Cocaine Directly Impairs Memory Extinction and Alters Brain DNA Methylation Dynamics in Honey Bees.

Drug addiction is a chronic relapsing behavioral disorder. The high relapse rate has often been attributed to the perseverance of drug-associated memories due to high incentive salience of stimuli learnt under the influence of drugs. Drug addiction has also been interpreted as a memory disorder since drug associated memories are unusually enduring and some drugs, such as cocaine, interfere with neuroepigenetic machinery known to be involved in memory processing. Here we used the honey bee (an established invertebrate model for epigenomics and behavioral studies) to examine whether or not cocaine affects memory processing independently of its effect on incentive salience. Using the proboscis extension reflex training paradigm we found that cocaine strongly impairs consolidation of extinction memory. Based on correlation between the observed effect of cocaine on learning and expression of epigenetic processes, we propose that cocaine interferes with memory processing independently of incentive salience by directly altering DNA methylation dynamics. Our findings emphasize the impact of cocaine on memory systems, with relevance for understanding how cocaine can have such an enduring impact on behavior.

Practice-centred evaluation and the privileging of care in health information technology evaluation.

UNLABELLED: Our contribution, drawn from our experience of the case study provided, is a protocol for practice-centred, participative evaluation of technology in the clinical setting that privileges care. In this context 'practice-centred' evaluation acts as a scalable, coordinating framework for evaluation that recognises health information technology supported care as an achievement that is contingent and ongoing. We argue that if complex programmes of technology-enabled service innovation are understood in terms of their contribution to patient care and supported by participative, capability-building evaluation methodologies, conditions are created for practitioners and patients to realise the potential of technologies and make substantive contributions to the evidence base underpinning health innovation programmes. BACKGROUND: Electronic Patient Records (EPRs) and telemedicine are positioned by policymakers as health information technologies that are integral to achieving improved clinical outcomes and efficiency savings. However, evaluating the extent to which these aims are met poses distinct evaluation challenges, particularly where clinical and cost outcomes form the sole focus of evaluation design. We propose that a practice-centred approach to evaluation - in which those whose day-to-day care practice is altered (or not) by the introduction of new technologies are placed at the centre of evaluation efforts - can complement and in some instances offer advantages over, outcome-centric evaluation models. METHODS: We carried out a regional programme of innovation in renal services where a participative approach was taken to the introduction of new technologies, including: a regional EPR system and a system to support video clinics. An 'action learning' approach was taken to procurement, pre-implementation planning, implementation, ongoing development and evaluation. Participants included clinicians, technology specialists, patients and external academic researchers. Whilst undergoing these activities we asked: how can a practice-centred approach be embedded into evaluation of health information technologies? DISCUSSION: Organising EPR and telemedicine evaluation around predetermined outcome measures alone can be impractical given the complex and contingent nature of such projects. It also limits the extent to which unforeseen outcomes and new capabilities are recognised. Such evaluations often fail to improve understanding of 'when' and 'under what conditions' technology-enabled service improvements are realised, and crucially, how such innovation improves care. SUMMARY: Our contribution, drawn from our experience of the case study provided, is a protocol for practice-centred, participative evaluation of technology in the clinical setting that privileges care. In this context 'practice-centred' evaluation acts as a scalable, coordinating framework for evaluation that recognises health information technology supported care as an achievement that is contingent and ongoing. We argue that if complex programmes of technology-enabled service innovation are understood in terms of their contribution to patient care and supported by participative, capability-building evaluation methodologies, conditions are created for practitioners and patients to realise the potential of technologies and make substantive contributions to the evidence base underpinning health innovation programmes.

Contrasting Effects of Histone Deacetylase Inhibitors on Reward and Aversive Olfactory Memories in the Honey Bee.

Much of what we have learnt from rodent models about the essential role of epigenetic processes in brain plasticity has made use of aversive learning, yet the role of histone acetylation in aversive memory in the honey bee, a popular invertebrate model for both memory and epigenetics, was previously unknown. We examined the effects of histone deacetylase (HDAC) inhibition on both aversive and reward olfactory associative learning in a discrimination proboscis extension reflex (PER) assay. We report that treatment with the HDAC inhibitors APHA compound 8 (C8), phenylbutyrate (PB) or sodium butyrate (NaB) impaired discrimination memory due to impairment of aversive memory in a dose-dependent manner, while simultaneously having no effect on reward memory. Treatment with C8 1 h before training, 1 h after training or 1 h before testing, impaired aversive but not reward memory at test. C8 treatment 1 h before training also improved aversive but not reward learning during training. PB treatment only impaired aversive memory at test when administered 1 h after training, suggesting an effect on memory consolidation specifically. Specific impairment of aversive memory (but not reward memory) by HDAC inhibiting compounds was robust, reproducible, occurred following treatment with three drugs targeting the same mechanism, and is likely to be genuinely due to alterations to memory as sucrose sensitivity and locomotion were unaffected by HDAC inhibitor treatment. This pharmacological dissection of memory highlights the involvement of histone acetylation in aversive memory in the honey bee, and expands our knowledge of epigenetic control of neural plasticity in invertebrates.

