‘Born to …’— Genetics and Behaviour

In its ascendancy, the study of human genetics is shifting from the inheritance of physical structure to that of behaviour and personality; seeking the secret machinery which joins the inherited code to the quirk of character. At the start of the century human behaviour was thought to be largely learned and to stem from upbringing, the blank slate of personality being moulded by parents and events. What had been learned could be unlearned and this accorded with the idea of free will expressed in Cassius' claim that ‘the fault, dear Brutus, is not in our stars, but in ourselves, that we are underlings’. Now, at the century's close, the influence of breeding is back in fashion, bringing the implacable effects of genetic determinism and bad blood. The implications for the successes and failings of the ‘normal’ population are far-reaching. In learning disability, many of these ideas are contained in the concept of the ‘behavioural phenotype’.     

‘Thank-you for Saying “No”…’

This case study describes an approach to one individual's non-compliant behaviour, which focuses upon reduction of excessive refusal through change of the caregiver interactional style and acknowledgement of the inherent ‘message value’ of escape and avoidance responses. Positive outcomes include not only increased participation, but also greater personal competence, choice and access to ordinary community facilities, with these gains being maintained at three-month follow up. Implications of the approach are discussed.     

Exercise modifies α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor expression in striatopallidal neurons in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine‐lesioned mouse

The α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic‐acid‐type glutamate receptor (AMPAR) plays a critical role in modulating experience‐dependent neuroplasticity, and alterations in AMPAR expression may underlie synaptic dysfunction and disease pathophysiology. Using the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) mouse model of dopamine (DA) depletion, our previous work showed exercise increases total GluA2 subunit expression and the contribution of GluA2‐containing channels in MPTP mice. The purpose of this study was to determine whether exercise‐dependent changes in AMPAR expression after MPTP are specific to the striatopallidal (D₂R) or striatonigral (D₁R) medium spiny neuron (MSN) striatal projection pathways. Drd₂‐eGFP‐BAC transgenic mice were used to delineate differences in AMPAR expression between striatal D₂R‐MSNs and D₁R‐MSNs. Striatal AMPAR expression was assessed by immunohistochemical (IHC) staining, Western immunoblotting (WB) of preparations enriched for postsynaptic density (PSD), and alterations in the current–voltage relationship of MSNs. We found DA depletion results in the emergence of GluA2‐lacking AMPARs selectively in striatopallidal D₂R‐MSNs and that exercise reverses this effect in MPTP mice. Exercise‐induced changes in AMPAR channels observed after DA depletion were associated with alterations in GluA1 and GluA2 subunit expression in postsynaptic protein, D₂R‐MSN cell surface expression, and restoration of corticostriatal plasticity. Mechanisms regulating experience‐dependent changes in AMPAR expression may provide innovative therapeutic targets to increase the efficacy of treatments for basal ganglia disorders, including Parkinson's disease. © 2013 Wiley Periodicals, Inc.     

Oligomeric α‐synuclein and β‐amyloid variants as potential biomarkers for Parkinson's and Alzheimer's diseases

Oligomeric forms of α‐synuclein and β‐amyloid are toxic protein variants that are thought to contribute to the onset and progression of Parkinson's disease (PD) and Alzheimer's disease (AD), respectively. The detection of toxic variants in human cerebrospinal fluid (CSF) and blood has great promise for facilitating early and accurate diagnoses of these devastating diseases. Two hurdles that have impeded the use of these protein variants as biomarkers are the availability of reagents that can bind the different variants and a sensitive assay to detect their very low concentrations. We previously isolated antibody‐based reagents that selectively bind two different oligomeric variants of α‐synuclein and two of β‐amyloid, and developed a phage‐based capture enzyme‐linked immunosorbent assay (ELISA) with subfemtomolar sensitivity to quantify their presence. Here, we used these reagents to show that these oligomeric α‐synuclein variants are preferentially present in PD brain tissue, CSF and serum, and that the oligomeric β‐amyloid variants are preferentially present in AD brain tissue, CSF, and serum. Some AD samples also had α‐synuclein pathology and some PD samples also had β‐amyloid pathology, and, very intriguingly, these PD cases also had a history of dementia. Detection of different oligomeric α‐synuclein and β‐amyloid species is an effective method for identifying tissue, CSF and sera from PD and AD samples, respectively, and samples that also contained early stages of other protein pathologies, indicating their potential value as blood‐based biomarkers for neurodegenerative diseases.     

