Rodents rely on Merkel cells for texture discrimination tasks

The cutaneous somatosensory system contains multiple types of mechanoreceptors that detect different mechanical stimuli (Johnson, 2001). These stimuli, either alone or in combination, are ultimately interpreted by the brain as different aspects of the sense of touch. Psychophysical and electrophysiological experiments in humans and other mammals implicate one of these mechanoreceptors, the Merkel cell/neurite complex, in two-point discrimination and the detection of curvature, shape, and texture (Johnson and Lamb, 1981; Johnson et al., 2000; Johnson, 2001). However, whether Merkel cell/neurite complex function is required for the detection of these stimuli is unknown. We genetically engineered mice that lack Merkel cells (Maricich et al., 2009; Morrison et al., 2009) to directly test the hypothesis that Merkel cell/neurite complexes are necessary to perform these types of sensory discrimination tasks. We found that mice devoid of Merkel cells could not detect textured surfaces with their feet while other measures of motor and sensory function were unaffected. Interestingly, these mice retained the ability to discriminate both texture and shape using their whiskers, suggesting that other somatosensory afferents can functionally substitute for Merkel cell/neurite complexes in this sensory organ. These findings suggest that Merkel cell/neurite complexes are essential for texture discrimination tasks involving glabrous skin but not whiskers.     

Sustained attention training and errorless learning facilitates self‐care functioning in chronic ipsilesional neglect following severe traumatic brain injury

Limb activation studies involving contralesional spatiomotor cueing document a reduction of neglect for left space (Robertson & North, 1992, 1993, 1994; Samuel et al., 2000). A number of studies applying this approach have produced positive findings (Robertson, Hogg, & McMillan, 1998; Robertson, North, & Geggie, 1992; Robertson, McMillan, MacLeod, Edgeworth, & Brock, 2002; Samuel et al., 2000). An alternative theoretical approach which aims to facilitate spatial awareness via the modulation of non‐lateralised deficits in sustained attention/arousal (Robertson et al., 1997; Samuelsson et al., 1998) has also shown promising results (Robertson et al., 1995; Wilson, Manly, Coyle, & Robertson, 2000) in terms of improved contralesional unilateral neglect as well as activities of daily living.     

The art of prescribing pharmacological management of adult ADHD: implications for psychiatric care.

QUESTION: For several years I have seen more adults presenting with attention-deficit/ hyperactivity disorder (ADHD). I realize that historically ADHD has been considered a childhood disorder, but I would like to know more about diagnosing and treating adult ADHD. ANSWER: Your observations about the prevalence and challenges that confront psychiatric nurses concerning the diagnosis and treatment of adult ADHD are correct. ADHD is a relatively common psychiatric disorder with a high occurrence of 2-6% in adults (Kessler et al., 2006). Though generally regarded as a childhood diagnosis, emerging evidence indicates that symptoms of ADHD remain into adulthood, affecting 4.4% of the adult population (Biederman, Monuteaux, et al., 2006). ADHD in adults frequently goes undiagnosed and untreated. This is largely associated with adults minimizing the severity of symptoms and being unaware that they actually have ADHD. Predictably, adult ADHD is associated with increased morbidity. Higher divorce rates, traffic violations, and negative occupational, economic, and psychosocial functions and concomitant psychiatric disorders are common findings in adults with ADHD (Kessler, Adler, Ames, Barkley, et al., 2005). Approximately 70-75% of adults presenting for treatment of ADHD have at least one co-existing psychiatric diagnosis (Kessler et al., 2006; Wilens, Biederman, & Spencer, 2002). Social phobia, bipolar disorder, major depression, and alcohol dependence are the most common co-existing psychiatric disorders in adults with ADHD (Kessler et al., 2006).     

