The Effects of Acute and Binge 3,4-methylenedioxymethamphetamine (MDMA) Exposure on Learning and Memory in Rats

<p>When rats are administered acute doses of MDMA they produce significantly more reference memory errors than working memory errors in the partially baited radial arm maze (Kay et al, 2009). The potential role of serotonin and dopamine in this effect was examined by administering the serotonin agonist Citalopram and the dopamine agonist GBR12909. GBR12909 produced significantly more reference memory errors, while Citalopram tended to produce more working memory errors. Administration of the D1 agonist A68930 and the D2 agonist Quinpirole predominantly produced reference memory errors, but to a lesser extent than acute MDMA administration. Low doses of both drugs produced a synergistic effect, more similar to that seen with acute MDMA administration. These findings suggest dopamine plays a role in the reference memory effect seen with MDMA exposure in the partially baited radial maze. In the second half of the thesis binge regimes of MDMA (4 x 10mg/kg) were administered to rats. When there was a gap of eight weeks between dosing and training the ability to acquire the radial arm maze was not significantly impaired. When this MDMA regime was repeated with a three-day gap between dosing and training it produced a significant but transient deficit in performance. When later challenged with acute doses of MDMA (4.0 mg/kg) the binge treated rats were less impaired than saline controls indicating drug tolerance. In an additional study that used a three-day delay between dosing and training a significant impairment in task acquisition was found. This deficit appeared to be long-term as the MDMA treated rats were impaired when the rules of task were changed suggesting a deficit in cognitive flexibility. Again when subjects were challenged with acute MDMA there was evidence of drug tolerance. The final study examined the effects of repeated MDMA exposure on task acquisition by administering acute doses of MDMA or saline once a week after rats had previously been treated with either a binge regime of MDMA or saline. MDMA exposure significantly impaired task acquisition and produced residual drug effects in the binge treated MDMA group the day after acute drug administration. However evidence of behavioural tolerance in this study was mixed due to a floor effect where performance of the binge MDMA group was so poor at the beginning of the study. In conclusion MDMA exposure impaired accuracy with reference memory processes were more affected than working memory processes. The underlying nature of this impairment remains unclear but it may be due to a long-term memory deficit, an impairment in understanding task rules or a perseverative pattern of responding. These findings imply human Ecstasy users may show deficits in acquiring information and may experience deficits in cognitive flexibility</p>

The Effects of Acute and Binge 3,4-methylenedioxymethamphetamine (MDMA) Exposure on Learning and Memory in Rats

<p>When rats are administered acute doses of MDMA they produce significantly more reference memory errors than working memory errors in the partially baited radial arm maze (Kay et al, 2009). The potential role of serotonin and dopamine in this effect was examined by administering the serotonin agonist Citalopram and the dopamine agonist GBR12909. GBR12909 produced significantly more reference memory errors, while Citalopram tended to produce more working memory errors. Administration of the D1 agonist A68930 and the D2 agonist Quinpirole predominantly produced reference memory errors, but to a lesser extent than acute MDMA administration. Low doses of both drugs produced a synergistic effect, more similar to that seen with acute MDMA administration. These findings suggest dopamine plays a role in the reference memory effect seen with MDMA exposure in the partially baited radial maze. In the second half of the thesis binge regimes of MDMA (4 x 10mg/kg) were administered to rats. When there was a gap of eight weeks between dosing and training the ability to acquire the radial arm maze was not significantly impaired. When this MDMA regime was repeated with a three-day gap between dosing and training it produced a significant but transient deficit in performance. When later challenged with acute doses of MDMA (4.0 mg/kg) the binge treated rats were less impaired than saline controls indicating drug tolerance. In an additional study that used a three-day delay between dosing and training a significant impairment in task acquisition was found. This deficit appeared to be long-term as the MDMA treated rats were impaired when the rules of task were changed suggesting a deficit in cognitive flexibility. Again when subjects were challenged with acute MDMA there was evidence of drug tolerance. The final study examined the effects of repeated MDMA exposure on task acquisition by administering acute doses of MDMA or saline once a week after rats had previously been treated with either a binge regime of MDMA or saline. MDMA exposure significantly impaired task acquisition and produced residual drug effects in the binge treated MDMA group the day after acute drug administration. However evidence of behavioural tolerance in this study was mixed due to a floor effect where performance of the binge MDMA group was so poor at the beginning of the study. In conclusion MDMA exposure impaired accuracy with reference memory processes were more affected than working memory processes. The underlying nature of this impairment remains unclear but it may be due to a long-term memory deficit, an impairment in understanding task rules or a perseverative pattern of responding. These findings imply human Ecstasy users may show deficits in acquiring information and may experience deficits in cognitive flexibility</p>

