Altered ratios of alternatively spliced long and short γ2 subunit mRNAs of the γ-amino butyrate type A receptor in prefrontal cortex of schizophrenics

The relative abundance of alternatively spliced long (γ2L) and short (γ2S) mRNAs of the γ2 subunit of the γ-amino butyrate type A (GABAA) receptor was examined in dorsolateral prefrontal cortex of schizophrenics and matched controls by using in situ hybridization histochemistry and semiquantitative reverse transcription–PCR (RT-PCR) amplification. A cRNA probe identifying both mRNAs showed that the transcripts are normally expressed at moderately high levels in the prefrontal cortex. Consistent with previous studies, overall levels of γ2 transcripts in prefrontal cortex of brains from schizophrenics were reduced by 28.0%, although this reduction did not reach statistical significance. RT-PCR, performed under nonsaturating conditions on total RNA from the same blocks of tissue used for in situ hybridization histochemistry, revealed a marked reduction in the relative proportion of γ2S transcripts in schizophrenic brains compared with controls. In schizophrenics, γ2S transcripts had fallen to 51.7% (±7.9% SE; P < 0.0001) relative to control levels. Levels of γ2L transcripts showed only a small and nonsignificant reduction of 16.9% (±12.0% SE, P > 0.05). These findings indicate differential transcriptional regulation of two functionally distinct isoforms of one of the major GABAA receptor subunits in the prefrontal cortex of schizophrenics. The specific reduction in relative abundance of γ2S mRNAs and the associated relative increase in γ2L mRNAs should result in functionally less active GABAA receptors and have severe consequences for cortical integrative function.

Glucose intolerance caused by a defect in the entero-insular axis: A study in gastric inhibitory polypeptide receptor knockout mice

Mice with a targeted mutation of the gastric inhibitory polypeptide (GIP) receptor gene (GIPR) were generated to determine the role of GIP as a mediator of signals from the gut to pancreatic β cells. GIPR−/− mice have higher blood glucose levels with impaired initial insulin response after oral glucose load. Although blood glucose levels after meal ingestion are not increased by high-fat diet in GIPR+/+ mice because of compensatory higher insulin secretion, they are significantly increased in GIPR−/− mice because of the lack of such enhancement. Accordingly, early insulin secretion mediated by GIP determines glucose tolerance after oral glucose load in vivo, and because GIP plays an important role in the compensatory enhancement of insulin secretion produced by a high insulin demand, a defect in this entero-insular axis may contribute to the pathogenesis of diabetes.

Optical images of visible and invisible percepts in the primary visual cortex of primates

We optically imaged a visual masking illusion in primary visual cortex (area V-1) of rhesus monkeys to ask whether activity in the early visual system more closely reflects the physical stimulus or the generated percept. Visual illusions can be a powerful way to address this question because they have the benefit of dissociating the stimulus from perception. We used an illusion in which a flickering target (a bar oriented in visual space) is rendered invisible by two counter-phase flickering bars, called masks, which flank and abut the target. The target and masks, when shown separately, each generated correlated activity on the surface of the cortex. During the illusory condition, however, optical signals generated in the cortex by the target disappeared although the image of the masks persisted. The optical image thus was correlated with perception but not with the physical stimulus.

Regulation of cyclooxygenase-2 (COX-2) in rat renal cortex by adrenal glucocorticoids and mineralocorticoids

Production of prostaglandins involved in renal salt and water homeostasis is modulated by regulated expression of the inducible form of cyclooxygenase-2 (COX-2) at restricted sites in the rat renal cortex. Because inflammatory COX-2 is suppressed by glucocorticoids, and prostaglandin levels in the kidney are sensitive to steroids, the sensitivity of COX expression to adrenalectomy (ADX) was investigated. By 2 weeks after ADX in mature rats, cortical COX-2 immunoreactivity increased 10-fold in the cortical thick ascending limb and macula densa. The constitutive isoform, COX-1, was unchanged. The magnitude of the changes and specificity of COX-2 immunoreactivity were validated by in situ hybridization histochemistry of COX-2 mRNA and Western blot analysis. Increased COX-2 activity (>5-fold) was documented by using a specific COX-2 inhibitor. The COX-2 up-regulation in ADX rats was reversed by replacement therapy with either corticosterone or deoxycorticosterone acetate. In normal rats, inhibition of glucocorticoid receptors with RU486 or mineralocorticoid receptors with spironolactone caused up-regulation of renal cortical COX-2. These results indicate that COX-2 expression in situ is tonically inhibited by adrenal steroids, and COX-2 is regulated by mineralocorticoids as well as glucocorticoids.