Role of CaCMKII in the cross talk between lonotropic nucleotide and nicotinic receptors in individual cholinergic terminals

Ionotropic P2X receptors for ATP are formed, to date, by seven different subunits named P2X (Torres et al., 1999; Cunha and Ribeiro, 2000; North and Surprenant, 2000; Pintor et al., 2000; Hervás et al., 2003; Miras-Portugal et al., 2003; Illes and Ribeiro, 2004), which are cloned from various mammalian species (Illes and Ribeiro, 2004). These subunits can occur as homo- or hetero-oligomeric assemblies of more than one subunit (North and Surprenant, 2000), except P2X (Miras-Portugal et al., 2003) receptor, which has been described not to coassemble with other subunits (Torres et al., 1999). They are abundantly expressed in the peripheral and central nervous systems and exhibit high permeability to Ca2+ ions (Cunha and Ribeiro, 2000). The existence of presynaptic ionotropic receptors for nucleotides, either for ATP or dinucleotides, has been reported in isolated synaptic terminals from mammalian brain, and both exhibit good permeability to Ca2+ ions (Pintor et al., 2000; Hervás et al., 2003; Miras-Portugal et al., 2003). Studies on isolated single terminals have confirmed the existence of independent and specific responses to ATP and dinucleotides on the same or different terminals (Miras-Portugal et al., 1999; Díaz-Hernández et al., 2002; Hervás et al., 2005; Sánchez-Nogueiro et al., 2005). The activation of presynaptic ionotropic nucleotide receptors can induce the release of other neurotransmitters such as acetylcholine, glutamate, or GABA. In these specific terminals, ionotropic nucleotide receptors can be modulated by interaction with metabotropic receptors, such as GABAB and adenosine receptors (Khakh and Henderson, 1998; Gómez-Villafuertes et al., 2001), and ionotropic, such as nicotinic cholinergic receptors (Díaz-Hernández et al., 2004; Sánchez-Nogueiro et al., 2005). Here, we discuss a relevant finding on the interaction between ionotropic nucleotide and nicotinic receptors in cholinergic synaptic terminals and the role of CaCMKII in this interaction.     

Dopamine genes and ADHD

Family, twin, and adoption studies have documented a strong genetic basis for ADHD/HKD, but these studies do not identify specific genes linked to the disorder. Molecular genetic studies can identify allelic variations of specific genes that are functionally associated with ADHD/HKD, and dopamine genes have been the initial candidates based on the site of action of the stimulants drugs, which for a half century have provided the primary pharmacological treatment for ADHD/HKD. Two candidate dopamine genes have been investigated and reported to be associated with ADHD/HKD: the dopamine transporter (DAT1) gene [Cook et al., American Journal of Human Genetics 1995;56:993-998, Gill et al., Molecular Psychiatry 1997;2:311-313] and the dopamine receptor D4 (DRD4) gene [LaHoste et al., Molecular Psychiatry 1996;1:121-124: Smalley et al., 1998;3:427-430; Swanson et al., Molecular Psychiatry 1998;3:38-41]. Speculative hypotheses [Swanson and Castellanos, NIH Consensus Development Conference: Diagnosis and Treatment of Attention Deficit Hyperactivity Disorder, November 1998. p. 37-42] have suggested that specific alleles of these dopamine genes may alter dopamine transmission in the neural networks implicated in ADHD/HKD (e.g. that the 10-repeat allele of the DAT1 gene may be associated with hyperactive re-uptake of dopamine or that the 7-repeat allele of the DRD4 gene may be associated with a subsensitive postsynaptic receptor). These and other variants of the dopamine hypothesis of ADHD will be discussed.     

Attention-deficit/hyperactivity disorder in the offspring following prenatal maternal bereavement: a nationwide follow-up study in Denmark

