Cerebral Cortex

Published by Oxford University Press (OUP)
Online ISSN: 1460-2199
Most functional imaging studies of the auditory system have employed complex stimuli. We used positron emission tomography to map neural responses to 0.5 and 4.0 kHz sine-wave tones presented to the right ear at 30, 50, 70 and 90 dB HL and found activation in a complex neural network of elements traditionally associated with the auditory system as well as non-traditional sites such as the posterior cingulate cortex. Cingulate activity was maximal at low stimulus intensities, suggesting that it may function as a gain control center. In the right temporal lobe, the location of the maximal response varied with the intensity, but not with the frequency of the stimuli. In the left temporal lobe, there was evidence for tonotopic organization: a site lateral to the left primary auditory cortex was activated equally by both tones while a second site in primary auditory cortex was more responsive to the higher frequency. Infratentorial activations were contralateral to the stimulated ear and included the lateral cerebellum, the lateral pontine tegmentum, the midbrain and the medial geniculate. Contrary to predictions based on cochlear membrane mechanics, at each intensity, 4.0 kHz stimuli were more potent activators of the brain than the 0.5 kHz stimuli.
Evidence from both human and animal studies indicates that catecholamine (dopamine and noradrenaline) imbalances in the fronto-striatal circuitry are associated with deficits in higher- order cognitive functions. The present study examined how catecholamines within this circuitry modulate attentional function, specifically the ability to develop, maintain, and shift an attentional set. Catecholamine depletions within the frontal cortex of the common marmoset impaired the ability to acquire an attentional set, and increased susceptibility to distraction from task-irrelevant stimuli. Analysis of set-shifting performance with stimulus dimensions of varying salience suggested that frontal catecholamine depletion selectively disrupts "top-down", but not "bottom-up" attentional processing. In contrast, the ability to acquire and shift an attentional set remained intact following dopaminergic depletion from the caudate nucleus. However, the reduced susceptibility to distraction from task-irrelevant stimuli displayed by monkeys with dopaminergic depletions of the caudate nucleus suggests that responding was under more rigid control by the currently rewarded stimulus. The results demonstrate opposite behavioural effects of 6-hydroxydopamine (6-OHDA) lesions in the frontal cortex and caudate nucleus in tasks requiring selective attention. Frontal catecholamine depletion caused an increase in distractibility while caudate dopamine loss induced greater focusing of responding.
Representative locations of dialysis probes in the mPFC ( A ) and OFC ( B ). 
Basal levels of 5-HT, 5-HIAA, DA and DOPAC in the mPFC and OFC of animals performing the delay-discounting task and yoked animals
Levels of 5-HT and 5-HIAA in the mPFC and OFC of subject in all three experimental groups. Data are expressed as the percentage change from baseline levels ± SEM. Sample 1 was the first sample to be taken during performance of the behavioural task. Samples 1 and 2 were collected when the delay to the large reward was 0 s, samples 3 and 4 when the delay to the large reward was 10 s, samples 5 and 6 when the delay to the large reward was 20 s, samples 7 and 8 when the delay to the large reward was 40 s, and samples 9 and 10 when the delay to the large reward was 60 s. 
Levels of DA and DOPAC in the mPFC and DOPAC in the OFC of subject in all three experimental groups. Data are expressed as the percentage change from baseline levels ± SEM. Sample 1 was the first sample to be taken during performance of the behavioural task. Samples 1 and 2 were collected when the delay to the large reward was 0 s, samples 3 and 4 when the delay to the large reward was 10 s, samples 5 and 6 when the delay to the large reward was 20 s, samples 7 and 8 when the delay to the large reward was 40 s, and samples 9 and 10 when the delay to the large reward was 60 s. 
Dysregulation of the prefrontal cortex (PFC) has been implicated in impulse control disorders, including attention deficit hyperactivity disorder. A growing body of evidence suggests that impulsivity is non-unitary in nature, and recent data indicate that the ventral and dorsal regions of the PFC are differentially involved in distinct aspects of impulsive behaviour, findings which may reflect differences in the monoaminergic regulation of these regions. In the current experiment, levels of dopamine, serotonin and their metabolites were measured in the medial PFC (n = 12) and orbitofrontal cortex (OFC) (n = 19) of rats using in vivo microdialysis during the delay-discounting model of impulsive choice, where impulsivity is defined as selection of small immediate over larger delayed rewards. Yoked groups were also dialysed to control for instrumental responding and reward delivery. Significant increases in 5-hydroxytryptamine efflux were observed in the mPFC, but not in the OFC, during task performance but not under yoked control conditions. In the OFC, 3,4-di-hydroxy-phenylocetic acid (DOPAC) levels increased in animals performing the task but not in yoked animals, whereas mPFC DOPAC levels increased in all subjects. These data suggest a double dissociation between serotonergic and dopaminergic modulation of impulsive decision-making within distinct areas of frontal cortex.
In the prefrontal cortex of subjects with schizophrenia, markers of the synthesis and re-uptake of GABA appear to be selectively altered in a subset of interneurons that includes chandelier cells. Determining the effect of these disturbances in presynaptic GABA markers on inhibitory signaling requires knowledge of the status of GABA(A) receptors at the postsynaptic targets of chandelier cells, the axon initial segments (AIS) of pyramidal neurons. Because the alpha(2) subunit of the GABA(A) receptor is preferentially localized at pyramidal neuron AIS, we quantified alpha(2) subunit immunoreactive AIS in tissue sections containing prefrontal cortex area 46 from 14 matched triads of subjects with schizophrenia, subjects with major depression and control subjects. Systematic, random sampling revealed that the mean number of alpha(2)-labeled AIS per mm(2) in subjects with schizophrenia was significantly (P = 0.007) increased by 113% compared to control subjects and non-significantly increased compared to subjects with major depression. Furthermore, within subjects with schizophrenia, the density of alpha(2)-labeled AIS was negatively correlated (r = -0.49, P = 0.038) with the density of chandelier axon terminals immunoreactive for the GABA membrane transporter. These data suggest that GABA(A) receptors are up-regulated at pyramidal neuron AIS in response to deficient GABA neuro-transmission at chandelier axon terminals in schizophrenia. Thus, disturbances in inhibition at the chandelier neuron-pyramidal neuron synapse may be a critical component of prefrontal cortical dysfunction in schizophrenia.
Proportions of principal cerebral structures: boy to girl and child to adult 
Proportions of grouped cerebral structures: boy to girl and child to adult 
Volumetric magnetic resonance image (MRI)-based morphometry was performed on the brains of 30 normal children (15 males and 15 males) with a mean age of 9 years (range 7-11 years). This age range lies in a late but critical phase of brain growth where not volumetric increment will be small but when the details of brain circuity are being fine-tuned to support the operations of the adult brain. The brain at this age is 95% the volume of the adult brain. The brain of the female child is 93% the volume of the male child. For more than 95% of brain structures, the volumetric differences in male and female child brain are uniformly scaled to the volume difference of the total brain in the two sexes. Exceptions to this pattern of uniform scaling are the caudate, hippocampus and pallidum, which are disproportionately larger in female than male child brain, and the amygdala, which is disproportionately smaller in the female child brain. The patterns of uniform scaling are generally sustained during the final volumetric increment in overall brain size between age 7-11 and adulthood. There are exceptions to this uniform scaling of child to adult brain, and certain of these exceptions are sexually dimorphic. Thus, with respect to major brain regions, the cerebellum in the female but not the male child is already at adult volume while the brainstem in both sexes must enlarge more than the brain as a whole. The collective subcortical gray matter structures of the forebrain of the female child are already at their adult volumes. The volumes of these same structures in the male child, by contrast, are greater than their adult volumes and, by implication, must regress in volume before adulthood. The volume of the central white matter, on the other hand, is disproportionately smaller in female than male child brain with respect to the adult volumes of cerebral central white matter. By implication, relative volumetric increase of cerebral central white matter by adulthood must be greater in the female than male brain. The juxtaposed progressive and regressive patterns of growth of brain structures implied by these observations in the human brain have a soundly established precedent in the developing rhesus brain. There is emerging evidence that sexually dimorphic abnormal regulation of these terminal patterns of brain development are associated with gravely disabling human disorders of obscure etiology.
(a) Detail of transition between frequencies used in all stimulus sequences. The top graph shows how the amplitude profile of each tone was ramped in cosine counterphase; the bottom graph shows the resulting waveform. Note the smooth change of frequency, devoid of discontinuities or any variation in amplitude envelope at the transition point. (b) Schematic representation of stimuli used. Each pair of panels shows an excerpt of a stimulus sequence represented on the left as a spectrogram (frequency as a function of time) and on the right as a Fourier spectrum (amplitude as a function of frequency; integrated over a 10 s time window). The top pair of panels represents the standard stimulus: two tones with a frequency separation f of 1200 cents (one octave), with a fastest temporal change of t = 667 ms. The three sets of panels along the left of the figure illustrate three levels of change on the temporal parameter, such that t = 333, 83 or 21 ms, the latter corresponding to the fastest value used, while f is held constant. The spectrogram shows how the stimuli change progressively faster, while the Fourier spectra show two fixed spectral peaks corresponding to the two frequencies, with only a minimal spread of energy as the rate of alternation is increased. The three sets of panels along the right side of the figure illustrate three levels of change on the spectral parameter, with the minimum frequency difference f decreasing to 600, 150 and 37.5 cents. The value of t is held constant at 667 ms. Note that the Fourier spectra show increasing numbers of more finely spaced frequency components as the spectral parameter changes.  
We used positron emission tomography to examine the response of human auditory cortex to spectral and temporal variation. Volunteers listened to sequences derived from a standard stimulus, consisting of two pure tones separated by one octave alternating with a random duty cycle. In one series of five scans, spectral information (tone spacing) remained constant while speed of alternation was doubled at each level. In another five scans, speed was kept constant while the number of tones sampled within the octave was doubled at each level, resulting in increasingly fine frequency differences. Results indicated that (i) the core auditory cortex in both hemispheres responded to temporal variation, while the anterior superior temporal areas bilaterally responded to the spectral variation; and (ii) responses to the temporal features were weighted towards the left, while responses to the spectral features were weighted towards the right. These findings confirm the specialization of the left-hemisphere auditory cortex for rapid temporal processing, and indicate that core areas are especially involved in these processes. The results also indicate a complementary hemispheric specialization in right-hemisphere belt cortical areas for spectral processing. The data provide a unifying framework to explain hemispheric asymmetries in processing speech and tonal patterns. We propose that differences exist in the temporal and spectral resolution of corresponding fields in the two hemispheres, and that they may be related to anatomical hemispheric asymmetries in myelination and spacing of cortical columns.
