CREB overexpression in dorsal CA1 ameliorates long-term memory deficits in aged rats.

The molecular mechanisms underlying age-related cognitive deficits are not yet fully elucidated. In aged animals, a decrease in the intrinsic excitability of CA1 pyramidal neurons is believed to contribute to age-related cognitive impairments. Increasing activity of the transcription factor cAMP response element-binding protein (CREB) in young adult rodents facilitates cognition, and increases intrinsic excitability. However, it has yet to be tested if increasing CREB expression also ameliorates age-related behavioral and biophysical deficits. To test this hypothesis, we virally overexpressed CREB in CA1 of dorsal hippocampus. Rats received CREB or control virus, before undergoing water maze training. CREB overexpression in aged animals ameliorated the long-term memory deficits observed in control animals. Concurrently, cells overexpressing CREB in aged animals had reduced post-burst afterhyperpolarizations, indicative of increased intrinsic excitability. These results identify CREB modulation as a potential therapy to treat age-related cognitive decline.

The motirod: a novel physical skill task that enhances motivation to learn and thereby increases neurogenesis especially in the female hippocampus.

Males and females perform differently on a variety of training tasks. In the present study we examined performance of male and female rats while they were trained with a gross motor skill in which they learn to maintain their balance on an accelerating rotating rod (the accelerating rotarod). During training, many animals simply step off the rod, thus terminating the training. This problem was addressed by placing cold water below the rod. We termed the new training procedure "motirod" training because the trained animals were apparently motivated to remain on the rod for longer periods of time. Groups of male and female adult Sprague-Dawley rats were trained on either the standard accelerating rotarod or the motirod for four trials per day on four consecutive days. Latency to fall from the rod (in seconds) was recorded. The motivating feature increased performance especially in females (p=.001). As a consequence of enhanced performance, females retained significantly more new cells in the dentate gyrus of the hippocampus than those trained on the accelerating rotarod or those that received no training. In addition, individuals that learned well retained more new cells, irrespective of sex or task conditions. Previous studies have established that new cells rescued from death by learning remain in the hippocampus for months and mature into neurons (Leuner et al., 2004a; Shors, 2014). These data suggest that sex differences in physical skill learning can arise from sex differences in motivation, which thereby influence how many new neurons survive in the adult brain. This article is part of a Special Issue entitled SI: Brain and Memory.

Age-related impairments on one hippocampal-dependent task predict impairments on a subsequent hippocampal-dependent task.

Age-related cognitive impairments are particularly prevalent in forms of learning that require a functionally intact hippocampal formation, such as spatial and declarative learning. However, there is notable heterogeneity in the cognitive abilities of aged subjects. To date, few studies have determined whether age-related impairments on one learning task relate to impairments on different learning tasks that engage overlapping cognitive processes. Here, we hypothesized that aged animals that were impaired on 1 hippocampal-dependent behavioral procedure would be impaired on a second hippocampal-dependent procedure. Conversely, aged animals that were unimpaired on 1 hippocampal-dependent task would be unimpaired with a subsequent hippocampal-dependent form of learning. To test these hypotheses, we trained young (2-3 months old) and aged (28-29 months old) F344XBN male rats with trace eyeblink conditioning, followed by the Morris water maze. Half of aged rats were impaired during trace conditioning. Nearly half of aged animals were also impaired during water maze probe testing. Performance during trace conditioning correlated with performance during water maze testing in aged animals. Further analyses revealed that, as a group, aged animals that were impaired on 1 hippocampal-dependent task were impaired on both tasks. Conversely, aged animals that were unimpaired on 1 task were unimpaired on both tasks. Together, these results suggest that aged-related impairments on 1 hippocampal-dependent task predict age-related impairments on a second hippocampal-dependent procedure. These results have implications for assigning personalized therapeutics to ameliorate age-related cognitive decline.

Preparing for adulthood: thousands upon thousands of new cells are born in the hippocampus during puberty, and most survive with effortful learning.

