Subcortical Neurons Research Articles

Corticofugal modulation of frequency processing in bat auditory system.

Auditory signals are transmitted from the inner ear through the brainstem to the higher auditory regions of the brain. Neurons throughout the auditory system are tuned to stimulus frequency, and in many auditory regions are arranged in topographical maps with respect to their preferred frequency. These properties are assumed to arise from the interactions of convergent and divergent projections ascending from lower to higher auditory areas; such a view, however, ignores the possible role of descending projections from cortical to subcortical regions. In the bat auditory system, such corticofugal connections modulate neuronal activity to improve the processing of echo-delay information, a specialized feature. Here we show that corticofugal projections are also involved in the most common type of auditory processing, frequency tuning. When cortical neurons tuned to a specific frequency are inactivated, the auditory responses of subcortical neurons tuned to the same frequency are reduced. Moreover, the responses of other subcortical neurons tuned to different frequencies are increased, and their preferred frequencies are shifted towards that of the inactivated cortical neurons. Thus the corticofugal system mediates a positive feedback which, in combination with widespread lateral inhibition, sharpens and adjusts the tuning of neurons at earlier stages in the auditory processing pathway.

Effects of single and repeated footshock on dopamine release and metabolism in the brains of Fischer rats.

Changes in the tissue levels of 3-methoxytyramine (3-MT), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and dopamine in the frontal cortex, hypothalamus, nucleus accumbens, and striatum were evaluated after 0.5-4 h of footshock (2 mA, for 3 s every 30 +/- 5 s) in Fischer rats. 3-MT, DOPAC, and HVA levels in the four brain areas peaked at 0.5 h and in most cases returned to baseline values within 4 h. No changes were found in dopamine levels. Repeated footshock stress was evaluated by administering 10 footshock sessions (0.5 h, two per day for 5 days). At the end of the 10th footshock session, 3-MT levels were higher than at the end of the first footshock session in three of the four brain regions, indicating sensitization of dopamine release. No differences were found between the first and 10th footshock sessions in DOPAC and HVA levels. Fourteen days after the 10th footshock session, the levels of 3-MT, DOPAC, and HVA were the same as in control rats in all four brain regions. A 0.5-h footshock challenge presented 14 days after the 10th footshock session attenuated DOPAC levels in the hypothalamus and nucleus accumbens. In contrast, DOPAC and HVA levels in the frontal cortex showed sensitization after footshock challenge, and a similar trend was apparent for 3-MT levels. These results indicate that repeated footshock stress induces generalized sensitization of dopamine release and turnover in some areas of the brain of Fischer rats. This sensitization may persist in the cortical but not subcortical dopamine neurons after discontinuation of the treatment.

Sources of subcortical projections to the superior colliculus in the ferret

We have identified brainstem and other subcortical afferents to the superior colliculus (SC) in the ferret, by examining the pattern of retrograde labelling that resulted from unilateral injections of red and green fluorescent latex microspheres or of wheat germ agglutinin conjugated to horseradish peroxidase into different regions of this midbrain nucleus. Labelled neurons were found in many structures, including somatosensory, visual and auditory nuclei. These subcortical inputs are almost all bilateral, although most are primarily ipsilateral. Despite some differences in organization, the subcortical projections to the ferret SC broadly resemble those described in other species. Following injections of red and green microspheres in either the rostral and caudal or the medial and lateral regions of the SC, double-labelled cells usually accounted for less than 10% of the total number of retrogradely labelled cells, indicating that most of the subcortical neurons project to discrete regions of the SC. Many of these afferents show some topographic organization, which is much more evident along the rostrocaudal axis of the SC than in the medial-lateral dimension. The intercollicular projection is restricted mainly to the rostral SC and demonstrates a point-to-point organization. Most of the subcortical structures caudal to the central region of the SC were labelled mainly by the tracers injected in caudal SC, while those rostral to this region, including the zona incerta and the pretectal nuclei, were labelled largely by injections in rostral SC. These findings suggest that projections originating from nuclei posterior to the central region of the SC terminate principally in caudal SC whereas afferents from structures anterior to the central region project largely to rostral SC.

