was higher for longer gradual rises, even when controlled for the amplitude of the gradual rises. Barrel cortex double-autopatch recordings show that gradual rises are shared across some, but not all, neurons. The gradual rises may represent a new kind of state, intermediate both in timescale and in proportion of neurons participating, which gates a neuron's ability to respond to subsequent inputs.NEW & NOTEWORTHY We analyzed subthreshold activity preceding spikes in hippocampus and barrel cortex of awake mice. Aperiodic voltage ramps extending over tens to hundreds of milliseconds consistently precede and facilitate spikes, in a manner dependent on both their amplitude and their duration. These voltage ramps represent a "mesoscale" activated state that gates spike production in vivo.

Natural whisker-guided behavior by head-fixed mice in tactile virtual reality.

During many natural behaviors the relevant sensory stimuli and motor outputs are difficult to quantify. Furthermore, the high dimensionality of the space of possible stimuli and movements compounds the problem of experimental control. Head fixation facilitates stimulus control and movement tracking, and can be combined with techniques for recording and manipulating neural activity. However, head-fixed mouse behaviors are typically trained through extensive instrumental conditioning. Here we present a whisker-based, tactile virtual reality system for head-fixed mice running on a spherical treadmill. Head-fixed mice displayed natural movements, including running and rhythmic whisking at 16 Hz. Whisking was centered on a set point that changed in concert with running so that more protracted whisking was correlated with faster running. During turning, whiskers moved in an asymmetric manner, with more retracted whisker positions in the turn direction and protracted whisker movements on the other side. Under some conditions, whisker movements were phase-coupled to strides. We simulated a virtual reality tactile corridor, consisting of two moveable walls controlled in a closed-loop by running speed and direction. Mice used their whiskers to track the walls of the winding corridor without training. Whisker curvature changes, which cause forces in the sensory follicles at the base of the whiskers, were tightly coupled to distance from the walls. Our behavioral system allows for precise control of sensorimotor variables during natural tactile navigation.

Insular cortex abnormalities in psychotic major depression: relationship to gender and psychotic symptoms.

Recent data suggests that psychotic major depression (PMD) may be a discrete disorder distinguishable from nonpsychotic major depression (NPMD), and that patients with PMD may be more similar to individuals with schizophrenia than individuals with NPMD. The insula is a brain region in which morphometric changes have been associated with psychotic symptom severity in schizophrenia and affective psychosis. It was hypothesized that insular volumes would be reduced in PMD compared to NPMD and controls, and insular volumes would correlate with psychosis but not depression severity. Insular gray matter volumes were measured in PMD and NPMD patients and matched healthy controls using magnetic resonance images and manual morphometry. Clinical measures of illness severity were obtained to determine their relationship with insular volume. Posterior insular volumes were significantly reduced in PMD compared to HC. There were also significant group-by-gender interactions for total, anterior and posterior insular volumes. Using Pearson product-moment correlations, anterior insular volumes did not correlate with depression severity. Left anterior insular volume was significantly correlated with total and positive symptom psychosis severity in the PMD group. Atypical insular morphometry may be related to the inability to distinguish between internally and externally generated sensory inputs characteristic of psychosis.

Atypical brain torque in boys with developmental stuttering.

The counterclockwise brain torque, defined as a larger right prefrontal and left parietal-occipital lobe, is a consistent brain asymmetry. Reduced or reversed lobar asymmetries are markers of atypical cerebral laterality and have been found in adults who stutter. It was hypothesized that atypical brain torque would be more common in children who stutter. Magnetic resonance imaging-based morphology measures were completed in boys who stutter (n = 14) and controls (n = 14), ages 8-13. The controls had the expected brain torque configurations whereas the boys who stutter were atypical. These results support the hypothesis that developmental stuttering is associated with atypical prefrontal and parietal-occipital lobe asymmetries.

Insular volume reduction in fragile X syndrome.

Fragile X syndrome (FraX) is the most common form of inherited mental deficit and is caused by mutations of the Fragile X Mental Retardation 1 (FMR1) gene on the X chromosome. While males and females with the full FMR1 mutation are affected differently because the disorder is X-linked, both suffer from varying degrees of cognitive impairment, attention deficits and social anxiety. The insula is a sensory integrative region that has been increasingly suggested as a critical area involved in anxiety manifestation. The current study was designed to examine possible changes in insular volume in FraX compared to age- and gender-matched typically developing healthy controls (HC) as well as age-, gender-, and intelligence-matched developmentally delayed controls (DD). An established native-space, manual morphometry method was utilized to quantify total and regional insular volumes using structural magnetic resonance imaging. Total, anterior and posterior insular volumes were found to be reduced in FraX compared to both HC and DD. The current data add to a growing literature concerning brain abnormalities in FraX and suggests that significant volume reduction of the insula is a component of the FraX neuroanatomical phenotype. This finding also provides an intriguing potential neural correlate for hyperarousal and gaze aversion, which are prominent behavioral symptoms of FraX.

