Neurosciences

Pain conditions occur at an increasing rate alongside people with temporal lobe epilepsy (TLE) and can include chronic headaches, migraines, and neuropathic pain. In order to begin to understand the concurrence, this experiment aimed to investigate the effect of long-term amygdala kindling, a model of TLE, on the affective and nociceptive components of pain in rats. Formalin-induced affective avoidance was investigated using the conditioned place aversion (CPA) test and found aversion in kindled, but not sham rats. Nociceptive behaviours were observed using the formalin test and found a peripheral reduction of pain, that persisted one-week following the last stimulation in kindled rats. Lower activation of c-Fos in the periaqueductal gray was seen in kindled rats, while no changes in protein kinase C δ activation was found. Amygdala kindling contributed to pain sensitivity changes that persisted into the interictal period, and male and female pain trends were found, requiring further investigation.

Author Keywords: affective pain, amygdala, amygdala kindling, formalin, nociceptive pain, periaqueductal gray

Stress can significantly affect neurobiological processes crucial for learning and memory. While repeated stress enhances fear memory, it impairs memory retrieval. In most studies, however, stress exposure typically preceded fear and extinction learning. Thus, the impact of previously acquired memories formed before exposure to stress is not well understood. The goal of this thesis is to examine how acute stress impacts the ability to retrieve previously acquired fear memories. The results showed that stress impaired recall of recent fear memories, but stress seven days after conditioning did not affect memory retrieval. Analysis of c-Fos expression revealed increased neuronal activity in the medial prefrontal cortex (mPFC) of rats exposed to stress. Additionally, stress exposure decreased mRNA expression of Reelin, a glycoprotein in the mPFC. Notably, administering recombinant Reelin improved fear memory recall. These findings highlight potential pathways for research and interventions on stress-induced memory impairments.

Author Keywords: c-Fos expression, Fear memory, Medial prefrontal cortex, Memory retrieval, Reelin, Stress

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

Freezing is a debilitating phenomenon that reduces quality of life for people withParkinson's disease (PwPD). This study tests the hypothesis that: 1) freezing is linked to executive dysfunction; 2) freezing is a global motor phenomenon, not limited to gait. We compared 14 PwPD to 16 controls. Several aspects of executive function were measured using pro- and anti-saccade tasks under gap and overlap timing conditions, where the gap effect is defined as the reduction in saccade latency associated with the removal of fixation before target presentation. As predicted, results showed larger anti-saccade gap effects in PwPD with than without FOG, and that the pro-saccade gap effect predicted FOG severity in PwPD with FOG. PwPD also demonstrated impaired performance on reaching and walking tasks designed to elicit freezing. These findings strengthen the evidence that executive dysfunction, measured by saccade tasks, is linked to freezing in PwPD.

Author Keywords: executive function, eye movements, freezing of gait, freezing of upper limbs, Parkinson's disease

Stress during adolescence has profound effects on psychological, behavioral, and neurobiological outcomes in adulthood. This study investigates the impact of adolescent stress on safety learning, anxiety- and depressive-like behaviors, and associated neurocircuitry using a rat model. Adolescent male Long Evans rats underwent an unpredictable intermittent stress regimen, followed by behavioral testing and immunohistological analyses in adulthood. It was confirmed that stress impaired safety learning and increased fear generalization. Behavioral assays revealed heightened anxiety- and depressive-like phenotypes in stressed rats, evidenced by reduced open-arm exploration in the elevated plus maze and increased immobility in the forced swim test, although limited changes in sucrose preference were noted during habituation. Immunohistological findings showed reductions in hippocampal neurogenesis (DCX+ cells) and disruptions in GABAergic interneuron plasticity (PV+/PNN+ populations) within the medial prefrontal cortex. These alterations suggest that adolescent stress leads to long-term changes in brain regions associated with emotional regulation and stress resilience.

