Developmental regulation of neural cell adhesion molecule in human prefrontal cortex

Neural cell adhesion molecule (NCAM) is a membrane-bound cell recognition molecule that exerts important functions in normal neurodevelopment including cell migration, neurite outgrowth, axon fasciculation, and synaptic plasticity. Alternative splicing of NCAM mRNA generates three main protein isoforms: NCAM-180, -140, and -120. Ectodomain shedding of NCAM isoforms can produce an extracellular 105–115 kilodalton soluble neural cell adhesion molecule fragment (NCAM-EC) and a smaller intracellular cytoplasmic fragment (NCAM-IC). NCAM also undergoes a unique post-translational modification in brain by the addition of polysialic acid (PSA)-NCAM. Interestingly, both PSA-NCAM and NCAM-EC have been implicated in the pathophysiology of schizophrenia. The developmental expression patterns of the main NCAM isoforms and PSA-NCAM have been described in rodent brain, but no studies have examined NCAM expression across human cortical development. Western blotting was used to quantify NCAM in human postmortem prefrontal cortex in 42 individuals ranging in age from mid-gestation to early adulthood. Each NCAM isoform (NCAM-180, -140, and -120), post-translational modification (PSA-NCAM) and cleavage fragment (NCAM-EC and NCAM-IC) demonstrated developmental regulation in frontal cortex. NCAM-180, -140, and -120, as well as PSA-NCAM, and NCAM-IC all showed strong developmental regulation during fetal and early postnatal ages, consistent with their identified roles in axon growth and plasticity. NCAM-EC demonstrated a more gradual increase from the early postnatal period to reach a plateau by early adolescence, potentially implicating involvement in later developmental processes. In summary, this study implicates the major NCAM isoforms, PSA-NCAM and proteolytically cleaved NCAM in pre- and postnatal development of the human prefrontal cortex. These data provide new insights on human cortical development and also provide a basis for how altered NCAM signaling during specific developmental intervals could affect synaptic connectivity and circuit formation, and thereby contribute to neurodevelopmental disorders.     

Pain-relieving drugs and the brain histaminergic system: multiple analgesic mechanisms from histamine,improgan and cimetidine

Inflammation Research -     

PSA-NCAM expression in the human prefrontal cortex

The prefrontal cortex (PFC) of adult rodents is capable of undergoing neuronal remodeling and neuroimaging studies in humans have revealed that the structure of this region also appears affected in different psychiatric disorders. However, the cellular mechanisms underlying this plasticity are still unclear. The polysialylated form of the neural cell adhesion molecule (PSA-NCAM) may mediate these structural changes through its anti-adhesive properties. PSA-NCAM participates in neurite outgrowth and synaptogenesis and changes in its expression occur parallel to neuronal remodeling in certain regions of the adult brain. PSA-NCAM is expressed in the hippocampus and temporal cortex of adult humans, but it has not been studied in the PFC. Employing immunohistochemistry on sections from the rostromedial superior frontal gyrus we have found that PSA-NCAM is expressed in the human PFC neuropil following a laminated pattern and in a subpopulation of mature neurons, which lack doublecortin expression. Most of these cells have been identified as interneurons expressing calbindin. The expression of PSA-NCAM in the human PFC is similar to that of rodents. Since this molecule has been linked to the neuronal remodeling found in experimental models of depression, it may also participate in the structural plasticity described in the PFC of depressed patients.     

Sensitivity to voice in human prefrontal cortex

We report two functional MRI (fMRI) experiments showing sensitivity to human voice in a region of human left inferior prefrontal cortex, pars orbitalis. The voice-enhanced response was observed for speech as well as non-linguistic vocalizations and was stronger for emotional than neutral vocalizations. This region could constitute a human prefrontal auditory domain similar to the one recently identified in the macaque brain.     