Human A β-amyloid and amyloid precursor protein accumulates in rat brain cells after cultured human leptomeningeal fibroblast implants

Cultured human leptomeningeal fibroblasts grafted into rat frontal cortex were localized to the implant pocket and to adjacent host leptomeninges. Immunohistochemical studies using a panel of human-specific and domain-specific APP antibodies revealed that all grafted cells expressed both APP and A β in situ. Remarkably, these antibodies also labeled rat pial and ependymal cells as well as reactive astrocytes adjacent to vessels. In addition, apical projections and cell bodies of many cortical pyramidal neurons contained human-specific APP immunoreactive material. Groups of subcortical neurons, particularly those of the amygdala, hippocampal formation and suprachiasmatic nuclei, were similarly labeled. The presence of human APP in host brains was confirmed by immunoblotting. Birefringent Congo Red staining was observed in the cortical neuropil and in leptomeningeal vessels. These data indicate that grafted leptomeningeal fibroblasts hyperexpress APP and A β which can diffuse into parenchyma and be taken up by specific rat cells.

Effects of dopamine depletion in the medial prefrontal cortex on the stress-induced increase in extracellular dopamine in the nucleus accumbens core and shell

In the present study we examined whether depletion of dopamine in the medial prefrontal cortex alters the neurochemical activity of mesoaccumbens dopamine neurons and/or their behavioral correlate, motor behavior. Infusion of 6-hydroxydopamine (1 μg) into the medial prefrontal cortex of rats pretreated with a norepinephrine uptake blocker produced a 70% loss of tissue dopamine, with relative sparing of the norepinephrine content (−23%) in that region. Using in vivo microdialysis, we monitored basal and evoked extracellular dopamine in the nucleus accumbens core and shell of control and lesioned rats. The concentration of basal extracellular dopamine in the nucleus accumbens core was similar in control and lesioned rats; however, basal dopamine efflux in the nucleus accumbens shell was approximately 30% higher in lesioned rats than in controls. Lesions did not alter the ability of systemic d-amphetamine (1.5 mg/kg, i.p.) to increase extracellular dopamine in the nucleus accumbens shell. In contrast, the dopamine depletion in the medial prefrontal cortex attenuated the amphetamine-induced increase in extracellular dopamine in the nucleus accumbens core, as well as the amphetamine-induced increase in locomotor activity. Lesions did not significantly alter the effects of tail pressure (30 min) on extracellular dopamine in the nucleus accumbens core. However, the depletion of dopamine in the medial prefrontal cortex potentiated the stress-induced increase in extracellular dopamine in the nucleus accumbens shell. These data demonstrate that mesocortical dopamine neurons influence (i) amphetamine-induced dopamine efflux in the nucleus accumbens core and (ii) stress-evoked dopamine efflux in the nucleus accumbens shell. It has been proposed that a disruption in the interaction between cortical and subcortical dopamine neurons is involved in the pathophysiology of schizophrenia. The present data raise the possibility that a disruption in the interaction between mesocortical dopamine neurons and dopamine neurons projecting to the nucleus accumbens shell is involved in those symptoms of schizophrenia that are influenced by stress.

Histochemical and immunohistochemical detection of neurons that produce nitric oxide: effect of different fixative parameters and immunoreactivity against non-neuronal NOS antisera.

This study focused on two points concerning the histochemical and immunohistochemical detection of neurons that produce nitric oxide (NO): (a) the effect of fixation and other methodological parameters on the staining pattern of both NADPH-diaphorase (NADPH-d) histochemistry and nitric oxide synthase (NOS) immunohistochemistry, and (b) the possibility that neurons display immunoreactivity against NOS antisera obtained from non-neuronal sources. Frontal sections of rat brains, fixed with 4% paraformaldehyde according to different protocols, were processed for single and double labeling using NADPH-d histochemistry and neuronal (nNOS), macrophagic (macNOS), and endothelial (eNOS) NOS immunohistochemistry. Our results show that variations in the fixative schedule, even within standard parameters, produce qualitative and quantitative changes in NADPH-d labeling. The effect of fixative on weakly stained neurons is different from that on heavily stained neurons. In subfixed brains, a large number of NOS-positive neurons lose their NADPH-d activity, whereas NOS immunolabeling remains unaltered. This finding may be particularly interesting in morphological studies that compare NADPH-d activity under experimental conditions that can affect brain perfusion. On the other hand, many cortical and subcortical neurons show macNOS immunoreactivity, most of it colocalized with nNOS.

