Non-human contributions to personality neuroscience: From fish through primates - a concluding editorial overview.

This special issue attempts to integrate personality, psychopathology, and neuroscience as means to improve understanding of specific traits and trait structures in humans. The key strategy is to dive into comparative research using a range of species to provide simple models. This strategy has, as its foundation, the fact that the most basic functions, and their supporting neural systems, are highly conserved in evolution. The papers collected in the issue show that, from fish, through rats, to primates, the homologies in brain systems and underlying functions (despite species-specific forms of expression) allow simpler cases to provide insights into the neurobiology behind more complex ones including human. Our introductory editorial paper to this special issue took a bottom-up approach, starting with the genetics of conserved brain systems and working up to cognition. Here, we deconstruct the different aspects of personality, progressing from more complex ones in primates to least complex in fish. With the primate section, we summarize papers that discuss the factors that contribute to sociability in primates and how they apply to healthy and pathological human personality traits. In the rat section, the focus is driven by psychopathology and the way that "high" strains selected for extreme behaviors can illuminate the neurobiology of motivated responses to environmental cues. The section on fish summarizes papers that look into the most fundamental emotional reactions to the environment that are governed by primitive and conserved brain structures. This raises metatheoretical questions on the nature of traits and to a section that asks "which animals have personalities." We believe that the issue as a whole provides a nuanced answer to this question and shines a new, comparative, light on the interpretation of personality structure and the effects on it of evolution.

U-Pb SHRIMP geochronology data from the eastern Central Kibalian Superterrane, Bomu-Kibalian Craton, northeastern DRC: Implications for the tectonic evolution of the Kilo Terrane.

This brief presents new U-Pb SHRIMP (Sensitive High-Resolution Ion Microprobe) geochronology data on zircons and titanites dated from the gold-rich Kilo Terrane in the eastern Central Kibalian Superterrane, northeastern DRC. Out of 40 rock samples (), only 36 samples produced zircons and titanites suitable for U-Pb SHRIMP dating (-). Raw ion-microprobe SHRIMP analyses of specific zircon/titanite grain-spots returned U-Th-Pb compositions and radiogenic isotope ratios (-), from which age dates (Table 3, Figs 8A-8HH and 13A-F) were derived. With the exception of Table 3, all Tables are presented in the Supplementary Material. The new age dates in this Brief can be used in advancing understanding of the gold metallogeny and implications to exploration targeting for large to giant gold deposits in the Bomu-Kibalian Craton.

Anterior thalamic nuclei neurons sustain memory.

A hippocampal-diencephalic-cortical network supports memory function. The anterior thalamic nuclei (ATN) form a key anatomical hub within this system. Consistent with this, injury to the mammillary body-ATN axis is associated with examples of clinical amnesia. However, there is only limited and indirect support that the output of ATN neurons actively enhances memory. Here, in rats, we first showed that mammillothalamic tract (MTT) lesions caused a persistent impairment in spatial working memory. MTT lesions also reduced rhythmic electrical activity across the memory system. Next, we introduced 8.5 Hz optogenetic theta-burst stimulation of the ATN glutamatergic neurons. The exogenously-triggered, regular pattern of stimulation produced an acute and substantial improvement of spatial working memory in rats with MTT lesions and enhanced rhythmic electrical activity. Neither behaviour nor rhythmic activity was affected by endogenous stimulation derived from the dorsal hippocampus. Analysis of immediate early gene activity, after the rats foraged for food in an open field, showed that exogenously-triggered ATN stimulation also increased Zif268 expression across memory-related structures. These findings provide clear evidence that increased ATN neuronal activity supports memory. They suggest that ATN-focused gene therapy may be feasible to counter clinical amnesia associated with dysfunction in the mammillary body-ATN axis.

Ketamine and neuroticism: a double-hit hypothesis of internalizing disorders.

