Temperature dependence of spin-orbit torques across the magnetic compensation point in a ferrimagnetic TbCo alloy film

The temperature dependence of spin-orbit torques (SOTs) and spin-dependent transport parameters is measured in bilayer Ta/TbCo ferrimagnetic alloy films with bulk perpendicular magnetic anisotropy. We find that the dampinglike (DL)-SOT effective field diverges as temperature is swept through the magnetic compensation temperature (T[subscript M]), where the net magnetization vanishes due to the opposing contributions from the Tb and Co sublattices. We show that DL-SOT scales with the inverse of the saturation magnetization (M[subscript s]), whereas the spin-torque efficiency is independent of the temperature-dependent M [subscript s]. Our findings provide insight into spin transport mechanisms in ferrimagnets and highlight low-M [subscript s] rare-earth/transition-metal alloys as promising candidates for SOT device applications.National Science Foundation (U.S.) (NSF-ECCS-1408172

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Ethological foundations of measuring obsessive-compulsive phenotypes in the deer mouse: a methodological perspective

PhD (Pharmacology), North-West University, Potchefstroom CampusPre-clinical models which leverage the study of animal behavior are invaluable tools to advance our understanding of a variety of psychological constructs. Such ethological investigations allow us to gain insight into abnormal biological processes which may contribute to the provocation of abnormal cognitive patterns which in turn may develop into a variety of ‘abnormal’ behaviors. Such behaviors, if allowed to proceed unchecked, typically progress into pathological states which interfere with the typical functioning of individuals, then termed psychiatric disorders. An example of such a disorder is obsessive-compulsive disorder (OCD), the focal point around which the investigations in this thesis were conceptualized. OCD is typically characterized by disruptions in both cognition (obsessions) and behavior (compulsions) leading to significant impairment in both executive function and quality of life. From an ethological perspective, OCD has been modelled in a handful of species applying several experimental frameworks and behavioral tests. Broadly speaking, these typically rely on the observation of repetitive behaviors and how they respond to established or prospective treatment strategies. As models become more established, investigations into the neurobiology of these modeled compulsive-like behaviors are initiated. Encouragingly, many analogous neurotransmission systems, receptors, brain regions and sub-circuits have been implicated in the expression of OCD-like behavior in these animal models, highlighting their translational relevance for the study of intricate psychiatric disorders such as OCD. However, a key short coming of such models remains the demonstration of the affective components of OCD, i.e. compulsions, within them. The species employed in the current investigation is the deer mouse (Peromyscus maniculatus bairdii), a validated but still rapidly developing model of OCD which offers select key advantages. Firstly, the compulsive-like behaviors exhibited by these animals are entirely naturalistic, not requiring any specific breeding, genetic knockout, pharmacological or behavioral induction. This exemplifies an ideal model, since it permits the careful study of abnormal behaviors in a context which is as similar as possible to the human condition, since the behaviors in question presumably originate naturally due to some unique underlying disturbance. Furthermore, deer mice naturally present with three different types of compulsive-like behaviors. These include excessive, highly stereotypical movements such as back flipping, the building of excessively large nests (LNB), and occurrence of high marble-burying (HMB). The two former behaviors have been validated by showing a response to chronic escitalopram (an SSRI; 50 mg/kg/day) treatment. As such, the current investigation set out to continue the development of the deer mouse model of OCD, by studying HMB, albeit indirectly, by dissecting the marble burying test (MBT), the behavioral test widely applied to test anti-compulsive and anti-anxiety drug action. This was done by means of an investigation into the methodological parameters of the test as well as a review of relevant literature pertaining to the application of the test. Secondly, LNB which represents a highly goal-directed behavior, ideal for the study of the motivational factors underlying compulsive murine behavior, was investigated in a novel experimental paradigm. The dissection of the MBT presented here represents a ‘back-to-basics’ approach concerning ethological studies. The test itself is relatively straight-forward, requiring a number of marbles to be placed on a flattened layer of bedding material (typically wood shavings) inside a test cage. Rodents are then introduced to these prepared cages and allowed a certain amount of time to interact. The number of marbles which are buried beneath the surface after the test session are tallied as an index of compulsive-like behavior. While being widely applied in the scientific literature, the MBT is striking in terms of the lack of methodological congruence between different laboratories. Resultantly, we argue here that special attention should be paid to even the most seemingly insignificant details of even well-established behavioral tests. Indeed, by investigating the use of several different burying substrates of differing densities in the MBT, we show that such a manipulation can robustly influence the outcomes of the test. Furthermore, we highlight that the subjective manner in which the test is scored is indeed subject to inter-observer variability. Following from the findings above, we performed a review of investigations in which the MBT was applied as the primary behavioral assay. Once again, it was highlighted that the test is employed with a wide range of experimental parameters in terms of the size of test cages, number of test repetitions, test duration, number and size of marbles, burying substrate and scoring criteria used. In terms of treatment response, the MBT reports anti-compulsive effects for a wide variety of drugs, some of which are not typically effective in the clinical setting. These findings are further complicated by the realization that many of these drugs, which require lengthy periods for onset of action, are administered acutely, often minutes before the test. Taking all of these findings into account, we argue for the standardization of many of the aforementioned variables, so as to improve the practical utility of the MBT as a screening test for anti-compulsive drug action. Another behavior exhibited by certain species such as mice and rabbits, concerns the excessive, diligent building of nests. As is the case with the MBT, the concept underlying LNB as a test for compulsive-like behavior is relatively simple. In brief, examining LNB involves the provision of an excess of nesting material to the housing cages of mice and recording the quantity of material that is used by each subject over the course of several nights. Animals that consistently use excessive quantities of material as appraised against the behavior of the larger population, are then selected for further investigation. Indeed, it has been shown that deer mice selected in this fashion show a reduction in nesting size following SSRI treatment. Since all mice that express LNB are housed under identical conditions to their normal counterparts, it stands to reason that there is some unique underlying dysfunction motivating the disinhibited building of nests. Towards investigating this premise, cohorts of normal and LNB were selected and tested in a novel testing environment. Here, the mice were placed into cages containing automated nesting material dispensers. To acquire nesting material, mice would have to execute lever-presses. After mice had learned this action-outcome association, their behavior was tested under two unique circumstances. Firstly, the nesting material was withdrawn from the dispensers so that lever-presses no longer resulted in any outcome. In the second instance, the levers delivered a mild electric shock each time a lever-press was executed. Interestingly, in this novel environment, LNB mice generally executed more lever presses than their NNB counterparts, particularly during the two unique phases described above. Mice were retested under identical circumstances following 28-days of chronic escitalopram treatment, showing preliminary evidence that the motivational drive to engage in nesting behavior abates, as was evinced by the lower number of lever-presses that were executed during the punishment phase. The study design above was intended to test whether LNB is characterized by unique cognition, inspired by the finding that OCD patients often show difficulty in changing their obsessive-compulsive behavioral routines, and that they are prone to endure negative consequences so that their compulsive rituals may be given attention. This represents a shift in ethological investigations, which in many cases rely primarily on appraising behavior at face-value, without attempting to divulge the cognitive factors which may play a role in the presence of such behaviors which are considered abnormal in the first place. In conclusion, this thesis argues that ethological studies should be continually refined to improve the validity of the findings made, regardless of how simple the core premise of the given model or behavioral test may be. Furthermore, the foundational basis of ethological studies should be conceptualized bearing in mind that animal behavior is often more conscientious than many behavioral tests take into account, and that careful study design can leverage this to carefully investigate behaviors at a deeper level, which in turn can add to our knowledge of psychiatric disorders.Doctora

