Excitatory and inhibitory effects of HCN channel modulation on excitability of layer V pyramidal cells

Dendrites of cortical pyramidal cells are densely populated by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, a.k.a. Ih channels. Ih channels are targeted by multiple neuromodulatory pathways, and thus are one of the key ion-channel populations regulating the pyramidal cell activity. Previous observations and theories attribute opposing effects of the Ih channels on neuronal excitability due to their mildly hyperpolarized reversal potential. These effects are difficult to measure experimentally due to the fine spatiotemporal landscape of the Ih activity in the dendrites, but computational models provide an efficient tool for studying this question in a reduced but generalizable setting. In this work, we build upon existing biophysically detailed models of thick-tufted layer V pyramidal cells and model the effects of over- and under-expression of Ih channels as well as their neuromodulation. We show that Ih channels facilitate the action potentials of layer V pyramidal cells in response to proximal dendritic stimulus while they hinder the action potentials in response to distal dendritic stimulus at the apical dendrite. We also show that the inhibitory action of the Ih channels in layer V pyramidal cells is due to the interactions between Ih channels and a hot zone of low voltage-activated Ca2+ channels at the apical dendrite. Our simulations suggest that a combination of Ih-enhancing neuromodulation at the proximal part of the apical dendrite and Ih-inhibiting modulation at the distal part of the apical dendrite can increase the layer V pyramidal excitability more than either of the two alone. Our analyses uncover the effects of Ih-channel neuromodulation of layer V pyramidal cells at a single-cell level and shed light on how these neurons integrate information and enable higher-order functions of the brain.publishedVersionPeer reviewe

Disruption of transfer entropy and inter-hemispheric brain functional connectivity in patients with disorder of consciousness

Severe traumatic brain injury can lead to disorders of consciousness (DOC) characterized by deficit in conscious awareness and cognitive impairment including coma, vegetative state, minimally consciousness, and lock-in syndrome. Of crucial importance is to find objective markers that can account for the large-scale disturbances of brain function to help the diagnosis and prognosis of DOC patients and eventually the prediction of the coma outcome. Following recent studies suggesting that the functional organization of brain networks can be altered in comatose patients, this work analyzes brain functional connectivity (FC) networks obtained from resting-state functional magnetic resonance imaging (rs-fMRI). Two approaches are used to estimate the FC: the Partial Correlation (PC) and the Transfer Entropy (TE). Both the PC and the TE show significant statistical differences between the group of patients and control subjects; in brief, the inter-hemispheric PC and the intra-hemispheric TE account for such differences. Overall, these results suggest two possible rs-fMRI markers useful to design new strategies for the management and neuropsychological rehabilitation of DOC patients.Comment: 25 pages; 4 figures; 3 tables; 1 supplementary figure; 4 supplementary tables; accepted for publication in Frontiers in Neuroinformatic

Task context load induces reactive cognitive control: An fMRI study on cortical and brain stem activity

When solving dynamic visuo-spatial tasks, the brain copes with perceptual and cognitive processing challenges. In the multiple-object tracking (MOT) task, the number of objects to be tracked (i.e. load) imposes attentional demands, but so does spatial interference from irrelevant objects (i.e. crowding). Presently, it is not clear whether load and crowding activate separate cognitive and physiological mechanisms. Such knowledge would be important to understand the neurophysiology of visual attention. Furthermore, it would help resolve conflicting views between theories of visual cognition, particularly concerning sources of capacity limitations. To address this problem, we varied the degree of processing challenge in the MOT task in two ways: First, the number of objects to track, and second, the spatial proximity between targets and distractors. We first measured task-induced pupil dilations and saccades during MOT. In a separate cohort we measured fMRI brain activity during MOT. The behavioral results in both cohorts revealed that increased load and crowding led to reduced accuracy in an additive manner. Load was associated with pupil dilations, whereas crowding was not. Activity in dorsal attentional areas and frequency of saccades were proportionally larger both with higher levels of load and crowding. Higher crowding recruited additionally ventral attentional areas that may reflect orienting mechanisms. The activity in the brainstem nuclei ventral tegmental area/substantia nigra and locus coeruleus showed clearly dissociated patterns. Our results constitute convergent evidence from independent samples that processing challenges due to load and object spacing may rely on different mechanisms

The role of norepinephrine in the pathophysiology of schizophrenia

Several lines of evidence have suggested for decades a role for norepinephrine (NE) in the pathophysiology and treatment of schizophrenia. Recent experimental findings reveal anatomical and physiological properties of the locus coeruleus-norepinephrine (LC-NE) system and its involvement in brain function and cognition. Here, we integrate these two lines of evidence. First, we review the functional and structural properties of the LC-NE system and its impact on functional brain networks, cognition, and stress, with special emphasis on recent experimental and theoretical advances. Subsequently, we present an update about the role of LC-associated functions for the pathophysiology of schizophrenia, focusing on the cognitive and motivational deficits. We propose that schizophrenia phenomenology, in particular cognitive symptoms, may be explained by an abnormal interaction between genetic susceptibility and stress-initiated LC-NE dysfunction. This in turn, leads to imbalance between LC activity modes, dysfunctional regulation of brain network integration and neural gain, and deficits in cognitive functions. Finally, we suggest how recent development of experimental approaches can be used to characterize LC function in schizophrenia

