Lehmann, Hugo

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

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

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

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

Memories pertaining to fearful events are some of the most salient and long-lasting memories, as they are critical to the survival of an organism. Seizures induce aberrant changes within temporal lobe and limbic brain structures that are critical for supporting fear memories. Seizures can occur at any time; therefore, it is imperative that research address how seizures impact previously learned information. The present series of experiments demonstrate that pentylenetetrazol-kindling induces retention deficits of previously acquired context fear memories in male rats. Kindling induced subsequent fear learning deficits but did not impact spatial learning. Additionally, following kindling, volumetric increase was observed within the hippocampal subfield CA3, as well as increased neural activation within the hippocampal subfield CA1. The results of this work suggests that chronic seizures can alter the function of neural networks important for supporting and retrieving previously acquired memories.

Author Keywords: amygdala, anterograde amnesia, context fear conditioning, hippocampus, retrograde amnesia, seizures

Damage to the hippocampus (HPC) typically causes retrograde amnesia for contextual fear conditioning. Reinstating the conditioning over several sessions, however, can mitigate the retrograde amnesic effects. Reinstatements, thus, establish a sufficiently strong memory in non-HPC systems to no longer require the HPC for expression, meaning that it has become HPC independent. This thesis aimed to determine the structures comprising the non-HPC system supporting reinstated context fear memory. The contribution of the perirhinal cortex (PRH) and the anterior cingulate cortex (ACC) were examined because of their established role in context memory. Initially, it was demonstrated that HPC damage indeed causes retrograde amnesia for single session, but not reinstated, contextual fear conditioning. Then, it was demonstrated that combined HPC and PRH damage causes retrograde amnesia for reinstated contextual fear conditioning, whereas combined HPC and ACC damage had lesser effects. Therefore, the PRH is a key structure within the non-HPC memory system for reinstated context fear memory.

Author Keywords: anterior cingulate cortex, contextual fear conditioning, hippocampus, memory, perirhinal cortex, retrograde amnesia

After active tool-use visual stimuli near a tool are processed more quickly and accurately than those farther away from a tool. Can these near-tool effects be modulated by training demands? To investigate this we asked the participants to complete a tool training task followed by a cross-modal interference task. During the training task the participants performed quick and accurate pointing movements to reach a strict or moderate criterion. The results indicated that the strict group made faster movements than the moderate group. During the cross-modal interference task visual distractors were presented along handheld tools in conjunction with vibrotactile stimuli on the hand. No significant compatibility effects were found for visual distractors near the hand or tool tip, and no consistent group differences were found. Our findings demonstrate the importance of using a novel tool during training, and that virtual stimuli may not be effective to elicit near-tool effects.

Author Keywords: bimodal neurons, cross-modal interference, near-tool effects, tool training, training demands

The assessment of visuomotor function can provide important information about neurological status. Several visuomotor tasks exist for testing in the laboratory, although attempts to make these tests portable to allow quick and reliable assessment have been limited. We developed an assessment tool using two laboratory visuomotor tests as a tablet application: the double-step task, and an interception task. Performance was assessed by measuring the participants' ability to reach toward unpredictably moving targets in each task. Response patterns were compared across equipment types to determine if participants were responding similarly to the moving targets in the standard laboratory and the tablet version of the tasks. On the double-step task, participants adjusted to the displaced target adequately in both the lab and tablet versions. On the interception task, participants intercepted non-accelerating targets, and performed worse on accelerating targets in both versions of the task. These findings suggest that the tablet version of these tasks assesses similar visuomotor processing as the respective laboratory version.

Author Keywords: concussion assessment, double-step task, interception task, visuomotor processing, visuomotor system