Psychiatric disorders can often be viewed as extremes of personality traits. The primary action of drugs that ameliorate these disorders may, thus, be to alter the patient's position on a relevant trait dimension. Here, we suggest that interactions between such trait dimensions may also be important for disorder. Internalizing disorders show important differences in terms of range of activity and speed of response of medications. Established antidepressant and anxiolytic medications are slow in onset and have differing effects across different internalizing disorders. In contrast, low-dose ketamine is rapidly effective and improves symptom ratings in all internalizing disorders. To account for this, we propose a "double hit" model for internalizing disorders: generation (and maintenance) require two distinct forms of neural dysfunction to coincide. One hit, sensitive to ketamine, is disorder-general: dysfunction of a neural system linked to high levels of the personality trait of neuroticism. The other hit is disorder-specific: dysfunction of one of a set of disorder-specific neural modules, each with its own particular pattern of sensitivity to conventional drugs. Our hypothesis applies only to internalizing disorders. So, we predict that ketamine will be effective in simple phobia and (perhaps partially) in anorexia nervosa, but would make no such prediction about other disorders where neuroticism might also be important secondarily (e.g. attention deficit hyperactivity disorder and schizophrenia).

Does behavioural inhibition system dysfunction contribute to Attention Deficit Hyperactivity Disorder?

The Reinforcement Sensitivity Theory of Personality has as its main foundation a Behavioural Inhibition System (BIS), defined by anxiolytic drugs, in which high trait sensitivity should lead to internalising, anxiety, disorders. Conversely, it has been suggested that low BIS sensitivity would be a characteristic of externalising disorders. BIS output should lead to increased arousal and attention as well as behavioural inhibition. Here, therefore, we tested whether an externalising disorder, Attention Deficit Hyperactivity Disorder (ADHD), involves low BIS sensitivity. Goal-Conflict-Specific Rhythmicity (GCSR) in an auditory Stop Signal Task is a right frontal EEG biomarker of BIS function. We assessed children diagnosed with ADHD-I (inattentive) or ADHD-C (combined) and healthy control groups for GCSR in: a) an initial smaller study in Dunedin, New Zealand (population ~120,000: 15 control, 10 ADHD-I, 10 ADHD-C); and b) a main larger one in Tehran, Iran (population ~9 [city]-16 [metropolis] million: 27 control, 18 ADHD-I, 21 ADHD-C). GCSR was clear in controls (particularly at 6-7 Hz) and in ADHD-C (particularly at 8-9 Hz) but was reduced in ADHD-I. Reduced attention and arousal in ADHD-I could be due, in part, to BIS dysfunction. However, hyperactivity and impulsivity in ADHD-C are unlikely to reflect reduced BIS activity. Increased GCSR frequency in ADHD-C may be due to increased input to the BIS. BIS dysfunction may contribute to some aspects of ADHD (and potentially other externalising disorders) and to some differences between the ADHD subtypes but other prefrontal systems (and, e.g. dopamine) are also important.

Values and value in simulated participant methodology: A global perspective on contemporary practices.

This article has been written for the 40th year of the publication of Medical Teacher. While we celebrate the contribution of simulated participants (SPs) to health professions education through values and value-based learning, we also offer critical reflection on elements of our practice, commencing with language. We argue for the use of the term simulated rather than standardized and acknowledge the dominant role of the SP as patient and the origins of the methodology. These shifts in terms and their implications in practice reflect changes in the conceptualization of SP-based methodology. Recently published standards for those who work with SPs (SP practitioners) are noted as an important milestone in our community's development. We consider contemporary practices addressing the complex notions of values and value in SP-based learning. We simultaneously refer to the work of SPs and SP practitioners. Phases of educational design including identifying learning objectives, scenario design, implementation, feedback and debriefing are used to illustrate methodological shifts. Within each of these phases, there are relational issues that have to date often gone unchecked and are under reported in literature. Finally, using the metaphor of a murmuration, we celebrate contemporary practices of the global SP practitioner community.

An improved human anxiety process biomarker: characterization of frequency band, personality and pharmacology.

