The role of basal ganglia circuitry in motivation

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

Efficient and accurate extraction of in vivo calcium signals from microendoscopic video data

In vivo calcium imaging through microendoscopic lenses enables imaging of previously inaccessible neuronal populations deep within the brains of freely moving animals. However, it is computationally challenging to extract single-neuronal activity from microendoscopic data, because of the very large background fluctuations and high spatial overlaps intrinsic to this recording modality. Here, we describe a new constrained matrix factorization approach to accurately separate the background and then demix and denoise the neuronal signals of interest. We compared the proposed method against previous independent components analysis and constrained nonnegative matrix factorization approaches. On both simulated and experimental data recorded from mice, our method substantially improved the quality of extracted cellular signals and detected more well-isolated neural signals, especially in noisy data regimes. These advances can in turn significantly enhance the statistical power of downstream analyses, and ultimately improve scientific conclusions derived from microendoscopic data

Measurement of differential cross sections for top quark pair production using the lepton plus jets final state in proton-proton collisions at 13 TeV

National Science Foundation (U.S.

Particle-flow reconstruction and global event description with the CMS detector

The CMS apparatus was identified, a few years before the start of the LHC operation at CERN, to feature properties well suited to particle-flow (PF) reconstruction: a highly-segmented tracker, a fine-grained electromagnetic calorimeter, a hermetic hadron calorimeter, a strong magnetic field, and an excellent muon spectrometer. A fully-fledged PF reconstruction algorithm tuned to the CMS detector was therefore developed and has been consistently used in physics analyses for the first time at a hadron collider. For each collision, the comprehensive list of final-state particles identified and reconstructed by the algorithm provides a global event description that leads to unprecedented CMS performance for jet and hadronic tau decay reconstruction, missing transverse momentum determination, and electron and muon identification. This approach also allows particles from pileup interactions to be identified and enables efficient pileup mitigation methods. The data collected by CMS at a centre-of-mass energy of 8 TeV show excellent agreement with the simulation and confirm the superior PF performance at least up to an average of 20 pileup interactions

Search for heavy resonances decaying to a top quark and a bottom quark in the lepton+jets final state in proton–proton collisions at 13 TeV

info:eu-repo/semantics/publishe

Evidence for the Higgs boson decay to a bottom quark–antiquark pair

info:eu-repo/semantics/publishe

Identification of heavy-flavour jets with the CMS detector in pp collisions at 13 TeV

Many measurements and searches for physics beyond the standard model at the LHC rely on the efficient identification of heavy-flavour jets, i.e. jets originating from bottom or charm quarks. In this paper, the discriminating variables and the algorithms used for heavy-flavour jet identification during the first years of operation of the CMS experiment in proton-proton collisions at a centre-of-mass energy of 13 TeV, are presented. Heavy-flavour jet identification algorithms have been improved compared to those used previously at centre-of-mass energies of 7 and 8 TeV. For jets with transverse momenta in the range expected in simulated $\mathrm{t}\overline{\mathrm{t}}$ events, these new developments result in an efficiency of 68% for the correct identification of a b jet for a probability of 1% of misidentifying a light-flavour jet. The improvement in relative efficiency at this misidentification probability is about 15%, compared to previous CMS algorithms. In addition, for the first time algorithms have been developed to identify jets containing two b hadrons in Lorentz-boosted event topologies, as well as to tag c jets. The large data sample recorded in 2016 at a centre-of-mass energy of 13 TeV has also allowed the development of new methods to measure the efficiency and misidentification probability of heavy-flavour jet identification algorithms. The heavy-flavour jet identification efficiency is measured with a precision of a few per cent at moderate jet transverse momenta (between 30 and 300 GeV) and about 5% at the highest jet transverse momenta (between 500 and 1000 GeV)

Pseudorapidity and transverse momentum dependence of flow harmonics in pPb and PbPb collisions

info:eu-repo/semantics/publishe

Charged-particle nuclear modification factors in PbPb and pPb collisions at √sNN=5.02 TeV

The spectra of charged particles produced within the pseudorapidity window |η| 20 GeV, RpA exhibits weak momentum dependence and shows a moderate enhancement above unity