Spatial selectivity in human ventrolateral prefrontal cortex

The functional organization of lateral prefrontal cortex is not well understood, and there is debate as to whether the dorsal and ventral aspects mediate distinct spatial and non-spatial functions, respectively. We show for the first time that recordings from human ventrolateral prefrontal cortex show spatial selectivity, supporting the idea that ventrolateral prefrontal cortex is involved in spatial processing. Our results also indicate that prefrontal cortex may be a source of control signals for neuroprosthetic applications.     

The role of the medial prefrontal cortex in human religious activity

Although religious practices are ubiquitous and universal throughout human history, their biological basis is little understood, particularly at the neural level. In this paper, I will first review the current understanding of the neural basis of human religious activity, and then present a hypothesis that the medial prefrontal cortex plays a vital role in the integrity of religious activity. In this hypothesis, optimal functions of the medial prefrontal cortex, such as error detection, compliance to social norms, self-reflection, and theory of mind, are a key prerequisite to the maintenance of integrated religious activity. Hyperreligiosity may result from the hyperfunction of the medial prefrontal cortex, including rigid legalism (excessive error detection), excessive concern over one's existence (excessive self-reflection), and delusional interpretation of God's mind (excess of theory of mind). Future research based on this hypothesis is proposed, and the potential implication of this hypothesis on our society is also discussed.     

Somatosensory processing in the human inferior prefrontal cortex

Three inferior prefrontal regions in the monkey receive afferents from somatosensory cortices: the orbitofrontal cortex (OFC), the ventral area of the principal sulcus, and the anterior frontal operculum. To determine whether these areas show responses to tactile stimuli in humans, we examined data from an ongoing series of PET studies of somatosensory processing. Unlike previous work showing ventral frontal activity to hedonic (pleasant/unpleasant) sensory stimulation, the tactile stimuli used in these studies had a neutral hedonic valence. Our data provide evidence for at least two discrete ventral frontal brain regions responsive to somatosensory stimulation: 1) the posterior inferior frontal gyrus (IFG) and adjacent anterior frontal operculum, and 2) the OFC. The former region (posterior IFG/anterior frontal operculum) may have a more specific role in attending to tactile stimuli.     

Differential laminar distribution of tyrosine hydroxylase-immunoreactive axons in infant and adult monkey prefrontal cortex.

Immunohistochemical techniques were used to evaluate the laminar distribution of tyrosine hydroxylase (TH)-immunoreactive axons in area 9 of infant and adult rhesus monkey prefrontal cortex. In neonatal animals, TH-positive axons had a bilaminar location in the superficial and deep cortical layers, whereas in the adults, labeled fibers were more evenly distributed across all layers. These differences reflected the fact that fiber density in the superficial layers was over 35% greater in neonates than in adults, but in the middle cortical layers, fiber density was over 100% greater in adults than in neonates. The most striking changes in fiber distribution appeared to occur during the first few months of life. These findings may reveal differences in the role of dopamine in the regulation of prefrontal cortical function in neonatal and adult monkeys.     

Anticipatory anxiety-induced changes in human lateral prefrontal cortex activity

It has been suggested that frontal brain asymmetry is associated with differences in basic emotional dimensions, particularly in activation of systems underlying avoidance-withdrawal behavior. We examined regional cerebral oxygenated hemoglobin (O2Hb) levels in human medial prefrontal cortex (MPFC) using near-infrared reflection spectroscopy (NIRS) prior to and during anticipatory anxiety to determine if NIRS could detect any anxiety-related changes. Transient anxiety was induced in 56 normal volunteers by anticipation and a painful shock to the right-hand's median nerve. Pre- and post-anxiety affective statuses were measured using the State-Trait Anxiety Inventory (STAI) and Temperature Character Inventory (TCI). NIRS recorded from the left and right frontal brain regions. Right MPFC O2Hb was significantly increased relative to left MPFC O2Hb during anticipation of the shock. Right-sided O2Hb increases were significantly correlated with the TCI Harm Avoidance subscale. These results support the hypothesis that O2Hb levels in the right frontal region correlate with anxiety or heightened negative affect.     

