Résumé indisponible. / Twelve percent of the world population suffers from migraine and its cost is estimated at $18 billion per year in Europe. The frequency of attacks may increase over time in some migraineurs, evolving from episodic migraine (0 to 14 days of migraine/month) to chronic migraine (more than 15 days of migraine/month). Propranolol is one of the major prophylactic treatments of migraine, used to decrease the frequency of the attacks. However, its mechanism of action is largely unknown. Thus, using an animal model of repeated chemical stimulation of the dura, along with behavioural, electrophysiological, and immunohistochemical approaches, we assessed the prophylactic effect of per os propranolol on central sensitisation. It was able to prevent (i) the aggravation and persistence of central sensitisation as well as (ii) the alteration of descending controls of pain (iii) dural stimulation-induced activation of the locus coeruleus (LC). Recording simultaneously from Sp5C and LC then allowed us to demonstrate that (iv) LC integrates both cutaneous and meningeal nociceptive information and (v) LC exerts a facilitatory effect on Sp5C excitability, while in pathological conditions, (vi) integration of trigeminal nociception by LC was decreased while (vii) the modulation of Sp5C by LC was altered. We then tested the effect on central sensitisation of propranolol microinjection in the LC. It (viii) prevented central sensitisation but (ix) couldn’t reverse it. Finally, we investigated the mechanism of action of propranolol in the LC; the results suggested that (x) propranolol alters intrinsic properties of LC, thereby dampening its ability to facilitate Sp5C. In conclusion, our results revealed the facilitatory influence of the LC on trigeminal nociception, suggesting that the LC could play a facilitating role in triggering migraine headaches.

Acute and chronic methylphenidate (MPD) administration was recorded simultaneously in freely moving adolescent rats previously implanted with permanent semi-microelectrodes using telemetric wireless technology for the rat's locomotor activity and for the locus coeruleus (LC) neuronal activity. The evaluation of neuronal events was separated based on the rat's behavioral response to chronic MPD exposure, with rats eliciting behavioral sensitization or behavioral tolerance. On experimental day (ED) 1, the locomotor and neuronal activity was recorded after saline (baseline) and MPD (0.6, 2.5, or 10.0 mg/kg) injection (i.p.). The rats were administered daily with a single dose of MPD for five consecutive days (ED2-ED6) to elicit behavioral sensitization or behavioral tolerance. Following three washout days with no drugs, the locomotor and neuronal activity recordings resumed on ED10 post saline and rechallenge MPD administration. The main findings were as follows. The same dose of chronic MPD administration elicited behavioral sensitization in some rats and behavioral tolerance in other rats. A total of 51.5%, 56.6%, and 86.3% of LC units responded significantly to acute 0.6, 2.5, and 10.0 mg/kg MPD respectively. A total of 51.5%, 72.4%, and 82.3% of LC units responded significantly by changing their baseline activity on ED10 compared to that on ED1 in 0.6, 2.5, and 10.0 mg/kg MPD dose groups respectively. A total of 53%, 67.1%, and 90.2% of LC units responded significantly to chronic 0.6, 2.5, and 10.0 mg/kg MPD respectively. The LC neuronal population recording following acute MPD on ED1 and rechallenge MPD on ED10 from the rats eliciting behavioral sensitization was significantly different from the neuronal population recorded from the rats eliciting behavioral tolerance. Overall, these findings show that the same dose of chronic MPD can elicit behavioral sensitization or behavioral tolerance. We were able to verify our hypothesis that the LC units recorded from the rats eliciting behavioral sensitization responded significantly different to MPD from the rats eliciting behavioral tolerance. This correlation suggests that LC neuronal activity plays an important role in the expression of behavioral sensitization and behavioral tolerance by chronic MPD exposure.

