Age-Related Decline in Brain Resources Modulates Genetic Effects on Cognitive Functioning

Individual differences in cognitive performance increase from early to late adulthood, likely reflecting influences of a multitude of factors. We hypothesize that losses in neurochemical and anatomical brain resources in normal aging modulate the effects of common genetic variations on cognitive functioning. Our hypothesis is based on the assumption that the function relating brain resources to cognition is nonlinear, so that genetic differences exert increasingly large effects on cognition as resources recede from high to medium levels in the course of aging. Direct empirical support for this hypothesis comes from a study by Nagel et al. (2008), who reported that the effects of the Catechol-O-Methyltransferase (COMT) gene on cognitive performance are magnified in old age and interacted with the Brain-Derived Neurotrophic Factor (BDNF) gene. We conclude that common genetic polymorphisms contribute to the increasing heterogeneity of cognitive functioning in old age. Extensions of the hypothesis to other polymorphisms are discussed. (150 of 150 words

Use-Dependent Plasticity Regulates Sleep Need in Drosophila Melanogaster

Although the necessary functions of sleep have not been identified, sleep has been shown to play an important role in the consolidation of memories. Recent studies have shown that, in addition to playing a strong role in sleep regulation, the circadian clock also influences processes associated with learning and memory. Thus, the neural circuits that control circadian rhythms are uniquely positioned to play an important role in coordinating interactions between sleep and memory. Drosophila melanogaster exhibit increased sleep following several days of social experience and require sleep to consolidate long-term memories: LTM) after Courtship Conditioning, an associative memory assay. We have found both that changes in sleep following social experience and that memory consolidation are reliant upon the expression of plasticity-related genes in Pigment Dispersing Factor: PDF)-expressing ventral lateral neurons: LNvs), a core component of the Drosophila circadian clock. Following social enrichment, LNv projections into the medulla exhibit structural plasticity as measured by an increase in the number of synaptic terminals and that downscaling of LNv terminal number after social enrichment requires sleep. We have also found that both LNv structural plasticity and increases in sleep following social enrichment degrade with age. Importantly, restoration of mechanisms that mediate plastic responses in young flies, such as dopaminergic signaling or expression of the transcription factor blistered, restore youthful plasticity to aged flies. These data indicate that Drosophila circadian circuitry influences sleep-wake behavior in an experience-dependent manner and that proper functioning of the LNvs is required for long-term behavioral plasticity. Our observation of sleep-dependent downscaling of LNv terminals following social enrichment also indicates that an important function of sleep is to downscale potentiated synaptic connections. Together, these results establish Drosophila as a robust model system for investigating the genes and neural circuits that mediate the relationship between plasticity and sleep

