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Assessment of attention and inhibitory control in rodent studies
NBTS 2013 Abstracts
Behavioral neuroimaging is an emerging discipline that fuses behavioral neuroscience and functional neuroimaging. While imaging methods such as positron emission tomography (PET) can provide unique, quantitative data relating to the functional state of the brain, their application to small animal models has notable limitations. General anesthesia can have a confounding effect on the functional information, and moreover largely precludes the simultaneous acquisition of behavioral data, which could provide a more enlightening multidimensional view of brain function. Research groups are now beginning to develop technologies that are capable of imaging the brain of a conscious and behaving animal in order to study the ways that behavior correlates with physical brain data, thereby developing an understanding of brain function deeper than would be possible with both techniques independently. After a review of some of the approaches to behavioral neuroimaging, an awake animal imaging system developed by our lab will be presented in more detail, namely the Rat Conscious Animal PET (RatCAP) system. The potential of this system will be discussed as well as some remaining challenges. http://dx.doi.org/10.1016/j.ntt.2013.03.033
NBTS 31 Minimally-invasive procedures for monitoring onset, time-course, and intensity of general anesthetic-induced developmental neurotoxicity: Imaging and behavior Merle G. Paule National Center for Toxicological Research, FDA, Jefferson, AR, USA A variety of general anesthetics approved for adult use are routinely used in the pediatric setting. Recent reports indicate that virtually all general anesthetics are capable of triggering abnormal neuronal apoptosis and other adverse effects during the brain growth spurt in animal models. Since high-resolution positron emission tomography (microPET) can provide in vivo molecular imaging at sufficient resolution to resolve neuronal activities in the rat brain, it has been proposed as a minimallyinvasive method for detecting neurotoxic events. Apoptotic cells have certain characteristics that render them amenable to targeting by specific PET tracers but, unfortunately, the ability of these compounds to access the brain (cross the blood–brain barrier) varies between species and those that are useful in rodents are not always useful in higher species such as primates. Here, we explored the utility of two PET tracers (Annexin V and DFNSH) to study aspects of apoptosis induced by general anesthesia in a postnatal day (PND) 7 rodent model. While effective in rats these compounds did not translate to the primate. Based on the presumption that glia are activated in the presence of dying or damaged brain cells, the ligand FEPPA, specific for the peripheral benzodiazepine receptor (a marker of activated glial cells), was used in follow-up studies as a surrogate for inflammation presumed to be associated with brain cell death. Here, FEPPA was shown to be effective in both the rodent and monkey models, suggesting possible translatability to clinical situations. PET imaging approaches, coupled with functional (behavioral) assessments, provide opportunity for repeated assessments in the same subjects over protracted periods and are being used to provide not only timecourse, severity and location information, but also a means for assessing the efficacy of countermeasures. These global approaches provide high content correlative data in a relatively small number of subjects.
