Evolution of genetic networks for human creativity.

The genetic basis for the emergence of creativity in modern humans remains a mystery despite sequencing the genomes of chimpanzees and Neanderthals, our closest hominid relatives. Data-driven methods allowed us to uncover networks of genes distinguishing the three major systems of modern human personality and adaptability: emotional reactivity, self-control, and self-awareness. Now we have identified which of these genes are present in chimpanzees and Neanderthals. We replicated our findings in separate analyses of three high-coverage genomes of Neanderthals. We found that Neanderthals had nearly the same genes for emotional reactivity as chimpanzees, and they were intermediate between modern humans and chimpanzees in their numbers of genes for both self-control and self-awareness. 95% of the 267 genes we found only in modern humans were not protein-coding, including many long-non-coding RNAs in the self-awareness network. These genes may have arisen by positive selection for the characteristics of human well-being and behavioral modernity, including creativity, prosocial behavior, and healthy longevity. The genes that cluster in association with those found only in modern humans are over-expressed in brain regions involved in human self-awareness and creativity, including late-myelinating and phylogenetically recent regions of neocortex for autobiographical memory in frontal, parietal, and temporal regions, as well as related components of cortico-thalamo-ponto-cerebellar-cortical and cortico-striato-cortical loops. We conclude that modern humans have more than 200 unique non-protein-coding genes regulating co-expression of many more protein-coding genes in coordinated networks that underlie their capacities for self-awareness, creativity, prosocial behavior, and healthy longevity, which are not found in chimpanzees or Neanderthals.

Transcranial Magnetic Stimulation and Deep Brain Stimulation in the treatment of alcohol dependence.

Alcohol dependence is a major social, economic, and public health problem. Alcoholism can lead to damage of the gastrointestinal, nervous, cardiovascular, and respiratory systems and it can be lethal, costing hundreds of billions to the health care system. Despite the existence of cognitive-behavioral therapy, psychosocial interventions, and spiritually integrated treatment to treat it, alcohol dependence has a high relapse rate and poor prognosis, albeit with high interindividual variability. In this review, we discuss the use of two neuromodulation techniques, namely repetitive transcranial magnetic stimulation (rTMS) and deep brain stimulation (DBS), and their advantages and disadvantages compared to first-line pharmacological treatment for alcohol dependence. We also discuss rTMS and DBS targets for alcohol dependence treatment, considering experimental animal and human evidence, with careful consideration of methodological issues preventing the identification of feasible targets for neuromodulation treatments, as well as inter-individual variability factors influencing alcoholism prognosis. Lastly, we anticipate future research aiming to tailor the treatment to each individual patient by combining neurofunctional, neuroanatomical and neurodisruptive techniques optimizing the outcome.

Emotional prosody modulates attention in schizophrenia patients with hallucinations.

Recent findings have demonstrated that emotional prosody (EP) attracts attention involuntarily (Grandjean et al., 2008). The automat shift of attention toward emotionally salient stimuli can be overcome by attentional control (Hahn et al., 2010). Attentional control is impaired in schizophrenia, especially in schizophrenic patients with hallucinations because the "voices" capture attention increasing the processing load and competing for top-down resources. The present study investigates how involuntary attention is driven by implicit EP in schizophrenia with auditory verbal hallucinations (AVH) and without (NAVH). Fifteen AVH patients, 12 NAVH patients and 16 healthy controls (HC) completed a dual-task dichotic listening paradigm, in which an emotional vocal outburst was paired with a neutral vocalization spoken in male and female voices. Participants were asked to report the speaker's gender while attending to either the left or right ear. NAVH patients and HC revealed shorter response times for stimuli presented to the attended left ear than the attended right ear. This laterality effect was not present in AVH patients. In addition, NAVH patients and HC showed faster responses when the EP stimulus was presented to the unattended ear, probably because of less interference between the attention-controlled gender voice identification task and involuntary EP processing. AVH patients did not benefit from presenting emotional stimuli to the unattended ear. The findings suggest that similar to HC, NAVH patients show a right hemispheric bias for EP processing. AVH patients seem to be less lateralized for EP and therefore might be more susceptible to interfering involuntary EP processing; regardless which ear/hemisphere receives the bottom up input.

