A dynamic model for delta rhythm fit to high-frequency cortical activity data shows discrete functional connectivity in mouse cortex

Spontaneous activity as recorded by fMRI has often been used to infer active connections (\u27functional connectivity\u27) in the human brain through correlations of activity measures. Some serious questions have been raised about the interpretation of these correlations, which are often apparent only on time scales of tens of seconds. Confirmation of correlations in measures of activity on shorter time-scales closer to those of neural activity would be very desirable. Numerous mechanisms have been proposed for various rhythms but in the past half-century little consensus has been reached on the mechanism of any major rhythm. The recent development of high-throughput imaging methods enable us for the first time to rigorously and quantitatively test ideas about the dynamics of brain rhythms. We have generated high-resolution data on neural activity over most of one hemisphere of mouse cortex by voltage-sensitive dyes, in both anesthetized and awake animals. In previous work [1] we have analyzed relations between activity measures at different locations in terms of correlations. Here we fit these data to a predictive model, in which we attempt to predict the next change in activity at every point on cortex from the current pattern of activity over cortex. We fit both linear and non-linear models, whose parameters represent the intrinsic dynamics of local cortical regions and the inputs from distal regions. We find that all regions of mouse cortex appear to have virtually identical patterns of intrinsic dynamics (Figure 1A). We find that even a simple linear fit gives surprisingly sparse patterns of inferred connectivity. Where we have clear anatomical information, these fitted patterns appear to match known anatomy. Furthermore this fit can be used to identify the most prominent functional inputs into anatomically diffusely-connected areas such as the parietal association area (Figure 1B). Poster presentation from the Twenty Third Annual Computational Neuroscience Meeting: CNS*201

Hippocampus-dependent emergence of spatial sequence coding in retrosplenial cortex.

Retrosplenial cortex (RSC) is involved in visuospatial integration and spatial learning, and RSC neurons exhibit discrete, place cell-like sequential activity that resembles the population code of space in hippocampus. To investigate the origins and population dynamics of this activity, we combined longitudinal cellular calcium imaging of dysgranular RSC neurons in mice with excitotoxic hippocampal lesions. We tracked the emergence and stability of RSC spatial activity over consecutive imaging sessions. Overall, spatial activity in RSC was experience-dependent, emerging gradually over time, but, as seen in the hippocampus, the spatial code changed dynamically across days. Bilateral but not unilateral hippocampal lesions impeded the development of spatial activity in RSC. Thus, the emergence of spatial activity in RSC, a major recipient of hippocampal information, depends critically on an intact hippocampus; the indirect connections between the dysgranular RSC and the hippocampus further indicate that hippocampus may exert such influences polysynaptically within neocortex

In vivo Large-Scale Cortical Mapping Using Channelrhodopsin-2 Stimulation in Transgenic Mice Reveals Asymmetric and Reciprocal Relationships between Cortical Areas

We have mapped intracortical activity in vivo independent of sensory input using arbitrary point channelrhodopsin-2 (ChR2) stimulation and regional voltage sensitive dye imaging in B6.Cg-Tg (Thy1-COP4/EYFP)18Gfng/J transgenic mice. Photostimulation of subsets of deep layer pyramidal neurons within forelimb, barrel, or visual primary sensory cortex led to downstream cortical maps that were dependent on synaptic transmission and were similar to peripheral sensory stimulation. ChR2-evoked maps confirmed homotopic connections between hemispheres and intracortical sensory and motor cortex connections. This ability of optogentically activated subpopulations of neurons to drive appropriate downstream maps suggests that mechanisms exist to allow prototypical cortical maps to self-assemble from the stimulation of neuronal subsets. Using this principle of map self-assembly, we employed ChR2 point stimulation to map connections between cortical areas that are not selectively activated by peripheral sensory stimulation or behavior. Representing the functional cortical regions as network nodes, we identified asymmetrical connection weights in individual nodes and identified the parietal association area as a network hub. Furthermore, we found that the strength of reciprocal intracortical connections between primary and secondary sensory areas are unequal, with connections from primary to secondary sensory areas being stronger than the reciprocal

Imaging rapid redistribution of sensory-evoked depolarization through existing cortical pathways after targeted stroke in mice

Evidence suggests that recovery from stroke damage results from the production of new synaptic pathways within surviving brain regions over weeks. To address whether brain function might redistribute more rapidly through preexisting pathways, we examined patterns of sensory-evoked depolarization in mouse somatosensory cortex within hours after targeted stroke to a subset of the forelimb sensory map. Brain activity was mapped with voltage-sensitive dye imaging allowing millisecond time resolution over 9 mm2 of brain. Before targeted stroke, we report rapid activation of the forelimb area within 10 ms of contralateral forelimb stimulation and more delayed activation of related areas of cortex such as the hindlimb sensory and motor cortices. After stroke to a subset of the forelimb somatosensory cortex map, function was lost in ischemic areas within the forelimb map center, but maintained in regions 200–500 μm from blood flow deficits indicating the size of a perfused, but nonfunctional, penumbra. In many cases, stroke led to only partial loss of the forelimb map, indicating that a subset of a somatosensory domain can function on its own. Within the forelimb map spared by stroke, forelimb-stimulated responses became delayed in kinetics, and their center of activity shifted into adjacent hindlimb and posterior-lateral sensory areas. We conclude that the focus of forelimb-specific somatosensory cortex activity can be rapidly redistributed after ischemic damage. Given that redistribution occurs within an hour, the effect is likely to involve surviving accessory pathways and could potentially contribute to rapid behavioral compensation or direct future circuit rewiring