Severe prenatal stress exposure has been found to increase the risk of neuropsychiatric conditions like schizophrenia. We examined the risk of attention-deficit/hyperactivity disorder (ADHD) in the offspring following prenatal maternal bereavement, as a potential source of stress exposure. We conducted a nationwide population-based cohort study including all 1,015,912 singletons born in Denmark from 1987 to 2001. A total of 29,094 children were born to women who lost a close relative during pregnancy or up to 1 year before pregnancy. These children were included in the exposed cohort and other children were in the unexposed cohort. We used Cox regression to estimate hazard ratios for ADHD, defined as the first-time ADHD hospitalization or first-time ADHD medication after 3 years of age. Boys born to mothers who were bereaved by unexpected death of a child or a spouse, had a 72% increased risk of ADHD [hazard ratio (HR) 1.72, 95% confidence interval (CI) 1.09–2.73]. Boys born to mothers who lost a child or a spouse during 0–6 months before pregnancy and during pregnancy had a HR of 1.47 (95% CI 1.00–2.16) and 2.10 (95% CI 1.16–3.80), respectively. Our findings suggest that prenatal maternal exposure to severe stress may increase the risk of ADHD in the offspring.     

The N-butylcarbamate derivative of galantamine acts as an allosteric potentiating ligand on α7 nicotinic receptors in hippocampal neurons

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive impairments that become severe enough to interfere with the daily activities of patients and eventually lead to death (Chung and Cummings, 2000). Arecent study reports that approx 24 million people suffer from dementia worldwide. If the mortality rate does not change and no curative or preventive treatment is developed, this number is expected to double every 20 yr worldwide (Ferri et al., 2005). Although the causes of AD remain obscure, it has been reported that incremental loss of cholinergic neurons and of nicotinic receptor (nAChR) function/expression in specific brain regions correlates well with the severity of the symptoms at early stages of the disease (Hellstr?m-Lindahl et al., 1999; Nordberg, 2001; Perry et al., 2001; Wevers et al., 1999). In patients with more advanced stages of AD, such a correlation between the magnitude of nAChR loss and of cognitive decline does not appear to exist (Sabbagh et al., 2001). The nicotinic cholinergic system plays a central role in modulating different forms of associative learning known to be impaired in AD patients, including the eyeblink classical conditioning (Woodruff-Pak, 2001), and in maintaining neuronal viability. Neuroprotection and cognitive improvement result from increasing the activity of different nAChR subtypes, including those bearing the alpha7 subunit (Carlson et al., 1998; Hejmadi et al., 2003; Kihara et al., 1997; Levin et al., 2006). Thus, increasing nAChR activity in the brain was proposed as a mechanism to slow down the progression of the disease (Maelicke and Albuquerque, 1996).     

Patient and provider characteristics related with prescribing of ADHD medication: Nationwide health insurance claims database study in Korea

Background

Little is known about the association between prescribing of attention deficit hyperactivity disorder (ADHD) medication and the patient's age, gender, and type of medical institution in Asia region.

Introduction

This study investigates the prevalence and factors of diagnosis and pharmacological treatment of ADHD in the pediatric population.

Methods

Using the Korea Health Insurance database, study participants were identified as pediatric patients (≤17 years) with at least 1 diagnosis of ADHD (ICD‐10, F90) from January 1, 2007 to December 31, 2011. The annual prevalence of ADHD diagnosis and medication was calculated. Annual differences in the prevalence between 2007 and 2011 with 95% confidence intervals (CIs) were estimated. We conducted multiple logistic regression analysis to estimate adjusted odds ratios (aORs) and their 95% CI to investigate predictors associated with prescribing of ADHD medication.

Results

The prevalence of ADHD medication prescribing increased by 26.57% (95% CI, 26.27‐26.88) from 0.53% in 2007 to 0.72% in 2011. The prevalence increased by 41.56% (95% CI, 40.51‐42.65) in females compared with 34.91% (95% CI, 34.47‐35.36) in males. Whereas the prevalence decreased in patients younger than 6 years old, it increased by 74.30% (95% CI, 72.84‐75.79) in the 13 to 17–year group. Males were more likely than females to be treated with ADHD medication (aOR, 1.12; 95% CI, 1.10‐1.13). Physician specialty (psychiatry vs non‐psychiatry) (aOR, 1.37; 95% CI, 1.34‐1.40) were associated with prescribing of ADHD medication.

Conclusion

Rapid increases in the diagnosis and pharmacological treatment of ADHD in the pediatric population have been observed. While demographic characteristics were similar to other countries, provider characteristics were different with others reporting that the majority of patients were treated by physicians specializing in psychiatry.     