Glial cell-line derived neurotrophic factor is essential for electroconvulsive shock-induced neuroprotection in an animal model of Parkinson's disease.

Sustained motor improvement in human patients with idiopathic Parkinson's disease has been described following electroconvulsive shock (ECS) treatment. In rats, ECS stimulates the expression of various trophic factors (TFs), some of which have been proposed to exert neuroprotective actions. We previously reported that ECS protects the integrity of the rat nigrostriatal dopaminergic system against 6-hydroxydopamine (6-OHDA)-induced toxicity; in order to shed light into its neuroprotective mechanism, we studied glial cell-line derived neurotrophic factor (GDNF) levels (the most efficient TF for dopaminergic neurons) in the substantia nigra (SN) and striatum of 6-OHDA-injected animals with or without ECS treatment. 6-OHDA injection decreased GDNF levels in the SN control animals, but not in those receiving chronic ECS, suggesting that changes in GDNF expression may participate in the ECS neuroprotective mechanism. To evaluate this possibility, we inhibit GDNF by infusion of GDNF function blocking antibodies in the SN of 6-OHDA-injected animals treated with ECS (or sham ECS). Animals were sacrificed 7 days after 6-OHDA infusion, and the integrity of the nigrostriatal system was studied by tyrosine hydroxylase immunohistochemistry and Cresyl Violet staining. Neuroprotection observed in ECS-treated animals was inhibited by GDNF antibodies in the SN. These results robustly demonstrate that GDNF is essential for the ECS neuroprotective effect observed in 6-OHDA-injected animals.

Prevalence of ergot derivatives in natural ryegrass pastures: detection and pathogenicity in the horse.

In the present study, we determined the incidence and effects of season and weather on clinical manifestations of endophyte-infected ryegrass toxicity, performed chemical detection and pharmacological bioassays on ryegrass extracts, and conducted trials on: (i) effects of domperidone or metochlopramide on ovarian inactivity induced by endophyte-infected ryegrass; (ii) efficacy of buspirone or dihydrochloro phenyl piperazine (m-CPP) for preventing suppressed milk production induced by endophyte-infected ryegrass; and (iii) efficacy of domperidone to induce ovulation during winter anestrus. Mares with toxicosis had prolonged gestation, embryonic losses, dystocia, poor mammary gland development, low milk production, prolonged uterine involution, and suppressed ovarian activity. Foals had respiratory failure, abnormalities of the skin, umbilicus, bone, and muscle, failure to thrive, blindness, testicular atrophy, and decreased serum total immunoglobulin concentrations. Endophyte-infected ryegrass and the incidence of toxicosis were correlated (r=0.861, P=0.03). Ergot alkaloids were not detected in extracts of endophyte-infected ryegrass by either thin-layer chromatography or spectrophotometry, but their presence was inferred in bioassays of extracts (dose-related increases in the contractile response of rat uterus). Mares given metoclopropamide (0.6 mg/kg/d), given orally every 8h for up to 7d) ovulated earlier (4-7d vs. 15-18d, P<0.001) than those given domperidone (1.1mg/kg/d) orally for up to 18d). Although both metoclopropamide and domperidone induced milk production, the latter did not induce ovarian cyclicity in healthy mares during seasonal anestrus. Based on these findings, we inferred that endophyte-infected ryegrass is associated with ergot alkaloid intoxication in horse.

Ultrastructural characterization of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-induced cell death in embryonic dopaminergic neurons.