Ventral pallidum regulates the default mode network, controlling transitions between internally and externally guided behavior

Daily life requires transitions between performance of well-practiced, automatized behaviors reliant upon internalized representations and behaviors requiring external focus. Such transitions involve differential activation of the default mode network (DMN), a group of brain areas associated with inward focus. We asked how optogenetic modulation of the ventral pallidum (VP), a subcortical DMN node, impacts task switching between internally to externally guided lever-pressing behavior in the rat. Excitation of the VP dramatically compromised acquisition of an auditory discrimination task, trapping animals in a DMN state of automatized internally focused behavior and impairing their ability to direct attention to external sensory stimuli. VP inhibition, on the other hand, facilitated task acquisition, expediting escape from the DMN brain state, thereby allowing rats to incorporate the contingency changes associated with the auditory stimuli. We suggest that VP, instant by instant, regulates the DMN and plays a deterministic role in transitions between internally and externally guided behaviors.

Association between motor task acquisition and hippocampal atrophy across cognitively unimpaired, amnestic Mild Cognitive Impairment, and Alzheimer's disease individuals

Hippocampal atrophy is a widely used biomarker for Alzheimer's disease (AD), but the cost, time, and contraindications associated with magnetic resonance imaging (MRI) limit its use. Recent work has shown that a low-cost upper extremity motor task has potential in identifying AD risk. Fifty-four older adults (15 cognitively unimpaired, 24 amnestic Mild Cognitive Impairment, and 15 AD) completed six motor task trials and a structural MRI. Motor task acquisition significantly predicted bilateral hippocampal volume, controlling for age, sex, education, and memory. Thus, this motor task may be an affordable, non-invasive screen for AD risk and progression.

Early Sensory Deprivation Leads to Differential Inhibitory Changes in the Striatum During Learning

The corticostriatal circuit has been identified as a vital pathway for associative learning. However, how learning is implemented when the sensory striatum is permanently impaired remains unclear. Using chemogenetic techniques to suppress layer five auditory cortex (AC) input to the auditory striatum, learning of a sound discrimination task was significantly impacted in freely moving Mongolian gerbils, in particular when this suppression occurs early on during learning. Whole-cell recordings sampled throughout learning revealed a transient reduction in postsynaptic (GABAA) inhibition in both striatal D1 and D2 cells in normal-hearing gerbils during task acquisition. In contrast, when the baseline striatal inhibitory strengths and firing rates were permanently reduced by a transient period of developmental sensory deprivation, learning was accompanied by augmented inhibition and increased firing rates. Direct manipulation of striatal inhibition in vivo and in vitro revealed a key role of the transient inhibitory changes in task acquisition. Together, these results reveal a flexible corticostriatal inhibitory synaptic plasticity mechanism that accompanies associative auditory learning.

Basal forebrain cholinergic neurons selectively drive coordinated motor learning in mice

Motor control requires precise temporal and spatial encoding across distinct motor centers that is refined through the repetition of learning. The coordination of circuit refinement across motor regions requires modulatory input to shape circuit activity. Here we identify a role for the basocortical cholinergic pathway in the acquisition of a coordinated motor skill in mice. Targeted depletion of basal forebrain cholinergic neurons results in significant impairments in training on the rotarod task of coordinated movement. Cholinergic neuromodulation is required during training sessions as chemogenetic inactivation of cholinergic neurons also impairs task acquisition. Rotarod learning drives coordinated refinement of corticostriatal neurons arising in both medial prefrontal cortex (mPFC) and motor cortex, and we have found that cholinergic input to both motor regions is required for task acquisition. Critically, the effects of cholinergic neuromodulation are restricted to the acquisition stage, as depletion of basal forebrain cholinergic neurons after learning does not affect task execution. Our results indicate a critical role for cholinergic neuromodulation of distant cortical motor centers during coordinated motor learning.