Phenomenology of prepubertal and early adolescent bipolar disorder: examples of elated mood,grandiose behaviors,decreased need for sleep,racing thoughts and hypersexuality

OBJECTIVE: Children are developmentally incapable of many manifestations of bipolar symptoms described in adults (e.g., children do not "max" out credit cards or have four marriages). To address this issue, our group investigated prepubertal and early adolescent age equivalents of adult mania behaviors. METHODS: Details of the methods appear in the companion article in this issue (Geller et al. 2002a). Subjects had a prepubertal and early adolescent bipolar disorder phenotype (PEA-BP) that was validated by reliable assessment (Geller et al. 2001b), 6-month stability (Geller et al. 2000c), and 1- and 2-year longitudinal diagnostic outcome (Geller et al. 2001a, 2002b). RESULTS: Examples of elation, grandiosity, decreased need for sleep, racing thoughts, and hypersexuality in PEA-BP subjects were compared to examples in prepubertal normal controls and to examples in late teenage/adult-onset mania. Because it is not intuitive that children can be pathologically happy or expansive, sections on guidelines for differentiating normal versus impairing elation and grandiosity are provided. CONCLUSION: Due to the high comorbidity of PEA-BP and attention deficit hyperactivity disorder (ADHD), recognition of mania symptoms that do not overlap with those for ADHD may aid in avoiding both under- and overdiagnosis of child bipolar disorder. A discussion of how "nonoverlapping with ADHD" Diagnostic and Statistical Manual of Mental Disorders (4th ed.) mania symptoms can be useful in the differential diagnosis of irritability is also provided.     

Stoichiometry and pharmacology of two human α4β2 nicotinic receptor types

The alpha4beta2 nicotinic acetylcholine receptor (nAChR) is the most abundant nAChR subtype in the brain, where it forms the high-affinity binding site for nicotine. The alpha4beta2 nAChR belongs to a gene family of ligand-gated ion channels that also includes muscle nAChRs, GABAA receptors, and glycine receptors and that assembles into pentameric structures. alpha4 and beta2 nAChR subunits expressed heterologously in Xenopus laevis oocytes assemble into a mixture of high- and low-affinity functional receptors, giving rise to biphasic ACh concentration-response curves (Zwart and Vijverberg, 1998; Buisson and Bertrand, 2001; Houlihan et al., 2001). High- and low-affinity alpha4beta2 nAChRs differ significantly in their functional and pharmacological properties (Zwart and Vijverberg, 1998; Buisson and Bertrand, 2001; Houlihan et al., 2001; Nelson et al., 2003) and result from the assembly of alpha4 and beta2 subunits into two distinct stoichiometric arrangements: (alpha4)2(beta2)3(high-affinity subtype) and (alpha4)3(beta2)2 (low-affinity subtype) (Nelson et al., 2003). In this study we have examined the functional and pharmacological properties of high- and low-affinity alpha4beta2 receptors using two-electrode voltage clamp procedures on Xenopus oocytes transfected with high (1:10) or low (10:1) ratios of alpha4/beta2 cDNAs, which yield high (1:10)- or low (10:1)- affinity receptors with monophasic ACh concentration- response curves. Furthermore, to determine the stoichiometry of high- and low-affinity receptors expressed heterologously by Xenopus oocytes, we have determined the stoichiometry of high- and low-affinity alpha4beta2 receptors by mutating a highly conserved hydrophobic residue in the middle (position 9') of the pore-lining domain, which increases agonist potency in a manner that allows predictions on subunit composition (Cooper et al., 1991; Revah et al., 1991; Labarca et al., 1995; Boorman et al., 2000).     