(a) The task-set switching paradigm. Cues, stimuli and required responses are shown. The colour of the stimulus-window indicates which task (naming letters or naming digits) has to be performed by the subject. A card with a green and a red rectangle with the words 'letter' and 'number' is placed beneath the computer screen to help subjects remember the colour–task associations. An example of a trial sequence in the 'crosstalk' condition is shown in the middle part of this figure. In this condition, 67% of trials include stimulus attributes associated with the irrelevant task (e.g. 'K4'). On 33% of the trials the irrelevant character is neutral (for example, '3#'). In the 'no-cross-talk' condition (not shown here) none of the stimuli include characters associated with the competing task and irrelevant characters are always non-alphanumeric. The required responses are shown in the bottom part of this figure. In this particular case the colour green is associated with naming letters and the colour red is associated with naming digits. (b) The probabilistic reversal paradigm. Four boxes were displayed at the top, the bottom, the left and the right of the screen. In two of the four boxes a red or green 'grating' pattern was displayed and subjects were asked to touch one of these two patterns. Each response was followed by computer feedback, consisting of both an auditory message (a high-or a low-pitch tone) and a visual message (the word 'correct' or 'wrong'). After 40 trials the contingencies were reversed.  
Task-set switching data. Patients 'off' medication exhibited significantly increased switch costs in the 'cross-talk' condition, but not in the 'no-cross-talk' condition [significant group × switch × 'cross-talk' interaction, F(1,27) = 11.2, P = 0.002]. (a) Mean reaction times in the 'crosstalk' condition. Patients exhibited significantly increased switch costs [F(1,54) = 10.7, P = 0.002] compared with controls. Moreover, patients 'off' medication exhibited increased switch costs compared with patients 'on' medication [F(1,27) = 13.24, P = 0.001]. (b) Mean reaction times in the 'no-cross-talk' condition. There were no significant differences in terms of switch costs between any of the groups.  
Failure rates on the probabilistic reversal paradigm. At the initial acquisition stage, no patients 'off' medication, one out of 14 patients 'on' medication, and one out of 23 controls failed to reach criterion. In contrast, at the reversal stage six out of 14 patients 'on' medication failed to reach criterion, while only two out of 15 patients 'off' medication and one out of 23 controls failed to reach criterion. The difference between controls and patients was significant (χ 2 (1) = 5.5, P = 0.02) and a second orthogonal contrast and inspection of the data show that this difference was due to significantly more patients 'on' medication failing the reversal stage than patients 'off' medication (χ 2 (1) = 3.8, P = 0.05) and than controls.  
We investigated how dopamine (DA) systems contribute to cognitive performance in the domain of learning and attentional flexibility by examining effects of withdrawing DA-ergic medication in patients with Parkinson's disease (PD). Medication remediated impairments in switching between two tasks, thought to depend on circuitry connecting the dorsolateral prefrontal cortex and the posterior parietal cortex to the dorsal caudate nucleus, which is profoundly DA-depleted in PD. By contrast, the same medication impaired probabilistic reversal learning that implicates orbitofrontal cortex- ventral striatal circuitry, which is relatively spared of DA loss in PD. Hence, DA-ergic medication improves or impairs cognitive performance depending on the nature of the task and the basal level of DA function in underlying cortico-striatal circuitry.
In order to investigate whether and how medial prefrontal cortex (mPFC) of the rat is involved in processing of information related to fear conditioning, we recorded from single units in the prelimbic and infralimbic cortex of fear-conditioned rats in response to an explicit conditional stimulus (CS; an auditory tone) or contextual cues (conditioning box). The majority of units changed their activities significantly in response to the CS in a delay or trace conditioning paradigm. Both transient and tonic activity changes, including delay cell activity, were observed as in other behavioral tasks. When exposed to the context without CS delivery, most units changed their activities as well. These results show that both tone and contextual information are processed in the rat mPFC in expectation of the delivery of an aversive stimulus (electric foot shock). Interestingly, fast spiking cells (putative inhibitory interneurons) and regular spiking cells (putative projection neurons) showed different patterns of responses. Fast spiking cells tended to show transient responses and increased their firing rates following CS presentation, whereas a complementary pattern was observed in the regular spiking cells. Our results enhance our understanding of the neural mechanisms underlying prediction of an aversive stimulus in the mPFC.
Electron microscopy was used in macaque monkey cortical area V1 to investigate what factors might determine the proportion of somatic membrane covered by inhibitory type 2 synapses. In a sample of 4654 excitatory neurons, synapse cover did not correlate consistently with cell variety (pyramid or spiny stellate), soma size, synaptic apposition length or thalamic input. There were significant differences in somatic synapse cover per layer, but the pattern of differences in cover among layers differed significantly between animals, suggesting that laminar environment alone is not a generally applicable determinant of amount of inhibitory synapse cover. The pattern of cover for cells in different layers was, however, similar between the two hemispheres of an individual monkey. Measures of inhibitory synapse cover on four sets of pyramidal neurons in layers 5 and 6, each with different efferent projection targets, showed that the sets differed significantly from other cells in their respective layers, and differed significantly from each other. These findings demonstrate that there is unique circuitry for different subsystems within single layers of cortex and provide a rationale for the rich variety of cortical GABAergic interneurons within single layers.
N-Methyl-D-aspartate (NMDA) receptors play a critical role in many cortical functions and are implicated in several neuropsychiatric diseases. In this study, the cellular expression of the NMDAR1 (NR1) and NMDAR2A and B (NR2A and B) subunits was investigated in the human cerebral cortex by immunocytochemistry with antibodies that recognize the NR1 or the NR2A and B subunits of the NMDA receptor. In frontal (areas 10 and 46) and temporal (area 21) association cortices and the cingulofrontal transition cortex (area 32), NR1 and NR2A/B immunoreactivity (ir) were similar and were localized to numerous neurons in all cortical layers. NR1- and NR2A/B-positive neurons were mostly pyramidal cells, but some nonpyramidal neurons were also labeled. Electron-microscopic observations showed that NR1 and NR2A/B ir were similar. In all cases, labeling of dendrites and dendritic spines was intense. In addition, both NR1 and NR2A/B were consistently found in the axoplasm of some axon terminals and in distal astrocytic processes. This investigation revealed that numerous NMDA receptors are localized to dendritic spines, and that they are also localized to axon terminals and astrocytic processes. These findings suggest that the effects of cortical NMDA activation in the human cortex do not depend exclusively on the opening of NMDA channels located at postsynaptic sites, and that the localization of NMDA receptors is similar in a variety of mammalian species.
Serotonergic 5-HT1A and 5-HT2A receptors are abundantly expressed in prefrontal cortex (PFC) and are targets of atypical antipsychotic drugs. They mediate, respectively, inhibitory and excitatory actions of 5-HT. The transcripts for both receptors are largely (approximately 80%) colocalized in rat and mouse PFC, yet their quantitative distribution in pyramidal and GABAergic interneurons is unknown. We used double in situ hybridization histochemistry to estimate the proportion of pyramidal and GABAergic neurons expressing these receptor transcripts in rat PFC. The number of GABAergic interneurons (expressing GAD mRNA) was a 22% of glutamatergic neurons (expressing vGluT1 mRNA, considered as putative pyramidal neurons). 5-HT2A receptor mRNA was present in a large percentage of pyramidal neurons (from 55% in prelimbic cortex to 88% in tenia tecta), except in layer VI, where it was localized only in 30% of those neurons. 5-HT2A receptor mRNA was present in approximately 25% of GAD-containing cells except in layer VI (10%). Likewise, approximately 60% of glutamatergic cells contained the 5-HT1A receptor transcript. We also found that approximately 25% of GAD-expressing cells contained the 5-HT1A receptor mRNA. These data help to clarify the role of 5-HT in prefrontal circuits and shed new light to the cellular elements involved in the action of atypical antipsychotics.
The entorhinal, perirhinal and parahippocampal cortices are anatomically positioned to mediate the bi-directional flow of information between the hippocampus and neocortex. Consistent with this organization, damage involving the parahippocampal region causes significant learning and memory impairment in young subjects. Although recent evidence indicates that neuron death in the hippocampus is not required to account for the effects of normal aging on learning and memory, other findings suggest that changes in parahippocampal interactions with the hippocampus may play a significant role. Prompted by this background, we tested the possibility that age-related deficits in hippocampal learning are coupled with neuron death in the parahippocampal region. The experiments took advantage of a well-characterized rat model of cognitive aging in combination with stereological methods for quantifying neuron number. The results demonstrate that total neuron number in the entorhinal, perirhinal and postrhinal cortices is largely preserved during normal aging. Furthermore, individual variability in hippocampal learning among the aged rats failed to correlate with neuron number in any region examined and there was no indication of selective or disproportionate loss among the aged animals with the most pronounced cognitive impairment. Taken together with earlier findings from the same study population, the results demonstrate that age-related cognitive decline can occur in the absence of significant neuron death in any major, cytoarchitectonically defined component of the hippocampal system. These findings provide an essential framework for identifying the basis of cognitive aging, suggesting that alterations in connectivity and other changes are more likely causative factors.
Specimens used
Regional expression of PCDH11X/Y
Double labeling of PCDH11X/Y. (A–D) Merged images showing co-localization of all PCDH11X/Y antibodies in the fetal cerebral cortex, 13 PCW female (A, Procad1a: green, anti-PCDH11X/Y: red; B, Procad1a: green, X11: red; C, Ex6: green, X11: red; D, Ex6: green, anti-PCDH11X/Y: red). (E and F) Merged images showing co-localization of PCDH11X/Y with DCX and NPY in the fetal cerebral cortex, 13 PCW female (E, Procad1a: green, DCX: red; F, Procad1a: green, NPY: red). Arrowheads in (E and F) highlight the co-expression of PCDH11X/Y in the SP and IZ with DCX and NPY, respectively. (G–K) Adult cerebral cortex, female (G, Procad1a: green; H, anti-PCDH11X/Y: red; I, merged image; J, calretinin: green, anti-PCDH11X/Y: red; K, calbindin: green, anti-PCDH11X/Y: red). Arrowheads in (J and K) highlight the expression of PCDH11X/Y in the absence of calretinin and calbindin, respectively. Scale bars: (A–J) 100 μm; (K): 25 μm. CP, cortical plate; IZ, intermediate zone; MZ, marginal zone; SP, subplate; SVZ, subventricular zone; VZ, ventricular zone.
Expression of PCDH11X/Y in the fetal brain. Cerebral cortex (A, 14 PCW female; B, 16 PCW male; C, 19 PCW male; D, 12 PCW male), hippocampal formation (E, 18 PCW female), cerebellum and pons (F, 18 PCW female), and medulla oblongata (G, 27 PCW male; H and I, 18 PCW female). Scale bars: (A, F–I): 3000 μm; (B, C): 5000 μm; (D) 100 μm; (E) 1000 μm. AN, abducens nucleus; ArN, arcuate nucleus; Cau, caudate; CCtx, cerebellar cortex; CN, cuneate nucleus; CP, cortical plate; DN, dentate nucleus; EN, emboliform nucleus; FD, fascia dentata; FN, facial nucleus; GN, gracile nucleus; Hc, hippocampal formation; IO, inferior olivary nucleus; IZ, intermediate zone; LGE, lateral ganglionic eminence; MGE, medial ganglionic eminence; MZ, marginal zone; PHG, parahippocampal gyrus; SB, subiculum; SP, subplate; STN, spinal trigeminal nucleus; SVZ, subventricular zone; Th, thalamus; VZ, ventricular zone.