Binary expression of olfactory bulb-protein tyrosine phosphatase in rat central nervous system: developmental gene regulation in neonate cerebral cortex and constitutive expression in olfactory-rhinencephalon

Olfactory bulb-protein tyrosine phosphatase (OB-PTP) is a receptor type PTPase dominantly expressed in olfactory bulb. Previously, we isolated and molecularly cloned a rat OB-PTP cDNA from an embryonal brain cDNA library. In the present study, we investigated its temporal and spatial gene expression by Northern blot and in situ hybridization analysis. The expression of OB-PTP gene was firstly detected in day 16 post coitum embryo and significantly increased during the late-gestational stage, attaining the highest level in the first week of neonate. The OB-PTP transcript was then down-regulated postnatally and was detected barely in an adult brain. In situ hybridization analysis showed that the transcript was characteristically localized in the postmitotic neurons of cerebral cortex and subcortical structures, and was down-regulated by day 28 when the cortical and subcortical structures have been organized. In the olfactory-rhinencephalon system including olfactory bulb and piriform cortex, the OB-PTP was preferentially expressed in the postmitotic neurons, and in contrast continuously expressed in the matured brain. Based on the evidence that DPTP1OD, the Drosophila homolog of OB-PTP, is localized in the axons of specific pioneer neurons in Drosophila embryo, the OB-PTP is presumably involved in the axonogenesis of cortical and subcortical neurons as well as olfactory neurons in mammalian central nervous system. The biological significance of transcriptional regulation in olfactory system is discussed in terms of continuous axonal connections by regenerating olfactory neurons.

Global incomplete cerebral ischemia produces predominantly cortical neuronal injury.

We determined the neuropathologic damage in a canine model of global incomplete ischemia commonly used in a variety of physiological experiments. We induced 20 minutes of incomplete ischemia in dogs (n = 9) by increasing intracranial pressure via intraventricular infusion of artificial cerebrospinal fluid to maintain a cerebral perfusion pressure of 10 mm Hg while keeping body temperature at 38 degrees C during and immediately after ischemia. After a 7-day recovery period, animals were perfusion-fixed for neuropathology. In hematoxylin and eosin preparations, ischemic neuronal injury was assessed, neurons were counted, and percentage of cell damage was determined. No focal neurological deficits or overt seizures were observed during the 7-day recovery period. In superior temporal gyrus, 49 +/- 11% and 70 +/- 10% damage (mean +/- SEM) was observed in layer III pyramidal cells in the crown and sulcus, respectively. All neocortical regions examined showed neuronal damage in layers III and/or V. In hippocampus, 59 +/- 11% damage of pyramidal neurons occurred in CA1, with dorsal (septal) hippocampus showing more injury than ventral (temporal) portions. The caudate nucleus (head) exhibited 27 +/- 7% neuronal injury. In cerebellar cortex (anterior lobule), 70 +/- 7% damage of Purkinje cells occurred, but different folia of cerebellum showed varying degrees of injury. Brain stem and thalamus were minimally affected despite reduced blood flow. Inflammatory changes (leukocytic infiltration and neuronal incrustations) were observed, but only when neuronal degeneration was severe. Pancellular necrosis and infarction did not occur. This animal model of ischemia causes reproducible neuronal injury primarily in cortical regions without pancellular necrosis and infarction. Damage to subcortical areas is less severe than to cortical areas, despite comparable reductions in regional cerebral blood flow. Therefore, in the presence of regionally uniform but incomplete cerebral ischemia, neocortical and hippocampal pyramidal neurons and cerebellar cortical Purkinje cells are more likely than subcortical neurons to degenerate; alternatively, pyramidal and Purkinje neurons degenerate before neostriatal neurons in this model. This neuronal degeneration may represent an intrinsic cellular mechanism without major contribution of cytotoxic pathways associated with inflammation.

Evidence for a Glutamatergic Pathway from the Guinea Pig Auditory Cortex to the Inferior Colliculus