Behavioral state dependency of neural activity and sensory (whisker) responses in superior colliculus.

Rats use their vibrissa (whiskers) to explore and navigate the environment. These sensory signals are distributed within the brain stem by the trigeminal complex and are also relayed to the superior colliculus in the midbrain and to the thalamus (and subsequently barrel cortex) in the forebrain. In the intermediate layers of the superior colliculus, whisker-evoked responses are driven by direct inputs from the trigeminal complex (trigeminotectal) and feedback from the barrel cortex (corticotectal). But the effects of the behavioral state of the animal on the spontaneous firing and sensory responses of these neurons are unknown. By recording from freely behaving rats, we show that the spontaneous firing of whisker sensitive neurons in superior colliculus is higher, or in an activated mode, during active exploration and paradoxical sleep and much lower, or in a quiescent/deactivated mode, during awake immobility and slow-wave sleep. Sensory evoked responses in superior colliculus also depend on behavioral state. Most notably, feedback corticotectal responses are significantly larger during the quiescent/deactivated mode, which tracks the barrel cortex responses on which they depend. Finally, sensory evoked responses depend not only on the state of the animal but also on the orienting response elicited by the stimulus, which agrees with the well known role of the superior colliculus in orienting about salient stimuli.

Neural correlates of active avoidance behavior in superior colliculus.

Active avoidance of harmful situations seems highly adaptive, but the underlying neural mechanisms are unknown. Rats can effectively use the superior colliculus during active avoidance to detect a salient whisker conditioned stimulus (WCS) that signals an aversive event. Here, we recorded unit and field potential activity in the intermediate layers of the superior colliculus of rats during active avoidance behavior. During the period preceding the onset of the WCS, avoids are associated with a higher firing rate than escapes (unsuccessful avoids), indicating that a prepared superior colliculus is more likely to detect the WCS and lead to an avoid. Moreover, during the WCS, a robust ramping up of the overall firing rate is observed for trials leading to avoids. The firing rate ramping is not caused by shuttling and may serve to drive downstream circuits to avoid. Therefore, a robust neural correlate of active avoidance behavior is found in the superior colliculus, emphasizing its role in the detection of salient sensory signals that require immediate action.

Detection of low salience whisker stimuli requires synergy of tectal and thalamic sensory relays.

Detection of a sensory stimulus depends on its psychophysical saliency; the higher the saliency, the easier the detection. But it is not known whether sensory relay nuclei differ in their ability to detect low salient whisker stimuli. We found that reversible lesions of either the somatosensory thalamus or superior colliculus blocked detection of a low salience whisker conditioned stimulus (WCS) in an active avoidance task, without affecting detection of a high salience WCS. Thus, thalamic and tectal sensory relays work synergistically to detect low salient stimuli during avoidance behavior, but are redundant during detection of highly salient stimuli. We also recorded electrophysiological responses evoked by high and low salience stimuli in the superior colliculus and barrel cortex of freely behaving animals during active exploration, awake immobility, and sensory detection in the active avoidance task. Field potential (FP) responses evoked in barrel cortex and superior colliculus by high intensity stimuli are larger and adapt more to frequency than those evoked by low-intensity stimuli. FP responses are also more suppressed and adapt less during active exploration, and become further suppressed in barrel cortex during successful detection of either high or low salient stimuli in the active avoidance task. In addition, unit recordings revealed that firing rate increases in superior colliculus during active exploration and especially during successful detection of either high or low salient stimuli in the active avoidance task. We conclude that detection of low salient stimuli is achieved by a sparse neural code distributed through multiple sensory relays.

Morphometry of human insular cortex and insular volume reduction in Williams syndrome.