Developing neuronal populations undergo significant attrition by natural cell death. Dopaminergic neurons in the substantia nigra pars compacta undergo apoptosis during synaptogenesis. Following this time window, destruction of the anatomic target of dopaminergic neurons results in dopaminergic cell death but the morphology is no longer apoptotic. We describe ultrastructural changes that appear unique to dying embryonic dopaminergic neurons. In primary cultures of mesencephalon, death of dopaminergic neurons is triggered by activation of glutamate receptors sensitive to alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and differs ultrastructurally from both neuronal apoptosis or typical excitotoxicity. AMPA causes morphological changes selectively in dopaminergic neurons, without affecting other neurons in the same culture dishes. Two hours after the onset of treatment swelling of Golgi complexes is apparent. At 3 h, dopaminergic neurons display loss of membrane asymmetry (coinciding with commitment to die), as well as nuclear membrane invagination, irregular aggregation of chromatin, and mitochondrial swelling. Nuclear changes continue to worsen until loss of cytoplasmic structures and cell death begins to occur after 12 h. These changes are different from those described in neurons undergoing either apoptosis or excitotoxic death, but are similar to ultrastructural changes observed in spontaneous death of dopaminergic neurons in the natural mutant weaver mouse.

Modulation of memory retrieval by pre-testing vasopressin: involvement of a central cholinergic nicotinic mechanism.

Lysine vasopressin (LVP, 0.003-1.0 mcg/kg, s.c.) and the central acting nicotinic cholinergic agonist nicotine (N, 1.0-30.0 mcg/kg, s.c.) enhanced, whereas the vasopressin receptor antagonist 1-beta-mercapto-beta, beta-cyclopentamethylenepropionic acid-2-(O-methyl)tyrosine, arginine vasopressin (AAVP, 0.01-0.3 mcg/kg, s.c.) impaired retention test performance on a one-trial step-through inhibitory avoidance task when injected into male Swiss mice 20 min before the retention test. Tests were done 48 h following training. In all cases, the effects on retention test performance were dose-dependent. Neither LVP, N nor AAVP when given prior to testing modified latencies to step-through of mice that had not received a footshock during training. These findings suggest that LVP, N and AAVP influence memory retrieval processes. The effect of LVP on memory retrieval was antagonized by the simultaneous administration of AAVP (0.01 mcg/kg, s.c.) or mecamilamine (5 mg/kg, s.c.), but not by hexamethonium (5 mg/kg, s.c.), atropine (0.5 mg/kg, s.c.) or methylatropine (0.5 mg/kq, s.c.). On the contrary, the effect of N was only prevented by mecamilamine (5 mg/kg, s.c.). These results suggest a modulatory role of vasopressin on the activity of central cholinergic nicotinic mechanisms which are critical for memory retrieval.

The enhancement of retention induced by vasopressin in mice may be mediated by an activation of central nicotinic cholinergic mechanisms.

Immediate post-training subcutaneous administration of lysine vasopressin (LVP, 0.003-1.00 microgram/kg) enhanced retention, whereas the vasopressin antagonist AAVP (0.01-0.30 microgram/kg) impaired it, in male Swiss mice tested 48 h after training in an inhibitory avoidance task. Both effects were dose-dependent. Neither LVP nor AAVP affected response latencies in mice not given the footshock on the training trial. The simultaneous administration of AAVP at a dose (0.01 microgram/kg) which had no effect on retention shifted the dose-response curve of LVP to the right. Nicotine (1.0-30.0 micrograms/kg, sc), a central nicotinic cholinergic agonist, also facilitated retention in a dose-related manner without affecting the retention performance of unshocked mice. The effect of nicotine was prevented by the central acting nicotinic cholinergic receptor antagonist mecamylamine (5 mg/kg, sc.). In contrast, neither hexamethonium (5 mg/kg, sc), a peripheral acting nicotinic receptor blocker, nor atropine (0.5 mg/kg, sc) or methylatropine (0.5 mg/kg, sc), two anticholinergic drugs which are known to act on muscarinic cholinergic receptors, prevented the effect of post-training nicotine. The effects of LVP and nicotine were time-dependent, suggesting that both treatments enhanced retention by influencing post-training processes involved in memory storage. Low doses of nicotine (1.50 microgram/kg, sc) or the central anticholinesterase physostigmine (35 micrograms/kg, sc) and LVP (0.003 microgram/kg, sc), which had no effect on retention when administered alone, produced a synergistic interaction when given together following training. The influence of LVP (0.03 microgram/kg, sc) on retention was prevented not only by AAVP (0.01 microgram/kg, sc) but also by mecamylamine (5 mg/kg, sc), whereas the effects of nicotine (10.0 micrograms/kg, sc) were prevented only by mecamylamine. These results suggest that the enhancement of retention induced by vasopressin is probably due to an activation of central nicotinic cholinergic mechanisms which are critical for memory formation.