We attempt to provide evidence that the projection from the guinea pig auditory cortex (AC) to the inferior colliculus (IC) may contain glutamatergic or GABAergic fibers. Seven days after unilateral AC aspiration, histological studies indicated almost complete AC destruction and preterminal degeneration of fibers and terminal fields in the dorsal cortex (DCIC), external cortex (ECIC), and central nucleus (CNIC) of the IC ipsilateral to the ablated AC. Contralaterally, degeneration appeared in the DCIC. AC ablation depressed the electrically evoked Ca(2+)-dependent release of D-[3H]aspartate (D-[3H]Asp) in the ipsilateral DCIC, ECIC, and CNIC, and D-[3H]Asp uptake in the CNIC. Together with other evidence that the corticocollicular pathway is excitatory, these findings suggest that this projection may contain glutamatergic and/or aspartatergic (Glu/Asp-ergic) fibers. Glutamic acid decarboxylase immunoreactivity was not apparent in presumed pyramidal cells of layer V of the AC retrogradely labeled with biotinylated dextran injected into the ipsilateral IC. Thus, corticocollicular neurons probably do not synthesize GABA and may not be GABAergic. However, AC ablation depressed [14C]GABA release from the ipsilateral DCIC and ECIC, and [14C]GABA uptake in the DCIC. These findings are consistent with the atrophy or down-regulation of some subcortical neurons that mediate GABAergic transmission in the IC.

Specificity of rabies virus as a transneuronal tracer of motor networks: transfer from hypoglossal motoneurons to connected second-order and higher order central nervous system cell groups.

The specificity of transneuronal transfer of rabies virus [challenge virus standard (CVS) strain] was evaluated in a well-characterized neuronal network, i.e., retrograde infection of hypoglossal motoneurons and transneuronal transfer to connected (second-order) brainstem neurons. The distribution of the virus in the central nervous system was studied immunohistochemically at sequential intervals after unilateral inoculation into the hypoglossal nerve. The extent of transneuronal transfer of rabies virus was strictly time dependent and was distinguished in five stages. At 1 day postinoculation, labelling involved only hypoglossal motoneurons (stage 1). Retrograde transneuronal transfer occurred from 2.0-2.5 days postinoculation (stage 2). In stages 2-4, different groups of second-order neurons were labelled sequentially, depending on the strength of their input to the hypoglossal nucleus. In stages 4 and 5, labelling extended to several cortical and subcortical cell groups, which can be regarded as higher order because they are known to control tongue movements and/or to provide input to hypoglossal-projecting cell groups. The pattern of transneuronal transfer of rabies virus resembles that of alpha-herpesviruses with regard to the nonsynchronous labelling of different groups of second-order neurons and the transfer to higher order neurons. In striking contrast to alpha-herpesviruses, the transneuronal transfer of rabies is not accompanied by neuronal degeneration. Moreover, local spread of rabies from infected neurons and axons to adjoining glial cells, neurons, or fibers of passage does not occur. The results show that rabies virus is a very efficient transneuronal tracer. Results also provide a new insight into the organization of cortical and subcortical higher order neurons that mediate descending control of tongue movements indirectly via hypoglossal-projecting neurons.

Peptidergic neurons of subcortical white matter in aging and Alzheimer's brain

Most of the neurons in the subcortical white matter of the adult cerebrum are remnants of the transient subplate cortex which appears during early cortical development. The peptidergic neurons in the subcortical white matter beneath the striate cortex were examined qualitatively and quantitatively with immunohistochemistry for substance P, cholecystokinin, somatostatin and neuropeptide Y in seven control patients and eight patients with Alzheimer's disease. The different peptidergic subcortical neurons still persisted in normal aging. In Alzheimer's disease, however, the substance P- and somatostatin-immunoreactive neurons were decreased in numbers and showed degenerative changes.

The topographic distribution of brain atrophy in cortical Lewy body disease: comparison with Alzheimer's disease.

The topographic distribution of brain atrophy was quantified by image analysis of fixed coronal brain slices from four patients dying with cortical Lewy body disease (CLBD) all with Alzheimer-type pathology and compared to that in four other patients of similar age and gender dying with Alzheimer's disease (AD) alone. The pattern of atrophy in CLBD (+AD) was broadly similar to that in AD alone, suggesting that tissue loss was due mostly to parallel Alzheimer-type pathological changes and that the presence of Lewy bodies in cortical and subcortical neurons contributed little, if anything, to the overall degree of atrophy.

Anatomical Evidence for Cerebellar and Basal Ganglia Involvement in Higher Cognitive Function

The possibility that neurons in the basal ganglia and cerebellum innervate areas of the cerebral cortex that are involved in cognitive function has been a controversial subject. Here, retrograde transneuronal transport of herpes simplex virus type 1 (HSV1) was used to identify subcortical neurons that project via the thalamus to area 46 of the primate prefrontal cortex. This cortical area is known to be involved in spatial working memory. Many neurons in restricted regions of the dentate nucleus of the cerebellum and in the internal segment of the globus pallidus were labeled by transneuronal transport of virus from area 46. The location of these neurons was different from those labeled after HSV1 transport from motor areas of the cerebral cortex. These observations define an anatomical substrate for the involvement of basal ganglia and cerebellar output in higher cognitive function.

