Michele A. Basso - US grants

PROJECT SUMMARY A major open - and very important - question in cognitive neuroscience is: how and where in the brain are decisions made? Recent electrophysiological evidence from a cerebral cortical area thought to play a key role in perceptual decision-making (LIP) suggests that the activity of neurons in area LIP do not reflect a gradual accumulation of evidence toward a decision. Furthermore, reversible inactivation of area LIP produces no change in decision-making performance, calling into question its causal role in visual perceptual decision- making. These unexpected results open the possibility that other sensorimotor areas play a critical role in the neuronal processing leading to perceptual decisions. Our goal is to expand on these recent findings and on our accomplishments made during previous award cycles to test the hypothesis that the basal ganglia (BG) and the superior colliculus (SC) play key roles in visual perceptual decision-making. We have two specific aims: 1) Determine the role of the superior colliculus (SC) in perceptual decision-making and, 2) determine the role of the inhibition from one output nucleus of the basal ganglia, the substantia nigra pars reticulata (nigra), to the SC in perceptual decision-making. We propose to use state of the art multiple neuron recording technologies to measure population activity in the SC and in the nigra while subjects perform visual perceptual decision tasks. We will employ analytical methods to model the behavioral data and make predictions about behavior using the population neuronal data. We will also employ cutting edge molecular genetic methods to manipulate neuronal activity to determine the causal role of these brain areas in perceptual decision-making.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Objective: To understand how higher order processes or cognition contribute to the control of voluntary movement. Because the execution of voluntary actions usually involves processes such as target selection, learning, memory, planning and expectation, motor systems are well suited for study of these processes. We investigate neuronal processes leading up to the execution of movements of the eyes, in particular, those eye movements that lead to rapid changes in the line of sight - saccades. We have a multi-technique approach to the study of these processes. First, we record electrical activity of single neurons while the subjects perform eye movement tasks designed to tap into cognitive processes. Second, we activate or inactivate particular regions of the brain to produce behaviors or interfere with ongoing behaviors and neural processing. Finally, because damage to certain brain regions produces profound clinical disorders such as Parkinson's disease and Huntington's disease, we study eye movements of both healthy and diseased human subjects to further our understanding of the role these structures play in both cognition and in producing the debilitating effects of these disorders. This research used WNPRC Animal Services.

DESCRIPTION (provided by applicant): The overall goal of my research program is to understand the role of the basal ganglia (BG) and superior colliculus (SC) in saccadic eye movement choice and decision-making. In this application we are focused on extending our recent results from multiple neuron recordings in SC to simultaneous, multiple neuronal recordings of SC and a BG structure that has inputs to the SC, the substantia nigra pars reticulata (SNr). We have one Specific Aim;to reveal the coordinated activity of neurons within the SNr-SC pathway during saccade choice and decision-making. To achieve our aim we propose the following: We will implement a decision task in which the difficulty level of the saccade choice is manipulated explicitly and the probability of the saccade choice in conditions of sensory certainty and uncertainty is varied. We will record simultaneously from multiple neurons in the SNr and the SC during performance of this task. We will test the hypothesis the activity of SC and SNr neurons is modulated by choice difficulty and performance. We predict that harder choices and poorer performance will be associated with higher levels of SNr activity and lower levels of SC activity. We will implement our Bayesian inference model and incorporates measured noised correlations to elucidate the role of the SNr-SC pathway in saccade choice. We expect our results will build on the growing body of evidence implicating sensorimotor brain regions in neuronal processing related to choice and decision- making. The results will also provide critical and detailed information about the relationship of the SNr to the SC and how this pathway contributes to saccade choices. They will also provide the first evidence for a role of the SNr in perceptual decision-making. Finally, since eye movement abnormalities are a prominent symptom in a number of BG and cortico-BG diseases such as Parkinson's disease, Tourette Syndrome and obsessive compulsive disorder our results should provide important insights into the mechanisms of symptomology in many disease states. PUBLIC HEALTH RELEVANCE: The experiments outlined in this proposal are designed to reveal insights into the role of the basal ganglia and superior colliculus in eye movement choice and perceptual decision-making. Because eye movement abnormalities are a prominent symptom in a number of basal ganglia and cortico-basal ganglia diseases such as Parkinson's disease, Tourette Syndrome and obsessive compulsive disorder, our results should provide important insights into the mechanisms of symptomology in many disease states.