Gating by induced Α–Γ asynchrony in selective attention

Visual selective attention operates through top–down mechanisms of signal enhancement and suppression, mediated by α‐band oscillations. The effects of such top–down signals on local processing in primary visual cortex (V1) remain poorly understood. In this work, we characterize the interplay between large‐scale interactions and local activity changes in V1 that orchestrates selective attention, using Granger‐causality and phase‐amplitude coupling (PAC) analysis of EEG source signals. The task required participants to either attend to or ignore oriented gratings. Results from time‐varying, directed connectivity analysis revealed frequency‐specific effects of attentional selection: bottom–up γ‐band influences from visual areas increased rapidly in response to attended stimuli while distributed top–down α‐band influences originated from parietal cortex in response to ignored stimuli. Importantly, the results revealed a critical interplay between top–down parietal signals and α–γ PAC in visual areas. Parietal α‐band influences disrupted the α–γ coupling in visual cortex, which in turn reduced the amount of γ‐band outflow from visual areas. Our results are a first demonstration of how directed interactions affect cross‐frequency coupling in downstream areas depending on task demands. These findings suggest that parietal cortex realizes selective attention by disrupting cross‐frequency coupling at target regions, which prevents them from propagating task‐irrelevant information.     

Wake‐promoting actions of noradrenergic α1‐ and β‐receptors within the lateral hypothalamic area

Central norepinephrine exerts potent wake‐promoting effects, in part through the actions of noradrenergic α₁‐ and β‐receptors located in the medial septal and medial preoptic areas. The lateral hypothalamic area (LHA), including the lateral hypothalamus, perifornical area and adjacent dorsomedial hypothalamus, is implicated in the regulation of arousal and receives a substantial noradrenergic innervation. To date the functional significance of this innervation is unknown. The current studies examined the degree to which noradrenergic α₁‐ and β‐receptor stimulation within the rat LHA modulates arousal. Specifically, these studies examined the wake‐promoting effects of intra‐tissue infusions (250 nL) of the α₁‐receptor agonist phenylephrine (10, 20 and 40 nmol) and the β‐receptor agonist isoproterenol (3, 10 and 30 nmol) in rats. Results show that stimulation of LHA α₁‐receptors elicits robust and dose‐dependent increases in waking. In contrast, β‐receptor stimulation within the LHA had relatively modest arousal‐promoting actions. Nonetheless, combined α₁‐ and β‐receptor stimulation elicited additive wake‐promoting effects. Arousal‐promoting hypocretin/orexin (HCRT)‐synthesising neurons are located within the LHA. Therefore, additional immunohistochemical studies examined whether α₁‐receptor‐dependent waking is associated with an activation of HCRT neurons as measured by Fos , the protein product of the immediate–early gene c‐fos. Analyses indicate that although intra‐LHA α₁‐receptor agonist infusion elicited a robust increase in Fos immunoreactivity (ir) in this region, this treatment did not activate HCRT neurons as measured by Fos‐ir. Collectively, these observations indicate that noradrenergic α₁‐receptors within the LHA promote arousal via actions that are independent of HCRT neuronal activation.     