Age-associated and cell-type-specific neurofibrillary pathology in transgenic mice expressing the human midsized neurofilament subunit

Alterations in neurofilaments are a common occurrence in neurons of the human nervous system during aging and diseases associated with aging. Such pathologic changes may be attributed to species-specific properties of human neurofilaments as well as cell-type-specific regulation of this element of the cytoskeleton. The development of transgenic animals containing human neurofilament subunits offers an opportunity to study the effects of aging and other experimental conditions on the human-specific form of these proteins in a rodent model. The present study shows that mice from the transgenic line NF(M)27, which express the human midsized neurofilament subunit at low levels (2-25% of the endogenous NF-M), develop neurofilamentous accumulations in specific subgroups of neurons that are age dependent, affecting 78% of transgenic mice over 12 months of age. Similar accumulations do not occur in age-matched, wild-type littermates or in 3-month-old transgenic mice. In 12-month-old transgenic mice, somatic neurofilament accumulations resembling neurofibrillary tangles were present predominantly in layers III and V of the neocortex, as well as in select subpopulations of subcortical neurons. Intraperikaryal, spherical neurofilamentous accumulations were particularly abundant in cell bodies in layer II of the neocortex, and neurofilament-containing distentions of Purkinje cell proximal axons occurred in the cerebellum. These pathological accumulations contained mouse as well as human NF subunits, but could be distinguished by their content of phosphorylation-dependent NF epitopes. These cytoskeletal alterations closely resemble the cell-type-specific alterations in neurofilaments that occur during normal human aging and in diseases associated with aging, indicating that these transgenic animals may serve as models of some aspects of the pathologic features of human neurodegenerative diseases.

Occurrence of prosaposin as a neuronal surface membrane component.

Prosaposin is a precursor of four saposins that are required for the lysosomal hydrolysis of sphingolipids by specific hydrolases. Besides its precursor role, prosaposin also exists as a secreted protein. The present investigation reveals that prosaposin also exists as an integral component of the surface membranes of neuronal cells. Subcellular fractionation studies demonstrate that the membrane-bound prosaposin occurs specifically in plasma membranes of NS20Y rat neuroblastoma cells. An immunohistochemical study of the neuroblastoma cells using rat prosaposin-specific antibodies also showed that a portion of prosaposin is located on the surface of neurites as well as on cell bodies. Similar histochemical studies with antibodies that specifically recognized human prosaposin revealed the presence of prosaposin in dendrites, axons, and cell bodies of subcortical and spinal cord neurons in both human adult brain and in fetal brain (24-wk gestation). These findings suggest an important role of prosaposin in neuronal development.

Lucifer yellow staining in fixed brain slices: Optimal methods and compatibility with somatotopic markers in neonatal brain

Developing dendritic trees often acquire their mature form by selective pruning and reorientation relative to anatomical boundaries, such as cortical ‘barrel’ walls. Whether similar constraints are imposed on the developing dendrites of subcortical somatosensory neurons is not clear, although it is known that the cells in trigeminal nucleus principalis (PrV) of adult rats have polarized trees. In attempting to resolve this issue we adopted and subsequently optimized a strategy of intracellular injection of Lucifer Yellow into PrV neurons and cerebellar granule cells in slices of fixed brain. Postinjectionally, immunohistochemical staining produced a stabilized image of the Lucifer Yellow injected cells and created the opportunity to apply also an antiserum to Jl-tenascin in order to detect whisker-related compartmental boundaries in the neonatal PrV. In 6-day-old rats, most PrV dendrites are polarized and they do not cross tenascin-stained, whisker-related, patch borders. Notable exceptions are dendrites from the minority of PrV cells that have large somata and are responsive to multiple whiskers.

Amyloid precursor protein in the cerebral cortex is rapidly and persistently induced by loss of subcortical innervation.

