Cloning and expression of a human kinesin heavy chain gene: interaction of the COOH-terminal domain with cytoplasmic microtubules in transfected CV-1 cells.

To understand the interactions between the microtubule-based motor protein kinesin and intracellular components, we have expressed the kinesin heavy chain and its different domains in CV-1 monkey kidney epithelial cells and examined their distributions by immunofluorescence microscopy. For this study, we cloned and sequenced cDNAs encoding a kinesin heavy chain from a human placental library. The human kinesin heavy chain exhibits a high level of sequence identity to the previously cloned invertebrate kinesin heavy chains; homologies between the COOH-terminal domain of human and invertebrate kinesins and the nonmotor domain of the Aspergillus kinesin-like protein bimC were also found. The gene encoding the human kinesin heavy chain also contains a small upstream open reading frame in a G-C rich 5' untranslated region, features that are associated with translational regulation in certain mRNAs. After transient expression in CV-1 cells, the kinesin heavy chain showed both a diffuse distribution and a filamentous staining pattern that coaligned with microtubules but not vimentin intermediate filaments. Altering the number and distribution of microtubules with taxol or nocodazole produced corresponding changes in the localization of the expressed kinesin heavy chain. The expressed NH2-terminal motor and the COOH-terminal tail domains, but not the alpha-helical coiled coil rod domain, also colocalized with microtubules. The finding that both the kinesin motor and tail domains can interact with cytoplasmic microtubules raises the possibility that kinesin could crossbridge and induce sliding between microtubules under certain circumstances

The Tie between Action and Language Is in Our Imagination

In this thesis, the embodied cognition proposal that action words are directly and automatically mapped into the perceiver\u2019s sensorimotor system, and understood via motor simulation, has been put under the lenses of neuropsychology, psychophysics, transcranial magnetic stimulation (TMS), and functional magnetic resonance imaging (fMRI) investigation. The objective was to establish whether the tie between language understanding and motor simulation is necessary for the former to be effective, to the extent that a virtual identity can be recognized between action and language systems..

Population-scale organization of cerebellar granule neuron signaling during a visuomotor behavior.

Granule cells at the input layer of the cerebellum comprise over half the neurons in the human brain and are thought to be critical for learning. However, little is known about granule neuron signaling at the population scale during behavior. We used calcium imaging in awake zebrafish during optokinetic behavior to record transgenically identified granule neurons throughout a cerebellar population. A significant fraction of the population was responsive at any given time. In contrast to core precerebellar populations, granule neuron responses were relatively heterogeneous, with variation in the degree of rectification and the balance of positive versus negative changes in activity. Functional correlations were strongest for nearby cells, with weak spatial gradients in the degree of rectification and the average sign of response. These data open a new window upon cerebellar function and suggest granule layer signals represent elementary building blocks under-represented in core sensorimotor pathways, thereby enabling the construction of novel patterns of activity for learning

Consensus Paper: Cerebellum and Social Cognition.

The traditional view on the cerebellum is that it controls motor behavior. Although recent work has revealed that the cerebellum supports also nonmotor functions such as cognition and affect, only during the last 5 years it has become evident that the cerebellum also plays an important social role. This role is evident in social cognition based on interpreting goal-directed actions through the movements of individuals (social "mirroring") which is very close to its original role in motor learning, as well as in social understanding of other individuals' mental state, such as their intentions, beliefs, past behaviors, future aspirations, and personality traits (social "mentalizing"). Most of this mentalizing role is supported by the posterior cerebellum (e.g., Crus I and II). The most dominant hypothesis is that the cerebellum assists in learning and understanding social action sequences, and so facilitates social cognition by supporting optimal predictions about imminent or future social interaction and cooperation. This consensus paper brings together experts from different fields to discuss recent efforts in understanding the role of the cerebellum in social cognition, and the understanding of social behaviors and mental states by others, its effect on clinical impairments such as cerebellar ataxia and autism spectrum disorder, and how the cerebellum can become a potential target for noninvasive brain stimulation as a therapeutic intervention. We report on the most recent empirical findings and techniques for understanding and manipulating cerebellar circuits in humans. Cerebellar circuitry appears now as a key structure to elucidate social interactions

Laryngeal somatosensory deficits in Parkinson’s disease: implications for speech respiratory and phonatory control

Parkinson’s disease (PD) is often associated with substantial impairment of speech respiratory and phonatory control. However, the degree to which these impairments are related to abnormal laryngeal sensory function is unknown. This study examined whether individuals with PD exhibited abnormal and more asymmetric laryngeal somatosensory function compared with healthy controls, and whether these deficits were associated with disease and voice severity. Nineteen PD participants were tested and compared with 18 healthy controls. Testing included endoscopic assessment of laryngeal somatosensory function, with aerodynamic and acoustic assessment of respiratory and phonatory control, and clinical ratings of voice and disease severity. PD participants exhibited significantly abnormal and asymmetric laryngeal somatosensory function compared with healthy controls. Sensory deficits were significantly associated with timing of phonatory onset, voice intensity, respiratory driving pressure, laryngeal resistance, lung volume expended per syllable, disease severity, and voice severity. These results suggest that respiratory and phonatory control are influenced by laryngeal somatosensory function, that speech-related deficits in PD are related to abnormal laryngeal somatosensory function, and that this function may degrade as a function of disease severity. Thus, PD may represent a model of airway sensorimotor disintegration, highlighting the important role of the basal ganglia and related neural networks in the integration of laryngeal sensory input for speech-related motor control

Collaboration of Cerebello-Rubral and Cerebello-Striatal Loops in a Motor Preparation Task