The ‘synaptic tagging-and-capture’ (STC) theory of cellular memory consolidation holds that memory persistence can be altered by prior or subsequent patterns of neural activity (Redondo & Morris 2011). The aim of this thesis was to develop a realistic model of everyday memory for mice and use the optogenetic toolbox to investigate the neuromodulatory circuitry that modulates persistence of everyday spatial memories. The task involved learning a win-stay rule with the daily goal of finding the location of food in the event arena. Using the developed task, it was confirmed that unrelated novel experiences can facilitate the persistence of spatial memory in a manner sensitive to pharmacological blockade of hippocampal dopamine D1/D5 receptors. Further analysis focused on identifying the specific neuromodulatory systems that mediate this effect. An influential model called the ‘hippocampus- VTA loop’ (Lisman & Grace 2005) points to the critical role of dopaminergic neurons in the ventral tegmental area (VTA), but recent evidence also implicates locus coeruleus (LC) as a potential source of dopamine in the hippocampus (Smith & Greene 2012). In order to identify the dopaminergic structure(s) that may mediate the novelty effect on memory persistence, single unit activity of optogenetically identified catecholaminergic (CAergic) neurons in mouse VTA and LC was recorded in a novelty exploration paradigm. Using tyrosine hydroxylase-Cre knock-in mice and a Cre-dependent adeno-associated viral vectors, CAergic neurons in VTA and LC were selectively tagged with channelrhodopsin-2 (ChR2). Conditional ChR2 expression made it possible to reliably identify CAergic neurons during unit recording sessions in freely moving animals. The main conclusion of the study is that that CAergic neurons in both VTA and LC selectively increase their firing rates in novel environments, relative to both a familiar environment and a home cage baseline. When normalised to their average baseline firing rates, LC neurons are more strongly activated by novelty than VTA neurons. In the final experiment outlined in this thesis, another cohort of Th-Cre mice, in which ChR2 was expressed in CAergic neurons of both VTA and LC using a Cre-dependent adeno-associated virus, was trained on the everyday appetitive spatial memory task. ChR2-mediated photoactivation of CAergic neurons in LC but not in VTA 30 min after encoding, substituting for novelty, was successful in enhancing the persistence of memory. Paradoxically, the effect of optogenetic LC activation was blocked by hippocampal microinfusion of dopamine D1/D5 receptor antagonist but not β-adrenergic receptor antagonist. Results of experiments described in this thesis support the principle of STC theory and collectively indicate that dopamine released from hippocampal terminals of LC neurons mediates the novelty effect on memory persistence. Importantly, they also point to a more general of role of LC in gating of entry to long-term memory.

Thesis (Ph. D.)--University of Missouri--Columbia, 2000. / "May 2000." Typescript. Vita. Includes bibliographical references (leaves 166-187). Also available on the Internet.

The hippocampus (HPC) is a brain area in the medial temporal lobe involved in spatial navigation, as well as the formation of episodic memories. A subset of the principal cells of the HPC, known as place cells, are active in specific locations of an environment, called the place fields. Dorsal hippocampal area CA1 contains place fields that are known to change their firing during spatial tasks where animals learn the location of a reward, known as goal-oriented learning (GOL) – CA1 place fields shift toward rewarded locations. Previous studies suggest that this preferentially occurs at novel rewarded locations in a familiar environment, but the mechanism is unknown. The locus coeruleus (LC) is a neuromodulatory nucleus in the brainstem that projects throughout the brain and releases norepinephrine and a small amount of dopamine. Stimulating locus coeruleus-hippocampal area CA1 projections (LC-CA1) was recently shown to improve performance on spatial memory tasks. Since performance on the GOL task is correlated with the degree of overrepresentation of rewarded locations, we hypothesized that the LC-CA1 projection was involved in reward-related place field reorganization. Using in vivo two photon calcium imaging, we recorded the activity of the LC-CA1 projection during a head fixed GOL task with two phases – during the first phase, a water reward was presented in one location (RZ1), and in the second phase, it was moved to a novel location (RZ2). In the first phase of the task, the LC-CA1 axons were correlated with running, but in the second phase they showed an increase in activity preceding RZ2. To determine whether the LC-CA1 is involved in place field reorganization that normally occurs in RZ2, we optogenetically activated the projection just before RZ1, and saw a pronounced place field reorganization right before the reward. Conversely, inhibition of LC-CA1 at RZ2 attenuated place field reorganization at this site. Finally, LC-CA1 stimulation away from the reward did not lead to place field reorganization, indicating that the LC influences place field shifts in conjunction with other signals that are differentially active around rewards. A full account of the effects of neuromodulation should also include astrocytes, since they respond to neuromodulators with large calcium signals that may be able to affect the function of neurons. We also recorded HPC astrocyte calcium activity during different behavioral tasks. Astrocytes showed occasional large calcium signals, with some differences in synchronicity and activity levels between hippocampal layers and behavioral paradigms. Future studies should determine whether the LC-CA1 projection affects place fields directly by affecting neural activity, indirectly via astrocytes, or both.