Expression of PCDH11X/Y in the adult brain. Frontal cortex (A, male), superior temporal gyrus (B, female) with prominent expression in pyramidal neurons (C, female), basal ganglia (D, male), thalamus (E, female), cerebellar cortex (F, male), hippocampal formation (G, female), midbrain (H, female), and medulla oblongata (I, male). Scale bars: (A) 200 μm; (B) 100 μm; (C) 50 μm; (D, E G–I) 5000 μm; (F) 25 μm. CA1-4, areas of Ammon's horn; Cau, caudate; DR, dorsal raphe; FD, fascia dentata; GL, granular layer; HN, hypoglossal nucleus; I–VI, cortical layers I–VI; IC, internal capsule; IO, inferior olivary nucleus; LD, lateral dorsal nucleus; MD, mediodorsal nucleus; ML, molecular layer; PL, Purkinje cell layer; Put, putamen; Red, red nucleus; SB, subiculum; SN, substantia nigra; WM, white matter.
Protocadherins 11X and 11Y are cell adhesion molecules of the δ1-protocadherin family. Pcdh11X is present throughout the mammalian radiation; however, 6 million years ago (MYA), a reduplicative translocation of the Xq21.3 block onto what is now human Yp11 created the Homo sapiens-specific PCDH11Y. Therefore, modern human females express PCDH11X whereas males express both PCDH11X and PCDH11Y. PCDH11X/Y has been subject to accelerated evolution resulting in human-specific changes to both proteins, most notably 2 cysteine substitutions in the PCDH11X ectodomain that may alter binding characteristics. The PCDH11X/Y gene pair is postulated to be critical to aspects of human brain evolution related to the neural correlates of language. Therefore, we raised antibodies to investigate the temporal and spatial expression of PCDH11X/Y in cortical and sub-cortical areas of the human fetal brain between 12 and 34 postconceptional weeks. We then used the antibodies to determine if this expression was consistent in a series of adult brains. PCDH11X/Y immunoreactivity was detectable at all developmental stages. Strong expression was detected in the fetal neocortex, ganglionic eminences, cerebellum, and inferior olive. In the adult brain, the cerebral cortex, hippocampal formation, and cerebellum were strongly immunoreactive, with expression also detectable in the brainstem.
Semantic memory refers to knowledge about people, objects, actions, relations, self, and culture acquired through experience. The neural systems that store and retrieve this information have been studied for many years, but a consensus regarding their identity has not been reached. Using strict inclusion criteria, we analyzed 120 functional neuroimaging studies focusing on semantic processing. Reliable areas of activation in these studies were identified using the activation likelihood estimate (ALE) technique. These activations formed a distinct, left-lateralized network comprised of 7 regions: posterior inferior parietal lobe, middle temporal gyrus, fusiform and parahippocampal gyri, dorsomedial prefrontal cortex, inferior frontal gyrus, ventromedial prefrontal cortex, and posterior cingulate gyrus. Secondary analyses showed specific subregions of this network associated with knowledge of actions, manipulable artifacts, abstract concepts, and concrete concepts. The cortical regions involved in semantic processing can be grouped into 3 broad categories: posterior multimodal and heteromodal association cortex, heteromodal prefrontal cortex, and medial limbic regions. The expansion of these regions in the human relative to the nonhuman primate brain may explain uniquely human capacities to use language productively, plan, solve problems, and create cultural and technological artifacts, all of which depend on the fluid and efficient retrieval and manipulation of semantic knowledge.
Details of subjects studied
Delineation of the human uncinate fasciculus. In (a–c), Palmgren-stained coronal sections at three antero-posterior levels show the uncinate fasciculus and surrounding structures. In (d), a higher-power micrograph shows the fibres of the uncinate fasciculus. In (a–c), bar = 1 cm; in (d), bar = 50 µm. A-T, amygdalo-temporal; STG, superior temporal gyrus; TCN, tail of the caudate nucleus.  
Area, fibre density and fibre number of the uncinate fasciculus in normal subjects and patients with schizophrenia
Cross-sectional area of the uncinate fasciculus in controls (circles) and patients with schizophrenia (triangles). Left and right hemisphere measurements from the same individual are joined by solid (men) or dashed (women) lines. The right side is larger than the left, repeated-measures ANOVA [F(1,21) = 32.66, P = 0.0001].  
Estimated fibre number of the uncinate fasciculus in controls (circles) and patients with schizophrenia (triangles). Left and right hemisphere measurements from the same individual are joined by solid (men) or dashed (women) lines. There are more fibres in the right than the left uncinate fasciculus, repeated measures ANOVA [F(1,21) = 21.20, P = 0.0002].  
The uncinate fasciculus interconnects the anterior temporal and inferior frontal lobes. The temporal lobes show a number of anatomical asymmetries, some of which are altered in schizophrenia. This study was performed to assess the size and symmetry of the uncinate fasciculus in normal subjects and in patients with the disorder. The area, fibre density and total fibre number of left and right uncinate fasciculi were estimated using stereological methods in 21 control subjects and 17 schizophrenics. The uncinate fasciculus was found to be asymmetrical in both sexes, being 27% larger and containing 33% more fibres in the right than the left hemisphere. Of the 25 brains from which both hemispheres were available, the size asymmetry was seen in 20 subjects and the greater number of fibres in 21 subjects. There was no significant effect of schizophrenia upon the uncinate fasiculus, nor interactions of diagnosis with side or sex. We conclude that the uncinate fasciculus is larger in the right hemisphere, perhaps indicating greater right-sided fronto-temporal connectivity. The unchanged size of the fasciculus in schizophrenia contrasts with commissural tracts, which are affected in this brain series in a sex-specific manner.
A previous study using a rodent five-choice test of attention found poor choice accuracy and increased perseverative responding following medial prefrontal cortex (mPFC) lesions. As this rat cortical area includes at least two anatomically distinguishable subregions, the present study investigated their specific contributions to performance of this task. Rats were trained on the five-choice task prior to receiving excitotoxic lesions or sham surgery. In the first experiment, lesions of the dorsal mPFC (Zilles's Cg1) resulted in poor accuracy, but no changes in perseverative responding. Introducing variable delays for stimulus presentation abolished these accuracy deficits, suggesting that Cg1-lesioned rats were impaired at using temporal cues to guide performance. In the second experiment, lesions of the ventral mPFC increased perseverative responding, but had only short-lasting effects on accuracy. Rats with complete mPFC lesions had both choice accuracy impairments and increased perseverative responding. Additional evidence of the functional dissociation of dorsal and ventral mPFC came from the analysis of the spatial and temporal distribution of the correct and incorrect responses. Only rats with ventral mPFC lesions showed delay-dependent deficits and bias towards a location that had recently been associated with reward. Taken together, these results suggest dissociable 'executive' functions of mPFC subregions. Circuits centred on Cg1 are critical for the temporal organization of behaviour, while networks involving the ventral mPFC are important for maintaining behavioural flexibility.
Graphs showing (A) the normal changes of Q and P (solid lines) during the 11 cell cycle neuronogenetic interval (NI) and the three cell cycle period (cycles 4, 5 and 6) during which Q was lowered (long dashes) or raised (short dashes) for the calculations shown in B–F. (B–D) The predicted output per cell cycle, the predicted volume of PVE expansion and the predicted cumulative output, respectively, for the normal neuronogenetic interval (solid line) and for neuronogenetic intervals that have Q lowered (long dashes) or Q raised (short dashes). (E, F) The predicted relative change in the thickness of the neocortical wall and the predicted changes in the laminar proportions, respectively, for the normal, lowered Q and raised Q scenarios as shown in A.  
The effects of underexpression of p27 in a knockout mouse on the developing (E14) and mature (P21) neocortex. (A) Photographs of the forebrain from wildtype (left) and p27 kip1 knockout mouse (right) at E14; the area of the dorsomedial cortex at which all analyses was performed is enclosed in the rectangle and is shown at higher magnification below. (B) High power photographs of the mature dorsomedial neocortex at P21 showing the relatively thicker cortex in the p27 kip1 knockout mouse (right) and the increase in the thickness of the supragranular layers (II–IV).  
The neurons of the neocortex are generated over a 6 day neuronogenetic interval that comprises 11 cell cycles. During these 11 cell cycles, the length of cell cycle increases and the proportion of cells that exits (Q) versus re-enters (P) the cell cycle changes systematically. At the same time, the fate of the neurons produced at each of the 11 cell cycles appears to be specified at least in terms of their laminar destination. As a first step towards determining the causal interrelationships of the proliferative process with the process of laminar specification, we present a two-pronged approach. This consists of (i) a mathematical model that integrates the output of the proliferative process with the laminar fate of the output and predicts the effects of induced changes in Q and P during the neuronogenetic interval on the developing and mature cortex and (ii) an experimental system that allows the manipulation of Q and P in vivo. Here we show that the predictions of the model and the results of the experiments agree. The results indicate that events affecting the output of the proliferative population affect both the number of neurons produced and their specification with regard to their laminar fate.
Behavioral and brain frequencies in reading. ( A ) Reading accuracy in one subject as a function of word presentation rate in the behavioral test. The vertical lines indicate the 3 rates representing the floor and ceiling level, and approximately half-way between those levels. ( B ) Reading accuracy versus presentation rate in all 9 subjects (mean ± SD). ( C ) Coherence spectra for a selected MEG sensor, in the subject depicted in ( A ). The number of coherent sensor--sensor connections is plotted as a function of frequency. Presentation of the story at the fast (red), medium (black), and slow rate (blue). ( D ) Coherence spectra in all 9 subjects (mean ± SD), plotted for the medium presentation rate. The spectra were normalized to the maximum number of connections in each subject. 
Distributions of coherence and power at sensor level. Example from one subject. ( A ) Spatial distribution of the number of coherent sensor--sensor connections in the 8--13 Hz range, at the medium presentation rate, displayed on the MEG helmet. The map was normalized to the highest number of connections per sensor. ( B ) Spatial distribution of normalized oscillatory power in the 8--13 Hz range, at the medium presentation rate. The planar gradiometers of the MEG system used in this study detect the maximum signal directly above an active brain area. 
Network in a single subject. ( A ) Initial reference points for the subject depicted in Figure 2. Focal maxima of connection density maps (CDEs) at 8--13 Hz in the left-hemisphere cortex for the medium-rate RSVP task (left) and isolated word/ nonword condition (right). The slices advance from lateral (top) to medial (bottom) areas. The CDE maps were normalized to the highest number of connections per voxel. ( B ) Significantly coherent nodal points in the left hemisphere for the medium-rate RSVP and isolated word/nonword conditions, and the final set of nodal points compiled from all conditions. 