Thiopental sodium reduces glutamate extracellular levels in rat intact prefrontal cortex

To investigate the effect of thiopental sodium on glutamate extracellular levels in the prefrontal cortex (PFC) of rats, a microdialysis probe was inserted into the PFC, the perfusate was collected every 10 min throughout the experiment with thiopental sodium ip or perfused into the PFC locally. The concentrations of glutamate in the perfusate were determined by reversed-phase high performance liquid chromatography. Thiopental sodium 30 mg kg⁻¹ ip significantly decreased glutamate levels in the perfusate after 10, 20, 30, and 40 min; glutamate levels in the perfusate were also decreased from 10 to 90 min after thiopental sodium 50 mg kg⁻¹ ip. Thiopental sodium with concentrations of 30, 100, or 300 μM perfused into the PFC also decreased glutamate levels in the perfusate significantly. The results suggest that thiopental sodium decreases glutamate extracellular levels in rat intact PFC.     

The role of the human ventromedial prefrontal cortex in memory for contextual information

There is a growing body of evidence that the ventromedial prefrontal cortex (VMPFC) is implicated in the new learning of visual items. Little is known, however, as to the involvement of that portion of the prefrontal cortex in the learning of temporal and spatial relationship of those items. The aim of the present study, therefore, was to investigate the role of the VMPFC in memory for temporal and spatial order. Patients who had undergone surgery of the anterior communicating artery aneurysm, and normal control subjects (C), participated in the study. The patients were subdivided into three groups: with resection of the left (LGR+) or right (RGR+) gyrus rectus, and without such a resection (GR-). Subjects were presented with two memory tests: a temporal order (TO) test and a spatial order (SO) test. In the TO test, the LGR+ and RGR+ groups performed worse than the C group, while the GR- group did not differ significantly from the C group. In the SO test, the LGR+ and RGR+ groups did not differ significantly from the C and GR- groups. However, the trend appears to be the same for both tests, although only the TO test provides statistically significant group differences. Our results thus suggest that the VMPFC is involved in memory for contextual information. Together with previous findings, the data suggest that the learning of the relationship between items as well as the learning of those items are mediated by overlapping areas of the VMPFC.     

Increased GABA levels in medial prefrontal cortex of young adults with narcolepsy

Study Objectives:

To explore absolute concentrations of brain metabolites including gamma amino-butyric acid (GABA) in the medial prefrontal cortex and basal ganglia of young adults with narcolepsy.

Design:

Proton magnetic resonance (MR) spectroscopy centered on the medial prefrontal cortex and the basal ganglia was acquired. The absolute concentrations of brain metabolites including GABA and glutamate were assessed and compared between narcoleptic patients and healthy comparison subjects.

Setting:

Sleep and Chronobiology Center at Seoul National University Hospital; A high strength 3.0 Tesla MR scanner in the Department of Radiology at Seoul National University Hospital.

Patients or Participants:

Seventeen young adults with a sole diagnosis of HLA DQB₁ 0602 positive narcolepsy with cataplexy (25.1 ± 4.6 years old) and 17 healthy comparison subjects (26.8 ± 4.8 years old).

Interventions:

N/A.

Measurements and Results:

Relative to comparison subjects, narcoleptic patients had higher GABA concentration in the medial prefrontal cortex (t = 4.10, P <0.001). Narcoleptic patients with nocturnal sleep disturbance had higher GABA concentration in the medial prefrontal cortex than those without nocturnal sleep disturbance (t = 2.45, P= 0.03), but had lower GABA concentration than comparison subjects (t = 2.30, P = 0.03).

Conclusions:

The current study reports that young adults with narcolepsy had a higher GABA concentration in the medial prefrontal cortex, which was more prominent in patients without nocturnal sleep disturbance. Our findings suggest that the medial prefrontal GABA level may be increased in narcolepsy, and the increased medial prefrontal GABA might be a compensatory mechanism to reduce nocturnal sleep disturbances in narcolepsy.