Dopamine and the Temporal Dependence of Learning and Memory

Animal behavior is largely influenced by the seeking out of rewards and avoidance of punishments. Positive or negative reinforcements, like a food reward or painful shock, impart meaningful valence onto sensory cues in the animal’s environment. The ability of animals to form associations between a sensory cue and a rewarding or punishing reinforcement permits them to adapt their future behavior to maximize reward and minimize punishments. Animals rely on the timing of events to infer the causal relationships between cues and outcomes –– sensory cues that precede a painful shock in time become associated with its onset and are imparted with negative valence, whereas cues that follow the shock in time are instead associated with its cessation and imparted with positive valence. While the temporal requirements for associative learning have been well characterized at the behavioral level, the molecular and circuit mechanisms for this temporal sensitivity remain incompletely understood. Using the simple architecture of the mushroom body, an olfactory associative learning center in Drosophila, I examined how the relative timing of olfactory inputs and dopaminergic reinforcement signals is encoded at the molecular, synaptic, and circuit level to give rise to learned odor associations. I show that in Drosophila, opposing olfactory associations can be formed and updated on a trial-by-trial basis depending on the temporal relationship between an odor cue and dopaminergic reinforcement during conditioning. Additionally, both negative and positive reinforcements equivalently instruct appetitive and aversive olfactory associations –– odors preceding a negative reinforcement or following a rewarding reinforcement acquire an aversive valence, while odors instead following a negative reinforcement or preceding a rewarding reinforcement become attractive. Furthermore, functional imaging revealed that synapses within the mushroom body are bidirectionally modulated depending on the temporal ordering of odor and dopaminergic reinforcement, leading to synaptic depression when an odor precedes dopaminergic activity or synaptic facilitation when dopaminergic activity instead precedes an odor. Through the synchronous recording of neural activity and behavior, I found that the bidirectional regulation of synaptic transmission within the mushroom body directly correlates with the emergence of learned olfactory behaviors. This temporal sensitivity arises from two dopamine receptors, DopR1 and DopR2, that couple to distinct second-messengers and direct either synaptic depression or potentiation. Loss of either receptor renders the synapses of the mushroom body capable of only unidirectional plasticity and prevents the behavioral flexibility of writing opposing associations depending on the temporal structure of conditioning. Together, these results reveal how the distinct intracellular signaling pathways of two dopamine receptors can detect the order of events within an associative learning circuit to instruct opposing forms of synaptic and behavioral plasticity, providing a mechanism for animals to use both the onset and offset of a reinforcement signal to instruct distinct associations. Additionally, this bidirectional modulation allows animals to flexibly update olfactory associations on a trial-bytrial basis when temporal relationships are altered, permitting them to contend with a complex and changing sensory world

Neurofly 2008 abstracts : the 12th European Drosophila neurobiology conference 6-10 September 2008 Wuerzburg, Germany

This volume consists of a collection of conference abstracts

Neuronal underpinning of reproductive state dependent olfactory behavior in Drosophila

A general question in neuroscience is how the flow of sensory information is encoded towards a behavioral response. These behavioral responses can be interpreted as decisions the organism needs to make to get a most beneficial outcome. Factors which can influence these decisions can be external or internal. Considering sensory information, external stimuli can elicit "innate" responses to a sensory input, which lead to a certain behavior. Interestingly, these responses can be overwritten given a certain experience or context. The internal state of an organism can be such a context. Internal states, such as age, stress, hunger, or reproductive state can have effects on chemosensory decision making behavior. Such behavior usually manifests itself by attraction or aversion towards a certain odor or taste. Occasionally, transient neuromodulation can affect these behaviors, by focusing an animal's attention to relevant sensory stimuli in its environment. This might facilitate remembering relevant vs. irrelevant stimuli. Here, we are investigating the role of such a sensory neuromodulation and the formation of memory in the female fruit fly, Drosophila melanogaster. Previous work from our lab has shown that mating changes the sensitivity of olfactory and gustatory neurons with the help of specific neuromodulators that act directly on these chemosensory neurons. However, this very transient neuromodulation leads to a long-term behavioral change in females: for instance, while virgin flies usually prefer low concentrations of polyamines, mated flies will prefer higher concentrations after the mating experience and will continue this behavior for up to two weeks until falling back to a virgin-like state. Drosophila's genetic toolset allows us to test the hypothesis that this transient sensory enhancement facilitates the formation of a long-lasting memory. Using a quantitative olfactory choice assay, my collaborators and I silenced and activated neuronal activity in different parts of the fly's associative memory center (i.e. the mushroom body). We revealed a possible neuronal pathway and its modulatory switch between virgin and mated state. These findings suggest that dopaminergic neurons, which are innervating the mushroom body, control virgin vs. mated female behavior by processing sensory input differentially before and after mating, respectively. Furthermore, our data suggests that courtship and pheromones are highly important signals to trigger the reproductive state dependent change in olfactory preference behavior. In addition, my collaborators and I wanted to use state-of-the-art techniques to shed light on the detection of nutrients valuable for the gravid fly by using bioinformatic tools and to promote these methods to the biological fields. As two-photon laser scanning microscopy is an important tool for neuroscientific research in the fly and beyond, I built such a microscope. Harnessing this experience, I have, in collaboration, written a guide for life scientists wishing to build or purchase such a microscope. A joint effort between established behavioral assays and technological advances, such as bioinformatic tools, can support and extend our understanding of neuronal circuits underlying reproductive state dependent behaviors

Genetic influences on neural plasticity.