Group-level nodal points of neural connectivity. Section overlays of brain areas in which the time courses of activation at 8--13 Hz were significantly coherent with those in other regions of the brain. This map represents intersubject consistency of spatial location of the nodes (color indicates number of subject). OT = inferior 
Words forming a continuous story were presented to 9 subjects at frequencies ranging from 5 to 30 Hz, determined individually to render comprehension easy, effortful, or practically impossible. We identified a left-hemisphere neural network sensitive to reading performance directly from the time courses of activation in the brain, derived from magnetoencephalography data. Regardless of the stimulus rate, communication within the long-range neural network occurred at a frequency of 8-13 Hz. Our coherence-based detection of interconnected nodes reproduced several brain regions that have been previously reported as active in reading tasks, based on traditional contrast estimates. Intriguingly, the face motor cortex and the cerebellum, typically associated with speech production, and the orbitofrontal cortex, linked to visual recognition and working memory, additionally emerged as densely connected components of the network. The left inferior occipitotemporal cortex, involved in early letter-string or word-specific processing, and the cerebellum turned out to be the main forward driving nodes of the network. Synchronization within a subset of nodes formed by the left occipitotemporal, the left superior temporal, and orbitofrontal cortex was increased with the subjects' effort to comprehend the text. Our results link long-range neural synchronization and directionality with cognitive performance.
The hippocampus and prefrontal cortex are two structures implicated in learning and memory and are related through a direct excitatory pathway. The characteristics of the synaptic influence of the hippocampus on pyramidal cells of the prefrontal cortex were determined using intracellular recordings in anesthetized rats. Single-pulse stimulation of the hippocampus induced an early EPSP of fixed latency in most of the recorded pyramidal cells (n = 106/116) thereby demonstrating a monosynaptic connection between hippocampal neurons and pyramidal cells of the prefrontal cortex. Furthermore, the EPSP was followed by a prolonged IPSP and suggests a simultaneous engagement of pyramidal and non-pyramidal neurons that may ultimately constrain the spread of excitation in response to hippocampal input. Paired-pulse stimulation induced short-term modifications in the synaptic responses and this short-term plasticity may contribute to the temporal filtering of information. Finally, tetanic stimulation of the hippocampus produced long-term potentiation of the monosynaptic EPSP with a concomitant potentiation of the IPSP, indicating that the hippocampo-prefrontal network can participate in the formation and consolidation of memories. In conclusion, the characteristics of the synaptic transmission in the hippocampo-prefrontal cortex pathway further supports the existence of a cooperative relationship between two structures known to be involved in higher cognitive processes.
Elucidation of infant brain development is a critically important goal given the enduring impact of these early processes on various domains including later cognition and language. Although infants' whole-brain growth rates have long been available, regional growth rates have not been reported systematically. Accordingly, relatively less is known about the dynamics and organization of typically developing infant brains. Here we report global and regional volumetric growth of cerebrum, cerebellum, and brainstem with gender dimorphism, in 33 cross-sectional scans, over 3 to 13 months, using T(1)-weighted 3-dimensional spoiled gradient echo images and detailed semi-automated brain segmentation. Except for the midbrain and lateral ventricles, all absolute volumes of brain regions showed significant growth, with 6 different patterns of volumetric change. When normalized to the whole brain, the regional increase was characterized by 5 differential patterns. The putamen, cerebellar hemispheres, and total cerebellum were the only regions that showed positive growth in the normalized brain. Our results show region-specific patterns of volumetric change and contribute to the systematic understanding of infant brain development. This study greatly expands our knowledge of normal development and in future may provide a basis for identifying early deviation above and beyond normative variation that might signal higher risk for neurological disorders.
The computational power of the neocortex arises from interactions of multiple neurons, which display a wide range of electrical properties. The gene expression profiles underlying this phenotypic diversity are unknown. To explore this relationship, we combined whole-cell electrical recordings with single-cell multiplex RT-PCR of rat (p13-16) neocortical neurons to obtain cDNA libraries of 26 ion channels (including voltage activated potassium channels, Kv1.1/2/4/6, Kvbeta1/2, Kv2.1/2, Kv3.1/2/3/4, Kv4.2/3; sodium/potassium permeable hyperpolarization activated channels, HCN1/2/3/4; the calcium activated potassium channel, SK2; voltage activated calcium channels, Caalpha1A/B/G/I, Cabeta1/3/4), three calcium binding proteins (calbindin, parvalbumin and calretinin) and GAPDH. We found a previously unreported clustering of ion channel genes around the three calcium-binding proteins. We further determined that cells similar in their expression patterns were also similar in their electrical properties. Subsequent regression modeling with statistical resampling yielded a set of coefficients that reliably predicted electrical properties from the expression profile of individual neurons. This is the first report of a consistent relationship between the co-expression of a large profile of ion channel and calcium binding protein genes and the electrical phenotype of individual neocortical neurons.
To realize the potential of microRNAs (miRs) as fine-tuning regulators of embryonic neuronal differentiation, it is critical to define their developmental function. Mmu-miR-134 (miR-134) is a powerful inducer of pluripotent stem cell differentiation. However, its functional role during embryonic, neuronal development is unknown. We demonstrate that mature, miR-134 transcript levels elevate during embryonic, neuronal differentiation in vitro and in vivo. To define the developmental targets and function of miR-134, we identified multiple brain-expressed targets including the neural progenitor cell-enriched, bone morphogenetic protein (BMP) antagonist Chordin-like 1 (Chrdl-1) and the postmitotic, neuron-specific, microtubule-associated protein, Doublecortin (Dcx). We show that, through interaction with Dcx and/or Chrdl-1, miR-134 has stage-specific effects on cortical progenitors, migratory neurons, and differentiated neurons. In neural progenitors, miR-134 promotes cell proliferation and counteracts Chrdl-1-induced apoptosis and Dcx-induced differentiation in vitro. In neurons, miR-134 reduces cell migration in vitro and in vivo in a Dcx-dependent manner. In differentiating neurons, miR-134 modulates process outgrowth in response to exogenous BMP-4 in a noggin-reversible manner. Taken together, we present Dcx and Chrdl-1 as new regulatory targets of miR-134 during embryonic, mouse, cortical, and neuronal differentiation and show a novel and previously undiscovered role for miR-134 in the stage-specific modulation of cortical development.
Differential representation sites of the hand-and foot-related laser-evoked pain in the contralateral putamen. Hand and foot representation of laser-evoked fMRI responses in ipsilateral and contralateral putamen overlaid on a normalized T 1weighted image. Mean distributions of peak activation are illustrated by a sphere centred around the mean coordinate. Foot-related distribution is depicted in green, hand-related responses in red. Data from left-and right-sided stimulation were pooled for this illustration. To spatially overlay results for both sides of stimulus application, the results of the right-sided stimulation were mirrored along the z-plane (R-L flipped). Accordingly, responses contralateral to noxious stimulation (independent of the side of stimulation) are shown on the right, while responses in the putamen ipsilateral to nociceptive stimulation are shown on the left side. See online Supplementary Material for a colour version of this figure. 
Areas showing a significant covariation with putamen activity during noxious stimulation of the hand. The results from the psycho-physiological interaction analysis overlaid on a normalized T 1-weighted image. Covariation of activity in the sensori-motor cortex and the parietal operculum with activity in the putamen are stronger during noxious stimulation of the hand. To spatially overlay results for both sides of stimulus application, the results of the right-sided stimulation were mirrored along the z-plane (R-L flipped). Accordingly, responses contralateral to noxious stimulation (independent of the side of stimulation) are shown on the right, while responses in the putamen ipsilateral to nociceptive stimulation are shown on the left side. See online Supplementary Material for a colour version of this figure. 
The ability to locate pain plays a pivotal role in immediate defence and withdrawal behaviour. However, it is unclear to what extent nociceptive information is relayed to and processed in subcortical structures relevant for motor preparation and possibly the generation of withdrawal behaviour. We used single-trial functional magnetic resonance imaging (fMRI) to assess whether nociceptive information is represented in the putamen in a somatotopic manner. We therefore applied thulium-YAG laser-evoked pain stimuli, which had no concomitant tactile component, to the dorsum of the left hand and foot to 15 healthy subjects in a randomized order. In addition, 11 subjects were stimulated on the right body side. Differential representations of hand- and foot-related blood oxygen level dependent (BOLD) responses within the putamen were assessed using a single subject approach. Nociceptive stimuli significantly activated the putamen bilaterally. However, a somatotopic organization for hand- and foot-related responses was only present in the contralateral putamen. Here the foot was located anteriorly and medially to the hand, which parallels results from anatomical and microstimulation studies in monkeys and also human imaging data on the arrangement of movement related activity in the putamen. This result provides evidence for the hypothesis that behaviourally relevant nociceptive information without additional information from the tactile system is represented in the putamen and made available for pain related motor responses.
(a) Changes of coherence for all three conditions where objects were presented: written, auditorily and as pictures. For a better anatomical orientation, electrode positions are depicted in relation to cortical structure as determined by a magnetic resonance imaging study (Homan et al., 1987). The shaded areas indicate the variance of electrode positions obtained with the 10/20 system with respect to the cortical surface. Note that the area does not reflect the area of electrical integration over cortical potentials measured by the electrode. Solid lines between cortical sites indicate a significant increase of coherence with respect to the resting condition, dashed lines indicate a decrease of coherence. Only changes in coherence that were significant with an error probability of P < 0.05 or better are depicted. Common to all three conditions dealing with objects is an increased coherence between electrodes above temporal and above parietal cortex (thick line) in the 13–18 Hz range, bilateral. (b) Same as (a) for the non-sense conditions. Common to the non-sense conditions is a similar increase in coherent activity, though mostly in the right hemisphere (thick line).  
Changes in EEG amplitude for the same conditions as in Figure 6. Amplitudes change at several sites during the various conditions. No common pattern, however, is present.  
(a) Changes in coherence during presentation of letter strings with respect to the resting condition. Compare with the changes during visually and auditorily presented non-sense words (Fig. 6b): all three word-like stimuli are similar in that they lack meaning while maintaining the physical structure of a word; the difference is that both non-sense words are pronounceable, whereas the letter strings have no auditory correlate. Only in the case of pronounceable non-sense words the same temporoparietal synchronization as during object perception was found. (b) Changes in amplitude.  
Interhemispheric changes in coherence with respect to the resting condition. Coherence increases between left and right temporal electrodes in nearly all conditions dealing with entities.  
Significant differences in coherence during presentation of words denoting objects compared to non-sense words (direct comparison of coherence values in a paired Wilcoxon test). (a) Auditory presentation. Semantic processing is reflected in a left temporal increase of coherence. (b) Written presentation. Semantic processing is reflected in a change in coherence at the same cortical site.  
A series of recordings in cat visual cortex suggest that synchronous activity in neuronal cell ensembles serves to bind the different perceptual qualities belonging to one object. We provide evidence that similar mechanisms seem also to be observable in human subjects for the representation of supramodal entities. Electroencephalogram (EEG) was recorded from 19 scalp electrodes (10/20 system) in 19 human subjects and EEG amplitude and coherence were determined during presentation of objects such as house, tree, ball. Objects were presented in three different ways: in a pictorial presentation, as spoken words and as written words. In order to find correlates of modality-independent processing, we searched for patterns of activation common to all three modalities of presentation. The common pattern turned out to be an increase of coherence between temporal and parietal electrodes in the 13-18 Hz beta1 frequency range. This is evidence that population activity of temporal cortex and parietal cortex shows enhanced coherence during presentation of semantic entities. Coherent activity in this low-frequency range might play a role for binding of multimodal ensembles.