Effects of antiparkinsonian agents on β‐amyloid and α‐synuclein oligomer formation in vitro

The aggregation of β‐amyloid protein (Aβ) and α‐synuclein (αS) are hypothesized to be the key pathogenic event in Alzheimer's disease (AD) and Lewy body diseases (LBD), with oligomeric assemblies thought to be the most neurotoxic. Inhibitors of oligomer formation, therefore, could be valuable therapeutics for patients with AD and LBD. Here, we examined the effects of antiparkinsonian agents (dopamine, levodopa, trihexyphenidyl, selegiline, zonisamide, bromocriptine, peroxide, ropinirole, pramipexole, and entacapone) on the in vitro oligomer formation of Aβ40, Aβ42, and αS using a method of photo‐induced cross‐linking of unmodified proteins (PICUP), electron microscopy, and atomic force microscopy. The antiparkinsonian agents except for trihexyphenidyl inhibited both Aβ and αS oligomer formations, and, among them, dopamine, levodopa, pramipexole, and entacapone had the stronger in vitro activity. Circular dichroism and thioflavin T(S) assays showed that secondary structures of Aβ and αS assemblies inhibited by antiparkinsonian agents were statistical coil state and that their seeding activities had disappeared. The antiparkinsonian agents could be potential therapeutic agents to prevent or delay AD and LBD progression. © 2013 Wiley Periodicals, Inc.     

Mechanisms of status epilepticus: α‐Amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor hypothesis

Prolonged seizures of status epilepticus (SE) result from failure of mechanisms of seizure termination or activation of mechanisms that sustain seizures. Reduced γ‐aminobutyric acid type A receptor–mediated synaptic transmission contributes to impairment of seizure termination. However, mechanisms that sustain prolonged seizures are not known. We propose that insertion of GluA1 subunits at the glutamatergic synapses causes potentiation of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic receptor (AMPAR)‐mediated neurotransmission, which helps to spread and sustain seizures. The AMPAR‐mediated neurotransmission of CA1 pyramidal neurons was increased in animals in SE induced by pilocarpine. The surface membrane expression of GluA1 subunit–containing AMPARs on CA1 pyramidal neurons was also increased. Blockade of N‐methyl‐d ‐aspartate receptors 10 minutes after the onset of continuous electrographic seizure activity prevented the increase in the surface expression of GluA1 subunits. N‐methyl‐d ‐aspartate receptor antagonist MK‐801 in conjunction with diazepam also terminated seizures that were refractory to MK‐801 or diazepam alone. Future studies using mice lacking the GluA1 subunit expression will provide further insights into the role of GluA1 subunit–containing AMPAR plasticity in sustaining seizures of SE.     

Disruption of morphine‐conditioned place preference by a δ2‐opioid receptor antagonist: study of μ‐opioid and δ‐opioid receptor expression at the synapse

The addictive properties of morphine limit its clinical use. Learned associations that develop between the abused opiate and the environment in which it is consumed are engendered through Pavlovian conditioning processes. Disruption of the learned associations between the opiate and environmental cues may be a therapeutic approach to prevent morphine dependence. Although a role for the δ‐opioid receptor in the regulation of the rewarding properties of morphine has already been shown, in this study we further characterized the role of the δ‐opioid receptor in morphine‐induced conditioned responses by examining the effect of a selective δ2‐opioid receptor antagonist (naltriben), using a conditioned place preference paradigm in rats. Additionally, we used a subcellular fractionation technique to analyze the synaptic localization of μ‐opioid and δ‐opioid receptors in the hippocampus, in order to examine the molecular mechanisms that may underlie this morphine‐induced conditioned behavior. Our data show that the administration of 1 mg/kg naltriben (but not 0.1 mg/kg) prior to morphine was able to block morphine‐induced conditioned place preference. Interestingly, this naltriben‐induced disruption of morphine conditioned place preference was associated with a significant increase in the expression of the δ‐opioid receptor dimer at the postsynaptic density. In addition, we also observed that morphine conditioned place preference was associated with an increase in the expression of the μ‐opoid receptor in the total homogenate. Overall, these results suggest that modulation of the δ‐opioid receptor expression and its synaptic localization may constitute a viable therapeutic approach to disrupt morphine‐induced conditioned responses.