SPINning factors: Factor analytic evaluation of the Social Phobia Inventory in clinical and nonclinical undergraduate samples

The Social Phobia Inventory (SPIN) was designed to assess three dimensions of social anxiety (i.e., fear, avoidance, and physiological arousal) as posited by the scale authors (Connor et al., 2000). Despite expectations of a 3-factor solution, analyses of the SPIN to date have provided support for 3- and 5-factor solutions (Radomsky et al., 2006). Moreover, a 3-item version, the Mini-SPIN (Connor et al., 2001), has good sensitivity and specificity for generalized social anxiety disorder (SAD), implying some item redundancy. Another recent psychometric analysis of the SPIN was performed in a diagnostically diverse clinical sample (Antony et al., 2006); however, the study did not include a comprehensive evaluation of the factor structure. The current study was designed to comprehensively assess the SPIN factor structure using exploratory (EFA) and confirmatory (CFA) factor analyses in undergraduate (N = 227) and clinical samples (N = 355) using current recommendations for factor analyses (Osborne et al., 2008). Results suggest a 10-item 3-factor solution may be an ideal fit for clinical samples; however, using the undergraduate sample, the same solution was significantly better than precedent solutions but nonetheless not ideal. Implications and recommendations for future research are discussed.     

Vesicular calcium transport shapes rapid acetylcholine secretion

Rapid secretion relies on the occurrence of spike-like Ca2+ transients in active zones (Llinás et al., 1992; Yazejian et al., 2000; Dunant and Bloc, 2003). Presynaptic Ca2+ nanodomains are to be restricted both in time and in space as to assure rapid onset and termination of transmitter release (Llinás et al., 1992; Pozzan et al., 1994; Yazejian et al., 2000; Dunant and Bloc, 2003). A very fast Ca2+-buffering mechanism should allow Ca2+ rise above approximately 100 microM for less than approximately 250 micros and then rapid reduction of Ca2+ to subthreshold levels of release (Llinás et al., 1992; Pozzan et al., 1994; Yazejian et al., 2000; Dunant and Bloc, 2003). Swift Ca2+ clearance by vesicular Ca2+/H+ antiport as a low-affinity, high-capacity extrusion mechanism was postulated in the past (Pozzan et al., 1994; Dunant and Bloc, 2003). We demonstrated pH gradient (DeltapH)-dependent Ca2+ uptake by mammalian brain synaptic vesicles (Gon?alves et al., 1998, 2000). Moreover, this antiport activity is effective at [Ca2+] ranging from approximately 100 to 800 microM (max. at approximately 500 microM) (Gon?alves et al., 1998, 2000). We now show that the time course of acetylcholine (ACh) secretion in Torpedo neuroelectrocytic synapse is modified by bafilomycin A1 (baf.), which compromises antiport activity. Along with this mechanism, synaptic vesicles also have a P-type Ca2+ ATPase, exhibiting half-maximal activation for 0.6 microM Ca2+ (Gon?alves et al., 2000). Here, we demonstrate the role of P-type Ca2+ ATPase in preventing desensitization of the release mechanism by inhibiting it with orthovanadate.     

Interaction between P2X and nicotinic acetylcholine receptors in glutamate nerve terminals of the rat hippocampus

Nicotinic acetylcholine receptors (nAChRs [constituted by pentameric association of alpha2-10 and beta2-4 subunits]) and P2X receptors (P2XRs [activated by ATP and constituted by multimeric association of P2X1-7 subunits]) are both ionotropic receptors permeable to cations, which have in common the disparity between the wealth of data showing their presence in the brain and little evidence of their participation in mediating synaptic transmission. This has led to the proposal that both nAChRs and P2XRs might primarily modulate rather than directly mediate synaptic transmission, which is in accordance with the predominant presynaptic localization of both receptor subtypes (Role and Berg, 1996; Cunha and Ribeiro, 2000). Interestingly, both functional neurochemical (Allgaier et al., 1995; Salgado et al., 2000; Diáz-Hernández et al., 2002) and electrophysiological studies (Barajas-Lopez et al., 1998; Searl et al., 1998; Zhou and Calligan, 1998; Khakh et al., 2000) indicated a close interaction between nAChRs and P2XRs, which is paralleled by a co-release of ATPand ACh from central terminals (e.g., Richardson and Brown, 1987). Because glutamate release in the hippocampus is controlled by both nAChRs (e.g., McGehee et al., 1995) and P2XRs (Khakh et al., 2003; Rodrigues et al., 2005), we investigated if there was a functional interaction between these two presynaptic ionotropic receptors in the control of glutamate release in the rat hippocampus.     