Effects of muscarinic blockade in perirhinal cortex during visual recognition

Stimulus recognition in monkeys is severely impaired by destruction or dysfunction of the perirhinal cortex and also by systemic administration of the cholinergic-muscarinic receptor blocker, scopolamine. These two effects are shown here to be linked: Stimulus recognition was found to be significantly impaired after bilateral microinjection of scopolamine directly into the perirhinal cortex, but not after equivalent injections into the laterally adjacent visual area TE or into the dentate gyrus of the overlying hippocampal formation. The results suggest that the formation of stimulus memories depends critically on cholinergic-muscarinic activation of the perirhinal area, providing a new clue to how stimulus representations are stored.

Synchronization of oscillatory responses in visual cortex correlates with perception in interocular rivalry

In subjects suffering from early onset strabismus, signals conveyed by the two eyes are not perceived simultaneously but in alternation. We exploited this phenomenon of interocular suppression to investigate the neuronal correlate of binocular rivalry in primary visual cortex of awake strabismic cats. Monocularly presented stimuli that were readily perceived by the animal evoked synchronized discharges with an oscillatory patterning in the γ-frequency range. Upon dichoptic stimulation, neurons responding to the stimulus that continued to be perceived increased the synchronicity and the regularity of their oscillatory patterning while the reverse was true for neurons responding to the stimulus that was no longer perceived. These differential changes were not associated with modifications of discharge rate, suggesting that at early stages of visual processing the degree of synchronicity rather than the amplitude of responses determines which signals are perceived and control behavioral responses.

Role of left inferior prefrontal cortex in retrieval of semantic knowledge: A reevaluation

A number of neuroimaging findings have been interpreted as evidence that the left inferior frontal gyrus (IFG) subserves retrieval of semantic knowledge. We provide a fundamentally different interpretation, that it is not retrieval of semantic knowledge per se that is associated with left IFG activity but rather selection of information among competing alternatives from semantic memory. Selection demands were varied across three semantic tasks in a single group of subjects. Functional magnetic resonance imaging signal in overlapping regions of left IFG was dependent on selection demands in all three tasks. In addition, the degree of semantic processing was varied independently of selection demands in one of the tasks. The absence of left IFG activity for this comparison counters the argument that the effects of selection can be attributed solely to variations in degree of semantic retrieval. Our findings suggest that it is selection, not retrieval, of semantic knowledge that drives activity in the left IFG.

Description of microcolumnar ensembles in association cortex and their disruption in Alzheimer and Lewy body dementias

The cortex of the brain is organized into clear horizontal layers, laminae, which subserve much of the connectional anatomy of the brain. We hypothesize that there is also a vertical anatomical organization that might subserve local interactions of neuronal functional units, in accord with longstanding electrophysiological observations. We develop and apply a general quantitative method, inspired by analogous methods in condensed matter physics, to examine the anatomical organization of the cortex in human brain. We find, in addition to obvious laminae, anatomical evidence for tightly packed microcolumnar ensembles containing approximately 11 neurons, with a periodicity of about 80 μm. We examine the structural integrity of this new architectural feature in two common dementing illnesses, Alzheimer disease and dementia with Lewy bodies. In Alzheimer disease, there is a dramatic, nearly complete loss of microcolumnar ensemble organization. The relative degree of loss of microcolumnar ensembles is directly proportional to the number of neurofibrillary tangles, but not related to the amount of amyloid-β deposition. In dementia with Lewy bodies, a similar disruption of microcolumnar ensemble architecture occurs despite minimal neuronal loss. These observations show that quantitative analysis of complex cortical architecture can be applied to analyze the anatomical basis of brain disorders.

Neonatal lead exposure impairs development of rodent barrel field cortex

Childhood exposure to low-level lead can permanently reduce intelligence, but the neurobiologic mechanism for this effect is unknown. We examined the impact of lead exposure on the development of cortical columns, using the rodent barrel field as a model. In all areas of mammalian neocortex, cortical columns constitute a fundamental structural unit subserving information processing. Barrel field cortex contains columnar processing units with distinct clusters of layer IV neurons that receive sensory input from individual whiskers. In this study, rat pups were exposed to 0, 0.2, 1, 1.5, or 2 g/liter lead acetate in their dam's drinking water from birth through postnatal day 10. This treatment, which coincides with the development of segregated columns in the barrel field, produced blood lead concentrations from 1 to 31 μg/dl. On postnatal day 10, the area of the barrel field and of individual barrels was measured. A dose-related reduction in barrel field area was observed (Pearson correlation = −0.740; P < 0.001); mean barrel field area in the highest exposure group was decreased 12% versus controls. Individual barrels in the physiologically more active caudoventral group were affected preferentially. Total cortical area measured in the same sections was not altered significantly by lead exposure. These data support the hypothesis that lead exposure may impair the development of columnar processing units in immature neocortex. We demonstrate that low levels of blood lead, in the range seen in many impoverished inner-city children, cause structural alterations in a neocortical somatosensory map.