a
Colorado College, Colorado Springs, CO, USA Cornell University, Ithaca, NY, USA
b
In regulatory studies, “learning and memory” should not be treated a unitary phenomenon that can be sufficiently measured with a single spatial memory task. Cognition constitutes a myriad of processes that tap distinct neural systems, some of which may be more sensitive to the effects of toxins than others. Ideally, regulatory studies should borrow from the field of behavioral neuroscience, which has developed and validated cognitive tasks to tap both overlapping and dissociable functions. In a given case, the task that is the most sensitive will depend on the nature of the brain damage that is produced. For example, automated tests of attention, such as the five-choice serial reaction time task (5-CSRTT), have been designed to distinguish between deficits in aspects of executive functioning (e.g., sustained and selective attention, cognitive flexibility and set shifting), inhibitory control, motor functioning, motivation, and the interface between cognition and affective functioning. The 5-CSRTT has been widely used in lesion and pharmacology studies, thus providing a rich database into which one can integrate one's data to shed light on the specific neural damage that is produced by a specific type of exposure. http://dx.doi.org/10.1016/j.ntt.2013.03.035
NBTS 33 Schedule-controlled learning & memory in a regulatory context Philip Bushnell U.S. Environmental Protection Agency, Research Triangle Park, NC, USA Control of behavior by the manipulation of contingencies provides powerful techniques for assessing the hazard of chemical toxicants on the nervous system. When applied to evaluate the consequences of developmental exposure, these techniques are best suited for characterizing persistent effects on cognitive functions including learning, memory and attention, due to their ability to specify effects on cognitive processes in relation to sensorimotor dysfunction or altered motivation. However, the extensive training required for their implementation renders most of these methods unsuitable for screening-level tests, so they are often excluded from routine toxicity assessments. This exclusion is supported by an absence of evidence that screening-level behavioral tests lack sufficient sensitivity to detect cognitive deficits for exposures during adulthood. However, the same case is difficult to make for developmental exposure: for example, it is unlikely that the persistent cognitive consequences of exposure to lead or PCBs during development could be predicted by a screening battery applied during adulthood. In addition, in recent work at the EPA, an operant reaction-time method has revealed evidence for impulsivity in the offspring of rats exposed to vapors of ethanol or gasoline in utero, in the absence of systematic effects on most other neurobehavioral or neurophysiological outcome measures. Thus tests of cognitive function may continue to be useful for developmental neurotoxicity testing. In addition, these tests can provide evidence to characterize effects, dose–response, and potential health impacts in support of regulatory decisions based on effects observed in humans or obtained from screening tests. This abstract does not represent or reflect EPA policy. http://dx.doi.org/10.1016/j.ntt.2013.03.036
http://dx.doi.org/10.1016/j.ntt.2013.03.034
NBTS 32 Assessment of attention and inhibitory control in rodent studies Lori Driscolla, Barbara Struppb
83
NBTS 34 Assessment of working memory and reversal learning in regulatory studies Edward Levin Duke University Medical Center, Durham, NC, USA
Behavioral neuroimaging is an emerging discipline that fuses behavioral neuroscience and functional neuroimaging. While imaging methods such as positron emission tomography (PET) can provide unique, quantitative data relating to the functional state of the brain, their application to small animal models has notable limitations. General anesthesia can have a confounding effect on the functional information, and moreover largely precludes the simultaneous acquisition of behavioral data, which could provide a more enlightening multidimensional view of brain function. Research groups are now beginning to develop technologies that are capable of imaging the brain of a conscious and behaving animal in order to study the ways that behavior correlates with physical brain data, thereby developing an understanding of brain function deeper than would be possible with both techniques independently. After a review of some of the approaches to behavioral neuroimaging, an awake animal imaging system developed by our lab will be presented in more detail, namely the Rat Conscious Animal PET (RatCAP) system. The potential of this system will be discussed as well as some remaining challenges. http://dx.doi.org/10.1016/j.ntt.2013.03.033
NBTS 31 Minimally-invasive procedures for monitoring onset, time-course, and intensity of general anesthetic-induced developmental neurotoxicity: Imaging and behavior Merle G. Paule National Center for Toxicological Research, FDA, Jefferson, AR, USA A variety of general anesthetics approved for adult use are routinely used in the pediatric setting. Recent reports indicate that virtually all general anesthetics are capable of triggering abnormal neuronal apoptosis and other adverse effects during the brain growth spurt in animal models. Since high-resolution positron emission tomography (microPET) can provide in vivo molecular imaging at sufficient resolution to resolve neuronal activities in the rat brain, it has been proposed as a minimallyinvasive method for detecting neurotoxic events. Apoptotic cells have certain characteristics that render them amenable to targeting by specific PET tracers but, unfortunately, the ability of these compounds to access the brain (cross the blood–brain barrier) varies between species and those that are useful in rodents are not always useful in higher species such as primates. Here, we explored the utility of two PET tracers (Annexin V and DFNSH) to study aspects of apoptosis induced by general anesthesia in a postnatal day (PND) 7 rodent model. While effective in rats these compounds did not translate to the primate. Based on the presumption that glia are activated in the presence of dying or damaged brain cells, the ligand FEPPA, specific for the peripheral benzodiazepine receptor (a marker of activated glial cells), was used in follow-up studies as a surrogate for inflammation presumed to be associated with brain cell death. Here, FEPPA was shown to be effective in both the rodent and monkey models, suggesting possible translatability to clinical situations. PET imaging approaches, coupled with functional (behavioral) assessments, provide opportunity for repeated assessments in the same subjects over protracted periods and are being used to provide not only timecourse, severity and location information, but also a means for assessing the efficacy of countermeasures. These global approaches provide high content correlative data in a relatively small number of subjects.