During corticogenesis, cells from the medial ganglionic eminence (MGE) migrate tangentially into the neocortical anlage. Here we report that gamma-aminobutyric acid (GABA), via GABAA receptors, regulates tangential migration. In embryonic telencephalic slices, bicuculline produced an outward current in migrating MGE-derived cells in the neocortex, suggesting the presence of and tonic activation by ambient GABA. Ambient GABA was also present in the MGE, although this required demonstration using as bioassay HEK293 cells expressing high-affinity alpha6/beta2/gamma2s recombinant GABAA receptors. The concentration of ambient GABA was 0.5+/-0.1 microM in both regions. MGE-derived cells before the corticostriate juncture (CSJ) were less responsive to GABA than those in the neocortex, and profiling of GABAA receptor subunit transcripts revealed different expression patterns in the MGE vis-à-vis the neocortex. These findings suggest a dynamic expression of GABAA receptor number or isoform as MGE-derived cells enter the neocortex and become tonically influenced by ambient GABA. Treatment with bicuculline or antibody against GABA did not affect migration of MGE-derived cells before the CSJ but decreased "crossing index," reflecting impeded migration past the CSJ into the neocortex. Treatment with diazepam or addition of exogenous GABA increased crossing index. We conclude that ambient GABA promotes cortical entry of tangentially migrating MGE-derived cells.
Whole brain statistical activation maps show general task-related activity in relation to baseline averaged across all 22 participants. Images are axial sections in the Talairach and Tournoux (1988) atlas space. Sections from left to right correspond to z =-4, z = 24 and z = 44. Colored pixels exceeded the statistical threshold and are superimposed on corresponding anatomy images. The left side of the image corresponds to the left side of the brain. Increases in activation (red color scale; areas labeled in yellow letters) were observed in the (A) left inferior frontal cortex, (B) extrastriate visual cortex, (C) left dorsal frontal cortex, (D) anterior cingulate, and (E) left motor cortex. Decreases in activation (blue color scale, areas labeled in blue letters) were noted in the (G) medial prefrontal cortex, (H) right parietal cortex, and (I) posterior cingulate. 
Regions predicting subsequent memory during processing. Table 1, verbal processing; Table 2, visual processing; Table 3, emotional processing; Table 4, self-referential processing. 
The ability to remember the past depends on cognitive operations that are recruited when information is initially encountered. In the current experiment, we investigated neural processes that subserve the memorability of a fundamental class of social information: self-knowledge. Participants evaluated the extent to which a series of personality characteristics were self-descriptive. Brain activation was measured using event-related functional magnetic resonance imaging (fMRI) and contrasted based on: (i) whether each word was later remembered or forgotten; and (ii) whether or not each item was judged to be self-relevant. Results revealed that activity in medial prefrontal cortex predicted both subsequent memory performance and judgements of self-relevance. These findings extend current understanding of the nature and functioning of human memory.
It is well known that lateral areas of the prefrontal cortex (LPFC) play a central role in working memory (a critical basis of various cognitive functions), but it remains unknown whether the LPFC of children of preschool age is responsible for working memory. To address this issue, we adopted a recently developed non-invasive imaging technique, optical topography (OT), which can potentially be applied to functional mapping in childhood. We firstly examined changes of activity in the LPFC using OT while adult subjects performed an item-recognition task, which requires working memory, under different memory-load conditions. We observed activation in the bilateral LPFC during performance of this task, the magnitude of which differed depending on memory-load. Then, we applied the same technique on 5- and 6-year-old children and observed the activation associated with working memory in the LPFC. Areas and properties of such activity were similar in adults and preschool children. Thus, for the first time, we demonstrate that the LPFC of preschoolers is active during working memory processes, indicating that in 5- and 6-year-old children, the LPFC has already developed processing of this important cognitive function.
Recurrent exposure of the developing fetus to cocaine produces persistent alterations in structure and function of the cerebral cortex. Neurons of the cerebral cortex are derived from two sources: projection neurons from the neuroepithelium of the dorsal pallium and interneurons from the ganglionic eminence of the basal telencephalon. The interneurons are GABAergic and reach the cerebral cortex via a tangential migratory pathway. We found that recurrent, transplacental exposure of mouse embryos to cocaine from embryonic day 8 to 15 decreases tangential neuronal migration and results in deficits in GABAergic neuronal populations in the embryonic cerebral wall. GABAergic neurons of the olfactory bulb, which are derived from the ganglionic eminence via the rostral migratory pathway, are not affected by the cocaine exposure suggesting a degree of specificity in the effects of cocaine on neuronal migration. Thus, one mechanism by which prenatal cocaine exposure exerts deleterious effects on cerebral cortical development may be by decreasing GABAergic neuronal migration from the ganglionic eminence to the cerebral wall. The decreased GABA neuron migration may contribute to persistent structural and functional deficits observed in the exposed offspring.
Schematic diagrams of the rat forebrain showing the largest extent of AChE-positive fiber loss within the medial PFC (adapted from Paxinos and Watson, 1998), following bilateral infusions of 50 ng (left hand diagrams) and 100 ng (right hand diagrams) 192 IgG–saporin. Numbers to the right of each figure refer to the anterior–posterior level forward of bregma (mm).  
Representative photomicrographs showing AChE-positive fibers (a, c, e) and PARV-immunoreactive neurons (b, d, f) in the ventromedial PFC of sham (upper panels), 50 ng (middle panels) and 100 ng (lower panels) 192 IgG–saporin lesioned rats. It can be seen in 192 IgG–saporin-lesioned animals that the density of AChE-positive fibers is clearly decreased in the infralimbic cortex (IL) in both lesion groups compared to the sham group. By contrast, PARV-IR neurons are unaffected by immunotoxin infusions in this region. Abbreviations: fmi, forceps minor of the corpus callosum; m, medial; v, ventral; IL, infralimbic cortex.  
Perseverative responses of sham (n = 9) and 192 IgG–saporin lesioned rats (50 ng or 100 ng, each n = 9) during sessions consisting of either a fixed location and fixed ITI ('A'), five locations and a fixed ITI ('B'), a fixed location and variable ITI ('C') or five locations and a variable ITI ('D'). §P < 0.05 versus pre-operative lesion subjects (100 ng group). *P < 0.05 versus sham subjects.  
Accuracy of sham (n = 9) and 192 IgG–saporin lesioned animals (50 or 100 ng, each n = 9) on the five-choice task (stimulus duration 0.5 s) following systemic administration of vehicle (normal saline, 1 ml/kg s.c.) or scopolamine hydrochloride (0.01–0.1 mg/kg). ANOVA revealed a significant interaction between lesion and dose [F (8,96) = 2.05; P = 0.049] and a significant main effect of dose for the 100 ng lesion group [F (4,32) = 19.01; P < 0.01]. §P < 0.05 versus sham controls (0.1 mg/kg dose level).  
Lesions of the basal forebrain (BF) cortical cholinergic system impair performance on a rodent five-choice visual attentional task. This study examines the effects on the same task of selective depletion of acetylcholine from the prefrontal cortex (PFC) using 192 IgG-saporin, the cholinergic immunotoxin. Rats were trained to detect brief visual stimuli, either presented unpredictably both temporally and spatially to increase attentional load, or under less demanding conditions where stimuli were temporally and spatially predictable. Following training, 192 IgG-saporin (50 ng or 100 ng/infusion) or its vehicle was infused bilaterally into the ventromedial PFC. The 100 ng lesion group exhibited post-operatively a transient increase in perseveration, specifically when the visual stimuli were temporally unpredictable. A vigilance decrement, as well as a reinstatement of perseverative responding occurred in both lesion groups under conditions of enhanced attentional load, specifically with high target frequency sustained over many trials. Lesioned subjects were also more impulsive with increased anticipatory errors. Systemic administration of the muscarinic receptor antagonist scopolamine further dissociated the groups with attentional accuracy in the 100 ng group decreasing relative to shams. These findings are consistent with an important modulatory influence of PFC function by BF cholinergic neurons, particularly during increased attentional demand.
Photographic documentation of cytochrome oxidase-stained layer IV barrels and the main types of layer IV spiny neurons labeled with biocytin. (A) Low-power micrograph showing the location of a symmetrical spiny stellate cell in the dorsolateral aspect of a large barrel. Separated by a narrow septum, a second barrel is partially visible. (B) High-power micrograph of the same neuron. Apart from the spherical dendrites, also the axon (arrow) is clearly labeled. Note the numerous axonal boutons visible in this and all other subsequent micrographs. (C) Asymmetric spiny stellate cell, located at the most lateral aspect of a barrel. (D) Centrally located star pyramidal cell. (E) Peripherally located pyramidal neuron. Roman numerals mark cortical layers. Scale bars: 250 µm (A, B); 50 µm (C, D).  
Axonal arbors of star pyramidal cells and their topographical relation to barrels and layers. (A) Asymmetric star pyramidal neuron which distributes virtually all dendritic and axonal branches toward its 'home' barrel column. (B) Symmetric neuron possessing a single direct 'transbarrel' collateral. Note that the horizontal infragranular collateral was truncated to save space. It continued for one and a half further barrels. (C) Symmetric neuron showing numerous 'transbarrel' collaterals. Medial is to the left, lateral to the right. The barrels, as seen with cytochrome oxidase-staining, are shaded gray. Roman numerals mark cortical layers. Upper and lower black line delineates pial surface or layer VI-white matter border, respectively. by guest on May 30, 2013  
Electrophysiological properties of thalamic input onto layer IV spiny neurons
Axonal arbors of pyramidal cells and their topographical relation to barrels and layers. All pyramidal cells (A–C) display abundant 'transcolumnar' collaterals. (A) Sparse, (B) intermediate and (C) extensive cases. Medial is to the left, lateral to the right. The barrels, as seen with cytochrome oxidase staining, are shaded gray. Roman numerals mark cortical layers. Upper and lower black line delineates pial surface or layer VI–white matter border, respectively. by guest on May 30, 2013  
Statistical methods to classify neurons in an observer-independent manner. (A) Cluster analysis (HCA) showing the complete separation of spiny stellate cells (blue) from star pyramidal (green) and pyramidal cells (red). (B) Canonical scores plot of discriminant analysis of the dendritic parameters of 32 spiny stellate (blue), 17 star pyramidal (green) and 16 pyramidal neurons (red). The plot shows the first two canonical variables and the confidence ellipses centered on the centroids of each group. Note that spiny stellate cells separate completely from the two types of pyramidal cells, whose morphological parameters show a higher degree of variability. (C) Graphical representation of the frequency of the dendritic 'angles-of-descent' from the somatic circumference. This shows a statistically significant separation of star pyramidal from pyramidal cells, (i) by the relative abundance of dendritic origins between 16 and 30° (*b) and (ii) by a highly significant relative lack of primary dendrites between 121 and 135° (***b) in star pyramidal cells. Note that in the latter segment also spiny stellate cells are significantly different from pyramidal neurons (*a).  