Temporal regulation of motor behavior on a modified forelimb dexterity test in mice

ABSTRACTHand and arm manual dexterity is a hallmark of humans and non-human primates. While rodents are less dexterous than primates, they provide powerful models for testing neural circuit function in behavioral output, including dexterous behaviors. In rodents, the single pellet reach task has been used extensively to study both dexterous forelimb motor learning as well as recovery from injury; however, mice exhibit high variability in task acquisition in comparison to rats and a significant percentage fail to learn the task. We have created a recessed version of the task that requires greater dexterity. This subtle modification increases both task difficulty as well as the proportion of mice that show an improvement with training. Furthermore, motor cortex inactivation shows a greater effect on the execution of the recessed forelimb reach task, with distinct effects on reach targeting vs grasping components depending on the timing of inhibitory activation. Kinematic analysis revealed differences in reach targeting upon transient cortical inhibition prior to reach onset. In summary, the recessed single pellet reach task provides a robust assessment of forelimb dexterity in mice and a tool for studying skilled motor acquisition and execution.

Acetylcholine is released in the basolateral amygdala in response to predictors of reward and enhances the learning of cue-reward contingency

The basolateral amygdala (BLA) is critical for associating initially neutral cues with appetitive and aversive stimuli and receives dense neuromodulatory acetylcholine (ACh) projections. We measured BLA ACh signaling and activity of neurons expressing CaMKIIα (a marker for glutamatergic principal cells) in mice during cue-reward learning using a fluorescent ACh sensor and calcium indicators. We found that ACh levels and nucleus basalis of Meynert (NBM) cholinergic terminal activity in the BLA (NBM-BLA) increased sharply in response to reward-related events and shifted as mice learned the cue-reward contingency. BLA CaMKIIα neuron activity followed reward retrieval and moved to the reward-predictive cue after task acquisition. Optical stimulation of cholinergic NBM-BLA terminal fibers led to a quicker acquisition of the cue-reward contingency. These results indicate BLA ACh signaling carries important information about salient events in cue-reward learning and provides a framework for understanding how ACh signaling contributes to shaping BLA responses to emotional stimuli.

Dog–Human Play, but Not Resting Post-Learning Improve Re-Training Performance up to One Year after Initial Task Acquisition in Labrador Retriever Dogs: A Follow-On Study

Arousing and emotional situations can improve cognitive performance and the memorability of events. Recently, the enhancement of training performance in Labrador Retriever dogs through 30 min of dog–human play immediately after acquiring a novel task, when compared to a resting period, was demonstrated. This follow-on study used the same pseudo-randomized, counterbalanced, between-subject study design, and 11 Labrador Retrievers were re-trained in the identical two-choice discrimination paradigm after a period of 1 year. The playful activities group needed significantly less trials and made significantly less errors to successfully reach the re-training criterion (Mann–Whitney U test, critical value of U at p < 0.05 is 5, U = 5, Z = 1.73, p = 0.04 and U = 4.5, Z = 1.8, p = 0.03, respectively). Following model simplification of a multiple factor/covariate general linear model analysis, the type of intervention, the number of trials needed to re-learn the task after 24 h, the average heart rate during the intervention a year ago, and age were significantly correlated to the number of trials and errors needed to resolve the task. A significant difference due to intervention allocation (heart rate during the intervention, trials needed to re-learn the task after 24 h) between the groups was confirmed. Age did not significantly differ between the groups; nevertheless, the effects of ageing cannot be fully excluded, given the low sample size. No effects of the trainer and of the cortisol concentrations (of the previous year) were observed. This is the first evidence that post-training activity may influence memory up to 1 year after task acquisition.