An Id-like current that is downregulated by Ca2+ modulates information coding at CA3–CA3 synapses in the rat hippocampus

Voltage-gated K+ channels localised on presynaptic nerve terminals control information coding by modulating presynaptic firing and synaptic efficacy in target neurones. We found that at CA3–CA3 connections in hippocampal slice cultures, a fast-activating, slowly inactivating K+ conductance similar to the so-called delay current (ID) is responsible for the delayed appearance of the first spike upon membrane depolarisation, for action potential repolarisation and for modulation of transmitter release. The Id-like current was downregulated by intracellular Ca2+, as indicated by the increased delay in the appearance of the first action potential following either the block of Ca2+ flux through voltage-dependent Ca2+ channels with Cd2+ or replacement of the bathing solution with one devoid of Ca2+. In both cases, this effect was reversed by blocking this conductance with a low concentration of 4-aminopyridine (4-AP, 10-50 μM). Application of 4-AP shortened the delay to the first spike generation, prevented the effect of Cd2+ and increased the spike duration. The earlier appearance of the first action potential was also observed in the presence of dendrotoxin-1 (100 nM). In voltage-clamp experiments larger currents were recorded in the absence of extracellular Ca2+, thus confirming the downregulation of the Id-like current by Ca2+ due to the positive shift of its inactivation. Spike broadening was associated with an enhancement of synaptic efficacy in target neurones, as assessed by the increase in EPSC amplitude and in the percentage of successes. Moreover, in the presence of 4-AP, EPSCs appeared with a longer latency and were more scattered. This conductance is therefore crucial for setting the timing and strength of synaptic transmission at CA3–CA3 connections. It is conceivable that switching off ID by increasing intracellular Ca2+ following activity-dependent processes may facilitate network synchronisation and crosstalk between CA3 pyramidal cells, leading to seizure activity

A systematic review and meta-analysis of extended high-frequency hearing thresholds in tinnitus with a normal audiogram

Objectives: Current evidence supports the growing application of extended high-frequency (EHF: 9-20 kHz) audiometry in hearing research, which likely results from the high vulnerability of this frequency region to damage induced by known auditory risk factors. The present systematic review and meta-analysis were performed to investigate whether adults with a normal audiogram and tinnitus show increased EHF hearing thresholds relative to control peers. Design: A comprehensive search was undertaken on electronic databases consisting of PubMed, ScienceDirect, Wiley, and Google Scholar using combined keywords: “tinnitus”, “extended high frequency”, “normal audiogram”, and “hidden hearing loss”.Results: From 261 papers found by searching databases, 9 studies met the inclusion criteria for the meta-analysis. A significant difference was observed between tinnitus and control groups in the effect size analysis of hearing thresholds at 10, 12.5, 14, 16, and 18 kHz (p≤0.001), and the I-square heterogeneity analysis was below 50% in all studies (p≥0.131). Visual inspection by the Funnel plot and Egger’s regression test (p≥0.211) also exhibited no publication bias in the meta-analyses. Conclusions: Our findings are in support of the idea that in most cases, tinnitus is associated with some degree of cochlear mechanical dysfunction, which may not be detected by conventional audiometry alone. This finding underscores the significance of EHF audiometry in clinical practice, which may help both early identification of individuals susceptible to developing tinnitus and reduce the number of new cases through preventive counseling programs

Non-diagnostic symptoms in a mouse model of autism in relation to neuroanatomy: the BTBR strain reinvestigated

Abstract Several mouse models of autism spectrum disorder (ASD), including the BTBR T + tf/J (BTBR) inbred strain, display a diverse array of behavioral deficits with particular face validity. Here we propose that phenotyping these preclinical models of ASD should avoid excessive reliance on appearance validity of the behavioral observations. BTBR mice were examined in three non-diagnostic symptoms modalities, beside an anatomical investigation for construct validity. The BTBR strain displayed poor sensorimotor integration as reflected by shorter stride length and greater latency on the balance beam task (BBT) when compared with C57BL/6 (B6) controls. Also, locomotor indices in the open-field task (OFT) revealed that BTBR mice traveled longer distances with a remarkably faster exploration than the B6 group in favor of hyperactivity and impulsiveness. Furthermore, analysis of spatial performance including search strategies in the Morris water task (MWT) indicated spatial impairment in the BTBR strain due to failure to employ spatial strategies during navigation. Quantitative cytoarchitectonics and volumetric examinations also indicated abnormal cortical and subcortical morphology in the BTBR mice. The results are discussed in relation to the neuroanatomical correlates of motor and cognitive impairments in the BTBR strain. We conclude that non-diagnostic autistic-like symptoms in the BTBR mouse strain can be impacted by autism risk factors in a similar way than the traditional diagnostic signs