Lesions of the cholinergic nucleus basalis of Meynert elevate the ex vivo synthesis of beta amyloid precursor protein (beta-APP) in the cerebral cortex, a major projection region. We have found that this elevation is reflected by increased levels of beta-APP mRNA. The induction is rapid (occurring 60 min after placement of the lesion) and persistent (remaining for at least 45 days after lesioning). Two other subcortical lesions, which result in reductions of cortical adrenergic and serotonergic innervation, similarly induced cortical beta-APP. The beta-APP induction is reversible and does not require loss of the subcortical neurons. Infusion of lidocaine, a calcium antagonist that disrupts neurotransmitter release, into the nucleus basalis of Meynert leads to the temporary reduction of released acetylcholine in the cortex. In this model, beta-APP mRNA levels are elevated shortly after the infusion of lidocaine (90 min) but return to preinfusion levels 7 days after the lidocaine treatment. However, metabolic stresses of the brain, including chronic physostigmine, glucocorticoid, and diabetogenic treatments, fail to induce the beta-APP response. These results suggest that the induction of beta-APP is a specific response to the loss of functional innervation in the cortex. Importantly, these studies show that cortical beta-APP is induced by lesions that mimic the neurochemical deficits most frequently observed in Alzheimer disease.

The distribution of dystrophin in the murine central nervous system: An immunocytochemical study

A mild non-progressive cognitive defect is a feature of the fatal X-linked disease, Duchenne muscular dystrophy. Recent studies have identified the genetic defect and the resulting loss of the protein dystrophin, and shown that dystrophin messenger RNA and protein are present in normal brain tissue. We have performed western immunoblotting and fluorescence immunocytochemistry using a sensitive antibody made against a large fragment of the dystrophin molecule to study the regional, cellular and subcellular distribution of dystrophin in the mammalian brain. The brains of B 10 (control) and mdx (dystrophin deficient null mutant) mouse brain were compared on a point-by-point basis to verify that only dystrophin and not autosomal dystrophin related protein or cross-reacting proteins were being identified. In addition three murine neurologic mutants, nervous, lurcher, and weaver, were studied to refine the localization of dystrophin. In western immunoblots, dystrophin is present in all regions of the brain and in greatest abundance in the cerebellum. Dystrophin, as demonstrated in immunofluorescence, is present in neurons, but not in glia or myelin, and forms punctate foci associated with the plasma membrane of perikarya and dendrites, but not axons. While dystrophin is abundant in cerebral cortical neurons and cerebellar Purkinje cells, it is absent from most subcortical neurons, the granule cells of fascia dentata, and cerebellar neurons other than Purkinje cells. The absence of dystrophin in the cerebellum of the Purkinje cell deficient mutants nervous and lurcher, and its presence in the granule cell deficient mutant weaver indicate that dystrophin is a component of Purkinje cells rather than closely apposed afferents to those cells. The distribution and localization of dystrophin suggests a role in organizing the plasma membrane, possibly as an anchor of the postsynaptic apparatus, a possible basis for the cognitive defect in Duchenne dystrophy.

MR imaging of the corpus callosum.

The corpus callosum is the major axonal commissure of the brain, connecting the two cerebral hemispheres and providing communication between the cortical and subcortical neurons. With MR imaging in the sagittal plane, the corpus callosum can be depicted in great detail. We review the normal anatomy, development, and process of myelination of the corpus callosum. The MR features of various pathologic conditions involving the corpus callosum are described. Finally, we discuss the evolving role of MR imaging in neuropsychiatric diseases with respect to the corpus callosum.

Distorted distribution of nicotinamide-adenine dinucleotide phosphate-diaphorase neurons in temporal lobe of schizophrenics implies anomalous cortical development.

The distribution of neurons expressing the enzyme nicotinamide-adenine dinucleotide phosphate-diaphorase (NADPH-d) in the lateral and medial temporal lobes of schizophrenic and matched control brains was investigated in a systematic blind analysis. Schizophrenics had significantly lower numbers of NADPH-d neurons in the hippocampal formation and in the neocortex of the lateral temporal lobe but significantly greater numbers of NADPH-d neurons in the white matter of the lateral temporal lobe and a tendency toward greater numbers in parts of the parahippocampal white matter. The distorted distribution of NADPH-d neurons in the lateral temporal lobe, which may be explained by developmental disturbances, such as impaired neuronal migration or an alteration in the death cycle of transitory subcortical neurons, is similar to that found in the prefrontal cortex of schizophrenics. Alterations of cortical ontogenesis, as reflected in the distribution of NADPH-d neurons, appear to be widespread among neocortical association fields in schizophrenics and may provide a clue to the cause of the disease.