Gangliosides normalize distorted single-cell intracellular free Ca2+ dynamics after toxic doses of glutamate in cerebellar granule cells.

Glutamate-induced delayed neurotoxicity after abusive and paroxismal activation of its receptors has been proposed to depend upon a sustained increase in intracellular free Ca2+ [( Ca2+]i). To elucidate the temporal and causal relationship between glutamate-induced changes in [Ca2+]i and neuronal death, we simultaneously studied the dynamics of [Ca2+]i changes in single neurons with the acetoxymethyl ester of fura-2 and the cell viability by imaging the nuclear penetration of propidium iodide. The main difference between toxic (50 microM) and nontoxic (5 microM) doses of glutamate is the lack of regulation in [Ca2+]i 20 min after glutamate is removed. This protracted rise in [Ca2+]i in a single cell is correlated with (r = 0.87, P less than 0.01, Spearman's test), and consequently predictive of, the time of appearance of neuronal death, as measured by propidium iodide fluorescence. In addition, the glutamate receptor antagonists dibenzocyclohepteneimine (MK-801) and 3,3-(2-carboxypiperazine-4-yl)propyl 1-phosphate reduce the acute increase of [Ca2+]i induced by glutamate but fail to revert the protracted increase of [Ca2+]i, elicited by toxic doses of glutamate. In contrast, the ganglioside GM1 and the semisynthetic lysoGM1 with N-acetylsphingosine (LIGA-4) and lysoGM1 with N-dichloroacetylsphingosine (LIGA-20) failed to change the immediate rise of [Ca2+]i elicited by glutamate but prevented the protracted increase in [Ca2+]i after toxic doses of glutamate. Voltage-dependent Ca2+ channel blockers (nifedipine, etc.) did not change the initial or protracted responses to glutamate.

Brain opioid peptides may participate in the reversal of pentylenetetrazol-induced amnesia.

Post-training administration of pentylenetetrazol (PTZ, 45 mg/kg, i.p.) disrupted 48-h retention, in mice, of an inhibitory avoidance response. The effect was reversed by any of the following treatments given 1 h prior to testing: a) a beta-endorphin injection (0.1 microgram/kg, i.p.), b) PTZ injection, or c) exposure to a novel experience (10 min in a stainless steel box with a wire mesh top). All treatments had a similar time course of effectiveness (up to at least 3 h) and their effects were blocked by naltrexone (0.1 mg/kg, i.p.) but not by naltrexone methyl bromide (10 mg/kg, i.p.). These findings suggest that the recovery of memory is probably due to an activation of central opioid mechanisms and, as a consequence, to the reinstatement of the neurohumoral conditions which were present during the post-training period. These results are consistent with previous evidence indicating that naltrexone given after training prevents the effects of PTZ on memory, and can be interpreted as showing that PTZ did not affect memory storage.

A novel non-invasive method to measure skin potential response: some pharmacological evidence.

Skin sympathetic activity in rats under various behavioral conditions was recorded using a novel non-invasive method. The arrangement of electrodes was: (+) chest, (-) back, (ref) abdomen, all three on the midline. Samples consisted of 801 values of skin potential, each one taken during one minute under one of the following conditions: basal or olfactory, visual or painful stimulation. The 2-way ANOVA shows that the SPR rank was enhanced significantly by either stress and by amphetamine 3 mg/kg, i.p. The effect of the combined treatment was much more pronounced than those of either of the individual treatments. The effects of the different stimuli (olfactory and painful) when compared to the basal recordings were often significant regardless of the treatment. We propose that the method allows checking not only the effects of sympathetic-stimulant drug but also changes in the stereotypy on the sympathetic responses induced by them in an awake, freely moving animal that is experiencing an emotional stress.