Citation:

Kim SJ; Lyoo IK; Lee YS; Sung YH; Kim HJ; Kim JH; Kim KH; Jeong DU. Increased GABA levels in medial prefrontal cortex of young adults with narcolepsy. SLEEP 2008;31(3):342-347.     

Postnatal alterations in dopaminergic markers in the human prefrontal cortex

Dopamine in the prefrontal cortex plays a critical role in normal cognition throughout the lifespan and has been implicated in the pathophysiology of neuropsychiatric disorders such as schizophrenia and attention deficit disorder. Little is known, however, about the postnatal development of the dopaminergic system in the human prefrontal cortex. In this study, we examined pre- and post-synaptic markers of the dopaminergic system in postmortem tissue specimens from 37 individuals ranging in age from 2 months to 86 years. We measured the levels of tyrosine hydroxylase, the rate limiting enzyme in dopamine biosynthesis, using Western immunoblotting. We also examined the gene expression of the three most abundant dopamine receptors (DARs) in the human prefrontal cortex: DAR1, DAR2 and DAR4, by in situ hybridization. We found that tyrosine hydroxylase concentrations and DAR2 mRNA levels were highest in the cortex of neonates. In contrast, the gene expression of DAR1 was highest in adolescents and young adults. No significant changes across age groups were detected in mRNA levels of DAR4. Both DAR1 and DAR2 mRNA were significantly lower in the aged cortex. Taken together, our data suggest dynamic changes in markers of the dopamine system in the human frontal cortex during postnatal development at both pre-and post-synaptic sites. The peak in DAR1 mRNA levels around adolescence/early adulthood may be of particular relevance to neuropsychiatric disorders such as schizophrenia in which symptoms manifest during the same developmental period.     

The human prefrontal cortex mediates integration of potential causes behind observed outcomes

Prefrontal cortex has long been implicated in tasks involving higher order inference in which decisions must be rendered, not only about which stimulus is currently rewarded, but also which stimulus dimensions are currently relevant. However, the precise computational mechanisms used to solve such tasks have remained unclear. We scanned human participants with functional MRI, while they performed a hierarchical intradimensional/extradimensional shift task to investigate what strategy subjects use while solving higher order decision problems. By using a computational model-based analysis, we found behavioral and neural evidence that humans solve such problems not by occasionally shifting focus from one to the other dimension, but by considering multiple explanations simultaneously. Activity in human prefrontal cortex was better accounted for by a model that integrates over all available evidences than by a model in which attention is selectively gated. Importantly, our model provides an explanation for how the brain determines integration weights, according to which it could distribute its attention. Our results demonstrate that, at the point of choice, the human brain and the prefrontal cortex in particular are capable of a weighted integration of information across multiple evidences.     

Sleep spindles in human prefrontal cortex: an electrocorticographic study

To investigate the sleep spindle activity of the human prefrontal cortex (PFC), we simultaneously recorded whole nights of polysomnographic and electrocorticographic (ECoG) activities during the natural sleep of epileptic patients. Subjects were nine patients with intractable epilepsy who had subdural electrodes surgically attached to the orbital (seven cases), medial (three cases), or dorsolateral (two cases) PFC, and in one case to the frontal pole. To examine spindle frequencies, fast Fourier transformation (FFT) and auto-correlation analyses were performed on the PFC ECoG and Cz EEG data, primarily on epochs of stage 2 sleep. Lower sigma band ECoG oscillations of about 12 Hz were widely distributed across all prefrontal cortical areas including the frontal limbic regions, but none of the PFC sigma frequency peaks coincided with the faster (about 14 Hz) Cz EEG sleep spindles. Combining our results with anatomical and electrophysiological facts, it is suggested that the thalamofrontal circuit involving the rostral reticular and the mediodorsal nucleus of the thalamus is responsible for the generation of 12 Hz frontal spindles in humans.     

