The development, maintenance, and survival of neurons depend on the function of neurotrophins such as nerve growth factor (NGF). One population of neurons that rely heavily on NGF for axonal growth and survival is the postganglionic sympathetic neurons. Trauma or disease resulting in injury to the peripheral nervous system causes an increase in the levels of this neurotrophin. This augmentation promotes the collateral sprouting of postganglionic sympathetic axons into those tissues having elevated levels of NGF. Often, NGF-induced sympathetic sprouting occurs in tissues that are normally innervated by these fibers however, high levels of NGF can also promote sprouting of axons into tissues that are normally devoid of sympathetic fibers, such as the sensory ganglia. When postganglionic sympathetic axons grow into the environment of sensory ganglia, they can converge and wrap around a subset of somata (i.e., cell bodies) belonging to primary sensory neurons. This phenomenon, referred to as sympathosensory plexuses is observed in adult mice and rats following peripheral nerve injury, and is also seen in adult transgenic mice that ectopically over express NGF. The overall aim for this project is to examine the morphological and neurochemical features, as well as the overall consequence of sympathosensory plexuses in nerve-injured adult mice and in adult transgenic mice that over express NGF. We hope that this novel information will add to our understanding of the underlying mechanisms associated with the formation of sympathosensory plexuses that occur following injury. / Thesis (Ph.D, Neuroscience Studies) -- Queen's University, 2013-07-23 18:51:47.902

The basal ganglia are a collection of interconnected subcortical nuclei which have been implicated inmotor, cognitive and limbic functions. The subthalamic nucleus is the sole excitatory structure within the basal ganglia. Given its central position influencingmany basal ganglia nuclei, it is likely to play an important role in the processing that is performed by the basal ganglia. In this thesis a theoretical analysis of the subthalamic nucleus is presented. In order to explore the multiple facets of processing that may be occurring, models that are designed to capture aspects of the subthalamic nucleus at different levels are developed. These include anatomical, network processing and single neuron multi–compartmental models. Through the integration of the results obtained from these models a new and coherent view of the processing of the subthalamic nucleus is presented. It is predicted that the subthalamic nucleus be considered as a massively connected excitatory network. Two distinct modes of asymptotic behaviour exist in such a network: a low resting state and a high self–sustained state. The single neuron multi– compartmental model demonstrates that the calcium T–type channel is the primary determinant of characteristic neuron behaviour. Such behaviour includes a slowaction potential, initial spike clustering, and a post-response quiescence. The network and single neuron results taken togetherprovide an intrinsicmechanismfor termination of uniform high activity generated by the excitatory network. It is therefore predicted that large regions of the subthalamic nucleus respond uniformly to stimuli, in the form of a pulse of activity with a sharp rise and fall. In addition, the single neuron model indicates that pulses will occur in pairs. It is proposedthat the subthalamic nucleus acts as a “braking mechanism”. It can induce, via intermediate structures, awide-spread pulse of inhibition on basal ganglia target nuclei. Furthermore, the sequence of two pulses can generate a window of disinhibition over the basal ganglia targets. The width of this time window may be under direct striatal control. Variable interpulse duration implies a role for the subthalamic nucleus in temporal processing.

published_or_final_version / Anatomy / Master / Master of Philosophy

An important function of the brain is to inhibit irrelevant behaviors. This thesis examines the role of the basal ganglia in response suppression using saccadic eye movements as a model of behavior. We measured the activity of single saccade-related neurons in primate Substantia Nigra pars reticulata (SNr), a main output structure of the basal ganglia, while the context surrounding the initiation and suppression of saccades was manipulated. Inserting a temporal gap of no stimuli between the disappearance of a central visual fixation point and the appearance of a peripheral visual target leads to a reduction in saccadic reaction times (SRT); the ‘gap’ effect. SNr pause neurons decreased their activity during the gap and this decrease correlated with SRT. This finding suggests the SNr may contribute directly to producing the gap effect and that signals related to the effect are propagating through a frontal-basal ganglia circuitry to impact pre-saccade processing. Interleaving pro-saccade (look towards a visual stimulus) and anti-saccade (look away from visual stimulus) trials allowed us to investigate how neural processes change when preparing to suppress a saccade instead of making one automatically. We show that SNr neurons exhibit activity consistent with both suppression of automatic responses and facilitation of voluntary responses, during anti-saccades. These data provide direct neurophysiological evidence for a dual role of inhibitory and disinhibitory basal ganglia outputs in the flexible shaping of behavior. Parkinson’s disease (PD) is a neurodegenerative disorder that impairs motor function due to depletion of dopamine in the striatum. Using an oculomotor countermanding paradigm, we found that PD patients were unable to suppress saccades to a peripheral target, providing evidence that the SNr performs a gating function that mediates the initiation and suppression of saccades. When pathology to the circuitry occurs, inhibitory control over saccades is affected. In Conclusion, using a variety of behavioral contexts, this thesis has demonstrated that the basal ganglia, specifically the SNr, mediates the suppression and voluntary initiation of saccades, possibly via an inhibitory gating mechanism, and that this role is important for successful interaction with a dynamic environment. / Thesis (Ph.D, Physiology) -- Queen's University, 2008-07-16 12:06:19.188

No description available.