Facilitation of inhibitory avoidance by hypertonic saline is reversed by a vasopressin and a nicotinic antagonist.

Hypertonic saline (1 ml of 0.25, 0.50, and 1.00 M NaCl, ip) facilitated retention of a one-trial, step-through inhibitory avoidance task when injected into male Swiss mice 10 min after training, as indicated by retention performance 48 h later. A similar result was obtained after a subcutaneous injection of lysine vasopressin (LVP, 0.03 microgram/kg). Neither hypertonic saline nor LVP modified latencies to step-through of mice that had not received a footshock during training. The enhancement of retention produced both by hypertonic saline and by LVP was prevented by the vasopressin receptor antagonist AAVP (0.01 microgram/kg, sc) given after training, but 10 min before the treatments. The effect of hypertonic saline was also prevented by the central acting cholinergic nicotinic receptor antagonist mecamylamine (5 mg/kg, sc). On the contrary, neither hexamethonium (5 mg/kg, sc), a peripheral acting nicotinic receptor blocker, nor atropine (0.5 mg/kg, sc) or methylatropine (0.5 mg/kg, sc), two anticholinergic drugs which are known to act on cholinergic muscarinic receptors, prevented the effect of post-training hypertonic saline. These results suggest that a peripheral osmotic stimulus, probably through an endogenous release of vasopressin, may be behaviorally significant, and are consistent with the view that vasopressin may modulate the activity of central cholinergic nicotinic mechanisms which are critical for the behavioral change observed.

Vasopressin modulates the activity of nicotinic cholinergic mechanisms during memory retrieval in mice.

Lysine vasopressin (0.03 micrograms/kg, sc) enhanced retention test performance on a one-trial step-through inhibitory avoidance task when injected into male Swiss mice 20 min before the retention test. Tests were done 48 h following training. A low dose of the vasopressin antagonist AAVP (0.01 microgram/kg, sc, 20 min prior to testing) did not significantly affect retention test performance, whereas a higher dose (0.03 microgram/kg, sc) impaired it. Neither lysine vasopressin nor AAVP when given prior to testing modified latencies to step-through of mice that had not received a footshock during training. The simultaneous administration of AAVP (0.01 microgram/kg, sc) prevented the enhancement of retention test performance induced by lysine vasopressin. The influence of lysine vasopressin on retention test performance was antagonized by the simultaneous administration of mecamylamine (5 mg/kg, sc) but not by hexamethonium (5 mg/kg, sc), atropine (0.5 mg/kg, sc), or methylatropine (0.5 mg/kg, sc). A modulatory role of vasopressin on the activity of central cholinergic nicotinic mechanisms which probably operate at the time of testing is suggested.

Mecamylamine prevents the enhancement of retention induced by lysine vasopressin in mice.

Lysine vasopressin (0.03 microgram/kg, sc) enhanced retention of a one-trial, step-through inhibitory avoidance task when injected into male Swiss mice immediately post-training, as indicated by retention performance 48 h later. A low dose of the vasopressin antagonist, AAVP (0.01 microgram/kg, sc), did not significantly affect retention, whereas a higher dose (0.03 microgram/kg, sc) impaired retention. Neither lysine vasopressin nor AAVP modified latencies to step-through of mice that had not received a footshock during training. The simultaneous injection of AAVP (0.01 microgram/kg, sc) prevented the enhancement of retention induced by lysine vasopressin. The influence of lysine vasopressin on retention was antagonized by the simultaneous administration of mecamylamine (5 mg/kg, sc) but not by hexamethonium (5 mg/kg, sc), atropine (0.5 mg/kg, sc), or methylatropine (0.5 mg/kg, sc). A modulatory role of vasopressin on the activity of central cholinergic nicotinic mechanisms which participate in memory formation is suggested.