Coexistence of linear zones and pinwheels within orientation maps in cat visual cortex

Revealing the layout of cortical maps is important both for understanding the processes involved in their development and for uncovering the mechanisms underlying neural computation. The typical organization of orientation maps in the cat visual cortex is radial; complete orientation cycles are mapped around orientation singularities. In contrast, long linear zones of orientation representation have been detected in the primary visual cortex of the tree shrew. In this study, we searched for the existence of long linear sequences and wide linear zones within orientation preference maps of the cat visual cortex. Optical imaging based on intrinsic signals was used. Long linear sequences and wide linear zones of preferred orientation were occasionally detected along the border between areas 17 and 18, as well as within area 18. Adjacent zones of distinct radial and linear organizations were observed across area 18 of a single hemisphere. However, radial and linear organizations were not necessarily segregated; long (7.5 mm) linear sequences of preferred orientation were found embedded within a typical pinwheel-like organization of orientation. We conclude that, although the radial organization is dominant, perfectly linear organization may develop and perform the processing related to orientation in the cat visual cortex.

A universal scaling law between gray matter and white matter of cerebral cortex

Neocortex, a new and rapidly evolving brain structure in mammals, has a similar layered architecture in species over a wide range of brain sizes. Larger brains require longer fibers to communicate between distant cortical areas; the volume of the white matter that contains long axons increases disproportionally faster than the volume of the gray matter that contains cell bodies, dendrites, and axons for local information processing, according to a power law. The theoretical analysis presented here shows how this remarkable anatomical regularity might arise naturally as a consequence of the local uniformity of the cortex and the requirement for compact arrangement of long axonal fibers. The predicted power law with an exponent of 4/3 minus a small correction for the thickness of the cortex accurately accounts for empirical data spanning several orders of magnitude in brain sizes for various mammalian species, including human and nonhuman primates.

Progressive entorhinal cortex lesions accelerate hippocampal sprouting and spare spatial memory in rats

Accelerating hippocampal sprouting by making unilateral progressive lesions of the entorhinal cortex spared the spatial memory of rats tested for retention of a learned alternation task. Subsequent transection of the sprouted crossed temporodentate pathway (CTD), as well as a simultaneous CTD transection and progressive entorhinal lesion, produced a persistent deficit on the memory task. These results suggest that CTD sprouting, which is homologous to the original perforant path input to the dentate gyrus of the hippocampus, is behaviorally significant and can ameliorate at least some of the memory deficits associated with hippocampal deafferentation.

Columnar distribution of serotonin-dependent plasticity within kitten striate cortex

Recent studies have identified the potential for an important role for serotonin (5-HT) receptors in the developmental plasticity of the kitten visual cortex. 5-HT2C receptors are transiently expressed in a patchy fashion in the visual cortex of kittens between 30–80 days of age complementary to patches demarcated by cytochrome oxidase staining. 5-HT, operating via 5-HT2C receptors, increases cortical synaptic plasticity as assessed both in brain slices and in vivo. Herein, we report that bath application of 5-HT substantially increases the probability of long-term potentiation within 5-HT2C receptor-rich zones of cortex, but this effect is not observed in the 5-HT2C receptor-poor zones. Instead, in these zones, 5-HT application increases the probability of long-term depression. These location-specific effects of 5-HT may promote the formation of compartment-specific cortical responses.

Parsing executive processes: Strategic vs. evaluative functions of the anterior cingulate cortex

Event-related functional MRI and a version of the Stroop color naming task were used to test two conflicting theories of anterior cingulate cortex (ACC) function during executive processes of cognition. A response-related increase in ACC activity was present when strategic processes were less engaged, and conflict high, but not when strategic processes were engaged and conflict reduced. This is inconsistent with the widely held view that the ACC implements strategic processes to reduce cognitive conflicts, such as response competition. Instead, it suggests that the ACC serves an evaluative function, detecting cognitive states such as response competition, which may lead to poor performance, and representing the knowledge that strategic processes need to be engaged.

Prefrontal cortex and episodic memory retrieval mode

A multistudy analysis of positron emission tomography data identified three right prefrontal and two left prefrontal cortical sites, as well as a region in the anterior cingulate gyrus, where neuronal activity is correlated with the maintenance of episodic memory retrieval mode (REMO), a basic and necessary condition of remembering past experiences. The right prefrontal sites were near the frontal pole [Brodmann's area (BA) 10], frontal operculum (BA 47/45), and lateral dorsal area (BA 8/9). The two left prefrontal sites were homotopical with the right frontal pole and opercular sites. The same kinds of REMO sites were not observed in any other cerebral region. Many previous functional neuroimaging studies of episodic memory retrieval have reported activations near the frontal REMO sites identified here, although their function has not been clear. Many of these, too, probably have signaled their involvement in REMO. We propose that REMO activations largely if not entirely account for the frontal hemispheric asymmetry of retrieval as described by the original hemispheric encoding retrieval asymmetry model.