Author Keywords: Adolescencent Stress, Anxiety-like Behaviour, Hippocampus, Medial Prefrontal Cortex, Neuroplasticity, Safety Learning

Damage to the hippocampus (HPC) causes retrograde amnesia for some memories, but spaced learning mitigates this. Contextual fear conditioning (CFC) studies in rats demonstrate that distributing conditioning over multiple sessions makes a memory less vulnerable to HPC damage, and it has been suggested this occurs through incremental strengthening of the memory outside the HPC via separate bouts of cellular consolidation. To explore this, we examined the number of, and temporal intervals between, spaced CFC sessions required to make a memory less vulnerable to HPC damage. Experiment 1 established six sessions spaced over three days as sufficient to create a memory no longer requiring the HPC. Experiments 2 and 3 found that spacing those six sessions in a single day also created a memory no longer requiring the HPC, but only when the sessions were separated by an interval believed to be sufficient for separate bouts of cellular consolidation to occur.

Author Keywords: consolidation, context fear, hippocampus, memory, retrograde amnesia, spaced learning

It is well known that pain can heighten sensitivity to stimuli that signal threat in most species. In rodents, exposure to predator odor, such as 2,5-dihydro-2,4,5-trimethylthiazoline (TMT), induces anxiety and alters pain sensitivity. This study explored the effect of predator odor stress on mechanical pain sensitivity in a rat model of acute inflammatory pain induced by suboptimal doses of Complete Freund's Adjuvant (CFA). Male Sprague-Dawley rats were injected intraplantarly with 50% or 25% (v/v) of CFA in the hindpaw and then exposed the next day to 5 minutes of either 10% TMT (synthetic fox urine) or a neutral odor. Both groups showed reduced paw withdrawal thresholds in the von Frey test. However, TMT-exposed rats displayed persistent mechanical hypersensitivity, which never returned to baseline (pre-CFA) levels when compared to CFA-rats exposed to the neutral odor or control rats exposed to TMT. In addition, TMT exposure after CFA induced greater anxiety-like behavior in the elevated plus maze without affecting locomotor activity in the open field or altering learned responses in a backward paired shock-tone conditioning task. Finally, systemic administration of a CCK2 antagonist before exposure to TMT partially rescued the mechanical hypersensitivity in these animals but had little effect on CFA-treated rats exposed to the neutral odor. These results suggest that naturalistic stress can lead to a long-lasting nociceptive sensitization that extends beyond the duration of the initial inflammatory injury. Our findings also highlight the importance of CCK2 signaling as a potential mediator of and therapeutic target for stress-induced pain hypersensitivity.

Author Keywords: allodynia, CCK, CFA, mechanical sensitivity, stress, TMT

ABSTRACT Patients who undergo chemotherapy often complain of a persistent 'brain fog' that can be present up to years after treatment ends. This fog is expressed as marked impairments in areas of learning, memory and mental health. As it stands, researchers have yet to determine the mechanism at fault for these impairments. The present experiment investigates if the neurogenesis that takes place in the subgranular zone of the hippocampus is suppressed as a result of chemotherapy treatment, and results in these impairments. In the following thesis, two models of chemotherapy are used to explore the treatment effects on Long-Evans rats. From here, three behavioural assessments and three measures of immunohistochemical techniques are used to explore the effects of Temozolomide on memory and anxious behaviour. Our findings support the current literature that suggests that Temozolomide suppresses adult hippocampal neurogenesis and results in cognitive and emotional impairments.

Author Keywords: adult hippocampal neurogenesis, Chemotherapy, Chemotherapy-Induced Cognitive Impairment, CICI, Long-Evans rats, Temozolomide

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

ABSTRACT Patients who undergo chemotherapy often complain of a persistent 'brain fog' that can be present up to years after treatment ends. This fog is expressed as marked impairments in areas of learning, memory and mental health. As it stands, researchers have yet to determine the mechanism at fault for these impairments. The present experiment investigates if the neurogenesis that takes place in the subgranular zone of the hippocampus is suppressed as a result of chemotherapy treatment, and results in these impairments. In the following thesis, two models of chemotherapy are used to explore the treatment effects on Long-Evans rats. From here, three behavioural assessments and three measures of immunohistochemical techniques are used to explore the effects of Temozolomide on memory and anxious behaviour. Our findings support the current literature that suggests that Temozolomide suppresses adult hippocampal neurogenesis and results in cognitive and emotional impairments.

Author Keywords: adult hippocampal neurogenesis, Chemotherapy, Chemotherapy-Induced Cognitive Impairment, CICI, Long-Evans rats, Temozolomide