Melvin, Neal
Bridging Behaviour and Mechanism in Relief Learning in Rats: A Combined Behavioural, Molecular, and Chemogenetic Approach
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
Impaired contextual fear discrimination learning after long-term amygdala kindling
Cognitive impairments, such as memory loss, are a frequent and devastating co-morbidity associated with epilepsy. The neurobiological mechanisms through which recurrent seizures induce cognitive impairments are not well understood. New neurons born after seizures develop abnormal morphological and functional characteristics that promote network hyperexcitability and hippocampal dysfunction. Previously, we found that kindling dramatically increases the rate of neurogenesis at early stages of seizure development, followed by a long-term suppression at later stages. These changes in the rate of cell proliferation coincides with aberrant modifications in the migration, excitability, and functional integration of these new neurons. It has been suggested that the long-term consequences of seizure-induced neurogenesis contributes to the development of cognitive impairment seen in chronic epilepsy. However, direct experimental evidence has been limited. The present series of experiments sough to determine if blocking aberrant seizure-induced neurogenesis can reduce cognitive deficits associated with chronic epilepsy. Our findings suggest that chronic seizures impair the ability of rats to differentiate between similar contexts. In addition, blocking aberrant seizure-induced neurogenesis through treatment with the cytotoxic agent temozolomide was capable of preventing some of the deficits in context discrimination learning when neurogenesis levels were reduced to non-epileptic control levels. This research provides further support of targeting aberrant neurogenesis as a novel treatment to restore cognitive functioning in individuals living with epilepsy.
Author Keywords: Amygdala kindling, Dentate gyrus, Hippocampus, Neurogenesis, Pattern separation, Seizures