Naturalistic operant responses in deer mice (Peromyscus maniculatus bairdii) and its response to outcome manipulation and serotonergic intervention

Investigating the motivational triggers underlying naturalistic compulsive-like behavior is generally regarded as challenging. To this extent, the current study aimed to establish a proof-of-concept for future investigation by probing unconditioned and naturalistic operant responses aimed at obtaining nesting material by normal (NNB) and large (LNB) nest building deer mice (Peromyscus maniculatus bairdii). LNB mice and NNB controls were individually placed in cages equipped with a lever-operated nesting material (cotton rope) dispenser and allowed to become accustomed to the response (lever press)-outcome (obtaining cotton rope) contingency over seven nights. Subsequently, the contingency was manipulated by withdrawing the nesting material (experiment 1) or punishing the lever-press response with a mild electrical foot shock (experiment 2). Mice were then treated for 28 days with escitalopram (50 mg/kg/d) and retested. Our results indicate that (1) LNB mice generally made more operant responses compared to NNB controls, (2) withdrawal of nesting material and institution of punishment bolstered responding in LNB but not NNB mice and (3) escitalopram treatment tended to reduce increased responding in LNB mice following experimental manipulation, while normalizing the total number of lever-press counts in the LNB cohort. Therefore, LNB seems to diverge from NNB, not only as a spontaneous phenotype, but also in terms of the motivation to obtain nesting material, despite demotivating feedback. That such differences were abrogated by chronic escitalopram intervention, indicates that the uniquely motivated operant interactions displayed by LNB mice, may be founded upon serotonergic mechanisms, a finding in line with the neurobiological theory of obsessive-compulsive disorde