Proefschrift Maastricht. / Omslag vermeldt: Henny Beckers. Met lit. opg. - Met samenvatting in het Nederlands.

No description available.

The basal ganglia are a set of subcortical nuclei in the forebrain of vertebrates that are highly conserved among mammals. Classically, dysfunction in the basal ganglia has been linked to motor abnormalities. However, it is now widely recognized that in addition to their role in motor behavior, these set of nuclei play a role in reinforcement learning and motivated behavior as well as in many diseases that present with abnormal motivation. In this dissertation, I first provide a review of the literature that describes the current state of research on the basal ganglia and the background for the original studies I later present. I describe the anatomy and physiology of the basal ganglia, including how structures are interconnected to form two parallel pathways, the direct and the indirect pathways. I further review published studies that have investigated how the basal ganglia regulate motor behavior and motivation. And finally, I also summarize findings on how disruption in basal ganglia circuitry function has been linked to a number of neuropsychiatric diseases, with special focus on the symptoms of schizophrenia. I then present original data and discuss the results of three studies investigating basal ganglia function and behavior. In the first study, I investigated the bridging collaterals, axon collaterals of direct-pathway medium spiny neurons (dMSNs) in the striatum that target the external segment of the globus (GPe), the canonical target of indirect-pathway medium spiny neurons (iMSNs). Previous work in the Kellendonk laboratory has linked these collaterals to increased dopamine D2 receptor (D2R) function and increased striatal excitability, as well as to abnormal locomotor response to stimulation of the direct pathway. I expanded on these findings by first demonstrating that bridging collaterals form synaptic contacts with GPe cells. I was also able to generate a viral vector to selectively increase excitability in specific populations of MSNs. I used this virus to show that chronically increasing excitability of the indirect pathway, but not the direct pathway, leads to a circuit-level change in connectivity by inducing the growth of bridging collaterals from dMSNs in the GPe. I also confirmed that increased density of bridging collaterals are associated with an abnormal locomotor response to stimulation of striatal dMSNs and further demonstrated that chronic pharmacologic blockade of D2Rs can rescue this abnormal locomotor phenotype. Furthermore, I found that motor training reverses the enhanced density of bridging collaterals and partially rescue the abnormal locomotor phenotype associated with increased collaterals, thereby establishing a new link between connectivity in the basal ganglia and motor learning. In the second study, I conducted a series of experiments in which I selectively increased excitability of the direct or indirect pathway in specific striatal sub-regions that have been implicated in goal-directed behavior, namely the DMS and NA core. I found that this manipulation was not sufficient to induce significant effects in different behavioral assays of locomotion and motivation, including the progressive ratio and concurrent choice tasks. These findings also suggest that increased bridging collateral density does not have a one-to-one relationship with the motivational deficit of D2R-OEdev mice, as previously hypothesized. In the third and final study, my original aim was to determine whether the motivational deficit of D2R-OEdev mice, induced by upregulation of D2Rs in the striatum, could be reversed by acutely activating Gαi-coupled signaling in the indirect pathway in these animals. I found that this manipulation increased motivation in D2R-OEdev mice but also in control littermates. This effect was due to energized behavioral performance, which, however, came at the cost of goal-directed efficiency. Moreover, selective manipulation of MSNs in either the DMS or NA core showed that both striatal regions contribute to this effect on motivation. Further investigation aimed at understanding how Gαi-coupled signaling affects striatal circuit function revealed that activating a Gαi-coupled receptor did not lead to a significant change in somatic MSN activity in vivo or to a change in neuronal excitability in vitro. In contrast, the GPe, which receives monosynaptic inhibition from the indirect pathway, showed disinhibited activity when Gαi signaling was activated in striatal iMSNs. In addition, as drug therapies for psychiatric diseases are not usually given acutely but involve long-term, continuous administrations, I also studied how chronically decreasing function of iMSNs would affect behavior. I showed that chronically activating a Gαi-coupled receptor in iMSNs does not lead to a measurable effect on locomotion or motivation, a behavioral desensitization response that can be recovered within 48 h and may be due to receptor desensitization to the drug or circuit-level compensation to a chronic decrease in iMSN function. Finally, I conclude this dissertation with a general discussion addressing how the findings from each study can be related to each other to provide a more complete understanding of how basal ganglia function regulate behavior, how disruption in the basal ganglia can underlie neuropsychiatric disease, and how strategies to target basal ganglia function should be employed to treat disorders of motivation. I conclude this dissertation by proposing new avenues of research for further exploring my findings.

