Positive modulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors differentially alters spatial learning and memory in juvenile rats younger and older than three weeks.

Remarkable performance improvements occur at the end of the third postnatal week in rodents tested in various tasks that require navigation according to spatial context. While alterations in hippocampal function at least partially subserve this cognitive advancement, physiological explanations remain incomplete. Previously, we discovered that developmental modifications to hippocampal glutamatergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in juvenile rats was related to more mature spontaneous alternation behavior in a symmetrical Y-maze. Moreover, a positive allosteric modulator of AMPA receptors enabled immature rats to alternate at rates seen in older animals, suggesting an excitatory synaptic limitation to hippocampal maturation. We then validated the Barnes maze for juvenile rats in order to test the effects of positive AMPA receptor modulation on a goal-directed spatial memory task. Here we report the effects of the AMPA receptor modulator, CX614, on spatial learning and memory in the Barnes maze. Similar to our prior report, animals just over 3 weeks of age display substantial improvements in learning and memory performance parameters compared to animals just under 3 weeks of age. A moderate dose of CX614 enabled immature animals to move more directly to the goal location, but only after 1 day of training. This performance improvement was observed on the second day of training with drug delivery or during a memory probe trial performed without drug delivery after the second day of training. Higher doses created more search errors, especially in more mature animals. Overall, CX614 provided modest performance benefits for immature rats in a goal-directed spatial memory task.

A Modified Barnes Maze for Juvenile Rats.

To better understand neural codes for spatial navigation and to address cognitive development questions, the neurobiology of postnatal hippocampal development is receiving increased attention. While the Morris Water Maze is the gold standard for assessing hippocampal integrity, potential confounds can be difficult to control for in juvenile rodents (around three weeks of age, when spatial navigation ability first emerges) and this wet maze is not amenable to electrophysiological recording. A dry maze alternative with minimal training, like the Barnes Maze adapted for juvenile rats, can help overcome these obstacles. This paper describes in detail the experimental procedure and data analyses for the adapted Barnes maze for juvenile animals.

A Barnes maze for juvenile rats delineates the emergence of spatial navigation ability.

The neural bases of cognition may be greatly informed by relating temporally defined developmental changes in behavior with concurrent alterations in neural function. A robust improvement in performance in spatial learning and memory tasks occurs at 3 wk of age in rodents. We reported that the developmental increase of spontaneous alternation in a Y-maze was related to changes in temporal dynamics of fast glutamatergic synaptic transmission in the hippocampus. We also showed that, during allothetic behaviors in the Y-maze, network oscillation power increased at frequency bands known to support spatial learning and memory in adults. However, there are no discrete learning and memory phases during free exploration in the Y-maze. Thus, we adapted the Barnes maze for use with juvenile rats. Following a single platform exposure in dim light on the day before training (to encourage exploration), animals were trained on the subsequent 2 d in bright light to find a hidden escape box and then underwent a memory test 24 h later. During escape training, the older animals learned the task in 1 d, while the younger animals required 2 d and did not reach the performance of older animals. Long-term memory performance was also superior in the older animals. Thus, we have validated the use of the Barnes maze for this developmental period and established a timeline for the ontogeny of spatial navigation ability in this maze around 3 wk of age. Subsequent work will pair in vivo recording of hippocampal oscillations and single units with this task to help identify how hippocampal maturation might relate to performance improvements.