24 August 2012. Training in adolescence can offset cognitive deficits in adulthood in a proposed rat model of schizophrenia, reports a study published August 22 in Neuron. Studying rats given ventral hippocampal lesions early in life, researchers led by André Fenton of New York University found that training these rats as adolescents to pay attention to certain cues while ignoring others prevented impairments observed in similar tasks when they were adults. The study casts adolescence as a stage of neurodevelopment when important and lasting changes can be made to promote cognition in adulthood.
Based on these data, the researchers suggest that prophylactic cognitive training in people at risk for schizophrenia, before they’ve had their first psychotic episode, may avoid some of the mental pitfalls of the disorder. Currently, cognitive training is given to people after they’ve become ill, and researchers are still hashing out the merits of the various methods, like cognitive behavioral therapy (see SRF related news story) and cognitive remediation (see SRF Webinar). Some have suggested that earlier training in adolescence may benefit cognitive function later in life, particularly for those skills that would have already matured prior to disease onset (see SRF related news story).
The new study uses the neonatal ventral hippocampus lesion (NVHL) model of schizophrenia, in which lesions given the first week of life give rise to schizophrenia-related abnormalities in adulthood, including enhanced dopamine-dependent responses, disrupted prepulse inhibition, and impaired social behavior, learning, and memory (Lipska, 2004). Though people with schizophrenia do not carry hippocampal lesions dating back to when they were infants, hippocampal abnormalities have been consistently found (Tamminga et al., 2010), and the NVHL model explores the possibility that early problems there could derail development throughout the brain. Like the delayed onset of schizophrenia, the abnormalities in NVHL rats do not emerge until later in life, thus providing a venue for researchers to study how delayed consequences might arise from early abnormalities.
First author Heekyung Lee and colleagues studied the ability of NVHL rats to learn to avoid a region of the test arena that delivered a mild (<0.4 mA) foot shock. The shock zone was defined in terms of the surrounding room, which had visual cues as a reference. The animals had to learn to ignore cues inside the circular arena, which slowly rotated, and pay attention to the room cues in order to avoid the shock zone.
Control adult rats quickly figured this out by the second or third trial, but adult NVHL rats needed about 12 tries. Throughout training, the NVHL rats entered the shock zone about four times as often as did controls, and when the shock zone location was changed on them, they took longer to avoid the new region than controls did. Control experiments suggested that this was not due to hyperactivity, or to impairments in motivation, spatial perception, memory, or navigation.
In adolescence (postnatal day 35), however, NVHL rats readily mastered the task, learning to avoid the shock zone as quickly as controls did. The researchers then found that this experience could serve as training for solving a similar T-maze task, which required focusing on some cues but ignoring others, in adulthood. The T-maze required the rats to learn which arm of the maze—left or right—delivered a shock; after 15 trials, the shock and non-shock arms were switched, requiring the rats to relearn the relevant cues. NVHL adults that had been trained with shock zone avoidance as adolescents performed the T-maze task as well as their control counterparts, which consisted of rats trained on shock zone avoidance as adolescents and rats that weren’t trained, but exposed to the test arena as adolescents without receiving any shocks. In contrast, NVHL rats that were merely exposed to the test arena as adolescents made more mistakes on the T-maze, averaging about one more wrong turn than the others. This difference extended to shock zone avoidance learning in adulthood, too: the NVHL rats trained as adolescents performed at control levels, whereas the NVHL rats that were only exposed to the test arena had difficulty learning the task.
Out of synch
These differences suggested that adolescent training had a lasting influence on the brain, leading the researchers to search for neural correlates of the training. Local field potential recordings in the left and right hippocampus became more synchronized while adult control rats performed the shock zone avoidance task, but this was not as pronounced for adult NVHL rats. Shock avoidance training in adolescence, however, seemed to boost synchrony: trained NVHL rats had increased synchrony across several frequency ranges compared to NVHL rats without training, and were comparable to trained controls. Because of these and other physiologic changes associated with adolescent training (e.g., in synchrony between hippocampus and neocortex, and in parvalbumin labeling in neocortical cells), the authors propose that training exerted its effects on neural circuitry responsible for synchronous brain oscillations, which contribute to cognitive control.
The findings suggest that neurodevelopment can be guided away from an aberrant course, but whether the adolescent brain is particularly pliable remains unclear. As researchers delineate the changes in brain structure and processing in human adolescence, a more complete picture of neurodevelopment will emerge, which may help identify the glitches that preface schizophrenia.—Michele Solis.
Lee H, Dvorak D, Kao HY, Duffy AM, Scharfman HE, Fenton AA. Early Cognitive Experience Prevents Adult Deficits in a Neurodevelopmental Schizophrenia Model. Neuron. 2012 Aug 22. Abstract