Deforming the hippocampal map

To investigate conjoint stimulus control over place cells, Fenton et al. (J Gen Physiol 116:191-209, 2000a) recorded while rats foraged in a cylinder with 45 degrees black and white cue cards on the wall. Card centers were 135 degrees apart. In probe trials, the cards were rotated together or apart by 25 degrees . Firing field centers shifted during these trials, stretching and shrinking the cognitive map. Fenton et al. (2000b) described this deformation with an ad hoc vector field equation. We consider what sorts of neural network mechanisms might be capable of accounting for their observations. In an abstract, maximum likelihood formulation, the rat's location is estimated by a conjoint probability density function of landmark positions. In an attractor neural network model, recurrent connections produce a bump of activity over a two-dimensional array of cells; the bump's position is influenced by landmark features such as distances or bearings. If features are chosen with appropriate care, the attractor network and maximum likelihood models yield similar results, in accord with previous demonstrations that recurrent neural networks can efficiently implement maximum likelihood computations (Pouget et al. Neural Comput 10:373-401, 1998; Deneve et al. Nat Neurosci 4:826-831, 2001).     

Local field potential beta activity in the subthalamic nucleus of patients with Parkinson's disease is associated with improvements in bradykinesia after dopamine and deep brain stimulation

Parkinson's disease is treated pharmacologically with dopamine replacement medication and, more recently, by stimulating basal-ganglia nuclei such as the subthalamic nucleus (STN). Depth recordings after this procedure have revealed excessive activity at frequencies between 8 and 35 Hz ([Brown et al., 2001], [Kuhn et al., 2004] and [Priori et al., 2004]) that are reduced by dopamine therapy in tandem with improvements in bradykinesia/rigidity, but not tremor (Kuhn et al., 2006). It has also been shown that improvements in motor symptoms after dopamine correlate with single unit activity in the beta range (Weinberger et al., 2006). We recorded local field potentials (LFPs) from the subthalamic nucleus of patients with Parkinson's disease (PD) after surgery to implant deep brain stimulating electrodes while they were on and off dopaminergic medication. As well as replicating Kuhn et al., using the same patients we were able to extend Weinberger et al. to show that LFP beta oscillatory activity correlated with the degree of improvement in bradykinesia/rigidity, but not tremor, after dopamine medication. We also found that the power of beta oscillatory activity uniquely predicted improvements in bradykinesia/rigidity, but again not tremor, after stimulation of the STN in a regression analysis. However improvements after STN stimulation related inversely to beta power, possibly reflecting the accuracy of the electrode placement and/or the limits of STN stimulation in patients with the greatest levels of beta oscillatory activity.     

Discriminating Among ADHD Alone,ADHD With a Comorbid Psychological Disorder,and Feigned ADHD in a College Sample

Since the early 2000s concern has increased that college students might feign ADHD in pursuit of academic accommodations and stimulant medication. In response, several studies have validated tests for use in differentiating feigned from genuine ADHD. Although results have generally been positive, relatively few publications have addressed the possible impact of the presence of psychological disorders comorbid with ADHD. Because ADHD is thought to have accompanying conditions at rates of 50% and higher, it is important to determine if the additional psychological disorders might compromise the accuracy of feigning detection measures. The present study extended the findings of Jasinski et al. (2011) to examine the efficacy of various measures in the context of feigned versus genuine ADHD with comorbid psychological disorders in undergraduate students. Two clinical groups (ADHD only and ADHD + comorbid psychological disorder) were contrasted with two non-clinical groups (normal controls answering honestly and normal participants feigning ADHD). Extending previous research to individuals with ADHD and either an anxiety or learning disorder, performance validity tests such as the Test of Memory Malingering (TOMM), the Letter Memory Test (LMT), and the Nonverbal Medical Symptom Validity Test (NV-MSVT) were effective in differentiating both ADHD groups from normal participants feigning ADHD. However, the Digit Memory Test (DMT) underperformed in this study, as did embedded validity indices from the Wechsler Adult Intelligence Scale-IV (WAIS-IV) and Woodcock Johnson Tests of Achievement-III (WJ-III).     