Functional imaging in humans and anatomical data in monkeys have implicated the insula as a multimodal sensory integrative brain region. The topography of insular connections is organized by its cytoarchitectonic regions. Previous attempts to measure the insula have utilized either indirect or automated methods. This study was designed to develop a reliable method for obtaining volumetric magnetic resonance imaging (MRI) measurements of the human insular cortex, and to validate that method by examining the anatomy of insular cortex in adults with Williams syndrome (WS) and healthy age-matched controls. Statistical reliability was obtained among three raters for this method, supporting its reproducibility not only across raters, but within different software packages. The procedure described here utilizes native-space morphometry as well as a method for dividing the insula into connectivity-based sub-regions estimated from cytoarchitectonics. Reliability was calculated in both ANALYZE (N=3) and BrainImageJava (N=10) where brain scans were measured once in each hemisphere by each rater. This highly reliable method revealed total, anterior, and posterior insular volume reduction bilaterally (all p's<.002) in WS, after accounting for reduced total brain volumes in these participants. Although speculative, the reduced insular volumes in WS may represent a neural risk for the development of hyperaffiliative social behavior with increased specific phobias, and implicate the insula as a critical limbic integrative region. Native-space quantification of the insula may be valuable in the study of neurodevelopmental or neuropsychiatric disorders related to anxiety and social behavior.

Vibrissa sensation in superior colliculus: wide-field sensitivity and state-dependent cortical feedback.

Rodents use their vibrissae (whiskers) to sense and navigate the environment. A main target of this sensory information is the superior colliculus in the midbrain, which rats can use to detect meaningful whisker stimuli in behavioral contexts. Here, we used field potential, single-unit, and intracellular recordings to show that, although cells in the intermediate layers of the superior colliculus respond relatively effectively to single whiskers, the cells respond much more robustly to simultaneous, or nearly simultaneous, wide-field (multiwhisker) stimuli. The enhanced multiwhisker response is temporally stereotyped, consisting of two short latency peaks caused by convergent trigeminal synaptic inputs and cortical feedback, respectively. The cells are highly sensitive to the degree of temporal dispersion and contact order of multiwhisker stimuli, which makes them excellent detectors of initial multiwhisker contact. In addition, their output is most robust during quiescent states because of the dependence of cortical feedback on forebrain activation, and this may serve as an alerting signal to drive orienting responses.

Early sensory pathways for detection of fearful conditioned stimuli: tectal and thalamic relays.

Sensory stimuli acquire significance through learning. A neutral sensory stimulus can become a fearful conditioned stimulus (CS) through conditioning. Here we report that the sensory pathways used to detect the CS depend on the conditioning paradigm. Animals trained to detect an electrical somatosensory stimulus delivered to the whisker pad in an active avoidance task were able to detect this CS and perform the task when a reversible or irreversible lesion was placed in either the somatosensory thalamus or the superior colliculus contralateral to the CS. However, simultaneous lesions of the somatosensory thalamus and superior colliculus contralateral to the CS blocked performance in the active avoidance task. In contrast, a lesion only of the somatosensory thalamus contralateral to the same CS, but not of the superior colliculus, blocked performance in a pavlovian fear conditioning task. In conclusion, during pavlovian fear conditioning, which is a situation in which the aversive outcome is not contingent on the behavior of the animal, the sensory thalamus is a critical relay for the detection of the CS. During active avoidance conditioning, a situation in which the aversive outcome is contingent on the behavior of the animal (i.e., the animal can avoid the aversive event), the sensory thalamus and the superior colliculus function as alternative routes for CS detection. Thus, even from early stages of sensory processing, the neural signals representing a CS are highly distributed in parallel and redundant sensory circuits, each of which can accomplish CS detection effectively depending on the conditioned behavior.

Skilled motor learning does not enhance long-term depression in the motor cortex in vivo.

Learning of motor skills may occur as a consequence of changes in the efficacy of synaptic connections in the primary motor cortex. We investigated if learning in a reaching task affects the excitability, short-term plasticity, and long-term plasticity of horizontal connections in layers II-III of the motor cortex. Because training in this task requires animals to be food-deprived, we compared the trained animals with similarly food-deprived untrained animals and normal controls. The results show that the excitability, short-term plasticity, and long-term plasticity of the studied horizontal connections were unaffected by motor learning. However, stress-related effects produced by food deprivation and handling significantly enhanced the expression of long-term depression in these pathways. These results are compatible with the hypothesis that the acquisition of a complex motor skill produces bi-directional changes in synaptic strength that are distributed throughout the complex neural networks of motor cortex, which remains synaptically balanced during learning. The results are incompatible with the idea that learning causes large unidirectional changes in the population response of these neural networks, which may occur instead during certain behavioral states, such as stress.