Coumarin effects on amino acid levels in mice prefrontal cortex and hippocampus

Coumarin is a compound known to be present in a wide variety of plants, microorganisms and animal species. Most of its effects were studied in organs and systems other than the central nervous system. The present work evaluated the effect of coumarin administration on the levels of gamma-aminobutyric acid (GABA), glutamate (GLU), glycine (GLY) and taurine (TAU) in the prefrontal cortex and hippocampus of mice. Male Swiss mice were treated with distilled water (controls), coumarin (20 or 40 mg/kg, i.p.) or diazepam (1 mg/kg, i.p.). Results showed that in the prefrontal cortex, coumarin at the lowest dose increased the levels of GLU and TAU, while GABA increased with both doses studied and GLY had its levels increased only at the dose of 40 mg/kg. Diazepam (DZP) increased the levels of GABA and TAU and decreased the levels of GLU and GLY in this area. In the hippocampus, only glutamate had its levels decreased after coumarin treatment, while diazepam increased the levels of GABA and TAU and decreased the levels of GLU in this brain region. We concluded that coumarin stimulates the release of endogenous amino acids, increasing the levels of inhibitory and excitatory amino acids in the prefrontal cortex, and decreasing glutamate levels in the hippocampus. Together, these results are of interest, considering that some neurodegenerative diseases and seizures are related to the imbalance of the amino acid levels in the CNS suggesting a perspective of a therapeutic use of coumarins in these disorders.     

Differential regulation of parvalbumin and calretinin interneurons in the prefrontal cortex during adolescence

Determining the normal developmental trajectory of individual GABAergic components in the prefrontal cortex (PFC) during the adolescent transition period is critical because local GABAergic interneurons are thought to play an important role in the functional maturation of cognitive control that occurs in this developmental window. Based on the expression of calcium-binding proteins, three distinctive subtypes of interneurons have been identified in the PFC: parvalbumin (PV)-, calretinin (CR)-, and calbindin (CB)-positive cells. Using biochemical and histochemical measures, we found that the protein level of PV is lowest in juveniles [postnatal days (PD) 25–35] and increases during adolescence (PD 45–55) to levels similar to those observed in adulthood (PD 65–75). In contrast, the protein expression of CR is reduced in adults compared to juvenile and adolescent animals, whereas CB levels remain mostly unchanged across the developmental window studied here. Semi-quantitative immunostaining analyses revealed that the periadolescent upregulation of PV and the loss of the CR signal appear to be attributable to changes in PV- and CR-positive innervation, which are dissociable from the trajectory of PV- and CR-positive cell number. At the synaptic level, our electrophysiological data revealed that a developmental facilitation of spontaneous glutamatergic synaptic inputs onto PV-positive/fast-spiking interneurons parallels the increase in prefrontal PV signal during the periadolescent transition. In contrast, no age-dependent changes in glutamatergic transmission were observed in PV-negative/non fast-spiking interneurons. Together, these findings emphasize that GABAergic inhibitory interneurons in the PFC undergo a dynamic, cell type-specific remodeling during adolescence and provide a developmental framework for understanding alterations in GABAergic circuits that occur in psychiatric disorders.     

Dual streams of auditory afferents target multiple domains in the primate prefrontal cortex

'What' and 'where' visual streams define ventrolateral object and dorsolateral spatial processing domains in the prefrontal cortex of nonhuman primates. We looked for similar streams for auditory-prefrontal connections in rhesus macaques by combining microelectrode recording with anatomical tract-tracing. Injection of multiple tracers into physiologically mapped regions AL, ML and CL of the auditory belt cortex revealed that anterior belt cortex was reciprocally connected with the frontal pole (area 10), rostral principal sulcus (area 46) and ventral prefrontal regions (areas 12 and 45), whereas the caudal belt was mainly connected with the caudal principal sulcus (area 46) and frontal eye fields (area 8a). Thus separate auditory streams originate in caudal and rostral auditory cortex and target spatial and non-spatial domains of the frontal lobe, respectively.