Optogenetic manipulations reveal temporally-distinct contributions of medial prefrontal cortex to working memory in young and aged rats.

Introduction:: Working memory is the temporary retention of information needed to conduct a task, and as such is crucial for different forms of decision-making and cognitive processing in daily life. Declines in working memory associated with aging affect quality of life in older adults by limiting their independence and efficiency in making decisions. Research in behavioral neuroscience supports the connection between age-related deficits in working memory and alterations in functions of the prefrontal cortex (PFC); however, the temporally-precise contributions of this brain region to working memory, and how such contributions change with age, are less well understood. Here we used an optogenetic approach to dissect the contributions of the PFC to temporally distinct phases of this cognitive function in a delayed response working memory task in young and aged rats.


Materials and Methods:: Young adult (6 mo.) and aged (24 mo.) male Fischer 344 x Brown Norway F1 hybrid rats were surgically implanted with bilateral guide cannulae targeting the medial prefrontal cortex (mPFC), through which the inhibitory opsin pAAV-CaMKIIa-eNpHR3.0-mCherry (halorhodopsin) or the excitatory opsin pAAV-CaMKIIa-ChR2-mCherry (channelrhodopsin) was injected and optic fibers were implanted. After recovery, rats were trained in standard operant chambers on a delayed response working memory task in which they had to recall the left/right position of a briefly-presented stimulus following a variable delay period (0-32 s) in order to earn a food reward. Upon reaching stable task performance, a within-subjects design was used to evaluate the effects of either mPFC inactivation (halorhodopsin, green laser: 561nm, 10mW) or stimulation (channelrhodopsin, blue laser: 473nm, 15mW, 2.5Hz) during discrete phases of the working memory task (encoding, retention delay, or recall).

Results, Conclusions, and Discussions:: The results show that mPFC stimulation during the retention delay interval improved working memory accuracy in aged rats (p= .022), whereas mPFC inactivation during information encoding impaired working memory accuracy in rats of both ages (p= .024). Interestingly, mPFC stimulation during recall enhanced working memory accuracy at long delays in young rats (p= .016), as did mPFC inactivation during the same period in aged rats (p= .019). Control experiments in which rats were transduced with non-opsin viruses showed no effects of light delivery alone on any component of working memory in rats of either age.

The results suggest that mPFC is critical during encoding information to be retained in working memory for later recall, and that working memory accuracy in aged rats can be enhanced via stimulation of mPFC during the retention delay interval. The fact that the latter effect was selective to aged rats suggests that mPFC activation during the retention delay period (when encoded information must be retained “on line” in working memory in order for successful recall to occur) remediates an age-specific deficit in maintaining such information.

This study supports the utility of PFC stimulation for improving working memory performance in aged adults. The differential effects of PFC manipulations in young and aged rats underscore the importance of evaluating potential therapeutic approaches across the full lifespan, as well as future work on neuroplasticity in aged individuals.




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