Assessment of attention and inhibitory control in rodent developmental neurotoxicity studies

- Effective screens for developmental neurotoxicity must be sensitive to multiple aspects of cognitive functioning.
- Executive functioning is vulnerable to chemical insults in humans, and should therefore be emphasized in animal tests.
- Automated tests of executive functioning can uncover effects of developmental exposures on specific executive functions.

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.