When siblings matter: Commentary on Golub and Sobin's 'Statistical modeling of litter as a random effect in mixed models to manage "intralitter likeness"'.

Responsible data practices include acknowledging and properly dealing with data structures in which the assumption of independence of observations is violated. Golub and Sobin uncover a common statistical faux pas in neurodevelopmental research - inconsistent and inadequate handling of the clustered variability associated with the use of multiple littermates - and propose a simple mixed model solution in which litter is included as a random factor.

Comparative morphology of gigantopyramidal neurons in primary motor cortex across mammals.

Gigantopyramidal neurons, referred to as Betz cells in primates, are characterized by large somata and extensive basilar dendrites. Although there have been morphological descriptions and drawings of gigantopyramidal neurons in a limited number of species, quantitative investigations have typically been limited to measures of soma size. The current study thus employed two separate analytical approaches: a morphological investigation using the Golgi technique to provide qualitative and quantitative somatodendritic measures of gigantopyramidal neurons across 19 mammalian species from 7 orders; and unbiased stereology to compare the soma volume of layer V pyramidal and gigantopyramidal neurons in primary motor cortex between 11 carnivore and 9 primate species. Of the 617 neurons traced in the morphological analysis, 181 were gigantopyramidal neurons, with deep (primarily layer V) pyramidal (n = 203) and superficial (primarily layer III) pyramidal (n = 233) neurons quantified for comparative purposes. Qualitatively, dendritic morphology varied considerably across species, with some (sub)orders (e.g., artiodactyls, perissodactyls, feliforms) exhibiting bifurcating, V-shaped apical dendrites. Basilar dendrites exhibited idiosyncratic geometry across and within taxonomic groups. Quantitatively, most dendritic measures were significantly greater in gigantopyramidal neurons than in superficial and deep pyramidal neurons. Cluster analyses revealed that most taxonomic groups could be discriminated based on somatodendritic morphology for both superficial and gigantopyramidal neurons. Finally, in agreement with Brodmann, gigantopyramidal neurons in both the morphological and stereological analyses were larger in feliforms (especially in the Panthera species) than in other (sub)orders, possibly due to specializations in muscle fiber composition and musculoskeletal systems.

Assessment of attention and inhibitory control in rodent developmental neurotoxicity studies.

In designing screens to assess potential neurotoxicants, the paramount goal is that the selected assessment tools detect dysfunction if it exists. This goal is particularly challenging in the case of cognitive assessments. Cognition is not a unitary phenomenon, and indeed there is growing evidence that different aspects of cognitive functioning are subserved by distinct neural systems. As a result, if a particular neurotoxicant selectively damages certain neural systems but not others, it can impair some cognitive, sensory, or affective functions, but leave many others intact. Accordingly, studies with human subjects use batteries of cognitive tests, cognizant of the fact that no one test is capable of detecting all forms of cognitive dysfunction. In contrast, assessment of cognitive functioning in non-human animal developmental neurotoxicity (DNT) studies typically consists of a single, presumably representative, "learning and memory" task that is expected to detect all potential effects on cognitive functioning. Streamlining the cognitive assessment in these studies saves time and money, but these shortcuts can have serious consequences if the aspect of cognitive functioning that is impaired is not tapped by the single selected task. In particular, executive functioning - a constellation of cognitive functions which enables the organism to focus on multiple streams of information simultaneously, and revise plans as necessary - is poorly assessed in most animal DNT studies. The failure to adequately assess these functions - which include attention, working memory, inhibitory control, and planning - is particularly worrisome in light of evidence that the neural systems that subserve these functions may be uniquely vulnerable to early developmental insults. We illustrate the importance of tapping these areas of functioning in DNT studies by describing the pattern of effects produced by early developmental Pb exposure. Rats exposed to lead (Pb) early in development were tested on a series of automated attention tasks, as well as on a radial arm maze task. The lead-exposed rats were not impaired in this demanding radial arm maze task, despite conditions which tapped the limits of both working and long-term memory. In contrast, the automated tests designed to assess rodent executive functioning revealed selective and functionally important deficits in attention and regulation of emotion or negative affect (produced by committing an error or not receiving an expected reward). This example underscores the importance of including tasks to specifically tap executive functioning in DNT batteries. Such tasks are not only sensitive but can also shed light on the specific nature of the dysfunction, and they can implicate dysfunction of specific neural systems, information which can be used to design therapeutic interventions. Although the use of such tasks increases the time and effort needed to complete the battery, the benefits outweigh the cost, in light of the greater sensitivity of the battery and the more complete characterization of effects.

Spared and impaired aspects of motivated cognitive control in schizophrenia.

