Memory reconsolidation in aversive and appetitive settings

Memory reconsolidation has been observed across species and in a number of behavioral paradigms. The majority of memory reconsolidation studies have been carried out in Pavlovian fear conditioning and other aversive memory settings, with potential implications for the treatment of post-traumatic stress disorder. However, there is a growing literature on memory reconsolidation in appetitive reward-related memory paradigms, including translational models of drug addiction. While there appears to be substantial similarity in the basic phenomenon and underlying mechanisms of memory reconsolidation across unconditioned stimulus valence, there are also notable discrepancies. These arise both when comparing aversive to appetitive paradigms and also across different paradigms within the same valence of memory. We review the demonstration of memory reconsolidation across different aversive and appetitive memory paradigms, the commonalities and differences in underlying mechanisms and the conditions under which each memory undergoes reconsolidation. We focus particularly on whether principles derived from the aversive literature are applicable to appetitive settings, and also whether the expanding literature in appetitive paradigms is informative for fear memory reconsolidation

Neurobiological mechanisms of conflict resolution and goal-directed behaviour

This thesis investigated theories regarding the neurobiological substrates of conflict resolution in rodents. An operant biconditional discrimination task was used that modelled elements of response conflict similar to that observed in the human Stroop task. Correct performance required the use of incidental (context) cues to guide performance during compound cues that signalled conflicting responses. This task was used to test hypotheses related to the role of dopamine, the frontal cortex and hippocampus in conflict resolution. In addition, a transgenic mouse model of frontotemporal dementia (tau V337M) was used to assess the effects of this mutation on frontal cortex-dependent conflict resolution. The first set of experiments examined the effects of dopaminergic agonists (d- amphetamine and phencyclidine) on conflict resolution in rats. It was found that the modulation of dopamine tone generally disrupted conditional responding as opposed to selectively disrupting conflict resolution. In order to understand how genetic models of human frontal cortex disorders influence conflict resolution, the conflict task was successfully adapted for use with mice. Lesions of the prefrontal cortex in mice selectively disrupted the use of context cues to resolve response conflict. Hippocampal lesions, however, did not disrupt contextual control of response conflict. In contrast to predictions, mice with the tau V337M mutation linked to frontotemporal dementia were not impaired at conflict resolution. However, these mice were impaired in acquisition of a spatial navigation task, indicative of abnormal hippocampal function. In summary, this thesis provides evidence that rats and mice are able to use incidental contextual cues to influence responding during situations in which punctate cues signal conflicting responses. Modulation of dopamine did not influence response conflict in this paradigm. Nevertheless, conflict resolution was reliant upon an intact frontal cortex (but not hippocampus) in rodents. Surprisingly, a mouse genetic model of frontotemporal dementia did not impair conflict resolution but did impair elements of the associative structures supporting performance

The prefrontal cortex and obesity: a health neuroscience perspective

The level of activity within an individual’s prefrontal cortex seems to be critical to dietary self-control and the likelihood of overconsumption and obesity. Lower activity can make individuals more vulnerable to the appeal of calorie-rich foods. Sustained overconsumption and obesity can cause changes in the prefrontal cortex that further discourage dietary self-regulation, creating a reciprocal relationship that reinforces the poor dietary choices and encourages overconsumption.https://ir.lib.uwo.ca/brainscanresearchsummaries/1000/thumbnail.jp

Appetitive Pavlovian goal-tracking memories reconsolidate only under specific conditions

Despite extensive evidence that appetitive memories undergo reconsolidation, two notable failures to observe reconsolidation have been reported: instrumental responding and goal-tracking. However, these studies do not provide conclusive evidence for a lack of memory reconsolidation due to the numerous boundary conditions that dictate whether a memory will undergo reconsolidation. In this study we sought to reexamine reconsolidation in an appetitive, Pavlovian conditioned approach procedure and the behavioral boundary conditions within which memories are destabilized and reconsolidated. This study demonstrated that a Pavlovian goal-tracking memory, previously thought to be resistant to destabilization, will undergo memory reconsolidation under discrete conditions that favor reconsolidation as opposed to extinction, and that this is dependent on the amount of training rats received. With restricted training, systemic administration of MK-801 impaired memory extinction. In contrast, with more extended training, MK-801 administration impaired memory reconsolidation. We also demonstrate that behavioral boundary conditions that exist for appetitive memory reconsolidation are much more complex than simple parametric calculations. Moreover, extinction per se is not a boundary on reconsolidation, in that MK-801 also has no behavioral effect under some conditions.</jats:p

