Fournier, Neil M.

Maladaptive fear can develop when nonthreatening stimuli are misinterpreted as dangerous. While fear extinction has been extensively studied, organisms can also learn safety through relief learning, in which cues signalling the termination of an aversive event acquire positive value. Although the medial prefrontal cortex (mPFC) is implicated in regulating responses to threat and safety cues, its role in relief learning remains unclear. In Experiment 1, I validated a relief conditioning paradigm in rats and demonstrated that relief-conditioned animals froze significantly less than fear-conditioned animals during retention. Experiment 2 revealed that relief learning selectively activated the prelimbic cortex (PrL). In Experiment 3, chemogenetic inhibition of the PrL reduced freezing across tones, supporting a causal role in relief expression. Experiment 4 demonstrated that extended training produced more stable and pronounced reductions in freezing than a one-day protocol. Together, these findings identify PrL circuits as key contributors to relief learning.Keywords: Maladaptive fear, relief learning, fear conditioning, medial prefrontal cortex (mPFC), fear extinction, rat model, behavioural freezing, Fos expression, neural circuitry, conditioned stimuli, aversive stimuli, neuroimaging.

Author Keywords: Conditioned stimuli, Fear condtioning, Maladaptive fear, Medial prefrontal cortex, Neural circuitry, Relief learning

To examine comorbid pain sensitivity, temporal lobe epilepsy was modeled with a 42-stimulation amygdala kindling paradigm using rats. Sham and kindled rats' mechanical allodynia was not different before the formalin conditioned place aversion (FCPA) test. FCPA behaviour was not different, but twenty-four hours later kindled rats showed mechanical allodynia. Thermal sensitivity 48 hours after FCPA was not different. A second experiment revealed no difference in pre- and interictal mechanical and thermal sensitivity. Kindled rats did display a higher frequency of pain behaviours in the formalin nociceptive test, and greater early growth response 1 expression in the anterior cingulate cortex (ACC). The final experiment examined FCPA behaviour of sham and kindled rats given an ACC infusion of control (EGFP), or inhibitory designer receptor exclusively activated by designer drug (hM4Di). Kindled-EGFP rats did not spend a different amount of time in either compartment but Kindled-hM4Di rats spent more time in the formalin-paired compartment.

Author Keywords: Affective Pain, Amygdala Kindling, Emotion, Epilepsy, Pain

Epilepsy is associated with a variety of cognitive, emotional, and pain-related symptoms, such as impaired memory and learning, increased risk of anxiety and depression, and increased pain sensitivity. Unfortunately, these symptoms are generally untreated with typical pharmacological interventions, which tend to target seizure activity (i.e., ictogenesis) and not the subsequent histopathological and behavioural alterations resulting from epilepsy (i.e., epileptogenesis). Evidence has demonstrated that targeting the endocannabinoid system can alleviate seizure symptoms as well as cognitive, emotional, and pain-related impairments independent of epilepsy. However, research examining the use of endocannabinoid-based treatment for these behavioural symptoms when they are associated with epilepsy is sparse. In the following thesis, two animal models of epilepsy, several behavioural assessments, and immunohistochemical techniques are utilized to assess the effectiveness of endocannabinoid-based treatment for epilepsy's interictal symptoms. The findings expand our knowledge and offer encouraging evidence for the usefulness of endocannabinoid-based treatment as an epileptogenesis-targeting pharmacological intervention.

Author Keywords: animal models, endocannabinoid system, histopathological alterations, interictal symptoms, temporal lobe epilepsy, treatment