Stephen N. Gomperts - US grants

[unreadable] DESCRIPTION (provided by applicant): This proposal seeks to explore the structure of neuronal activity in the ventral tegmental area (VTA) and its relationship with neuronal activity in the hippocampus (HC) during reinforced spatial learning. The VTA dopamine (DA) system is a key substrate of reinforcement learning that appears to underlie the internal map of value that animals use to select goals. The HC also functions in reinforced spatial learning, as it is necessary for navigation and episodic memory. In freely moving animals, in the spatial domain, VTA activity may additionally contribute to navigation towards goals. VTA GABA neurons may play a critical role in directing and regulating the encoding of value. They project to the same structures as DA cells, including the HC, and inhibit DA neurons. Locally, VTA GABA neurons may participate in the DA cell computation of reward prediction error (RPE) and may regulate DA cell output. Through their projections, GABA neurons may also dynamically select target structures for DA signaling and may provide them with DA-independent reward-related information. This study will employ multielectrode recordings of neuronal ensembles in the VTA and HC to elucidate their interactions through 3 specific aims. First, it will assess the capacity for VTA DA and GABA neurons to represent trajectories predictive of future reward. Then, it will explore the role of GABA neuronal activity in the RPE representation. Lastly, it will examine VTA-HC interactions in reinforced spatial learning in normal conditions and after pharmacological perturbations of DA function. The immediate goal of the candidate is to obtain training in multielectrode recording in the VTA and HC of awake behaving rats, sponsored by Dr. Matthew Wilson, with complementary clinical training in movement and memory disorders, sponsored by Dr. John Growdon. The many resources of the lab and MIT neuroscience community will thus be enhanced by those of Harvard University and Massachusetts General Hospital. The long- term goal is to learn how the VTA contributes to normal and aberrant cognitive control, through its intrinsic circuitry and interactions with other brain regions. Given the pivotal role of the DA system in reinforcement learning, cognitive control, Parkinson's disease, drug addiction, and schizophrenia, and the importance of the HC in episodic memory, spatial navigation, and schizophrenia, insights into VTA function and the mechanisms by which it communicates with brain areas such as the HC will have high clinical relevance. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Multiple neurodegenerative brain disorders present with parkinsonism, including idiopathic Parkinson disease, Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD). Diagnosis and differentiation of these disorders in life is difficult, especially early in their course. They are distinguished neuropathologically by he chemical composition and regional distribution of deposited proteins, with alpha-synuclein the protein associated with PD, and paired helical filament (PHF) tau in neurofibrillary tangles (NFT) and glial tufts associated with PSP and CBD (for which they are known as 'tauopathies'). Future therapeutics will likely be tailored to the underlying molecular pathology of each disease. The capacity to make a secure molecular diagnosis of these illnesses in life would be a significant advance, with immediate relevance for clinical trials as well as for future molecularly-based therapies. A recently developed radiopharmaceutical known as [F18] T807 binds brain PHF tau in living humans, and may be a valuable tool for establishing a molecular diagnosis antemortem. In this project, we will evaluate whether PHF tau deposition measured with [F18] T807 differentiates PSP and CBD from PD and healthy control subjects (HCS); and explore the relation of PHF tau deposition to indices of clinical impairment, cortical thinning, and amyloid burden in these disorders. Subjects with PSP, CBD, and PD will undergo standardized neurological examination, detailed neuropsychological testing, [F18] T807 PET, [C11] PiB PET, and structural brain MRI, and will be compared to previously acquired clinical and PET data of an aged-matched HCS cohort to test the following hypotheses: (1) [F18] T807 PET will differentiate subjects with suspected tauopathy due to PSP and CBD from subjects with suspected synucleinopathy due to idiopathic PD and from HCS, with PHF tau burden in PSP and CBD correlating with the known NFT topology of those diseases, (2) the distribution of PHF tau burden will correlate with specific motor and cognitive features of PSP and CBD; and (3) regional PHF tau burden will be associated with cortical thinning. We will use amyloid PET imaging to exclude AD masquerading as PSP or CBD. Together, these efforts will establish the potential for developing [F18] T807 PET imaging as a biomarker and diagnostic tool for the parkinsonian tauopathies.