Previous analyses of the spiny layer IV neurons have almost exclusively focused on spiny stellate cells. Here we provide detailed morphological data characterizing three subpopulations of spiny neurons in slices of adolescent rats: (i) spiny stellate cells (58%), (ii) star pyramidal cells (25%) and (iii) pyramidal cells (17%), which can be distinguished objectively by the preferential orientation of their dendritic stems. Spiny stellate cells lacked an apical dendrite and frequently confined their dendritic and axonal arbors to the respective column. Star pyramidal and pyramidal cells possessed an apical dendrite, which reached the supragranular layers. Their axonal arbors were similar, showing both a columnar component and transcolumnar branches with direct transbarrel projections. However, a small fraction of star pyramidal cells possessed few or even no transcolumnar branches. Electrophysiologically, all three types of neurons were either regular-spiking or intrinsically burst-spiking without a significant relation to the morphological subtypes. The basic synaptic properties of thalamic inputs were also independent of the type of target layer IV spiny neuron. All remained subthreshold and showed paired-pulse depression. In conclusion, the columnar axonal arborization of spiny stellate cells is supplemented by a significant oblique to horizontal projection pattern in pyramidal-like neurons. This offers a structural basis for either segregation or early context-dependent integration of tactile information, in a cell-type specific manner.
A major challenge for any anatomical study of spatial neglect in neurological patients is that human lesions vary tremendously in extent and location between individuals. Approaches to this problem used in previous studies were to focus on subgroups of patients that are more homogeneous either with respect to the branch territory affected by the stroke or with respect to existing additional neurological symptoms (e.g. additional visual field defects). It could be argued that such strategies might bias the conclusions on the critical substrate associated with spatial neglect. The present study thus addressed the high variability inherent in naturally occurring lesions by using an unselected, but very large sample size and by comparing a neglect group with a non-neglect group using voxelwise statistical testing. We investigated an unselected 7 year sample of 140 consecutively admitted patients with right hemisphere strokes. Seventy-eight had spatial neglect, 62 did not show the disorder. The incidence of visual field defects was comparable in both groups. For assessing lesion location, in a first step, we used conventional lesion density plots together with subtraction analysis. Moreover, due to the large size of the sample voxelwise statistical testing was possible to objectively estimate which brain regions are more frequently compromised in neglect patients relative to patients without neglect. The results demonstrate that the right superior temporal cortex, the insula and subcortically putamen and caudate nucleus are the neural structures damaged significantly more often in patients with spatial neglect.
The use of computational approaches in the analysis of high resolution magnetic resonance images (MRI) of the human brain provides a powerful tool for in vivo studies of brain anatomy. Here, we report results obtained with a voxel-wise statistical analysis of hemispheric asymmetries in regional 'amounts' of gray matter, based on MRI scans obtained in 142 healthy young adults. Firstly, the voxel-wise analysis detected the well-known frontal (right > left) and occipital (left > right) petalias. Secondly, our analysis confirmed the presence of left-greater-than-right asymmetries in several posterior language areas, including the planum temporale and the angular gyrus; no significant asymmetry was detected in the anterior language regions. We also found previously described asymmetries in the cingulate sulcus (right > left) and the caudate nucleus (right > left). Finally, in some brain regions we observed highly significant asymmetries that were not reported before, such as in the anterior insular cortex (right > left). The above asymmetries were observed in men and women. Our results thus provide confirmation of the known structural asymmetries in the human brain as well as new findings that may stimulate further research of hemispheric specialization.
The relationship between cognition and a functional polymorphism in the catechol-O-methlytransferase (COMT) gene, val108/158met, is one of debate in the literature. Furthermore, based on the dopaminergic differences associated with the COMT val108/158met genotype, neural differences during cognition may be present, regardless of genotypic differences in cognitive performance. To investigate these issues the current study aimed to 1) examine the effects of COMT genotype using a large sample of healthy individuals (n = 496-1218) and multiple cognitive measures, and using a subset of the sample (n = 22), 2) examine whether COMT genotype effects medial temporal lobe (MTL) and frontal activity during successful relational memory processing, and 3) investigate group differences in functional connectivity associated with successful relational memory processing. Results revealed no significant group difference in cognitive performance between COMT genotypes in any of the 19 cognitive measures. However, in the subset sample, COMT val homozygotes exhibited significantly decreased MTL and increased prefrontal activity during both successful relational encoding and retrieval, and reduced connectivity between these regions compared with met homozygotes. Taken together, the results suggest that although the COMT val108/158met genotype has no effect on cognitive behavioral measures in healthy individuals, it is associated with differences in neural process underlying cognitive output.
People's sensitivity to reinforcing stimuli such as monetary gains and losses shows a wide interindividual variation that might in part be determined by genetic differences. Because of the established role of the dopaminergic system in the neural encoding of rewards and negative events, we investigated young healthy volunteers being homozygous for either the Valine or Methionine variant of the catechol-O-methyltransferase (COMT) codon 158 polymorphism as well as homozygous for the C or T variant of the SNP -521 polymorphism of the dopamine D4 receptor. Participants took part in a gambling paradigm featuring unexpectedly high monetary gains and losses in addition to standard gains/losses of expected magnitude while undergoing functional magnetic resonance imaging at 3 T. Valence-related brain activations were seen in the ventral striatum, the anterior cingulate cortex, and the inferior parietal cortex. These activations were modulated by the COMT polymorphism with greater effects for valine/valine participants but not by the D4 receptor polymorphism. By contrast, magnitude-related effects in the anterior insula and the cingulate cortex were modulated by the D4 receptor polymorphism with larger responses for the CC variant. These findings emphasize the differential contribution of genetic variants in the dopaminergic system to various aspects of reward processing.
In the corpus callosum, astrocytic calcium waves propagate via a mechanism involving ATP-release but not gap junctional coupling. In the present study, we report for the neocortex that calcium wave propagation depends on functional astrocytic gap junctions but is still accompanied by ATP-release. In acute slices obtained from the neocortex of mice deficient for astrocytic expression of connexin43, the calcium wave did not propagate. In contrast, in the corpus callosum and hippocampus of these mice, the wave propagated as in control animals. In addition to calcium wave propagation in astrocytes, ATP-release was recorded as a calcium signal from 'sniffer cells', a cell line expressing high-affinity purinergic receptors placed on the surface of the slice. The astrocyte calcium wave in the neocortex was accompanied by calcium signals in the 'sniffer cell' population. In the connexin43-deficient mice we recorded calcium signals from sniffer cells also in the absence of an astrocytic calcium wave. Our findings indicate that astrocytes propagate calcium signals by two separate mechanisms depending on the brain region and that ATP release can propagate within the neocortex independent from calcium waves.
Illustration of the main components of the sustained attention task ( A ), summary of the main experimental events and illustration of the detailed sequence of events during an individual dialysis session ( B ). ( A ) Following a variable ITI, a signal (illumination of a panel light for 500--25 ms) was presented (top sequence) or not (non-signal; lower row). Both levers were extended 2 s later and animals were required to press one lever to report a hit and the other one to report a correct rejection to receive reward (see arrows exemplifying one set of rules). Incorrect responses (misses, false alarms) and omission were not rewarded. Levers were withdrawn following a lever press or after 4 s. ( B ) As detailed in Materials and Methods, animals were implanted with three guides and, during a subsequent recovery period and daily behavioral training sessions, habituated to performing the task while dummy cannula were inserted and connected to syringes and pumps located outside the sound-attenuating chambers. Probes were inserted into the prefrontal cortex and perfused, infusion needles were inserted into the BF, and saline, 3 or 30 nmol of APV, respectively, was infused immediately after the collection of the first performance-related dialysate (T1; see insert). During an individual dialysis session, the probe and the infusion needles were inserted early in the morning, the animal was placed into the operant chamber, and probes and needles were connected to syringes and pump. During the next 3 h, the probe was perfused and dialysates were discarded. The four collections prior to task onset were used to determine the stability of ACh efflux and basal ACh efflux. Five 8 min collections were taken during task performance. BF infusions were carried out immediately after completion of T1. An additional six collections were taken after completion of the task. 
Illustration and examples of the placement of probes into the medial prefrontal cortex and guide cannula and infusion needles into the BF. ( A ) A schematic illustration of the placement of probes (3 mm membranes) into the prefrontal cortex at a 20 ° anterior--posterior angle. As coronal sections were cut at no angle in order to visualize BF cannula placements ( C , D ), prefrontal sections representing the dorsal- ventral placements of probes are unavailable. ( B ) The location of the posterior--ventral placement of the tip of the probe in to the prelimbic cortex. Based on the placement of probes and prior data examining the approximate region perfused by such probes (Neigh-McCandless et al. , 2002), ACh was collected from anterior cingulate and prelimbic regions. ( D ) An example showing the placement of guide cannula for the insertion of infusion needles into the BF. The tip of the guide is readily visible (arrow), and the tract produced by the infusion needle is also apparent. In ( C ), the diameters of the schematically drawn guide cannula and infusion needle are drawn to approximate scale. Furthermore, a microphotograph of a section showing the spread of FluoroGold (0.5 l l; 0.1%; FluoroChrome, Englewood, CO) infused into the BF was superimposed and adjusted to scale. Although the different physico-chemical properties of FluoroGold limit the generalization of these data, the spread of the tracer suggested that the infusions affected primarily the ventro-medial globus pallidus that contain the cholinergic neurons of the ventral nucleus basalis of Meynert and the substantia innominata. Furthermore, the spread of the tracer conformed with other evidence about the spread of intraparenchymal drug infusions (Routtenberg, 1972; Pecina and Berridge, 2000). 
Basal and attentional performance-associated changes in ACh efflux (mean ± SEM). The top graph illustrates ACh release during the four collections intervals prior to task onset (B1--B4), separated by dialysis session type (or infusion condition; saline, APV 3, 20 nmol). Additionally, the average increase in ACh release during the first 8 min task block, and prior to the infusions of saline or APV (T1), is depicted. ACh efflux was significantly increased during T1 when compared with baseline, and this increase did not differ between animals that received saline or APV immediately after the collection of T1 dialysates. As shown in the lower graph, the performance-associated increase in ACh efflux remained relatively stable following the infusion of saline into the BF. In contrast, further increases in ACh efflux were observed following infusions of 3 or 20 nmol of APV, and while the animals’ performance was impaired as a result of APV infusions [a, significantly different from T1; b, significantly different from T2 ( P \ 0.05), as indicated by dependent t -tests]. 
Performance at baseline and following infusions of saline into the BF. In signal trials, the number of correct responses (hits) varied with signal duration. Infusions of saline did not produce main effects on performance.
