Tactile object localization by anticipatory whisker motion.

Rodents use rhythmic protractions of their whiskers to locate objects in space. The amplitude of these protractions is reduced when whiskers contact objects, leading to a tendency of whiskers to only lightly touch the environment. While the impact of this process on the sensory input has been studied, little is known about how sensory input causes this change in the motor pattern. Here, using high-speed imaging of whisking in mice, we simultaneously measured whisker contacts and the resulting whisking motion. We found that mice precisely target their whisker protractions to the distance at which they expect objects. This modulation does not depend on the current sensory input and remains stable for at least one whisking cycle when there is no object contact or when the object position is changed. As a result, the timing and other information carried by whisker contacts encodes how well each protraction was matched to the object, functioning as an error signal. Whisker contacts can thus encode a mismatch between expected object locations and the actual environment.

Nogo receptor 1 limits tactile task performance independent of basal anatomical plasticity.

The genes that govern how experience refines neural circuitry and alters synaptic structural plasticity are poorly understood. The nogo-66 receptor 1 gene (ngr1) is one candidate that may restrict the rate of learning as well as basal anatomical plasticity in adult cerebral cortex. To investigate if ngr1 limits the rate of learning we tested adult ngr1 null mice on a tactile learning task. Ngr1 mutants display greater overall performance despite a normal rate of improvement on the gap-cross assay, a whisker-dependent learning paradigm. To determine if ngr1 restricts basal anatomical plasticity in the associated sensory cortex, we repeatedly imaged dendritic spines and axonal varicosities of both constitutive and conditional adult ngr1 mutant mice in somatosensory barrel cortex for two weeks through cranial windows with two-photon chronic in vivo imaging. Neither constant nor acute deletion of ngr1 affected turnover or stability of dendritic spines or axonal boutons. The improved performance on the gap-cross task is not attributable to greater motor coordination, as ngr1 mutant mice possess a mild deficit in overall performance and a normal learning rate on the rotarod, a motor task. Mice lacking ngr1 also exhibit normal induction of tone-associated fear conditioning yet accelerated fear extinction and impaired consolidation. Thus, ngr1 alters tactile and motor task performance but does not appear to limit the rate of tactile or motor learning, nor determine the low set point for synaptic turnover in sensory cortex.

Deficits in tactile learning in a mouse model of fragile X syndrome.

The fragile X mental retardation 1 mutant mouse (Fmr1 KO) recapitulates several of the neurologic deficits associated with Fragile X syndrome (FXS). As tactile hypersensitivity is a hallmark of FXS, we examined the sensory representation of individual whiskers in somatosensory barrel cortex of Fmr1 KO and wild-type (WT) mice and compared their performance in a whisker-dependent learning paradigm, the gap cross assay. Fmr1 KO mice exhibited elevated responses to stimulation of individual whiskers as measured by optical imaging of intrinsic signals. In the gap cross task, initial performance of Fmr1 KO mice was indistinguishable from WT controls. However, while WT mice improved significantly with experience at all gap distances, Fmr1 KO mice displayed significant and specific deficits in improvement at longer distances which rely solely on tactile information from whiskers. Thus, Fmr1 KO mice possess altered cortical responses to sensory input that correlates with a deficit in tactile learning.

Mapping functional brain activation using [14C]-iodoantipyrine in male serotonin transporter knockout mice.

BACKGROUND: Serotonin transporter knockout mice have been a powerful tool in understanding the role played by the serotonin transporter in modulating physiological function and behavior. However, little work has examined brain function in this mouse model. We tested the hypothesis that male knockout mice show exaggerated limbic activation during exposure to an emotional stressor, similar to human subjects with genetically reduced transcription of the serotonin transporter. METHODOLOGY/PRINCIPAL FINDINGS: Functional brain mapping using [(14)C]-iodoantipyrine was performed during recall of a fear conditioned tone. Regional cerebral blood flow was analyzed by statistical parametric mapping from autoradiographs of the three-dimensionally reconstructed brains. During recall, knockout mice compared to wild-type mice showed increased freezing, increased regional cerebral blood flow of the amygdala, insula, and barrel field somatosensory cortex, decreased regional cerebral blood flow of the ventral hippocampus, and conditioning-dependent alterations in regional cerebral blood flow in the medial prefrontal cortex (prelimbic, infralimbic, and cingulate). Anxiety tests relying on sensorimotor exploration showed a small (open field) or paradoxical effect (marble burying) of loss of the serotonin transporter on anxiety behavior, which may reflect known abnormalities in the knockout animal's sensory system. Experiments evaluating whisker function showed that knockout mice displayed impaired whisker sensation in the spontaneous gap crossing task and appetitive gap cross training. CONCLUSIONS: This study is the first to demonstrate altered functional activation in the serotonin transporter knockout mice of critical nodes of the fear conditioning circuit. Alterations in whisker sensation and functional activation of barrel field somatosensory cortex extend earlier reports of barrel field abnormalities, which may confound behavioral measures relying on sensorimotor exploration.

Dynamic mapping of cortical development before and after the onset of pediatric bipolar illness.