Post-traumatic stress disorder (PTSD) is a psychiatric condition caused by exposure to a traumatic event. Veterans are at especially high risk of PTSD. In Canada, in a survey conducted in 2016, 16% of Regular Force Veterans released during 1998-2015 reported having PTSD, which is at least two times higher than the estimated prevalence rate in the general population. Individuals with PTSD experience a range of debilitating symptoms, such as the intrusion of unwanted and distressing memories, persistent flashbacks, hypervigilance and nightmares. The neuropathophysiological mechanisms underlying symptoms of PTSD are not well understood, which remains a significant barrier to developing effective treatments. Hallmark PTSD symptoms such as hyperarousal and sleep disturbances may be related to dysregulation of noradrenaline (NA), a neurotransmitter produced in the locus coeruleus (LC) known to modulate cognition, arousal and sleep. This thesis examines the possible associations between dysregulation in rapid-eye-movement (REM) sleep and dysfunction in NA-containing neurons in the LC among veterans with PTSD. Twenty-two operationally deployed veterans with a history of PTSD were recruited through the Royal Ottawa Mental Health Centre in Ontario, Canada. A novel, non-invasive neuroimaging method, neuromelanin-sensitive magnetic resonance imaging (NM-MRI), was used to detect a by-product of NA called neuromelanin (NM) in the LC of each participant. Then a contrast-to-noise ratio (CNR) was calculated to obtain a marker of the NA function. The LC was segmented into three subdivisions to assess whether the association between NM and REM sleep may differ across regions of the LC. As hypothesized, we observed different associations between NM and REM sleep across regions of the LC. After controlling for antidepressant usage, there was (i) a moderate, negative, significant correlation between the percentage of REM sleep and rostral LCCNR, r(19) = -.476, p = .029, (ii) a weak positive non-significant correlation between the percentage of REM sleep and caudal LCCNR, r(19) = .33, p = .145, and (iii) no significant correlation between REM sleep percentage and LCCNR in the middle LC, r(19) = -.04, p = .876. This thesis is the first study to show that NM and REM sleep may be related in veterans with PTSD and that this relationship may vary across subdivisions of the LC. These results improve understanding of REM sleep among individuals with PTSD. The results may stimulate the investigation of novel pharmacotherapy focused on sleep disturbances in PTSD, the development of personalized treatments for PTSD, and the search for clinical biomarkers of PTSD based on brain function. The current study also made methodological contributions that may be applicable beyond the research on PTSD to the field of REM sleep and the NA system. Specifically, the current study showed the suitability of the NM-MRI method for examining the connections between NM and REM sleep, and it showed that segmenting the LC can lead to a more nuanced understanding of its role in the human body.

Thesis (Ph. D.)--University of Missouri--Columbia, 2000. / Typescript. Vita. Includes bibliographical references (leaves 166-187). Also available on the Internet.

Chronic Traumatic Encephalopathy (CTE) is a neurodegenerative disease that is associated with repetitive traumatic brain injury like those sustained in sport, military combat, and other activities with repetitive head impact exposure. Repetitive head impacts typically cause mild traumatic brain injury (mTBI) resulting in both concussive and subconcussive injury. Repeated mTBIs injuries appear to cause an abnormal accumulation of proteins, including hyperphosphorylated tau (p-tau) and TDP-43, progressive axonal failure with gradual structural degradation, microvascular disruption, breach of blood-brain barrier, neuroinflammation and microglial activation; each of these manifestations lead to axonal degeneration and neuronal death, which impairs neuronal pathways and are likely to give rise to CTE symptoms. CTE can be microscopically characterized mainly by p-tau accumulation in perivascular spaces and at the depths of the cortical sulci. Clinical presentation of CTE may include behavioral, mood, cognitive, or motor symptoms. Some of the common symptoms include impulsivity, aggression, anxiety, depression, memory impairment, dementia, and suicidality. The Locus Coeruleus (LC), a nucleus in the pons of the brainstem, is suspected to be involved in CTE. The LC provides the main source of norepinephrine to the entire brain and is critical for its control over arousal, behaviors, attention, and memory. Dysfunction of the locus coeruleus has shown to cause a wide array of symptoms, many of which are similar to those seen in CTE. Furthermore, the LC is affected in many other neurodegenerative diseases and is believed to be responsible for the progressive and widespread nature of the various diseases and their clinical symptoms. Although the LC has been implicated in CTE there have been no studies examining LC pathology in relation to the disease progression or its symptoms. We hypothesize LC CTE pathology should increase with the severity of CTE. Furthermore, increased CTE pathology in the LC should create disturbances to the LC and the LC-NE system and manifest clinically. Specifically, LC CTE pathology may be associated with age of onset of general behavioral and cognitive symptoms as well as individual symptoms and outcomes including impulsivity, depression, depressed mood and death by suicide. To determine this, a postmortem study was performed on 184 individuals with a history of RHI and no comorbid diseases examining the relationship between AT8-immunopositive tau density in the LC and various clinical variables. The study found that LC AT8 density showed a significant positive correlation with duration of repetitive head impact (RHI) exposure when controlled for age. There also was a significant increase in LC AT8-immunoreactive tau in cases with stage III and IV CTE compared to those with no CTE and stage I and II CTE, and AT8 density was predictive of CTE stage when controlled for age. There were no significant relationships found between density of LC AT8-immunoreactive tau and age of any CTE symptom onset or individual symptom (impulsivity, depressed mood, MDD, death by suicide) presence. Future studies should continue to evaluate CTE pathology in the LC and its effects on both the pathological and clinical characteristics of the disease.

Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 4 uppsatser.

Thesis (doctoral)--Rijksuniversiteit te Groningen.