Lateralization of brain activity during motor planning of proximal and distal gestures

Praxis functions are predominantly processed by the left hemisphere. However, limb apraxia is found in less than 50% of patients with left hemisphere damage, and also, although infrequently, in patients with right hemisphere damage. We studied brain representation of preparation/planning of tool-use pantomime separating the gestures involving mostly distal limb control (e.g., using scissors) from those involving proximal limb control (e.g., hammering). During the fMRI scan transitive pantomimes were performed with the dominant and the non-dominant hand by right-handed healthy subjects. Random and voxel-based analysis through laterality index (LI) calculation, demonstrated that for both limbs, distal gesture planning was in general left lateralized, while for the proximal condition the representation was found to be more bilateral particularly in the inferior frontal gyrus. LI distributions across subjects indicated that while the majority of subjects are left-hemispheric dominant for praxis, there are a minority with the opposite lateralization. Functional connectivity analysis showed that while the correlation between homolog areas involved in gesture production was high irrespective of gesture type, their correlation to the supplementary motor area was high in proximal but not distal conditions. Therefore, transitive gestures, when pantomimed to verbal commands, are differentially represented inter and intra hemispherically depending on whether the gesture is performed with the right or left arm or whether it involves predominantly distal or proximal limb movements. Furthermore, the representation of the different types of gestures may be related to a modulation of the connectivity between areas involved in motor planning.Fil: Mäki Marttunen, Verónica. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; ArgentinaFil: Villarreal, Mirta Fabiana. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Leiguarda, Ramón Carlos. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentin

The role of norepinephrine in the pathophysiology of schizophrenia

Several lines of evidence suggest a role for norepinephrine (NE) in the pathophysiology of schizophrenia, and in pharmacological interventions. In the present paper, we review recent findings about the locus coeruleus-norepinephrine (LC-NE) system and its involvement in brain function and cognition to give a more integrated account of the possible role of NE in schizophrenia. First, we review the functional and structural properties of the LC-NE system and its impact on functional brain networks, cognition, stress, and neurodevelopment, with special emphasis on recent experimental and theoretical advances. Subsequently, we present an update about the role of these properties for the pathophysiology of schizophrenia, focusing on the cognitive and motivational deficits observed in schizophrenia. Finally, we suggest how recent development of experimental approaches can be used to characterize LC function in schizophrenia

Pupil size reflects activation of subcortical ascending arousal system nuclei during rest

Neuromodulatory nuclei that are part of the ascending arousal system (AAS) play a crucial role in regulating cortical state and optimizing task performance. Pupil diameter, under constant luminance conditions, is increasingly used as an index of activity of these AAS nuclei. Indeed, task-based functional imaging studies in humans have begun to provide evidence of stimulus-driven pupil-AAS coupling. However, whether there is such a tight pupil-AAS coupling during rest is not clear. To address this question, we examined simultaneously acquired resting-state fMRI and pupil-size data from 74 participants, focusing on six AAS nuclei: the locus coeruleus, ventral tegmental area, substantia nigra, dorsal and median raphe nuclei, and cholinergic basal forebrain. Activation in all six AAS nuclei was optimally correlated with pupil size at 0–2 s lags, suggesting that spontaneous pupil changes were almost immediately followed by corresponding BOLD-signal changes in the AAS. These results suggest that spontaneous changes in pupil size that occur during states of rest can be used as a noninvasive general index of activity in AAS nuclei. Importantly, the nature of pupil-AAS coupling during rest appears to be vastly different from the relatively slow canonical hemodynamic response function that has been used to characterize task-related pupil-AAS coupling

Greater Attention to Relevant Emotion Due to Orbitofrontal Lesion

Injury to the orbitofrontal cortex (OFC) is a frequent consequence of head injury and may lead to dysfunctional regulation of emotional and social behavior. Dysfunctional emotional behavior may partly be related to the role of the OFC in emotion-attention interaction, as reported previously. In order to better understand its role in emotion-attention and emotion-cognitive control interactions, we investigated attention allocation to task-relevant and task-irrelevant threat-related emotional stimuli during a task requiring cognitive control in patients with lesion to the OFC. We measured the behavioral performance and event-related potentials (ERP) of 13 patients with OFC lesion and 11 control subjects during a Go/NoGo visual discrimination task. In the task, line drawings of threatening (spider) and neutral (flower) figures served as either task-relevant Go or NoGo signals, or as task-irrelevant distractors. Overall performance did not differ between the groups. In contrast to the control group performance, the orbitofrontal group performance was improved by relevant threat signal in comparison with neutral signal. Further, task-relevant threat signals evoked larger frontocentral N2-P3 amplitude in the orbitofrontal group. Taken together, behavioral and electrophysiological results suggest that patients with OFC injury allocated more attentional and cognitive control resources in the context of task-relevant emotional stimuli. This study provides new evidence for the role of the OFC in emotion-attention and emotion-cognitive control interactions. Further, the OFC seems to contribute to the balance between voluntary and involuntary attention networks in context of emotional stimuli. Better understanding of alterations in emotion-attention interaction offers insight into affective dysfunction due to OFC lesion