The effects of infusions of the NMDA receptor antagonist APV into the BF on the relative number of hits interacted with signal duration and block. This figure shows the relative number of hits to 500 ms signals, prior and following the perfusion of saline, 3 or 20 nmol of APV (see the arrow marking the infusion time), across blocks of trials. Following infusions of the lower dose of APV, decreases in hits to 500 ms signals did not reach statistical significance and appeared to have fully recovered two blocks following infusion. Hit rates to 500 ms signals remained depressed throughout the remainder of the session following infusions of the higher concentration of APV (a, significantly different from T1). Hits to 50 and 25 ms signals were not systematically affected by APV (not shown), thereby giving rise to a significant interaction between the effects of APV, block and signal duration.
Previous research has demonstrated that attentional performance depends on the integrity of the cortical cholinergic input system and that such performance is associated with increases in cortical acetylcholine (ACh) release. The present experiment tested the hypothesis that the attentional impairments produced by bilateral basal forebrain infusions of the NMDA receptor antagonist DL-2-amino-5-phosphonovaleric acid (APV) are associated with attenuation of performance-associated increases in ACh release. Rats were trained in a sustained attention task and equipped with three guide cannula for the bilateral infusion of the NMDA receptor antagonist APV (0, 3, 20 nmol) and for the insertion of a dialysis probe into the medial prefrontal cortex (mPFC). APV or vehicle was infused remotely following completion of the first of five blocks of trials. During the first block, attentional performance was associated with a 140% increase in ACh efflux. Infusions of APV decreased the animals' ability to detect signals and augmented the increases in ACh efflux observed prior to infusions. These data indicate a dissociation between levels of attentional performance and increases in mPFC ACh release. Augmentation of performance-associated increases in mPFC cholinergic transmission is hypothesized to mediate the increased demands on attentional 'effort' that are required to maintain performance under challenging conditions.
Understanding the mechanism of how fear memory can be extinguished could provide potential therapeutic strategies for the treatment of posttraumatic stress disorders. Here we show that infusion of CB1 receptor antagonist into the infralimbic (IL) subregion of the medial prefrontal cortex (mPFC) retarded cue-alone-induced reduction of fear-potentiated startle. Conversely, cannabinoid agonist WIN55212-2 (WIN) facilitated the extinction. Unexpectedly, administration of WIN without cue-alone trials reduced startle potentiation in a dose-dependent manner. The effect of cannabinoid agonists was mimicked by endocannabinoid uptake or fatty acid amide hydrolase inhibitors. Rats were trained with 10 conditioned stimulus (CS(+)) (yellow light)-shock pairings. Extinction training with CS(+) (yellow light)-alone but not CS(-) (blue light)-alone trials decreased fear-potentiated startle. Intra-IL infusion of WIN before CS(-)-alone trials decreased startle potentiation, suggesting that the cannabinoid agonist decreased conditioned fear irrespective of whether the rats underwent CS(+)- or CS(-)-alone trials. Cannabinoid agonists activated extracellular signal-regulated kinases (ERKs) in mPFC slices, and ERK inhibitor blocked the effect of cannabinoid agonists on fear-potentiated startle. These results suggest that CB1 receptors acting through the phosphorylation of ERK are involved not only in the extinction of conditioned fear but also in the adaptation to aversive situations in general.
Anxiety is linked to compromised interactions between the amygdala and the dorsal and ventral medial prefrontal cortex (mPFC). While numerous task-based neuroimaging studies show that anxiety levels predict amygdala–mPFC connectivity and response magnitude, here we tested the hypothesis that anxiety would predict functional connectivity between these brain regions even during rest. Resting-state functional magnetic resonance imaging scans and self-reported measures of anxiety were acquired from healthy subjects. At rest, individuals with high anxiety were characterized by negatively correlated amygdala–ventral mPFC functional connectivity, while low anxious subjects showed positively correlated activity. Further, high anxious subjects showed amygdala–dorsal mPFC activity that was uncorrelated, while low anxious subjects showed negatively correlated activity. These data show that amygdala–mPFC connectivity at rest indexes normal individual differences in anxiety.
Representative control, 16p11.2 deletion, and 16p11.2 duplication auditory response profiles. Artifact-corrected source waveforms to a 1000-Hz tone in the RH for a control (left column, 11.78 y.o.), 16p11.2 deletion carrier (middle column, 9.62 y.o.), and 16p11.2 duplication carrier (right column, 13.98 y.o.). All participants are within 1 SD of the mean population age. Source time courses are in the top row and source-sink distribution in the bottom row (source = red; sink = blue). M100 latency for the
Participants with evaluable data distribution summary
Latency versus age regression, stimulus condition, and hemispheric means for each case. Age-matched controls are delineated in gray circles with a solid outline, 16p11.2 deletion carriers by orange triangles with a dashed outline, and 16p11.2 duplication carriers by light blue squares with a dotted outline. (a) For all 3 cases, there is an inverse relationship between M100 latency (across stimulus conditions and hemispheres) and age, with the slopes between the cases not significantly different (F 2, 93 = 1.197, P = 0.307). (b) M100 latency for each case and stimulus condition. For each stimulus condition, 16p11.2 deletion carriers exhibit a delay in M100 latency relative to age-matched controls, whereas 16p11.2 duplication carrier latencies are not significantly different. (c) As with the mean M100 latencies in (a) and for each stimulus condition (b), similar patterns of M100 latency delay are present in 16p11.2 deletion carriers for each hemisphere.
Least-squares means for each case
M100 least-squares means and LMM residuals separated by case means. ( Upper panel ) Least-squares means ± one standard error derived from main-effects model of Hemisphere + Stimulus Condition + Case + Age + Site + (Stimulus Condition + Hemisphere | Subject). Coloring and line conventions are the same as in Figure 2. Case means illustrate 1) the large delay exhibited by 16p11.2 deletion carriers ( ∼ 21 ms) and 2) that 16p11.2 duplication carrier latency means are not signi fi cantly different from controls. ( Lower panel ) Kernel density estimates (Gaussian window, 512 points, bandwidth calculated using Silverman ’ s rule of thumb) of residuals plus case means for each case. This visualization demonstrates 1) the separation of 16p11.2 deletion M100 latencies from controls and 2) the similar residual variance in all subpopulations. A Brown – Forsythe test for homogeneity of variance did not yield a signi fi cant difference in residual variance between each of the populations ( F 2,531 = 0.192, P = 0.825) but Kolmogorov – Smirnov tests on these distributions indicated the distributions 
Individuals with the 16p11.2 BP4-BP5 copy number variant (CNV) exhibit a range of behavioral phenotypes that may include mild impairment in cognition and clinical diagnoses of autism spectrum disorder (ASD). To better understand auditory processing impairments in populations with this chromosomal variation, auditory evoked responses were examined in children with the 16p11.2 deletion, 16p11.2 duplication, and age-matched controls. Stimuli consisted of sinusoidal binaural tones presented passively while children underwent recording with magnetoencephalography (MEG). The primary indicator of auditory processing impairment was the latency of the ∼100-ms "M100" auditory response detected by MEG, with the 16p11.2 deletion population exhibiting profoundly delayed M100 latencies relative to controls. This delay remained even after controlling for potential confounds such as age and cognitive ability. No significant difference in M100 latency was observed between 16p11.2 duplication carriers and controls. Additionally, children meeting diagnostic criteria for ASD (16p11.2 deletion carriers) exhibited nonsignificant latency delays when compared with the corresponding CNV carriers not meeting criteria for ASD. Present results indicate that 16p11.2 deletion is associated with auditory processing delays analogous to (but substantially more pronounced than) those previously reported in "idiopathic" ASD. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
Studies on the role of 17β-estradiol (E2) in the hippocampus have mainly focused on CA1 and CA3 regions, whereas in dentate gyrus (DG), its role is largely unknown. Here, we examined potential functions of E2 in DG, particularly during development. Immunohistochemistry and in situ hybridization revealed abundance of estrogen receptor (ER)α, but not ERβ, expression in DG. Similar to CA1, analysis of synapse densities revealed a reduction in spine synapse number in DG molecular layer of immature rats and adult mice after inhibition of estradiol synthesis using letrozole. Interestingly, strong expression of ERα was found in Cajal-Retzius (CR) cells, which regulate neuronal migration and synaptogenesis via the extracellular matrix protein reelin. Immunoreactivity of aromatase, the final enzyme of estradiol synthesis, was strongest in mature granule cells. In hippocampal slice cultures, exogenous application of E2 caused an increase in reelin expression in CR cells, which was abolished after blockade of ERs using ICI182,780. Vice versa, inhibition of aromatase activity by letrozole resulted in reduced reelin expression, suggesting that E2 deriving from hippocampal sources contributes to the regulation of reelin as well as to the maintenance of spine synapses in DG. E2 further regulated Notch1, a signaling protein involved in neuronal differentiation.
Number of GABAI+I and of the overall population of neurons per cubic millimeter of tissue in striate conex of the monkey. Means and SEM values are given for the IOtal COfticalthickness \I-VII and for each cortical lamina [layers I. upper half III and lower (2) half of ".f/f. IVA. IVB. upper and lower halves of IVC. V. and upper and lower halves of VI]. These numbers were obtained using the disector method.
The number of GABA-immunoreactive [GABA(+)] neurons and synapses was determined in functionally distinct subregions delineated as rich and poor in cytochrome oxidase (CO) in the visual cortex of adult macaque monkeys. The average numerical density (number per unit volume, Nv) of GABA(+) neurons and synapses was not significantly different between the CO-rich and -poor regions. Twenty percent of the total number of cortical neurons and 17% of the synapses were GABA(+). On average, each visual cortical neuron receives 3900 synapses, 660 of them being GABA(+). The latter were distributed on the target cell in a pattern that predicts the site of GABA influences in cortex. The major targets of GABA(+) synapses were dendritic shafts, comprising nearly two-thirds of the postsynaptic elements. About every fourth and every eighth GABA(+) synapse was devoted to dendritic spines and to neuronal somata, respectively. Axon initial segments, although the exclusive targets of GABA(+) cells, comprise less than 0.1% of structures postsynaptic to GABA(+) boutons. From this distribution, we estimate that in each cubic millimeter of striate cortex there were about 20 million GABA(+) synapses on dendritic spines, 47 million on dendritic trunks, 9 million on somata, and fewer than 0.1 million on axon initial segments. The sites of influences of GABA-immunonegative [GABA(-)] synapses were different in that they target mainly dendritic spines and dendritic trunks. About two-thirds of GABA(-) synapses were on dendritic spines, and the remainder were devoted to dendritic trunks. Only a minute fraction innervate somata. We estimate that in 1 mm3 of striate cortex there were about 235 million GABA(-) synapses on spines, 133 million on dendrites, and about 2 million on somata. The proportions of GABA(+) neurons and synapses and their target distribution did not appreciably differ from those of the visual cortex of the cat even though the numerical density of neurons was 2.5 times higher in the monkey.
