Louis D. Matzel - US grants

memory; molecular psychobiology; learning; conditioning; visual photoreceptor; calcium flux; gamma aminobutyrate; serotonin; membrane potentials; arachidonate; guanine nucleotide binding protein; Hermissenda;

It has been long established that the expression of a memory does not necessarily reflect the underlying strength of the memory trace. In particular, it is known that a conditioned response based on an associative memory might reflect not only the associative "strength" of the memory, but also such factors as the animal's motivation to respond, competition between other cues present at the time of training or testing, and whether the memory was stored in a form which is readily retrievable. In the present series of experiments, we will examine several such determinants of responding in a simple organism using an associative learning task. For nearly thirty years, a "simple systems" approach has dominated the exploration of the neurophysiological mechanisms underlying memory formation. For instance, using model systems such as habituation and sensitization in Aplysia and associative eyeblink conditioning in the rabbit, many of the biophysical and biochemical events which are critical to memory formation have been elucidated, and in the case of vertebrate models, an appreciation of the anatomical substrates of certain memories has been achieved. While this approach has been quite successful, much of what psychologists consider to be fundamental memory processes have received relatively little attention. In the present proposal, several general classes of experiments are planned, focusing on the Interaction between training variables (i.e., number and distribution of training trials) and the induction and subsequent retentIon of an associative memory in Hermissenda. Many of these variables have been assessed at the behavioral level in vertebrate species. For instance, it is well established that retention is influenced by the number of initial training trials, and the rate at which the successive trials are presented. Moreover, it has been demonstrated that postconditioning exposure to components of the initial learning event (e.g., the CS, the US, or the training context) can either facilitate or retard subsequent responding depending on such factors as the number of exposures to these stimuli, and the strength of the original memory trace. Using Hermissenda we will attempt to establish parameters by which facilitated reacquisition following memory degradation may be observed, and to determined when post- training cuing treatments (i.e., brief exposure to the CS, the US, or the training context) are effective. These experiments, which are conceptually based in the vertebrate learning literature, are to be undertaken in Hermissenda for several reasons. First, given the capacity to condition Hermissenda using in vitro techniques, it should be possible to examine biophysical and biochemical properties of cells involved in memory formation during each stage of memory processing. Second, associative learning in Hermissenda occurs within a narrow range of parameters, and depending on the number of training trials, the effective retention interval can be as short as several minutes or as long as seven to ten days. In total, these two features (capacity for neurophysiological analysis during in vitro procedures and strict control of the capacity for retention) provides a unique opportunity to study the neurophysiological mechanisms underlying these simple psychological processes.

Animal research on age-related learning deficits has typically focused on the impact of age on specific learning systems. While informative, this work necessarily limits any conclusions regarding the effects of aging on general cognitive/learning abilities. This focus on specific learning systems impacts critically on our understanding of age-related deficits, given that it is estimated that 25-50% of this decline is attributable to an impairment of general cognitive ability, i.e., an ability that transcends specific learning systems or domains. The elucidation of the brain substrates for age-related cognitive deficits thus requires a conceptually-sound approach from which to parse deficits in general abilities from those which impact specific (limited) domains. Absent any attention to general influences on learning/cognitive processes, as much as 50% of decline in cognitive abilities that accrue with aging will necessarily go unexplained, mitigating the development of effective treatment strategies. Among human populations, a general influence on individuals' learning abilities reflects one of the most dominant cognitive traits ever identified. However, comparable evidence from animal subjects is sparse, and age-dependent variations in general learning factors have never been described in laboratory animals. We have recently developed a unique test battery that is sensitive to a general learning factor in mice, and this factor is psychometrically comparable to that described in humans. In Aims 1 and 2 of the present proposal, we summarize our plans to characterize the general learning/cognitive abilities of laboratory mice that range in age from young to old, and describe analysis regimens that will provide preliminary indications of the differential sources of variability that impinge on these abilities across the life span. These studies are a critical prelude to future work directed at the elucidation of the brain substrates for age-related declines in general cognitive/learning abilities.