Understanding the relationship between A? and memory dysfunction in Alzheimer?s disease remains an essential objective. Although animal models of Alzheimer?s that over-express the amyloid precursor protein show perturbed calcium in individual neurons, memory is fundamentally a neural systems property of the intact hippocampus, and how A? impacts the integrity of neural systems calcium activity in the functioning hippocampus is unknown. During exploratory behavior, neurons represent space as place fields, coordinating their action potentials with the hippocampal theta oscillation, a rhythm dependent on acetylcholinergic (ACh) inputs from the medial septum; but during quiet wakefulness and slow wave sleep, ACh levels fall and theta is replaced with a physiological state in which neurons fire instead with sharp- wave ripple events. Given that ACh?s contribution to hippocampal function extends to Alzheimer?s, with ACh esterase inhibitors providing the mainstay of therapy and associated with significant improvements in memory, we hypothesize that the cholinergic system impacts the neurophysiological effects of A? deposition, such that A??s effects on dynamic calcium activity in the functioning hippocampus will depend on hippocampal state and cholinergic tone across the sleep-wake cycle. In addition, since fluctuations in cytoplasmic calcium may derive both from neuronal depolarization and from calcium-induced calcium release, calcium activity may be an imperfect surrogate for electrophysiological activity. To address these issues, we will study (1) the relationship between neuronal calcium activity and hippocampal electrophysiology in freely behaving normal animals, (2) how this relationship is impacted by A??in two Alzheimer?s disease mouse models, and (3) how ACh impacts A?'s effects on calcium activity and action potentials. To investigate these aims, we will combine chronic electrophysiological techniques with newly available miniature microscope imaging technologies (Inscopix head mounted mini-microscope) and robust, genetically encoded calcium fluorophores (GCAMP6f). We will acquire local field potentials together with single unit recordings and calcium imaging of hippocampal neurons as A? over-expressing mice and littermate controls perform a behavioral task and across their sleep-wake cycles. We will attempt to rescue A?-associated abnormalities with a ?-secretase1 inhibitor now in clinical trials, and we will employ pharmacology to evaluate the impact of ACh on A??s effects on hippocampal physiology. Together, these efforts will establish the effects of A??on neuronal action potential activity and calcium activity across the sleep-wake cycle, providing key insights into Alzheimer?s disease and identifying new targets for its treatment.

Project Summary/Abstract A fundamental goal of research focused on the pathophysiology of Parkinson?s disease (PD) is to understand how environmental and genetic factors implicated in PD contribute to its development and its course. Functional modifications to the genome that do not involve a change in the DNA sequence, known as epigenetic changes, have proven to be a powerful mechanism by which environmental exposure can impact gene expression. Histone deacetylases (HDACs) are a family of epigenetic enzymes that regulate gene expression in the human brain by chemically modifying chromatin, the network of proteins and DNA in chromosomal structure, in response to life experience and the environment. In PD, histone acetylation is markedly increased in midbrain dopamine neurons, in association with down-regulation of multiple HDACs. The neurotoxin MPTP recapitulates these findings, providing a mechanism by which environmental factors may contribute to PD pathogenesis. Furthermore, HDAC inhibitors have had therapeutic success in PD models. These observations raise the possibility that HDAC levels will be regionally altered in PD, reflecting both the topography of pathology in the brain and the severity of clinical impairment. Until recently, the levels and distribution of HDACs in the brain could not be quantified until after death. The development of [11C]Martinostat, the first radiotracer that labels HDACs in living humans, has now made this possible. [11C]Martinostat shows specific HDAC binding with low nanomolar affinity and is under active study in the healthy elderly and several patient populations. The overall goals of this proposal are to evaluate brain HDAC levels and regional distribution with [11C]Martinostat in well-characterized patients with PD, and to explore the relation of regional [11C]Martinostat binding to indices