The dentate gyrus of the hippocampal formation generates new granule neurons throughout life. The number of neurons produced each day is inversely related to age, with thousands more produced during puberty than during adulthood, and many fewer produced during senescence. In adulthood, approximately half of these cells undergo apoptosis shortly after they are generated. Most of these cells can be rescued from death by effortful and successful learning experiences (Gould et al., 1999; Waddell and Shors, 2008; Curlik and Shors, 2011). Once rescued, the newly-generated cells differentiate into neurons, and remain in the hippocampus for at least several months (Leuner et al., 2004). Here, we report that many new hippocampal cells also undergo cell death during puberty. Because the juvenile brain is more plastic than during adulthood, and because many experiences are new, we hypothesized that a great number of cells would be rescued by learning during puberty. Indeed, adolescent rats that successfully acquired the trace eyeblink response retained thousands more cells than animals that were not trained, and those that failed to learn. Because the hippocampus generates thousands more cells during puberty than during adulthood, these results support the idea that the adolescent brain is especially responsive to learning. This enhanced response can have significant consequences for the functional integrity of the hippocampus. Such a massive increase in cell proliferation is likely an adaptive response as the young animal must emerge from the care of its mother to face the dangers, challenges, and opportunities of adulthood.

Physical skill training increases the number of surviving new cells in the adult hippocampus.

The dentate gyrus is a major site of plasticity in the adult brain, giving rise to thousands of new neurons every day, through the process of adult neurogenesis. Although the majority of these cells die within two weeks of their birth, they can be rescued from death by various forms of learning. Successful acquisition of select types of associative and spatial memories increases the number of these cells that survive. Here, we investigated the possibility that an entirely different form of learning, physical skill learning, could rescue new hippocampal cells from death. To test this possibility, rats were trained with a physically-demanding and technically-difficult version of a rotarod procedure. Acquisition of the physical skill greatly increased the number of new hippocampal cells that survived. The number of surviving cells positively correlated with performance on the task. Only animals that successfully mastered the task retained the cells that would have otherwise died. Animals that failed to learn, and those that did not learn well did not retain any more cells than those that were untrained. Importantly, acute voluntary exercise in activity wheels did not increase the number of surviving cells. These data suggest that acquisition of a physical skill can increase the number of surviving hippocampal cells. Moreover, learning an easier version of the task did not increase cell survival. These results are consistent with previous reports revealing that learning only rescues new neurons from death when acquisition is sufficiently difficult to achieve. Finally, complete hippocampal lesions did not disrupt acquisition of this physical skill. Therefore, physical skill training that does not depend on the hippocampus can effectively increase the number of surviving cells in the adult hippocampus, the vast majority of which become mature neurons.

Learning increases the survival of newborn neurons provided that learning is difficult to achieve and successful.

Learning increases neurogenesis by increasing the survival of new cells generated in the adult hippocampal formation [Shors, T. J. Saving new brain cells. Scientific American, 300, 46-52, 2009]. However, only some types of learning are effective. Recent studies demonstrate that animals that learn the conditioned response (CR) but require more trials to do so retain more new neurons than animals that quickly acquire the CR or that fail to acquire the CR. In these studies, task parameters were altered to modify the number of trials required to learn a CR. Here, we asked whether pharmacological manipulations that prevent or facilitate learning would decrease or increase, respectively, the number of cells that remain in the hippocampus after training. To answer this question, we first prevented learning with the competitive N-methyl-D-aspartate (NMDA) receptor antagonist (RS)-3-(2-carboxypiperazin-4-yl) propyl-1-phosphonic acid. As a consequence, training did not increase cell survival. Second, we facilitated learning with the cognitive enhancer D-cycloserine, which increases NMDA receptor activity via its actions at the glycine binding site. Administration of D-cycloserine each day before training increased the number of learned responses and the number of cells that survived. All animals that learned the CR retained more of the new cells, but those that learned very quickly retained fewer than those that required more training trials to learn. Together, these results demonstrate that NMDA receptor activation modifies learning and as a consequence alters the number of surviving cells in the adult hippocampus.

Associative learning increases adult neurogenesis during a critical period.

Learning increases the number of immature neurons that survive and mature in the adult hippocampus. One-week-old cells are more likely to survive in response to learning than cells in animals that are exposed to training but do not learn. Because neurogenesis is an ongoing and overlapping process, it is possible that learning differentially affects new cells as a function of their maturity. To address this issue, we examined the effects of associative learning on the survival of cells at different stages of development. Training did not alter the number of cells that were produced during the training experience. Cells that were 1-2 weeks of age at the time of training survived after learning but cells that were younger or older did not. In contrast, cells that were produced during training were less likely to survive than cells in untrained animals. Additionally, the number of cells that were generated after learning in trained animals was not different from the number in untrained animals. Finally, survival was not increased if the memory was expressed when the cells were about 1-week-old. Together, these results indicate that new neurons are rescued from death by initial acquisition, not the expression or reacquisition, of an associative memory and only during a critical period. Overall, these results suggest the presence of a feedback system, which controls how many new neurons become incorporated into the adult brain in response to learning.