Browsing by Author "Thompson, Roger J."

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    Assessing Functional Roles for Synaptic Scaling and Local Processing in CRHPVN Neurons
    (2019-08-30) Rasiah, Neilen Paul; Bains, Jaideep; Beique, Jean-Claude; Wilson, Richard J. A.; Thompson, Roger J.; Teskey, G. Campbell
    The brain, comprised of billions of neurons in highly-interconnected networks, receives information about the environment and the organism’s internal state, and makes ongoing adjustments that allow for optimum function and information storage. These adjustments, if inappropriately managed, can also destabilize neural networks, resulting in pathology. This thesis is primarily focused on understanding mechanisms that maintain stability, while adaptive adjustments are integrated in a key stress-processing neural population, the corticotropin-releasing hormone neurons in the paraventricular nucleus of the hypothalamus (CRHPVN). Activation of these neurons during stress drives the production of glucocorticoids (CORT). The production of CORT is typically self-limiting, but under some conditions, CORT release continues unabated. This offers an opportunity to study underlying synaptic and cellular adjustments that contribute to stability in these circuits. I used chemogenetics to assess how CRHPVN neurons respond to decreased excitability. There was an increase in the strength of glutamatergic synapses that was consistent with multiplicative scaling, which has previously been described to maintain stability. Next, I asked whether pathophysiological manipulations would force similar adjustments to this system. I examined how persistent CORT feedback, a feature of chronic stress, influences CRHPVN neurons. Following 7 days CORT, CRHPVN neurons showed a decrease in intrinsic excitability, which coincided with multiplicative scaling at glutamate synapses. In the next chapter, I assessed population activity of CRHPVN neurons in live mice. CORT had no effect on the activity of these neurons. However, CRHPVN-neuron activity in baseline, and during mild stress, was diminished when scaling was prevented during CORT. This indicates that scaling maintains stability in these conditions. In the final data chapter, I optimized the use of miniature head-fixed microscopes to obtain the first recordings from identified CRHPVN neurons. These recordings reveal that CRHPVN neurons show disparate responses to stress. These studies provide novel information regarding the activity of CRHPVN neurons in freely behaving mice. They indicate this population is more diverse than previously described, and that individual neurons (or subpopulations) may discretely encode stressor-specific information. Furthermore, they provide the first evidence for a homeostatic scaling-like mechanism that maintains stability in the face of an internal challenge to homeostasis.
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    Chloride Dynamics and the Control of CRH Activity
    (2019-07-05) Lanz, Aaron Justin; Bains, Jaideep; Gordon, Grant Robert J.; Thompson, Roger J.; Epp, Jonathan Richard
    CRH neurons of the PVN release the neuropeptide CRH to initiate the endocrine stress response and to modulate local glutamatergic synapses. The cellular mechanisms that promote CRH release during an acute stress are unknown. Here we show that CRH neurons begin to burst following an acute stress in vitro. Using cell-attached recordings and a novel optogenetic strategy, we demonstrate that KCC2 is suppressed following an acute stress and that this functional downregulation is sufficient to promote bursting in CRH neurons. Further, we show that KCC2 suppression leads to local CRH release in the PVN to promote short-term plasticity at glutamate synapses. This study offers a new tool to study chloride homeostasis in brain slices and provides evidence that KCC2 activity dynamics can alter cell spiking and synaptic plasticity in the healthy brain.
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    Corticofugal postsynaptic potentials and their frequency specific impact on auditory midbrain neurons
    (2018-07-04) Qi, Jiyao; Yan, Jun; Stell, William K.; Thompson, Roger J.; Zhang, Zizhen; Eggermont, Jos Jan
    Neuroanatomical studies reveal a great amount of descending (corticofugal) projections from the primary auditory cortex (AI) to all subcortical regions such as the central nucleus of the inferior colliculus (ICc). In the past 20 years, physiological studies have shown that the corticofugal system implements a highly frequency-specific modulation of sound information processing in the ascending auditory system. Specifically, focal electrical stimulation of the AI (ESAI) facilitates subcortical neurons when the best frequency (BF) of subcortical neurons is identical to the BF of cortical neurons (physiologically matched). In contrast, ESAI inhibits subcortical neurons when their BFs are different (unmatched). ESAI also shifts the BFs of unmatched subcortical neurons towards the BF of cortical neurons. While previous physiological findings have been achieved using extracellular recordings, to date, little is known about the cellular mechanism(s) underlying such highly, frequency-specific corticofugal modulation. An immediate question this raises is: what corticofugal postsynaptic potentials may be found in matched and unmatched subcortical neurons? A subsequent, critical question to ask is how the corticofugal postsynaptic potentials interplay with ascending (tone-evoked) postsynaptic potentials. This thesis sets out to answer these two questions by examining the corticocolliculuar (AI-to-ICc) synaptic activities in a mouse model. The membrane potential of ICc neurons was recorded by in vivo whole-cell patch current-clamp. I found that ESAI primarily evoked excitatory postsynaptic potential (EPSP) in ICc neurons. ESAI-evoked ICc EPSPs were larger in matched than in unmatched neurons. I further examined how ESAI-evoked EPSPs influence the tone-evoked EPSPs of ICc neurons. My data show that ESAI-evoked EPSPs facilitated tone-evoked EPSPs of matched neurons, but inhibited tone-evoked EPSPs of unmatched neurons. My findings reveal for the first time that corticofugal postsynaptic potentials are excitatory and frequency-dependent, and they interact with the ascending synaptic inputs in a frequency-specific manner.