The ability to upregulate cognitive control in motivationally salient situations was examined in individuals with schizophrenia (patients) and healthy controls. Fifty-four patients and 39 healthy controls were recruited. A computerized monetary response conflict task required participants to identity a picture, over which was printed a matching (congruent), neutral, or incongruent word. This baseline condition was followed by an incentive condition, in which participants were given the opportunity to win money on reward-cued trials. These reward-cued trials were interleaved with nonreward cued trials. Reaction times (RT) were examined for both incentive context effects (difference in RT between baseline and nonreward cue trials in the incentive condition) and incentive cue effects (difference in RT between nonreward and reward cue trials in the incentive condition). Compared with baseline, controls showed a speeding of responses during both the nonreward (incentive context effect) and reward cued (incentive cue effect) trials during the incentive condition, but with a larger incentive context than incentive cue effect, suggesting a reliance on proactive control strategies. Although patients also showed a speeding of responses to both nonreward and reward cued trials, they showed a significantly smaller incentive context effect than controls, suggesting a reduction in the use of proactive control and a greater reliance on the use of "just-in-time," reactive control strategies. These results are discussed in light of the relationship between motivation and cognitive impairments in schizophrenia, and the potential role of impairments in prefrontally mediated active maintenance mechanisms.

Acute postnatal exposure to the pentaBDE commercial mixture DE-71 at 5 or 15 mg/kg/day does not produce learning or attention deficits in rats.

Polybrominated diphenyl ethers (PBDEs), flame retardant chemicals added to polymer products, have become ubiquitous in the environment, and they are bioaccumulating in humans and wildlife. Therefore, understanding their biological effects is important for public health. We have previously observed learning deficits in rats exposed to DE-71, a commercial PBDE mixture consisting primarily of pentabrominated diphenyl ethers, at a dose of 30 mg/kg/day from postnatal day (PND) 6 to 12. The purpose of the current study was to determine if this effect could be seen with lower doses of DE-71. Long-Evans rats were administered daily oral doses of corn oil alone or DE-71, 5 or 15 mg/kg/day, dissolved in corn oil, from PND 6 to 12. As young adults, the rats were administered a series of five-choice visual learning and attention tasks. No effects of DE-71 were found on learning, attention, or inhibitory control. Given that developmental DE-71 exposure at similar doses and for shorter time periods has been shown in other laboratories to affect locomotion and hyperactivity, the current results suggest that cognitive functions may not be as sensitive as neuromotor functions to the effects of acute DE-71 exposure.

Brief postnatal PBDE exposure alters learning and the cholinergic modulation of attention in rats.

Polybrominated diphenyl ethers (PBDEs), chemicals commonly used as flame retardants, are ubiquitous in the environment and bioaccumulate in humans and wildlife. However, little is known about their potential toxicological properties. In the present study, male Long-Evans rats orally administered the commercial PBDE mixture DE-71 or corn oil for 1 week, beginning at postnatal day (PND) 6, were tested on a visual discrimination task and two sustained attention tasks. After completion of these tasks, the rats were administered a drug challenge with the muscarinic antagonist scopolamine (0, 0.01, 0.03, 0.05 mg/kg), which was injected subcutaneously 30 min prior to testing on the second sustained attention task. The DE-71-exposed rats demonstrated deficits in learning but not in sustained attention when compared to controls. Scopolamine impaired the animals' ability to detect the brief visual cues in controls, as evidenced by decreases in accuracy and increases in omission errors. However, the DE-71-exposed rats were subsensitive to the effects of scopolamine on omission errors, particularly on trials in which a long delay preceded the cue, suggesting alterations in the cholinergic modulation of sustained attention. For the DE-71-exposed rats, the lack of sustained attention deficits in the absence of the drug, coupled with the subsensitivity to scopolamine's effects on sustained attention, suggest that although this PBDE mixture produced lasting alterations in cholinergic functioning, either (1) these alterations were not of sufficient magnitude to be behaviorally relevant, or (2) behavioral deficits resulting from these alterations were overcome by the development of compensatory neural mechanisms or response strategies in adulthood.

Impaired sustained attention and error-induced stereotypy in the aged Ts65Dn mouse: a mouse model of Down syndrome and Alzheimer's disease.

This study compared performance of 15- to 17-month-old Ts65Dn mice to that of littermate controls on an automated sustained attention task in which the location, onset time, and duration of brief visual cues varied unpredictably. Ts65Dn mice committed more omission errors than controls, particularly on trials with the briefest cues. Videotape data revealed that the trisomic mice attended less than controls during the period before cue presentation and engaged in stereotypic jumping and grooming immediately after making an error. These findings reveal that Ts65Dn mice are impaired in sustaining attention and exhibit heightened reactivity to committing an error, and support the validity of this mouse model for studying Down syndrome and Alzheimer's disease. The attention task, coupled with the videotape analyses of task performance, provides a useful paradigm for studying attention and reactivity to errors in mice.