Involvement of DNA methylation in memory processing in the honey bee.

DNA methylation, an important and evolutionarily conserved epigenetic mechanism, is implicated in learning and memory processes in vertebrates, but its role in behaviour in invertebrates is unknown. We examined the role of DNA methylation in memory in the honey bee using an appetitive Pavlovian olfactory discrimination task, and by assessing the expression of DNA methyltransferase3, a key driver of epigenetic reprogramming. Here we report that DNA methyltransferase inhibition reduces acquisition retention and alters the extinction depending on treatment time, and DNA methyltransferase3 is upregulated after training. Our findings add to the understanding of epigenetic mechanisms in learning and memory, extending known roles of DNA methylation to appetitive and extinction memory, and for the first time implicate DNA methylation in memory in invertebrates.

Effect of age, behaviour and social environment on honey bee brain plasticity.

We examined the effects of behaviour, age and social environment on mushroom body volume in adult bees. The mushroom bodies are regions of the central brain important for sensory integration and learning. Their volume was influenced by behaviour throughout life: always larger in forager bees than age-matched nurse bees, even in old bees up to 93 days of age as adults. Mushroom body development was influenced by the social environment in the first 8 days of adult life, with different environments having markedly different effects on mushroom body size. Compared to hive-reared bees, isolation slowed mushroom body growth, but bees reared in isolation confined with a single dead bee showed a dramatic increase in mushroom body volume comparable to that seen in active foragers. Despite their precocious mushroom body development, these bees did not show improved performance in an olfactory learning test. Since simple environmental manipulations can both accelerate and delay mushroom body growth in young bees, and since mushroom body volume is sensitive to behaviour throughout life, the honey bee has great potential as a model for exploring the interactions between environment, behaviour and brain structure.

Effects of cocaine on honey bee dance behaviour.

The role of cocaine as an addictive drug of abuse in human society is hard to reconcile with its ecological role as a natural insecticide and plant-protective compound, preventing herbivory of coca plants (Erythroxylum spp.). This paradox is often explained by proposing a fundamental difference in mammalian and invertebrate responses to cocaine, but here we show effects of cocaine on honey bees (Apis mellifera L.) that parallel human responses. Forager honey bees perform symbolic dances to advertise the location and value of floral resources to their nest mates. Treatment with a low dose of cocaine increased the likelihood and rate of bees dancing after foraging but did not otherwise increase locomotor activity. This is consistent with cocaine causing forager bees to overestimate the value of the floral resources they collected. Further, cessation of chronic cocaine treatment caused a withdrawal-like response. These similarities likely occur because in both insects and mammals the biogenic amine neuromodulator systems disrupted by cocaine perform similar roles as modulators of reward and motor systems. Given these analogous responses to cocaine in insects and mammals, we propose an alternative solution to the paradox of cocaine reinforcement. Ecologically, cocaine is an effective plant defence compound via disruption of herbivore motor control but, because the neurochemical systems targeted by cocaine also modulate reward processing, the reinforcing properties of cocaine occur as a ;side effect'.

The effects of rearing temperature on developmental stability and learning and memory in the honey bee, Apis mellifera.

Honey bee workers maintain the brood nest of their colony within a narrow temperature range of 34.5+/-1.5 degrees C, implying that there are significant fitness costs if brood is reared outside the normal range. However, the effects of abnormal incubation temperatures are subtle and not well documented. Here we show that short-term learning and memory abilities of adult workers are affected by the temperature they experienced during pupal development. In contrast, long-term learning and memory is not significantly affected by rearing temperature. Furthermore, we could detect no effects of incubation temperature on fluctuating asymmetry, as a measure of developmental stability, in workers, queens or drones. We conclude that the most important consequence of abnormal rearing temperatures are subtle neural deficiencies affecting short-term memory rather than physical abnormalities.

Effects of NMDA receptor antagonists on olfactory learning and memory in the honeybee (Apis mellifera).

In contrast to vertebrates the involvement of glutamate and N-methyl-D-aspartate (NMDA) receptors in brain functions in insects is both poorly understood and somewhat controversial. Here, we have examined the behavioural effects of two noncompetitive NMDA receptor antagonists, memantine (low affinity) and MK-801 (high affinity), on learning and memory in honeybees (Apis mellifera) using the olfactory conditioning of the proboscis extension reflex (PER). We induced memory deficit by injecting harnessed individuals with a glutamate transporter inhibitor, L-trans-2,4-PDC (L-trans-2,4-pyrrolidine dicarboxylate), that impairs long-term (24 h), but not short-term (1 h), memory in honeybees. We show that L-trans-2,4-PDC-induced amnesia is 'rescued' by memantine injected either before training, or before testing, suggesting that memantine restores memory recall rather than memory formation or storage. When injected alone memantine has a mild facilitating effect on memory. The effects of MK-801 are similar to those of L-trans-2,4-PDC. Both pretraining and pretesting injections lead to an impairment of long-term (24 h) memory, but have no effect on short-term (1 h) memory of an olfactory task. The implications of our results for memory processes in the honeybee are discussed.