[unreadable] DESCRIPTION (provided by applicant): Animal research on age-related cognitive deficits has typically focused on the impact of aging on specific learning tasks or domains. While informative regarding the brain substrates for task- specific (or even domain-specific) learning impairments, this approach provides little insight into the impact of aging on general cognitive/learning abilities. The prevailing focus on isolated tasks or domains has limited our understanding of "cognitive aging", as it has been estimated that 35-60% of age-related declines in cognitive performance are attributable to a diminishment of individuals' general cognitive ability, i.e., the capacity for cognitive performance that transcends the specific demands of any single task or domain. We have developed unique testing and analysis regimens that are sensitive to a general learning factor that accounts for >32% of the variance in the general cognitive performance of young adult laboratory mice. We have begun to apply this approach to studies of animals across the life span, and have isolated a general cognitive factor in 20 month old BALB-C mice that accounts for greater than 40% of the variance in the general cognitive abilities of these animals. While comparable in structure to that of young animals, in old animals this "general cognitive factor" consistently accounts for a greater proportion of the total variance in the cognitive performance of aged animals, suggesting that general cognitive abilities become increasingly dominant across the animal's life span. Moreover, we have established that in aged animals, general cognitive abilities become increasingly reliant on aspects of working memory, particularly, working memory span (resistance to decay) and working memory capacity (resistance to interference). Furthermore, general cognitive declines do not accrue homogeneously across the life span, such that some percentage of aged animals retain their cognitive abilities, while in others, these abilities decline rapidly, an effect associated with increasing body mass and decreases in general activity. We now hypothesize that the general cognitive decline in aged animals is the consequence of perturbations in the efficacy of the working memory system, including working memory span, capacity, and selective attention. We will test these possibilities in Aims 1 and 2, and in so doing, will gain critical insight into the processes that underlie age-related cognitive declines. It will then be possible in Aim 3 to test specific behavioral strategies (including manipulations of body weights, activity, and working memory efficacy) to innoculate animals against these declines, and possibly, to mitigate the progression of age-related declines that were previously instantiated. This work will provide a conceptually and empirically strong foundation for subsequent elucidation of the brain substrates for age-related cognitive impairments (as described in our Ancillary Aim), and ultimately, the development of strategies to overcome these impairments. PUBLIC HEALTH RELEVANCE: A critical need has emerged to develop strategies with which to treat the normal but pervasive cognitive impairments that are associated with aging. To do so, we must quantify the cognitive deficits associated with aging, understand the variability (i.e., individual differences) in the emergence of cognitive aging, and elucidate the psychological processes that underlie cognitive aging. The goal of this research program is to quantify cognitive declines across the life span, and to generate behavioral intervention strategies that facilitate the successful maintenance of cognitive abilities into old age. [unreadable] [unreadable] [unreadable]

SUMMARY ABSTRACT In both humans and laboratory animals, quantitative measures of intelligence are predicted by a) the expression of the dopamine Drd1a and related genes in the prefrontal cortex (PFC; Kolata et al., 2010), and b) by the affinity of the D1 receptor to dopamine in the medial and dorsolateral PFC (Klingberg & McNab, 2009; Wass et al., 2013. Relatedly, working memory training promotes improvements in intelligence that coincide with increases in the affinity of the D1 receptor in the PFC (McNab et al., 2009; Wass et al., 2013). Despite the increase in Drd1a gene expression and the increased affinity/sensitivity of the D1 receptors in subregions of the PFC that are associated with higher cognitive abilities, membrane-bound D1 receptors are not differentially expressed as a function of animals' cognitive abilities (Wass et al., 2010). In combination with the above results, this latter observation suggests that a sub-membrane level influence on the trafficking of (sequestered) D1 receptors differentially regulates the availability of these receptors across animals that exhibit variations in general cognitive performance. This hypothesis suggests that the pool of immature D1 receptors available to meet the demands of cognitive challenges may underlie (at least in part) variations in ?intelligence?, and may be available to respond to cognitive demands (e.g., working memory training). The elucidation of this dynamic process will not only aid in our understanding of intelligence, but will help to establish a framework with which to promote improvements in general cognitive performance. The dopamine receptor interacting protein, DRiP78, binds to the immature D1 receptor and sequesters the receptor in the endoplasmic reticulum (ER). The DRiP78 binding cite is shared by antibodies to the D1 protein, and thus renders the receptor undetectable to these antibodies (and thus may account for our inability to detect increases in receptor expression). We will determine whether a correlation exists between animals' general cognitive ability and the expression of DRiP78, with the goal of determining whether an undetectable pool of immature receptors resides in the ER of animals of high cognitive abilities. Relatedly, we will determine if animals of higher general cognitive ability exhibit an increase in the rate of D1 receptor turnover (which would potentiate the receptor's affinity to dopamine). Lastly, we will determine if the rate of receptor turnover and/or membrane-bound receptors is elevated as a consequence of high cognitive demands (such as during working memory training), and whether the degree of elevation is predicted by animals' innate cognitive ability. Consistent with the R03 Program, this is a tightly-focused series of experiments that will clarify our understanding of the instantiation and malleability of general cognitive performance. These experiments will elucidate a biological basis for the interaction between environmental experience and the genome in the regulation of individual differences in general cognitive abilities, and are preliminary to the development of molecular/pharmacological and behavioral strategies to promote improvements in general cognitive abilities.