A critical inquiry into marble-burying as a preclinical screening paradigm of relevance for anxiety and obsessive-compulsive disorder: mapping the way forward

Rodent marble-burying behavior in the marble-burying test (MBT) is employed as a model or measure to study anxiety- and compulsive-like behaviors or anxiolytic and anticompulsive drug action. However, the test responds variably to a range of pharmacological interventions, and little consensus exists regarding specific methodologies for its execution. Regardless, the test is widely applied to investigate the effects of pharmacological, genetic, and behavioral manipulations on purported behaviors related to the said neuropsychiatric constructs. Therefore, in the present review we attempt to expound the collective translational significance of the MBT. We do this by (1) reviewing burying behavior as a natural behavioral phenotype, (2) highlighting key aspects of anxiety and obsessive–compulsive disorder from a translational perspective, (3) reviewing the history and proof of concept of the MBT, (4) critically appraising potential methodological confounds in execution of the MBT, and (5) dissecting responses of the MBT to various pharmacological interventions. We conclude by underlining that the collective translational value of the MBT will be strengthened by contextually valid experimental designs and objective reporting of dat

Large nest building and high marble-burying: two compulsive-like phenotypes expressed by deer mice (Peromyscus maniculatus bairdii) and their unique response to serotoninergic and dopamine modulating intervention

This study aimed to further dissect the deer mouse (Peromyscus maniculatus bairdii) model of compulsive-like behavior with respect to two persistent-like behavioral phenotypes viz. large nest building (LNB) and high marble-burying (HMB), which may be relevant to understanding the neurobiology of different symptom dimensions in obsessive-compulsive and related disorders. Since LNB is sensitive to chronic, high dose escitalopram intervention but HMB is not, we assessed whether the two behaviors could be further distinguished based on their response to 4 weeks of uninterrupted serotoninergic intervention (i.e. escitalopram; ESC; 50 mg/kg/day), dopaminergic antagonism, i.e. flupentixol; FLU; 0.9 mg/kg/day), dopaminergic potentiation (i.e. rasagiline; RAS; 5 mg/kg/day), and their respective combinations with escitalopram (ESC/FLU and ESC/RAS). Here we show LNB to be equally responsive to chronic ESC and ESC/FLU. HMB was insensitive to either of these interventions but was responsive to ESC/RAS. Additionally, we report that scoring preoccupied interaction with marbles over several trials is an appropriate measure of compulsive-like behavioral persistence in addition to the standard marble burying test. Taken together, these data provide further evidence that LNB and HMB in deer mice have distinctive neurobiological underpinnings. Thus, the naturally occurring compulsive-like behaviors expressed by deer mice may be useful in providing a platform to test unique treatment targets for different symptom dimensions of OCD and related disorder

Association between Genetic Variants and Cisplatin-Induced Nephrotoxicity: A Genome-Wide Approach and Validation Study

This study aims to evaluate genetic risk factors for cisplatin-induced nephrotoxicity by investigating not previously studied genetic risk variants and further examining previously reported genetic associations. A genome-wide study (GWAS) was conducted in genetically estimated Europeans in a discovery cohort of cisplatin-treated adults from Toronto, Canada, followed by a candidate gene approach in a validation cohort from the Netherlands. In addition, previously reported genetic associations were further examined in both the discovery and validation cohorts. The outcome, nephrotoxicity, was assessed in two ways: (i) decreased estimated glomerular filtration rate (eGFR), calculated using the Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI) and (ii) increased serum creatinine according to the Common Terminology Criteria for Adverse Events v4.03 for acute kidney injury (AKI-CTCAE). Four different Illumina arrays were used for genotyping. Standard quality control was applied for pre- and post-genotype imputation data. In the discovery cohort (n = 608), five single-nucleotide polymorphisms (SNPs) reached genome-wide significance. The A allele in rs4388268 (minor allele frequency = 0.23), an intronic variant of the BACH2 gene, was consistently associated with increased risk of cisplatin-induced nephrotoxicity in both definitions, meeting genome-wide significance (β = −8.4, 95% CI −11.4–−5.4, p = 3.9 × 10−8) for decreased eGFR and reaching suggestive association (OR = 3.9, 95% CI 2.3–6.7, p = 7.4 × 10−7) by AKI-CTCAE. In the validation cohort of 149 patients, this variant was identified with the same direction of effect (eGFR: β = −1.5, 95% CI −5.3–2.4, AKI-CTCAE: OR = 1.7, 95% CI 0.8–3.5). Findings of our previously published candidate gene study could not be confirmed after correction for multiple testing. Genetic predisposition of BACH2 (rs4388268) might be important in the development of cisplatin-induced nephrotoxicity, indicating opportunities for mechanistic understanding, tailored therapy and preventive strategies