Mouse Performance on a Novel Touchscreen Continuous Performance Task is Dependent on Signaling in the Prelimbic Cortex

Attention is the cognitive processing that facilitates the ability to target and attend to relevant environmental stimuli, while filtering out irrelevant or distracting stimuli. Control over selective attention is theorized to be dependent on organized neural communication that stems from the medial prefrontal cortex (mPFC). To evaluate selective and sustained attention, mice were trained on the novel touchscreen rodent continuous performance task (rCPT), a task designed to emulate the human CPT. In the rodent version, images are continuously presented on a touchscreen, where mice have been trained to selectively respond to one image type while suppressing responses to all others. Following training on the rCPT, bilateral cannulas were implanted into the prelimbic region of the mPFC. Immediately prior to cognitive testing, a mixture of GABA A and B agonists were infused into the prelimbic to temporarily inactivate the structure. Inactivating the prelimbic cortex significantly impaired performance on this task, resulting in a reduced ability to discriminate the target from non-target images, as well as a reduction in speed and overall responding. Currently, mice expressing optogenetic receptors are being used to evaluate how parvalbumin interneuron activity within the prelimbic cortex influences attentional performance on the rCPT. As the parvalbumin interneuron population is heavily implicated in generating coordinated neuronal activity and supporting cognition, it is predicted that inhibiting these interneurons and altering synchronous prelimbic activity will impair rCPT performance

Functional dissociation of behavioral effects from acetylcholine and glutamate released from cholinergic striatal interneurons

In the striatum, cholinergic interneurons (CINs) have the ability to release both acetylcholine and glutamate, due to the expression of the vesicular acetylcholine transporter (VAChT) and the vesicular glutamate transporter 3 (VGLUT3). However, the relationship these neurotransmitters have in the regulation of behavior is not fully understood. Here we used reward-based touchscreen tests in mice to assess the individual and combined contributions of acetylcholine/glutamate co-transmission in behavior. We found that reduced levels of the VAChT from CINs negatively impacted dopamine signalling in response to reward, and disrupted complex responses in a sequential chain of events. In contrast, diminished VGLUT3 levels had somewhat opposite effects. When mutant mice were treated with haloperidol in a cue-based task, the drug did not affect the performance of VAChT mutant mice, whereas VGLUT3 mutant mice were highly sensitive to haloperidol. In mice where both vesicular transporters were deleted from CINs, we observed altered reward-evoked dopaminergic signalling and behavioral deficits that resemble, but were worse, than those in mice with specific loss of VAChT alone. These results demonstrate that the ability to secrete two different neurotransmitters allows CINs to exert complex modulation of a wide range of behaviors

A novel translational assay of response inhibition and impulsivity: effects of prefrontal cortex lesions, drugs used in ADHD, and serotonin 2C receptor antagonism

Animal models are making an increasing contribution to our understanding of the psychology and brain mechanisms underlying behavioral inhibition and impulsivity. The aim here was to develop, for the first time, a mouse analogue of the stop-signal reaction time task with high translational validity in order to be able to exploit this species in genetic and molecular investigations of impulsive behaviours. Cohorts of mice were trained to nose-poke to presentations of visual stimuli. Control of responding was manipulated by altering the onset of an auditory ‘stop-signal’ during the go response. The anticipated systematic changes in action cancellation were observed as stopping was made more difficult by placing the stop-signal closer to the execution of the action. Excitotoxic lesions of medial prefrontal cortex resulted in impaired stopping, whilst the clinically effective drugs methylphenidate and atomoxetine enhanced stopping abilities. The specific 5-HT2C receptor antagonist SB242084 also led to enhanced response control in this task. We conclude that stop-signal reaction time task performance can be successfully modelled in mice and is sensitive to prefrontal cortex dysfunction and drug treatments in a qualitatively similar manner to humans and previous rat models. Additionally, using the model we show novel and highly discrete effects of 5-HT2C receptor antagonism that suggest manipulation of 5-HT2C receptor function may be of use in correcting maladaptive impulsive behaviors and provide further evidence for dissociable contributions of serotonergic transmission to response control