Anxiety disorders are among the most common mental illness in the western world with a major impact on disability. But their diagnosis has lacked objective biomarkers. We previously demonstrated a human anxiety process biomarker, goal-conflict-specific electroencephalography (EEG) rhythmicity (GCSR) in the stop-signal task (SST). Here we have developed and characterized an improved test appropriate for clinical group testing. We modified the SST to produce balanced numbers of trials in clearly separated stop-signal delay groups. As previously, right frontal (F8) GCSR was extracted as the difference in EEG log Fourier power between matching stop and go trials (that is, stop-signal-specific power) of a quadratic contrast of the three delay values (that is, power when stopping and going are in balanced conflict compared with the average of when stopping or going is greater). Separate experiments assessed drug sensitivity (n=34) and personality relations (n=59). GCSR in this new SST was reduced by three chemically distinct anxiolytic drugs (administered double-blind): buspirone (10 mg), triazolam (0.25 mg) and pregabalin (75 mg); had a frequency range (4-12 Hz) consistent with rodent model data; and positively correlated significantly with neuroticism and nonsignificantly with trait anxiety scores. GCSR, measured in our new form of the SST, should be suitable as a biomarker for one specific anxiety process in the testing of clinical groups and novel drugs and in the development of measures suitable for individual diagnosis.

Effects of thalamic lesions on repeated relearning of a spatial working memory task.

Anterior thalamic (ATN) dysfunction produces memory deficits in rats and humans. The current study shows that, with a substantial delay between post-surgery tests, controls show repeated relearning on a spatial working memory task whereas rats with neurotoxic ATN lesions showed repeated relearning deficits. Rats were pre-trained to criterion, but not over trained, on the spatial task. ATN lesions produced the expected spatial memory and relearning deficits about two weeks post-surgery and again either one or 15 weeks later. Control rats also showed forgetting post-surgery and after a 15 week break, relearning the task on each occasion. Controls with only a 1 week break before their final re-test showed negligible forgetting. Thus, a short break between re-tests replicated previous findings with ATN lesions, but a long break allows repeated comparison of rates of learning from a common starting point in sham and ATN-lesioned animals, providing a useful paradigm for future testing of pro-cognitive treatments.

A comparison of phenylketonuria with attention deficit hyperactivity disorder: do markedly different aetiologies deliver common phenotypes?

Phenylketonuria (PKU) is a well-defined metabolic disorder arising from a mutation that disrupts phenylalanine metabolism and so produces a variety of neural changes indirectly. Severe cognitive impairment can be prevented by dietary treatment; however, residual symptoms may be reported. These residual symptoms appear to overlap a more prevalent childhood disorder: Attention Deficit/Hyperactivity Disorder (ADHD). However, the aetiology of ADHD is a vast contrast to PKU: it seems to arise from a complex combination of genes; and it has a substantial environmental component. We ask whether these two disorders result from two vastly different genotypes that converge on a specific core phenotype that includes similar dysfunctions of Gray's (Gray, 1982) Behavioural Inhibition System (BIS), coupled with other disorder-specific dysfunctions. If so, we believe comparison of the commonalities will allow greater understanding of the neuropsychology of both disorders. We review in detail the aetiology, treatment, neural pathology, cognitive deficits and electrophysiological abnormalities of PKU; and compare this with selected directly matching aspects of ADHD. The biochemical and neural pathologies of PKU and ADHD are quite distinct in their causes and detail; but they result in the disorder in the brain of large amino acid levels, dopamine and white matter that are very similar and could explain the overlap of symptoms within and between the PKU and ADHD spectra. The common deficits affect visual function, motor function, attention, working memory, planning, and inhibition. For each of PKU and ADHD separately, a subset of deficits has been attributed to a primary dysfunction of behavioural inhibition. In the case of ADHD (excluding the inattentive subtype) this has been proposed to involve a specific failure of the BIS; and we suggest that this is also true of PKU. This accounts for a substantial proportion of the parallels in the superficial symptoms of both disorders and we see this as linked to prefrontal, rather than more general, dysfunction of the BIS.

Dissociation of hypertension and fixed interval responding in two separate strains of genetically hypertensive rat.

The behaviour of spontaneously hypertensive rats (SHR) may model attention-deficit hyperactivity disorder. For example, SHR are hyperactive in an open field and show high terminal rates of responding on certain fixed-interval schedules. Open field behaviour has been dissociated from the accompanying spontaneous hypertension but fixed interval responding has not. We compared the fixed interval responding of two unrelated strains of genetically hypertensive rat, the SHR (n = 6) and the New Zealand genetically hypertensive rat (GH, n = 5), with their normotensive control strains, the Wistar Kyoto (WKY, n = 6) and Wistar (n = 5), respectively. Both hypertensive rat strains showed increased terminal lever-pressing rates on a multiple fixed-interval schedule (FI-EXT) compared to controls. In order to investigate the association of hypertension and the behavioural characteristics in question, an F-2 hybrid strain was obtained by cross-breeding GH and Wistar rats. When these F-2 hybrids (n = 33) were tested on the FI-EXT schedule, terminal lever-pressing rate was not correlated with blood pressure. The independent segregation of these phenotypical characteristics in the hybrids suggests independent genetic control. By contrast, other behavioural characteristics, including high lever-pressing rates during the extinction component and a tendency to emit responses in bursts, did cosegregate with terminal lever-pressing rates. Taken together, these findings suggest that the genetic loci for high blood pressure and responding on the FI-EXT schedule in these two unrelated rat strains are close but distinct.