International audienceIn this study, we used fMRI to identify brain regions associated with concentration (sustained attention) during a motor preparation task. In comparison with a non-concentration task, increased activities were observed (P < 0.05, FWEcorrected P values) in cerebellar lobules VI and VII, motor cortex, pre-supplementary motor area (pre-SMA), thalamus, red nucleus (RN), and caudate nucleus (CN). Moreover, analysis of effective connectivity inter-areal (psychophysiological interactions) showed that during preparation, concentration-related brain activity increase was dependent on Cerebellothalamo-pre-SMA-RN and Pre-SMA-CN-thalamo-M1 loops. We postulate that, while pre-SMA common to both loops is specifically involved in the movement preparation and readiness for voluntary movement through the striatum, the cerebellar lobule VI in conjunction with RN, likely through a cerebellar-rubro-olivary-cerebellar loop, might be implicated in concentration-related optimization of upcoming motor performances

Speech perception under adverse conditions: Insights from behavioral, computational, and neuroscience research

Adult speech perception reflects the long-term regularities of the native language, but it is also flexible such that it accommodates and adapts to adverse listening conditions and short-term deviations from native-language norms. The purpose of this article is to examine how the broader neuroscience literature can inform and advance research efforts in understanding the neural basis of flexibility and adaptive plasticity in speech perception. Specifically, we highlight the potential role of learning algorithms that rely on prediction error signals and discuss specific neural structures that are likely to contribute to such learning. To this end, we review behavioral studies, computational accounts, and neuroimaging findings related to adaptive plasticity in speech perception. Already, a few studies have alluded to a potential role of these mechanisms in adaptive plasticity in speech perception. Furthermore, we consider research topics in neuroscience that offer insight into how perception can be adaptively tuned to short-term deviations while balancing the need to maintain stability in the perception of learned long-term regularities. Consideration of the application and limitations of these algorithms in characterizing flexible speech perception under adverse conditions promises to inform theoretical models of speech. © 2014 Guediche, Blumstein, Fiez and Holt

Activity map of a cortico-cerebellar loop underlying motor planning

The neocortex and cerebellum interact to mediate cognitive functions. It remains unknown how the two structures organize into functional networks to mediate specific behaviors. Here we delineate activity supporting motor planning in relation to the mesoscale cortico-cerebellar connectome. In mice planning directional licking based on short-term memory, preparatory activity instructing future movement depends on the anterior lateral motor cortex (ALM) and the cerebellum. Transneuronal tracing revealed divergent and largely open-loop connectivity between the ALM and distributed regions of the cerebellum. A cerebellum-wide survey of neuronal activity revealed enriched preparatory activity in hotspot regions with conjunctive input–output connectivity to the ALM. Perturbation experiments show that the conjunction regions were required for maintaining preparatory activity and correct subsequent movement. Other cerebellar regions contributed little to motor planning despite input or output connectivity to the ALM. These results identify a functional cortico-cerebellar loop and suggest the cerebellar cortex selectively establishes reciprocal cortico-cerebellar communications to orchestrate motor planning.</p

A FN-MdV pathway and its role in cerebellar multimodular control of sensorimotor behavior

The cerebellum is crucial for various associative sensorimotor behaviors. Delay eyeblink conditioning (DEC) depends on the simplex lobule-interposed nucleus (IN) pathway, yet it is unclear how other cerebellar modules cooperate during this task. Here, we demonstrate the contribution of the vermis-fastigial nucleus (FN) pathway in controlling DEC. We found that task-related modulations in vermal Purkinje cells and FN neurons predict conditioned responses (CRs). Coactivation of the FN and the IN allows for the generation of proper motor commands for CRs, but only FN output fine-tunes unconditione

BASAL GANGLIA PATHWAYS: BEYOND THE CLOSED-LOOP CIRCUITS WITH THE CEREBRAL CORTEX

Concepts of basal ganglia (BG) functions have been strongly influenced by their anatomical interconnections with the cerebral cortex. Views regarding these interconnections have changed dramatically over the past century. Specifically, advances in transneuronal tracing with neurotropic viruses have demonstrated that the BG participate in parallel closed-loop circuits with cerebral cortical areas that underlie motor and cognitive functions (Middleton and Strick, 2000b). Using transneuronal tracing techniques, we have identified two new pathways that allow the BG to influence motor and cognitive processes. First, we used the retrograde transneuronal transport of rabies virus (RV) to show that the BG participates in open-loop circuits with the dorsal prefrontal cortex (PFC). Specifically, the ventral striatum (VStr) projects to the dorsal PFC, but does not receive input back from the dorsal PFC. Our results expand on the finding that there exist open-loop circuits between the BG and motor cortical areas (Kelly and Strick, 2004; Miyachi et al., 2006; Saga et al., 2011). These open-loop circuits provide a pathway for BG limbic processing to influence both motor and cognitive functions. Second, we used retrograde transneuronal transport of RV to reveal a pathway that enables BG output to influence cerebellar (CB) function. Specifically, the subthalamic nucleus (STN) sends a disynaptic projection to the CB cortex. These results are important because until recently, it was generally accepted that the BG and the CB were not directly connected. The pathway from the BG to the CB complements the recent discovery that the CB sends a disynaptic projection to the striatum (Hoshi et al., 2005). Together, these pathways provide the anatomical substrate for substantial interactions between the BG and the CB, in both the motor and nonmotor domains. Overall, we identified two novel output pathways from the BG: from the VStr to the dorsal PFC and from the STN to the CB cortex. These pathways provide the BG with the potential to influence motor and nonmotor processes, outside of the traditional closed-loop circuits with the cerebral cortex. Considerable evidence suggests that these pathways are likely to have important effects on both normal and abnormal aspects of behavior