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    Dynamic Oxygen Changes with Status Epilepticus, Seizures, and the Postictal State
    (2020-08-28) Wolff, Marshal David; Teskey, G. Campbell; Thompson, Roger J.; Gordon, Grant Robert J.
    The adult human brain consumes a highly disproportionate amount of oxygen and glucose relative to its size. Maintenance of the partial pressure of oxygen (pO2) within the normoxic range is critical for brain health; too little oxygen leads to hypoxia, which impairs energy production and can result in neuronal damage and death, and too much oxygen leads to hyperoxia, which can lead to similar levels of neuronal injury. Research into how oxygen and the vascular system contributes to neurological diseases is growing, one being epilepsy. Epilepsy is a neurological disease characterized by the occurrence of self-generated recurrent seizures, which have historically been viewed as electrical events. However, it has recently been shown that following the termination of a seizure, there is a long-lasting vasoconstriction in the brain regions that expressed seizure activity, which leads to hypoperfusion and severe hypoxia. This period of postictal hypoxia is also responsible for behavioural impairments during the postictal state. I wanted to further investigate this phenomenon and establish how the hypoxic period affects behaviour, as well as determine what happens to brain pO2 following other types of ictal events, including status epilepticus and electrical kindling. Prolonged hippocampal status epilepticus produces a long-lasting hyperoxia, and the self-generating epileptiform activity which emerges later is associated with alterations in oxygen dynamics. Repeated hippocampal seizures, induced by electrical kindling, causes a drop in interictal hippocampal pO2 as well as an impairment in associative memory. These changes to brain and behaviour can be blocked by the repeated attenuation of postictal hypoxia following each kindled seizure. Finally, following a single focal seizure of the hippocampus, pharmacological blockade of postictal hypoxia prevents behavioural deficits in the novel object context-mismatch task as well as the Morris water task. These findings show that seizure-driven changes to brain oxygenation have severe consequences for epilepsy pathology and behavioural dysfunction and could serve as biomarkers for electrical ictal activity. This research will hopefully open the door to the production and use of new therapies and treatments for people living with epilepsy.
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    Impact of Intermittent Hypoxia on Human Cardiorespiratory and Cerebrovascular Function
    (2016) Beaudin, Andrew Edward; Poulin, Marc J.; Hanly, Patrick J.; Wilson, Richard J. A.; Anderson, Todd J.; Thompson, Roger J.; Horner, Richard L.
    Obstructive sleep apnoea (OSA) is a chronic sleep disorder characterized by intermittent hypoxia (IH) exposure during sleep and is an independent risk factor for cardiovascular and cerebrovascular disease. IH in untreated OSA is advanced as the principal pathway leading to the greater risk of vascular disease associated with OSA. Additionally, IH is implicated in the propagation of OSA severity by increasing ventilatory instability, in part, by enhancing ventilatory chemosensitivity. Therefore, the focus of this thesis was to investigate the mechanisms through which IH functions and the role of IH in disrupting vascular and ventilatory regulation in OSA. The molecular pathways through which IH disrupts vascular and ventilatory regulation are poorly understood, but IH-induced inflammation is believed to be a primary contributor. Using a human experimental model of IH during wakefulness and a clinical population of untreated OSA patients, Study 1 investigated the role of cyclooxygenase (COX)-1 and COX-2 derived prostanoids (mediators of the inflammatory response and vascular regulation) in IH-induced alterations in cardiovascular and cerebrovascular regulation. Additionally, Study 2 examined the role of inflammation in IH-induced respiratory plasticity. Study 3 investigated the effects of nocturnal oxygen therapy (to remove IH) and continuous positive airway pressure (CPAP; gold standard OSA treatment) on cardiorespiratory and cerebrovascular responses to hypoxia in newly diagnosed OSA patients. Finally, Study 4 assessed the feasibility of adapting our human IH model to sleep while incorporating the ability to assess cardiovascular and cerebrovascular responses to hypoxia and hypercapnia during sleep. Studies 1-3 add substantial knowledge to this important area of research. Specifically, they reveal that 1) cyclooxygenase (COX)-1 and COX-2 differentially regulate blood pressure and cerebrovascular responses to acute and chronic IH; 2) inflammation does not contribute to IH-induced respiratory plasticity following an acute (6h) IH exposure; and 3) both nocturnal oxygen and CPAP treatment of OSA may lower blood pressure during isocapnic-euoxia and the hypoxic ventilatory response, but neither modality effects vascular responses to hypoxia. Lastly, Study 4 showed it is feasible to apply our human IH model to sleep and to concurrently assess vascular responses to hypoxia and hypercapnia during sleep.