of motor and cognitive impairment. Subjects with early and advanced PD will undergo standardized neurological examination, detailed neuropsychological testing, and combined [11C]Martinostat PET-MRI, and will be compared to previously acquired clinical and PET data of an aged-matched NC cohort to test the following hypotheses: (1) The order of global brain HDAC expression will increase from NC to early PD to advanced PD; (2) Changes in the distribution of HDAC levels detected with PET will correlate with the known topology of pathologic changes in PD, including dopamine cell loss and striatal denervation and regional alpha-synuclein accumulation according to Braak staging (early nigra, entorhinal cortex, anterior cingulate; with later frontal, temporal, occipital, and parietal cortex); (3) Asymmetry of striatal HDAC accumulation will correlate with asymmetry of motor impairment; (4) Global cortical HDAC levels in PD will correlate with global cognitive impairment, with lower levels in cognitively normal PD and NC than PD-MCI and PDD; (5) Hallucinations in PD subjects will be associated with elevated HDAC levels in occipital cortical regions. Together, these efforts will clarify the contribution of dysregulation of epigenetic control of gene expression in PD and will establish the potential for developing [11C]Martinostat PET imaging as a PD biomarker and diagnostic tool.

Project Summary/Abstract Accumulating evidence suggests that epigenetic changes - functional modifications to the genome that do not change the DNA sequence and that provide a powerful mechanism by which environmental exposure can impact gene expression ? may contribute to dementia with Lewy bodies (DLB) and Parkinson disease (PD). Histone deacetylases (HDACs) are a family of epigenetic enzymes that regulate gene expression by chemically modifying chromatin, the network of proteins and DNA in chromosomal structure, in response to life experience and the environment. In DLB and PD at autopsy, histone acetylation is markedly dysregulated. However, it remains unclear whether histone acetylation-associated epigenetic changes accumulate with progression of disease including to dementia, for example reflecting the severity and topography of Lewy body pathology, nor whether HDAC changes relate to the accumulation of motor, cognitive, and behavioral impairments in these diseases. It is also unknown whether HDAC expression changes in life in DLB are distinct from those of Parkinson disease dementia (PDD). The recent development of [11C]Martinostat, the first radiotracer that labels HDACs in living humans, has enabled the antemortem assessment of HDAC levels and distribution in the human brain. [11C]Martinostat shows specific HDAC binding with low nanomolar affinity and is actively under study in several patient populations. The overall goals of this proposal are thus 1) to evaluate brain HDAC levels and regional distribution with [11C]Martinostat in well-characterized PD, PDD, and DLB subjects, contrasted with Alzheimer?s disease and age-matched normal control (NC) subjects, and 2) to relate regional [11C]Martinostat binding to Lewy body disease clinical features and amyloid burden. Subjects with DLB, PDD, cognitively normal PD, Alzheimer?s, and NC will undergo standardized neurological examination, detailed neuropsychological testing, combined [11C]Martinostat PET-MRI, and amyloid imaging with [11C]PiB PET. Building on preliminary [11C]Martinostat PET imaging and pathological data, we will test the following hypotheses: (1) The order of global brain HDAC expression will increase from AD to NC to cognitively normal PD to PDD to DLB; (2) Changes in regional HDAC expression detected with PET will correlate with the known topology of pathologic changes; (3) Cortical and striatal amyloid deposition will not qualitatively impact these results but will be associated with within- group reductions in regional HDAC expression; (4) HDAC expression in the putamen will correlate with the severity of motor impairment; asymmetry of nigral and striatal HDAC expression will correlate with asymmetry of motor impairment; (5) Global cortical and caudate HDAC levels will correlate with measures of cognitive impairment; (6) Posterior cortical HDAC expression will be associated with psychosis including visual hallucinations; (7) Differential HDAC expression in DLB and PDD will account for timing differences in the appearance of dementia relative to motor impairment in these diseases. Together, these efforts will shed light on the contribution of dysregulated epigenetic control of gene expression during life to PD, PDD, and DLB.