Differential discrimination of fast and slow synaptic waveforms by two low-voltage-activated calcium channels.

Electrophysiological analysis of human embryonic kidney 293 cells stably expressing recombinant channels was used to compare how the biophysical properties of the low-voltage-activated Ca(2+) channels encoded by the alpha(1G) (Ca(V)3.1) or alpha(1I) (Ca(V)3.3) subunits shape their responses to excitatory synaptic potentials. In medium containing 2 mM extracellular Ca(2+) standard current-voltage relationships demonstrated both channel types to be clearly low-voltage activated with significant slowly activating current responses being observed at -66 mV. At all test potentials examined, activation of Ca(V)3.3 was substantially slower than that of Ca(V)3.1. To probe how these different T-type channels might respond to excitatory postsynaptic potentials (EPSPs), mock EPSPs with different kinetic profiles were created from the sum of exponentials. These waveforms were then used as command templates in voltage-clamp experiments. Ca(V)3.1-mediated channels responded effectively to both rapidly decaying mock EPSPs and slowly decaying EPSPs. In contrast, Ca(V)3.3-mediated channels were poorly gated by rapidly decaying EPSPs but were effectively activated by the more prolonged synaptic response. When activated with mock EPSPs Ca(V)3.3-mediated currents were more resistant to steady-state depolarisation of the pre-stimulus holding potential. Ca(V)3.3 currents were also more resistant to repetitive application of prolonged EPSPs, which caused substantial inactivation of Ca(V)3.1-mediated currents. The addition of a single mock action potential to the peak of a rapidly decaying EPSP voltage-clamp template greatly enhanced the currents produced by either Ca(V)3.1 or Ca(V)3.3-expressing cells. This facilitatory effect was considerably greater for Ca(V)3.3-mediated channels. From these data we suggest that the slow activation kinetics of Ca(V)3.3-mediated T-type channels enable them to respond selectively to either slow or suprathreshold synaptic potentials.

Neuroprotective actions in vivo and electrophysiological actions in vitro of 202W92.

202W92 (R-(-)-2,4-diamino-6-(fluromethyl)-5-(2,3,5-trichlorophenyl)pyrimidine) is a novel compound in the same chemical series as the antiepileptic drug lamotrigine and the neuroprotective sipatrigine. Here 202W92 was quantitatively assessed as a neuroprotective agent in focal cerebral ischaemia, and as an inhibitor of sodium and calcium channels and of synaptic transmission. In the rat permanent middle cerebral artery occlusion (MCAO) model of acute focal ischaemia, 202W92 reduced infarct volume by 75% in cortex and by 80% in basal ganglia, with ED(50) approximately 2 mg/kg (single i.v. dose, 10 min post-occlusion). In whole-cell current recordings from single cells, 202W92 completely and reversibly inhibited voltage gated sodium channels (IC(50) 3 x 10(-6) M) in rat freshly-isolated cortical neurons and in the GH(3) pituitary cell line. 202W92 also inhibited a nifedipine-sensitive fraction (approximately 35%) of native high-voltage-activated (HVA) calcium current in rat cortical neurons (IC(50) 15 x 10(-6) M) and weakly inhibited low-voltage-activated (LVA) calcium currents of the recombinant alpha1I-mediated T-type (IC(50)>100 x 10(-6) M). The drug inhibited the amplitude and frequency of 4-aminopyridine-evoked glutamatergic excitatory post-synaptic currents (EPSCs). In conclusion, 202W92 is an effective neuroprotective agent when administered post-ischaemia and a potent sodium channel inhibitor in vitro.