BACKGROUND: There are, to date, no pre-post onset longitudinal imaging studies of bipolar disorder at any age. We report the first prospective study of cortical brain development in pediatric bipolar illness for 9 male children, visualized before and after illness onset. METHOD: We contrast this pattern with that observed in a matched group of healthy children as well as in a matched group of 8 children with 'atypical psychosis' who had similar initial presentation marked by mood dysregulation and transient psychosis (labeled as 'multi-dimensionally impaired' (MDI)) as in the bipolar group, but have not, to date, developed bipolar illness. RESULTS: Dynamic maps, reconstructed by applying novel cortical pattern matching algorithms, for the children who became bipolar I showed subtle, regionally specific, bilaterally asymmetrical cortical changes. Cortical GM increased over the left temporal cortex and decreased bilaterally in the anterior (and sub genual) cingulate cortex. This was seen most strikingly after the illness onset, and showed a pattern distinct from that seen in childhood onset schizophrenia. The bipolar neurodevelopmental trajectory was generally shared by the children who remained with MDI diagnosis without converting to bipolar I, suggesting that this pattern of cortical development may reflect affective dysregulation (lability) in general. CONCLUSIONS: These dynamic trajectories of cortical development may explain age-related disparate findings from cross-sectional studies of bipolar illness, and suggest the importance of mood disordered non-bipolar control group in future studies.

Dynamic mapping of hippocampal development in childhood onset schizophrenia.

Prior cross-sectional anatomic brain imaging studies of the hippocampus in schizophrenia have generally shown loss in total hippocampal volume although the progressive course of these changes remains unknown. We report the first prospective sub-regional maps of hippocampal development in childhood onset schizophrenia (COS), reconstructed from serial brain MRI scans of 29 children with COS scanned every 2 years (87 scans) and compared to 31 controls matched for age, sex, and scan interval (94 scans). As expected, the COS subjects showed significant bilateral deficits (9-10%) in total hippocampal volume which remained consistent between age 9 and 26. However sub-regional maps showed heterogeneous changes with loss of hippocampal volume in both anterior as well as posterior ends while the body of the hippocampus gained in volume suggesting that hippocampal subunits are differentially affected in schizophrenia.

Dynamic mapping of normal human hippocampal development.

The hippocampus, which plays an important role in memory functions and emotional responses, has distinct subregions subserving different functions. Because the volume and shape of the hippocampus are altered in many neuropsychiatric disorders, it is important to understand the trajectory of normal hippocampal development. We present the first dynamic maps to reveal the anatomical sequence of normal human hippocampal development. A novel hippocampal mapping technique was applied to a database of prospectively obtained brain magnetic resonance imaging (MRI) scans (100 scans in 31 children and adolescents), scanned every 2 yr for 6-10 yr between ages 4 and 25. Our results establish that the structural development of the human hippocampus is remarkably heterogeneous, with significant differences between posterior (increase over time) and anterior (loss over time) subregions. These distinct developmental trajectories of hippocampal subregions may parallel differences in their functional development.

Mapping hippocampal and ventricular change in Alzheimer disease.

We developed an anatomical mapping technique to detect hippocampal and ventricular changes in Alzheimer disease (AD). The resulting maps are sensitive to longitudinal changes in brain structure as the disease progresses. An anatomical surface modeling approach was combined with surface-based statistics to visualize the region and rate of atrophy in serial MRI scans and isolate where these changes link with cognitive decline. Sixty-two [corrected] high-resolution MRI scans were acquired from 12 AD patients (mean [corrected] age +/- SE at first scan: 68.7 +/- 1.7 [corrected] years) and 14 matched controls (age: 71.4 +/- 0.9 years) [corrected] each scanned twice (1.9 +/- 0.2 [corrected] years apart, when all subjects are pooled [corrected] 3D parametric mesh models of the hippocampus and temporal horns were created in sequential scans and averaged across subjects to identify systematic patterns of atrophy. As an index of radial atrophy, 3D distance fields were generated relating each anatomical surface point to a medial curve threading down the medial axis of each structure. Hippocampal atrophic rates and ventricular expansion were assessed statistically using surface-based permutation testing and were faster in AD than in controls. Using color-coded maps and video sequences, these changes were visualized as they progressed anatomically over time. Additional maps localized regions where atrophic changes linked with cognitive decline. Temporal horn expansion maps were more sensitive to AD progression than maps of hippocampal atrophy, but both maps correlated with clinical deterioration. These quantitative, dynamic visualizations of hippocampal atrophy and ventricular expansion rates in aging and AD may provide a promising measure to track AD progression in drug trials.

Dynamic mapping of human cortical development during childhood through early adulthood.

We report the dynamic anatomical sequence of human cortical gray matter development between the age of 4-21 years using quantitative four-dimensional maps and time-lapse sequences. Thirteen healthy children for whom anatomic brain MRI scans were obtained every 2 years, for 8-10 years, were studied. By using models of the cortical surface and sulcal landmarks and a statistical model for gray matter density, human cortical development could be visualized across the age range in a spatiotemporally detailed time-lapse sequence. The resulting time-lapse "movies" reveal that (i) higher-order association cortices mature only after lower-order somatosensory and visual cortices, the functions of which they integrate, are developed, and (ii) phylogenetically older brain areas mature earlier than newer ones. Direct comparison with normal cortical development may help understanding of some neurodevelopmental disorders such as childhood-onset schizophrenia or autism.