To study how the visual areas of the 2 hemispheres interact in processing visual stimuli we have recorded local field potentials in the callosally connected parts of areas 17 and 18 of the ferret during the presentation of 3 kinds of stimuli: 2.5 degrees squares flashed for 50 ms randomly in the visual field (S1), 4 full-field gratings differing in orientation by 45 degrees and identical in the 2 hemifields (S2) and gratings as above but whose orientation and/or direction of motion differed by 90 degrees in the 2 hemifields (S3). The gratings remained stationary for 0.5 s and then moved in 1 of the 2 directions perpendicular to their orientation for 3 s. We compared the responses in baseline conditions with those obtained whereas the contralateral visual areas were inactivated by cooling. Cooling did not affect the responses to S1 but it modified those to S2 and to S3 generally increasing early components of the response while decreasing later components. These findings indicate that interhemispheric processing is restricted to visual stimuli which achieve spatial summation and that it involves complex inhibitory and facilitatory effects, possibly carried out by interhemispheric pathways of different conduction velocity.
Retinal lesions induce a topographic reorganization in the corresponding lesion projection zone (LPZ) in the visual cortex of adult cats. To gain a better insight into the reactivation dynamics, we investigated the alterations in cortical activity throughout area 17. We implemented in situ hybridization and real-time polymerase chain reaction to analyze the spatiotemporal expression patterns of the activity marker genes zif268 and c-fos. The immediate early gene (IEG) data confirmed a strong and permanent activity decrease in the center of the LPZ as previously described by electrophysiology. A recovery of IEG expression was clearly measured in the border of the LPZ. We were able to register reorganization over 2.5-6 mm. We also present evidence that the central retinal lesions concomitantly influence the activity in far peripheral parts of area 17. Its IEG expression levels appeared dependent of time and distance from the LPZ. We therefore propose that coupled changes in activity occur inside and outside the LPZ. In conclusion, alterations in activity reporter gene expression throughout area 17 contribute to the lesion-induced functional reorganization.
Position of stimuli in the combined cortical imaging and VSDs mapping experiments. Three stimuli were flashed at different azimuths, separately or in a sequence (see text). Stimuli in the left hemifield were aimed at the hemisphere of recording (contralateral hemisphere) and those in the right hemifield at the other hemisphere (ipsilateral hemisphere). Stimuli near the midline of the visual field presumably reached both hemispheres (compare with Fig. 1). Stimulus width is 1.5 deg, and center-to-center stimulus separation is 4 deg. 
Example of CRFs dynamics visualized with LFP in the experiment 0820 (the same as Supplementary Fig. 1). The upper panels show the responses to the left (Lt) stimulus and the lower panels those to the right (Rt) stimulus (shown in Fig. 2). Each circle corresponds to the location of a penetration and colors code for the amplitude of the response. Locations of the histologically defined cytoarchitectonic borders are shown schematically in the 10-ms delay panel. Examples of LFPs from different penetrations (2, 6, and 18; color coded) are shown in the right-hand panels, with the arrows denoting the time interval shown in detail. Notice that the right stimulus (the closest to the visual field midline) activates a more posterior territory in area 18, near the border with area 17, than the left stimulus, as expected from the retinotopic organization of this area (Manger et al. 2002). The extent of both CRFs and polarity of the responses changes with time after stimulus onset. L 5 lateral and A 5 anterior. 
Example of PRF dynamics. Color-coded amplitude of the LFP (scale bar on the left), with each circle corresponding to stimulus positions 0 ° , 2 ° , 6 ° , 4 ° , and 8 ° from the center stimulus. Different activation profiles are shown after the onset of stimulation (in ms). Notice that LFP amplitude and latency both depend on stimulus eccentricity. 
In mammals, the visual field is split along the midline, each hemisphere representing the contralateral hemifield. We determined that, in the ferret, an 8- to 10-deg-wide strip of visual field near the midline is represented in both hemispheres. Bright squares (1.5 deg) were flashed at different azimuths within the central 20 deg of the visual field. Stimuli were flashed either alone or sequentially, and the responses were analyzed with the voltage-sensitive dye (VSD) RH 795 and/or by recording local field potentials (LFPs). In both VSD and LFP experiments, each stimulus evoked a cortical response field that extended over visual areas 17 and 18 up to a surface of 1-1.5 mm(2) and then shrank again. Amplitude of the responses decreased approaching the visual midline and the latency increased. These positional differences are likely to originate from the spatiotemporal structure of the peripheral response fields (PRFs) that form a mosaic in areas 17 and 18, interrupted near the visual midline. Unexpectedly, interhemispheric connections appear not to modify these PRFs' effects and may not contribute to the responses to discrete, flashed stimuli.
Visual areas 17, 18, 19 and 21 of the ferret can be distinguished on the grounds of cytoarchitecture, myeloarchitecture and cytochrome oxidase reactivity, and with transneuronal tract-tracing from the eye. Each visual area contains callosally connected, as well as acallosal, regions. The callosal connections originate mainly from layers 2 and 3 and, more widely, from layer 6. Callosally projecting neurons and callosal terminals are organized in three roughly medio-laterally oriented bands. The posterior and intermediate bands straddle the 17/18 and 19/21 border, respectively; the third band extends along the medial bank of the lateral suprasylvian sulcus. These bands are linked by a variable number of bridges of connections that demarcate acallosal islands. The distribution of callosal connections predicts the existence of vertical meridian representations corresponding to each of the bands and of non-isotropic representations of the visual field within the bridges and islands.
We have previously demonstrated that prefrontal serotonin depletion impairs orbitofrontal cortex (OFC)-mediated serial discrimination reversal (SDR) learning but not lateral prefrontal cortex (PFC)-mediated attentional set shifting. To address the neurochemical specificity of this reversal deficit, Experiment 1 compared the effects of selective serotonin and selective dopamine depletions of the OFC on performance of the SDR task. Whereas serotonin depletions markedly impaired performance, OFC dopamine depletions were without effect. The behavioral specificity of this reversal impairment was investigated in Experiment 2 by examining the effect of OFC serotonin depletion on performance of a modified SDR task designed to distinguish between 3 possible causes of the impairment. The results showed that the reversal deficit induced by prefrontal serotonin depletion was not due to a failure to approach a previously unrewarded stimulus (enhanced learned avoidance) or reduced proactive interference. Instead, it was due specifically to a failure to inhibit responding to the previously rewarded stimulus. The neurochemical and behavioral specificity of this particular form of cognitive inflexibility is of particular relevance to our understanding of the aetiology and treatment of inflexible behavior apparent in many neuropsychiatric and neurodegenerative disorders involving the PFC.
Three morphological types of axons have been recognized in previous studies of the serotoninergic (5-HT) innervation of the cat cerebral cortex (Mulligan and Törk, 1988; DeFelipe et al., 1991): thick, nonvaricose axons, fine axons with small varicosities, and beaded axons with large, spherical varicosities. In the present study, the laminar density and distribution of the three 5-HT fiber types in area 17 are characterized. In both coronal and sagittal immunostained sections, 5-HT axons exhibit an overall gradient of decreasing density from layer I to the white matter. The three 5-HT axon types exhibit distinctive innervation patterns. (1) Fine axons with small varicosities comprise the greatest number of fibers in each layer (56-98%). They usually have oblique or radial trajectories, but some horizontally oriented fibers run through layers I, III, VI, and the white matter. (2) Non-varicose axons, the preterminal portions of the beaded axons with the large varicosities (Mulligan and Törk, 1988), comprise only about 7% of the total 5-HT fiber population in area 17, and are found mainly in layer I and in the white matter where they form a horizontally oriented plexus. (3) Large varicose axons ("beaded" axons) are rare (about 3% of the total 5-HT population) and are restricted to layers I and V. Although large varicose axons often form elaborate pericellular basketlike arbors around the soma and dendrites of neurons in other parts of the cat cerebral cortex (Mulligan and Törk, 1987, 1988), such arrays are rare in area 17. When observed in area 17, pericellular arrays are typically simple structures with a few large varicosities apparently contacting only the somata of a small population of layer I neurons. Comparison of these results with reports of 5-HT innervation of area 17 in other species suggests that the 5-HT innervation of the cortex is highly species specific.
Experimental subjects 
Retrograde tracers were injected into middle suprasylvian (MS) cortex of two groups of experimental adult cats that had incurred removal of visual areas 17 and 18 on either the day of birth (P1), or at 1 month of age (P28). Tracers were also injected into the same region of intact and adult ablated control cats. The locations and numbers of labeled neurons in the experimental and control groups were compared. Following lesions on P1, but at no other age, increased numbers of neurons projected to MS cortex. Virtually all of the additional neurons were located in the superficial layers of the ventral posterior suprasylvian (vPS) cortex. These results demonstrated that (1) neurons with ipsilateral transcortical axons have the potential to reconfigure their projections after early, localized cortical damage elsewhere in the cortex of the same hemisphere; (2) this reconfiguration involves expansion of specific projections and is not a generalized capacity of all cortical neurons; (3) the expansion is modality specific; and finally, (4) the ability of cortical neurons to reorganize projections is limited in time. The expanded projection from vPS to MS cortex may contribute to neuronal compensations and the sparing of visually guided behaviors previously demonstrated in cats with neonatal visual cortex damage, and is a testament to the latent capacities immature cerebral cortex neurons possess to establish new projections following restricted damage to the cerebral cortex early in life.
The long-term morphological consequences on laminar thickness and neuron survival were assessed in cerebral cortical area PMLS following excision of visual cortical areas 17, 18, and 19 from adult and adolescent cats and from neonatal kittens. Following excisions from kittens, layers III, V, and VI in area PMLS were reduced in thickness and there was a significant loss of neurons from layers III and VI. Following excisions from adolescent cats, layers V and VI were thinner than normal, whereas excisions from adult cats resulted in a detectable thinning only of layer V and no neuron loss from any layer. In a parallel study, the configuration of projections between area PMLS and areas 17, 18, and 19 in adult cats and newborn kittens was analyzed and related to the patterns of neuron survival and death in area PMLS following the excisions. In adult cats, projections from areas 17, 18, and 19 terminate in all layers, but they are heaviest into layer III in area PMLS. Layers III and VI contain the largest number of neurons that form the origin of the reciprocal projections back to areas 17, 18, and 19. In area PMLS of the newborn kitten, the laminar distribution of cells projecting to areas 17, 18, and 19 resembles the pattern in the adult cat, although the laminar pattern of the terminations is poorly differentiated. The pattern of cell death following the excisions from the kittens can be most easily explained on the basis of the mature configuration of the reciprocal pathways and on the neurons' maturational status at the time areas 17, 18, and 19 were removed. Thus, immature cortical neurons that are deprived of their targets and inputs undergo degenerative changes. These changes are most severe in infancy, and they can be predicted on the basis of the final patterns of projections the neurons would have developed with the damaged region. This loss of neurons in early-lesioned animals in regions of cortex anatomically connected to the damaged tissue implies that there may be cognitive deficits associated with the secondary degeneration in addition to the deficits caused by the primary lesion.
Top-cited authors
Alan Charles Evans
  • McGill University
Simon B Eickhoff
  • Forschungszentrum Jülich
Bruce Fischl
  • Boston University
Michael P Milham
  • Child Mind Institute
Francisco Xavier Castellanos
  • NYU Langone Medical Center