In this thesis, I have used a combination of computational models such as mean field and spikingnetwork simulations to study various sub-circuits of basal ganglia. I first studied the striatum(chapter 2), which is the input nucleus of basal ganglia. The two types of Medium SpinyNeurons (MSNs), D1 and D2-MSNs, together constitute 98% of the neurons in striatum. Thecomputational models so far have treated striatum as a homogenous unit and D1 and D2 MSNs asinterchangeable subpopulations. This implied that a bias in a Go/No-Go decision is enforced viaexternal agents to the striatum (eg. cortico-striatal weights), thereby assigning it a passive role.New data shows that there is an inherent asymmetry in striatal circuits. In this work, I showedthat striatum due to its asymmetric connectivity acts as a decision transition threshold devicefor the incoming cortical input. This has significant implications on the function of striatum asan active participant in influencing the bias towards a Go/No-Go decision. The striatal decisiontransition threshold also gives mechanistic explanations for phenomena such as L-Dopa InducedDyskinesia (LID), DBS-induced impulsivity, etc. In chapter 3, I extend the mean field model toinclude all the nuclei of basal ganglia to specifically study the role of two new subpopulationsfound in GPe (Globus Pallidus Externa). Recent work shows that GPe, also earlier consideredto be a homogenous nucleus, has at least two subpopulations which are dichotomous in theiractivity with respect to the cortical Slow Wave (SWA) and beta activity. Since the data for thesesubpopulations are missing, a parameter search was performed for effective connectivities usingGenetic Algorithms (GA) to fit the available experimental data. One major result of this studyis that there are various parameter combinations that meet the criteria and hence the presenceof functional homologs of the basal ganglia network for both pathological (PD) and healthynetworks is a possibility. Classifying all these homologous networks into clusters using somehigh level features of PD shows a large variance, hinting at the variance observed among the PDpatients as well as their response to the therapeutic measures. In chapter 4, I collaborated on aproject to model the role of STN and GPe burstiness for pathological beta oscillations as seenduring PD. During PD, the burstiness in the firing patterns of GPe and STN neurons are shownto increase. We found that in the baseline state, without any bursty neurons in GPe and STN,the GPe-STN network can transition to an oscillatory state through modulating the firing ratesof STN and GPe neurons. Whereas when GPe neurons are systematically replaced by burstyneurons, we found that increase in GPe burstiness enforces oscillations. An optimal % of burstyneurons in STN destroys oscillations in the GPe-STN network. Hence burstiness in STN mayserve as a compensatory mechanism to destroy oscillations. We also propose that bursting inGPe-STN could serve as a mechanism to initiate and kill oscillations on short time scales, asseen in the healthy state. The GPe-STN network however loses the ability to kill oscillations inthe pathological state. / <p>QC 20160509</p>

Cholecystokinin (CCK)-like immunoreactive materials have been localized in neurons with cell bodies in the colon and axons in the IMG of the guinea pig. The physiological significance of neuronal CCK in sympathetic prevertebral ganglia is unknown. The goal of the present studies is to test the hypothesis the CCK is a neurotransmitter in the IMG of guinea pig and rabbit. In vitro IMG preparations with or without a segment of the colon attached were utilized to conduct intracellular recordings of potentials elicited in the neurons by pressure-ejected CCK₈. The peptide triggered a depolarization with rapid onset (1-5 s) and a rate of rise (1.6 ± 0.4 mV/s) in 95% of the neurons tested. Values of the ED₅₀ for effecting depolarization average 1.1 ± 0.5 pmoles. In 59% of the cells, the depolarization was associated with a decrease in R(in) and in 20% with an increase. The remaining cells showed no change in R(in). G(Na) and G(K) were increased and decreased, respectively; potential-dependence characteristics revealed a null potential of 36 ± 9 mV in those cells exhibiting a decrease in R(in). Gastrin, caerulein, and CCK₂₇₋₃₃ effected similar depolarization. CCK₈-evoked depolarization imitated the depolarization produced either by colon distension or by nerve stimulation. Upon repeated administration of CCK₈, the response of the cells to the peptide underwent tachyphylaxis. In addition, CCK₈ desensitized the depolarization evoked by stimulation in 50% of the cells. Furthermore, in an equal percentage of neurons, CCK₈ depressed responses of the colon distension-induced depolarization. The CCK₈ has both pre- and postsynaptic sites of action is supported by lowering Ca²⁺ and administering TTX (3 μM), which caused no effect and depressed 30% of CCK-induced depolarization respectively. Spantide (SP antagonist) blocked the response to SP, but not to CCK₈, in 5 out of 6 neurons, indicating separate receptor sites for SP and CCK₈. Moveover, completely desensitizing the cell response to SP or VIP did not cross desensitize its response to CCK₈ as observed in 6 neurons. In the rabbit IMG, the physiological significance of CCK₈ excitation is unknown, since colon distension did not elicit any depolarization. These results support the hypothesis that CCK₈ or a related peptide is a neurotransmitter mediating reflex activity between the colon and the IMG in guinea pig.