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    Pannexin-1 suppresses network excitability in a TRPV1-dependent manner
    (2021-01-13) Tucker, Catharine M.; Thompson, Roger J.; Bains, Jaideep Singh; Altier, Christophe
    Epilepsy is characterized by recurrent seizures, which disrupt brain function. Deviations in neuronal excitability and imbalances in excitation and inhibition have been shown to promote seizure generation. However, the molecular determinants of these alterations remain elusive. Pannexin-1 (Panx1), the large pore ion/metabolite channel, has been recognized as a molecular hub in epileptogenesis. However, the mechanisms by which Panx1 affects excitation and/or inhibition are not clearly understood. Previous findings from our lab suggest that blocking Panx1 enhances the excitatory tone in CA1 pyramidal neurons following afferent stimulation. We also found that Panx1 ablation exacerbates epileptogenesis in an electrical kindling model of seizures. Here, I propose to determine how blocking Panx1 alters neuronal excitability and whether it plays a role in epileptiform activity. This thesis will explore if inhibiting functional Panx1 pushes neuronal excitability towards a more easily excitable seizure-prone state. The overall hypothesis is that blocking Panx1 promotes epileptiform activity by enhancing neuronal network excitability. Here, we report that Panx1 inhibition promotes burst firing in the hippocampus following afferent stimulation. This bursting effect was found to operate in a transient receptor potential vanilloid-1 (TRPV1)-dependent manner. Pharmacological block and genetic ablation of TRPV1 was found to ameliorate this effect. We also report that removing Panx1 function has no significant effect on intrinsic neuronal excitability. Recognizing Panx1 channel involvement in balancing excitability in the brain may give rise to a new therapeutic target to reduce aberrant neuronal activity. As a third of epileptic patients experience pharmacoresistant epilepsy, understanding the mechanisms of synaptic communication that change a healthy brain into a seizure-prone brain can provide insight into novel targets for the prevention of neuronal hyperexcitability. Determining a full mechanism of synaptic modifications that leads to a hyperexcitable brain could be beneficial for drug development that can lead to better treatments and overall patient outcomes.  
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    The Presynaptic and Postsynaptic Signaling of Amyloid β Protein During Ischemia
    (2019-06-11) Palmer, Laura Ann; Thompson, Roger J.; Teskey, G. Campbell; Stys, Peter K.
    Amyloid β has been implicated in the pathophysiology of Alzheimer disease (AD) by disrupting synapses and enhancing cell death. Genetic mutations that are causative of familial Alzheimer disease are associated with enhanced Aβ burden. Since only 5% of AD cases are genetic, efforts must be made to understand environmental risk factors and other co-morbidities that could elevate Aβ. For instance, ischemic stroke is associated with increased risk of developing AD, which is thought to be due to enhanced production of Aβ. Loss of key energy substrates during ischemia initiate overactive synaptic glutamate release, reversed glutamate uptake, ionic dysregulation, and the anoxic depolarization. The anoxic depolarization is mediated by a number of channels, including NMDARs and pannexin-1 (Panx1) to induce Ca2+ dysregulation and downstream cell death. The role of Aβ during the events of acute ischemia is unknown, and is assumed to be pathological due to similar features of ischemia and AD. However, Aβ has been shown to depress synapses and enhance cell survival during excitotoxicity. The overarching hypothesis of this thesis is that Aβ acts to depress aberrant synaptic events during ischemia and reduces excitotoxicity. Here, I show that Aβ potently reduces excitotoxic currents during the anoxic depolarization and prevents Panx1-dependent secondary currents in response to NMDA overstimulation. Aβ does not directly inhibit Panx1 but regulates its opening by acting as an antagonist for mGluR1. This Aβ-mGluR1 interaction also enhances GABAergic signalling to reduce excitotoxic glutamate release, however, presynaptic release does not determine the magnitude of the anoxic depolarization. These data reveal a novel modulation of Panx1 opening by mGluR1, which is regulated by Aβ. Aβ production could be increased during hypoxia to reduce activation of Panx1, thereby attenuating the anoxic depolarization and downstream cell death pathways. With prolonged/repeated ischemic events, Aβ could reach toxic levels and coincide with hallmark pathophysiology of AD.