Chlordiazepoxide specifically impairs nonspatial reference memory in the cued radial arm maze in rats.

Anxiolytic benzodiazepines, at low doses, reportedly impair the radial arm maze with nonspatial visual/tactile but not spatial cues. We replicated the former result controlling for changes in drug state and cue effectiveness. Rats learned an eight-arm radial maze with reward in only four arms. The reward varied in spatial position from trial to trial but was always cued by a piece of sandpaper at the entry to the arm. Chlordiazepoxide (5 mg/kg, ip) impaired acquisition. Rats that switched from saline during acquisition to chlordiazepoxide showed an impairment of performance that only lasted for 1 day. Removal of the cues reduced the performance of controls and switched rats to the level of the rats that received chlordiazepoxide during acquisition but did not affect the latter. These data suggest that chlordiazepoxide does indeed impair nonspatial reference memory in the radial arm maze while leaving working memory, and, possibly, spatial reference memory, intact but that the previous report of this effect was the result of a change in drug state rather than of the drug itself.

Kinetic modification of the alpha(1I) subunit-mediated T-type Ca(2+) channel by a human neuronal Ca(2+) channel gamma subunit.

1. Voltage-sensitive Ca(2+) channels (VSCCs) are often heteromultimeric complexes. The VSCC subtype specifically expressed by skeletal muscle has long been known to contain a gamma subunit, gamma(1), that is only expressed in this tissue. Recent work, initiated by the identification of the mutation present in the stargazer mouse, has led to the identification of a series of novel potential Ca(2+) channel gamma subunits expressed in the CNS. 2. Based on bioinformatic techniques we identified and cloned the human gamma(2), gamma(3) and gamma(4) subunits. 3. TaqMan analysis was used to quantitatively characterise the mRNA expression patterns of all the gamma subunits. All three subunits were extensively expressed in adult brain with overlapping but subunit-specific distributions. gamma(2) and gamma(3) were almost entirely restricted to the brain, but gamma(4) expression was seen in a broad range of peripheral tissues. 4. Using a myc epitope the gamma(2) subunit was tagged both intracellularly at the C-terminus and on a predicted extracellular site between the first and second transmembrane domains. The cellular distribution was then examined immunocytochemically, which indicated that a substantial proportion of the cellular pool of the gamma(2) subunit was present on the plasma membrane and provided initial evidence for the predicted transmembrane topology of the gamma subunits. 5. Using co-transfection techniques we investigated the functional effects of each of the gamma subunits on the biophysics of the T-type VSCC encoded by the alpha(1I) subunit. This revealed a substantially slowed rate of deactivation in the presence of gamma(2). In contrast, there was no significant corresponding effect of either gamma(3) or gamma(4) on alpha(1I) subunit-mediated currents.

Inhibition of human alpha1E subunit-mediated ca2+ channels by the antipsychotic agent chlorpromazine.

Chlorpromazine is a neuroleptic antipsychotic agent with a long history of clinical use. Its primary mode of action is thought to be through modulation of monoaminergic inter-neuronal communication; however, its side-effect profile indicates substantial activities in other systems. Recent work has begun to uncover actions of this compound on ion channels. In this light we have investigated the actions of chlorpromazine on the recombinant alpha1E subunit-encoded voltage-sensitive Ca2+ channel (VSCC) that is believed to encode drug-resistant R-type currents found in neurones and other cells. Chlorpromazine produced a dose-dependent antagonism of these channels that was reversed on drug removal. The mean IC50 was close to 10 microM. At this concentration, the level of antagonism observed was dependent on the membrane potential, with greater inhibition being observed at more negative test potentials. Furthermore, chlorpromazine induced substantial changes in the steady-state inactivation properties of alpha1Ebeta3-mediated currents, although it was not seen to elicit a corresponding change in inactivation kinetics. These results are discussed with regard to the possible clinical mechanisms of chlorpromazine actions.

Potent inhibition of a recombinant low voltage-activated Ca(2+) channel by SB-209712.