Neural plasticity refers to the capability of the brain to alter function or structure in response to a range of events and is a crucial component of both functional recovery after injury and skill learning in healthy individuals. A number of factors influence neural plasticity and recovery of function after brain injury. The current review considers the impact of genetic factors. Polymorphisms in the human genes coding for brain-derived neurotrophic factor and apolipoprotein E have been studied in the context of plasticity and stroke recovery and are discussed here in detail. Several processes involved in plasticity and stroke recovery, such as depression or pharmacotherapy effects, are modulated by other genetic polymorphisms and are also discussed. Finally, new genetic polymorphisms that have not been studied in the context of stroke are proposed as new directions for study. A better understanding of genetic influences on recovery and response to therapy might allow improved treatment after a number of forms of central nervous system injury

Neuromodulation of Spike-Timing-Dependent Plasticity: Past, Present, and Future.

Spike-timing-dependent synaptic plasticity (STDP) is a leading cellular model for behavioral learning and memory with rich computational properties. However, the relationship between the millisecond-precision spike timing required for STDP and the much slower timescales of behavioral learning is not well understood. Neuromodulation offers an attractive mechanism to connect these different timescales, and there is now strong experimental evidence that STDP is under neuromodulatory control by acetylcholine, monoamines, and other signaling molecules. Here, we review neuromodulation of STDP, the underlying mechanisms, functional implications, and possible involvement in brain disorders.BBSR

Inter-individual differences in associative memory : structural and functional brain correlates and genetic modulators

Our memory for personal experiences (e.g., the first day at school) is termed episodic memory. This form of memory involves the recollection of single information as well as the connection between these pieces of information (e.g., what happened when, and where), referred to as associative memory. Associative memory declines markedly in aging; however, some individuals have proficient associative memory even until late life. These individual differences in associative-memory performance are also observable at younger ages. The underlying sources of these individual differences remain unclear. In this thesis, we aimed to identify the neural underpinnings of individual differences in associative memory, with special regard to brain structure, function, and neurochemistry. In the first part of the thesis, we investigated structural brain correlates of and dopaminergic contributions to associative memory in healthy older adults (studies I and II). In study I, we examined the relationship between regional gray-matter volume and associative memory. Individuals with better associative memory had larger gray-matter volume in dorsolateral and ventrolateral prefrontal cortex, suggesting that organizational and strategic processes distinguish older adults with good from those with poor associative memory. In study II, we examined the influence of dopamine (DA) receptor genes on item and associative memory. Individuals with less beneficial DA genotypes performed worse in the associative-memory task compared with carriers of more beneficial genotypes. Because no such group differences were found with regard to item memory, this suggests that dopaminergic neuromodulation is particularly important for associative memory in older adults. In the second part of the thesis, we examined in a sample of younger adults how different task instructions influence associative encoding, as well as the structural-functional coupling between task-relevant brain regions during associative-memory formation (studies III and IV). In study III, we investigated the effect of encoding instruction on associative memory. Specifically, we examined functional brain correlates of intentional and incidental encoding and demonstrated differential involvement of anterior hippocampus in intentional relative to incidental associative encoding. This suggests that the intent to remember associative information triggers a binding process accomplished by this brain region. Finally, in study IV we explored how gray-matter volume is associated with brain activity during associative-memory formation. We observed a relationship between gray-matter volume in the medial-temporal lobe (MTL) and functional brain activity in the inferior frontal gyrus (IFG). Importantly, this structure-function coupling correlated with performance, such that younger individuals with a stronger MTL-IFG coupling had better associative memory. Collectively, these four studies show that the neural underpinnings of individual differences in associative memory are many-faceted, interacting with each other and vary with regard to age and specific features of the associative task