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    Social Buffering of Stress-Induced Changes in the Paraventricular Nucleus of the Hypothalamus
    (2022-06-28) Loewen, Spencer P.; Bains, Jaideep S.; Hill, Matthew N.; Thompson, Roger J.; Teskey, G. Campbell; Christianson, John P.
    Social species, by definition, utilize social interactions with others that are essential for survival and reproductive success. Social interactions can mitigate the harmful effects of stress through a process known as social buffering. Our understanding of the cellular mechanisms that underlie social buffering, however, is poor. Acute stress primes glutamate synapses onto corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus (PVN) of the hypothalamus (CRHPVN neurons), resulting in stress-induced metaplasticity. This priming of synapses, which manifests as short-term potentiation (STP) of excitatory transmission elicited by high-frequency afferent stimulation, is buffered in female but not male mice by the presence of a naive partner. The cellular substrates underlying this sex-specific buffering of these synaptic changes have not been elucidated. Increasing evidence suggests that neurons in the PVN are sensitive to neuromodulation by locally released substances. Here, I tested the hypothesis that local vasopressin (VP) signaling in the PVN contributes to social buffering of synaptic metaplasticity in females. I used whole-cell patch clamp recordings from CRHPVN neurons to examine the effects of VP on STP in these cells. I found that selective pharmacological blockade of VP 1a receptors prevented social buffering of STP. Conversely, exogenous VP mimicked the effects of social buffering and reduced STP in CRHPVN neurons from single-housed stressed females but had no effect in males. These synaptic actions rely on direct VP signaling on CRHPVN neurons that reduce the AMPA/NMDA ratio. In addition, I extended the effects of social buffering to cognitive functions and examined how changes in CRHPVN neuron activity influence memory retrieval. I found that social buffering improves stress-induced impairments in long-term memory retrieval in female mice, but not in males. Furthermore, optogenetic silencing of CRHPVN neurons in single-housed stressed female mice reduced STP and replicated the social buffering effect by improving memory retrieval after stress. Collectively, the work in this thesis contributes to our understanding of the mechanism that underlies sex-specific social buffering of STP and provides evidence that the effects of social buffering may be determined by changes in CRHPVN neuron activity.
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    The Role of RVLM and PACAP in Sympathetic Long-Term Facilitation after Exposure to Acute Intermittent Hypoxia Hypercapnia
    (2018-02-21) Derakhshan, Fatemeh; Wilson, Richard J. A.; Duff, Henry J.; Thompson, Roger J.
    Intermittent hypoxia (IHx) and hypercapnia (Hc) episodes are typically a consequence of obstructive sleep apnea (OSA) in adults and immature respiratory control in pre-term infants. IHxHc contributes to immediate and long-term co-morbidities including increased sympathetic output, hypertension, long-term cardiorespiratory instability and stroke. Exposure to an acute phase of IHxHc results in sympathetic long-term facilitation (LTF). Despite intensive investigation, the mechanisms linking IHxHc to increased sympathetic activity and cardiorespiratory instability remain poorly understood. In my thesis project, I explored the role of rostral ventrolateral medulla (RVLM) neurons in development of sympathetic LTF after exposure to IHxHc. I report that PACAP, a highly conserved excitatory neuropeptide, which can function as an "emergency response" co-transmitter in the sympathoadrenal axis, plays a significant role in activating the sympathetic responses to IHxHc, with a prominent role in the RVLM. First, I showed that PACAP plays a critical role during IHx and can save the life of PACAP-KO mice exposed to acute IHx. To the best of our knowledge, PACAP is the first neuropeptide, which is required to survive acute IHx. Second, intermittent stimulation of RVLM area, mirrors the effect of IHxHc with inducing LTF and is sufficient for development of sympathetic LTF, emphasizing on an important role of RVLM neurons in the induction and maintenance of a sympathetic surge after IHxHc. Third, I showed that PACAP action at the RVLM level is necessary for the maintenance of induced sympathetic LTF after exposure to IHxHc. Fourth, I demonstrated that carotid sinus denervation decreases the baseline sympathetic nerve activity but does not suppress the sympathetic nerve response to hypoxia. This finding was explained with the consecutive discovery of spinal cord oxygen sensors. The spinal cord oxygen sensors (SOS) are active over the physiological range and have several qualities of primary oxygen sensors, including a highly-sensitive and rapid physiologic response to changes in oxygen levels. The discovery of PACAP’s role in the maintenance of sympathetic LTF and the existence of SOS introduces a new chapter in current cardiorespiratory research. This new realm has implications for translational studies, such as those investigating sustained sympathetic nerve activity in heart failure,aiming to help patients with chronic obstructive pulmonary disease (COPD), OSA, paroxysmal sympathetic hyperactivity (PSH), and neonates at risks for sudden infant death syndrome (SIDS).