Phosphorylation and function of α4β2 receptor

The neuronal nicotinic acetylcholine receptor (nAChR) alpha4 and beta2 subunits expressed in heterologous expression systems assemble into high- and low-affinity receptors (Zwart and Vijverberg, 1998; Buisson and Bertrand, 2001; Houlihan et al., 2001; Nelson et al., 2003), which reflects the assembly of two distinct subunit stoichiometries of alpha4beta2 receptor (Nelson et al., 2003). The high-affinity receptor ([alpha4]2[beta2]3) is about 100-fold more sensitive to ACh than the low-affinity receptor ([alpha4]3[beta2]2) (Zwart and Vijverberg, 1998; Buisson and Bertrand, 2001; Houlihan et al., 2001; Nelson et al., 2003). Recent evidence implicated 14-3-3 proteins as modulators of the relative abundance of nAChR subunits in the endoplasmic reticulum (ER), where ligand-gated ion channels assemble. The 14-3-3 proteins influence ER-to-plasma membrane trafficking of multimeric cell-surface proteins (O'Kelly et al., 2002). 14-3-3 proteins bind components of these multimeric proteins, and this interaction overrides dibasic COP1 retention signal to permit forward transport of the protein (O'Kelly et al., 2002). In the case of alpha4beta2 nAChRs, 14-3-3 binds the alpha4 subunit, and this association is dependent on phosphorylation of a serine residue within a protein kinase A(PKA) consensus sequence in the large cytoplasmic domain of the alpha4 subunit, which is also a binding motif recognized by 14-3-3 (Jeancloss et al., 2001; O'Kelly et al., 2002). The interplay among PKA, alpha4 subunits, and 14-3-3 proteins increases cell-surface expression of alpha4beta2 nAChRs by increasing steady-state levels of the alpha4 subunit available for assembly with beta2 subunits (Jeancloss et al., 2001). Because it is not known how 14-3-3-dependent changes in the steady-state levels of the alpha4 subunit might affect the functional type of alpha4beta2 receptors, we have investigated the effects of mutations of the 14-3-3 binding motif in the alpha4 subunit on alpha4beta2 nAChR function.     

Altered DARPP-32 expression in the superior temporal gyrus in schizophrenia

Many neuroimaging studies have revealed structural abnormalities in the superior temporal gyrus (STG) in schizophrenia ( [Kasai et al., 2003b] and [Kasai et al., 2003a]; Sun et al., 2009). Neurophysiological studies of mismatch negativities (MMN) generated in the STG have suggested impaired function of N-methyl-d-aspartate (NMDA) receptors (Javitt et al., 1996). Although many postmortem studies have been conducted on the pathogenesis of schizophrenia, relatively few reports have studied molecular alterations in the STG ( [Bowden et al., 2008], [Deng and Huang, 2006], [Kang et al., 2009], [Katsel et al., 2005], [Le Corre et al., 2000], [Nudmamud and Reynolds, 2001] and [Sokolov et al., 2000]). The STG shows pronounced changes in gene expression when compared to other regions implicated in schizophrenia (Katsel et al., 2005). Dopamine and a cAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32) is thought to be closely associated with pathophysiological changes in the dopamine and glutamate systems in schizophrenia because, when activated by phosphorylation, DARPP-32 acts as a critical regulator of D1 dopamine receptor and NMDA receptor activity (Greengard et al., 1999). The molecular pathways involving DARPP-32 appear important in the pathogenesis of schizophrenia. Here, we show dramatic alterations in DARPP-32 expression in the STG of postmortem brains from patients with schizophrenia. To clarify the detailed histological and cellular expression of DARPP-32 in the STG in schizophrenia, we immunohistochemically examined postmortem brains by using specific antibodies. We compared the density of immunoreactive cells of the STG (BA22) from 11 schizophrenia patients with those from 11 age- and sex-matched controls, and found significantly lower densities of DARPP-32-immunoreactive (IR) cells and threonine (Thr) 34-phosphorylated DARPP-32-IR cells in the STG in the schizophrenia group. Thus, the DARPP-32-related pathogenesis in schizophrenia may be more severe in the STG than previously found in the prefrontal cortex.     