T-type Ca(2+) currents were recorded in 2 mM Ca(2+) from HEK293 cells stably expressing the low voltage-activated Ca(2+) channel sub-unit alpha(1I). These currents were inhibited by the known Ca(2+) channel antagonist mibefradil with an IC(50) close to 1 microM. SB-209712 (1,6,bis¿1-[4-(3-phenylpropyl)piperidinyl]¿hexane), a compound originally developed as a high voltage-activated Ca(2+) channel blocker, proved to be a more potent T-type channel antagonist, exhibiting an IC(50) in the region of 500 nM. The antagonism produced by SB-209712 was reversed following drug removal and the observed antagonism exhibited little or no voltage-dependence with respect to either holding or test potential. These data indicate that SB-209712 is amongst the most potent known non-peptide T-type channel antagonists and thus may have some use in understanding the role of these channels in cellular function.

Arterial hypoxaemia in endurance athletes is greater during running than cycling.

The effect of both training discipline and exercise modality on exercise-induced hypoxaemia (EIH) was examined in seven runners and six cyclists during 5 min high intensity treadmill and cycle exercise. There were no significant interactions between training discipline, exercise modality and arterial P(O(2)) (Pa(O(2))) when subject groups were considered separately but when pooled there were significant differences between exercise modalities. After min 2 of exercise arterial hydrogen ion concentration, minute ventilation, alveolar P(O(2)) (PA(O(2))) and Pa(O(2)) were all lower with treadmill running with the largest differential for the latter occurring at min 5 (treadmill, 80.8+/-1.8; cycle, 90.2+/-2.5, mmHg, N=13, P< or = 0.05). At every min of exercise, the differences in Pa(O(2)) between the ergometers were strongly associated with similar differences in PA(O(2)) and alveolar to arterial P(O(2)) (PA(O(2))-Pa(O(2))). It is concluded that the greater EIH with treadmill running is a consequence of the combined effect of a reduced lactic acidosis-induced hyperventilation and greater ventilation-perfusion inequality with this exercise mode.

Common firing patterns of hippocampal cells in a differential reinforcement of low rates of response schedule.

Lesion studies show that the hippocampus is critically involved in timing behavior, but so far there has been little analysis of how it might encode time. We recorded the activity of 266 CA1 neurons, 51 CA3 neurons, and 219 entorhinal neurons from rats performing on a differential reinforcement of low rates (DRL) 15 sec schedule in which reinforcement was contingent on responses that occurred at least 15 sec after the preceding response. The unit data were analyzed using two different methods. First, each unit was subjected to an ANOVA that examined the effects of the following: (1) the outcome of the previous response (reward or nonreward); (2) the outcome of the response on which the firing of the cell was synchronized; and (3) time. This showed that, for CA1, CA3, and entorhinal cortex, changes in unit activity were related to all aspects of the task, with the firing of >90% of units recorded in each region being related to at least one of the three factors. Second, intercorrelations between the firing profiles of individual units revealed several functional categories of hippocampal neurons but no clear categories of entorhinal neurons. Of the hippocampal categories, the most common profile was an initial increase in unit activity at the beginning of the DRL interval, followed by a gradual decrease throughout the interval. We suggest that this profile reflects temporal decay in circuits that may code details of the previous trial and that could be used to "time" the DRL interval.

Inhibition of recombinant low-voltage-activated Ca(2+) channels by the neuroprotective agent BW619C89 (Sipatrigine).

T-type Ca(2+) currents were recorded in 2 mM Ca(2+) from HEK 293 cells stably expressing recombinant low-voltage-activated Ca(2+) channel subunits. Current-voltage relationships revealed that these currents were low-voltage activated in nature and could be reversibly antagonised by mibefradil, a known T-type channel blocker. At a test potential of -25 mV alpha(1I)-mediated Ca(2+) currents were rapidly and reversibly inhibited by 1-100 microM BW619C89 (IC(50)=14 microM, Hill coefficient 1.3). In contrast to its actions on N-type Ca(2+) channels, a near IC(50) dose (10 microM) of BW619C89 produced no alterations in either the kinetics or voltage-dependence of T-type currents. In additional single dose experiments, currents mediated by rat alpha(1G), human alpha(1H) or human alpha(1I) channel subunits were also inhibited by BW619C89. Overall our data indicate that T-type Ca(2+) channels are more potently blocked by BW619C89 than either type-II Na(+) channels or N-type Ca(2+) channels. It seems, therefore, that inhibition of low-voltage-activated Ca(2+) channels is likely to contribute to the anticonvulsant and neuroprotective actions of this and related compounds.