a
Colorado College, Colorado Springs, CO, USA Cornell University, Ithaca, NY, USA
b
In regulatory studies, “learning and memory” should not be treated a unitary phenomenon that can be sufficiently measured with a single spatial memory task. Cognition constitutes a myriad of processes that tap distinct neural systems, some of which may be more sensitive to the effects of toxins than others. Ideally, regulatory studies should borrow from the field of behavioral neuroscience, which has developed and validated cognitive tasks to tap both overlapping and dissociable functions. In a given case, the task that is the most sensitive will depend on the nature of the brain damage that is produced. For example, automated tests of attention, such as the five-choice serial reaction time task (5-CSRTT), have been designed to distinguish between deficits in aspects of executive functioning (e.g., sustained and selective attention, cognitive flexibility and set shifting), inhibitory control, motor functioning, motivation, and the interface between cognition and affective functioning. The 5-CSRTT has been widely used in lesion and pharmacology studies, thus providing a rich database into which one can integrate one's data to shed light on the specific neural damage that is produced by a specific type of exposure. http://dx.doi.org/10.1016/j.ntt.2013.03.035
NBTS 33 Schedule-controlled learning & memory in a regulatory context Philip Bushnell U.S. Environmental Protection Agency, Research Triangle Park, NC, USA Control of behavior by the manipulation of contingencies provides powerful techniques for assessing the hazard of chemical toxicants on the nervous system. When applied to evaluate the consequences of developmental exposure, these techniques are best suited for characterizing persistent effects on cognitive functions including learning, memory and attention, due to their ability to specify effects on cognitive processes in relation to sensorimotor dysfunction or altered motivation. However, the extensive training required for their implementation renders most of these methods unsuitable for screening-level tests, so they are often excluded from routine toxicity assessments. This exclusion is supported by an absence of evidence that screening-level behavioral tests lack sufficient sensitivity to detect cognitive deficits for exposures during adulthood. However, the same case is difficult to make for developmental exposure: for example, it is unlikely that the persistent cognitive consequences of exposure to lead or PCBs during development could be predicted by a screening battery applied during adulthood. In addition, in recent work at the EPA, an operant reaction-time method has revealed evidence for impulsivity in the offspring of rats exposed to vapors of ethanol or gasoline in utero, in the absence of systematic effects on most other neurobehavioral or neurophysiological outcome measures. Thus tests of cognitive function may continue to be useful for developmental neurotoxicity testing. In addition, these tests can provide evidence to characterize effects, dose–response, and potential health impacts in support of regulatory decisions based on effects observed in humans or obtained from screening tests. This abstract does not represent or reflect EPA policy. http://dx.doi.org/10.1016/j.ntt.2013.03.036
http://dx.doi.org/10.1016/j.ntt.2013.03.034
NBTS 32 Assessment of attention and inhibitory control in rodent studies Lori Driscolla, Barbara Struppb
83
NBTS 34 Assessment of working memory and reversal learning in regulatory studies Edward Levin Duke University Medical Center, Durham, NC, USA