Intact performance on an indirect measure of race bias following amygdala damage

Recent brain imaging and lesion studies provide converging evidence for amygdala involvement in judgments of fear and trust based on facial expression [Adolphs et al., Nature 393 (1998) 470; Adolphs et al., Neuropsychologia 37 (1999) 1111; Breiter et al., Neuron 17 (1996) 875; Winston et al., Nat. Neurosci. 5 (3) (2002) 277]. Another type of social information apparent in face stimuli is social group membership. Imaging studies have reported amygdala activation to face stimuli of different racial groups [Hart et al., NeuroReport 11 (11) (2000) 2351]. In White American subjects, amygdala activation to Black versus White faces was correlated with indirect, implicit measures of racial evaluation [Phelps et al., J. Cogn. Neurosci. 12 (5) (2000) 729]. To determine if the amygdala plays a critical role in indirect social group evaluation, as suggested by the imaging results, a patient with bilateral amygdala damage and control subjects were given two measures of race bias. All subjects were female, White Americans. The Modern Racism Scale (MRS) is a direct, self-report measure of race attitudes and beliefs. The Implicit Association Test (IAT) is an indirect, automatic evaluation task. Performance on the two tasks did not differ between the patient with amygdala damage and control subjects. All subjects showed a pro-Black bias on the direct, explicit measure of race beliefs, the MRS, and a negative evaluation towards Black faces on the indirect measure of race evaluation, the IAT. These results indicate that even though amygdala activation to Black versus White faces is correlated with performance on indirect measures of race bias [Phelps et al., J. Cogn. Neurosci. 12 (5) (2000) 729], the amygdala is not critical for normal performance on the IAT.     

Socioeconomic status during lifetime and cognitive impairment no-dementia in late life: the population-based aging in the Chianti Area (InCHIANTI) Study

Thousand and twelve dementia-free elderly (60–98 years old) enrolled in the InChianti Study (Italy) were evaluated at baseline (1998–2000) and at 3-year follow-up (2001–2003) with the aim of analyzing the association of lifetime socioeconomic status (SES) with prevalent and incident cognitive impairment no-dementia (CIND). SES was defined from information on formal education, longest held occupation, and financial conditions through life. CIND was defined as age-adjusted Mini-Mental State Examination score one standard deviation below the baseline mean score of participants without dementia. Logistic regression and Cox proportional-hazards models were used to estimate the association of SES with CIND. Demographics,occupation characteristics (i.e., job stress and physical demand), cardiovascular diseases, diabetes, apolipoprotein E (APOE)genotype, smoking, alcohol consumption, depressive symptoms, and C-reactive protein were considered potential confounders.Prevalence of CIND was 17.7%. In the fully adjusted model, low education (OR = 2.1; 95% confidence intervals, CI = 1.4 to 3.2)was associated with prevalent CIND. Incidence rate of CIND was 66.0 per 1000 person-years. Low education (HR = 1.7; 95% CI = 1.04 to 2.6) and manual occupation (HR = 1.9; 95% CI = 1.0 to 3.6) were associated with incident CIND. Among covariates,high job-related physical demand was associated with both prevalent and incident CIND (OR = 1.6; 95% CI = 1.1 to 2.4 and HR= 1.5; 95% CI = 1.0 to 2.3). After stratification for education, manual occupation was still associated with CIND among participants with high education (HR = 2.2; 95% CI = 1.2 to 4.3 versus HR= 1.4; 95% CI = 0.2 to 10.4 among those with low education). Proxy markers of lifetime SES (low education, manual occupation and high physical demand) are cross-sectional correlates of CIND and predict incident CIND over a three-year follow-up.