DESCRIPTION (provided by applicant): The overall goal of this research plan is to understand the role of the basal ganglia (BG) and superior colliculus (SC) in saccadic eye movement choice and decision-making. This application focuses on developing an in vitro brain slice model with which we will extend our recent in vivo results and investigate the biophysics of a circuit involved in choice and decision-making. This proposal aims to link the properties of neurons and their circuits to behavior in order to elucidate the role of the SC and the BG in eye-movement related cognitive processes. We have four specific aims;1) Map response patterns across the SC. Voltage imaging will be used to map the spatial patterns of signal spread following electrical stimulation in the superficial SC (sSC) and intermediate SC (iSC). This aim will provide a basic assessment of the spatial extent of both intra- and inter-laminar circuitry within the SC;2) Evaluate inhibition and excitation in SC activity patterns. In this aim we will test for the existence of three specific interlaminar pathways: an excitatory pathway arising from the sSC extending to the iSC, an inhibitory pathway arising from the iSC and extending into the sSC and an excitatory pathway arising from the iSC and extending into the sSC. We will use voltage imaging in conjunction with patch clamping to study responses to sSC and iSC stimulation, and resolve these responses into contributions mediated by glutamatergic and GABAergic synapses. Experiments with synaptic receptor antagonists will assess the role of glutamatergic and GABAergic transmission in both intra- and interlaminar circuits;3) Determine the influence of BG output on the response pattern across the SC. The experiments of this aim will test the hypothesis that translation of visual information from sSC into motor information in iSC is modulated by inhibition from the substantia nigra pars reticulata of the BG. We will apply electrical stimulation in the nigra to determine how the nigra modulates SC responses to sSC and iSC stimulation;4) Map response patterns across the SC in monkey SC. We will develop an in vitro preparation of the SC using monkey tissue. Experiments as outlined in aims 1 and 2 will be performed. We will test the hypothesis that the underlying circuits in monkey and rodent SC are homologous. Because the BG and its target structures are implicated in many neurological and psychiatric disease states, the results of our experiments should lead to important insights into the functioning of these circuits and the biophysical mechanisms underlying complex behavioral and cognitive processing in both health and disease. PUBLIC HEALTH RELEVANCE: A sine qua non of higher mental function is our ability to make decisions. Extreme fluctuations in choice behavior may underlie certain neurological and psychiatric diseases such as schizophrenia, attention deficit disorder, Tourette Syndrome and obsessive compulsive disorder. Eye movement abnormalities are also associated with these cortico-basal ganglia diseases. Therefore, a deeper understanding of the basal ganglia - superior colliculus pathway and circuitry and ultimately their role in higher mental function, may lead to better diagnostics, better ways to assess therapies and should provide important insights into the mechanisms of symptomology in these disease states.

DESCRIPTION (provided by applicant): The oculomotor system is arguably the best understood motor control system. Traditionally, oculomotor scientists studied each eye movement subsystem in isolation. Only recently have scientists turned their attention to more complex problems such as the neuronal control of combined vergence and saccadic eye movements or the neuronal control of combined saccadic and smooth pursuit eye movements. Advances in these areas are opening up new topics of inquiry to the field of oculomotor neuroscience such as target selection - how does the brain select a single visual stimulus to guide eye movements? Is the process of selection the same for different eye movement subsystems or is it a shared mechanism? Do binocular disparity signals provide a low-level target selection mechanism for saccades or pursuit? Questions such as these are generating much excitement in the field and are producing results that have implications for the fields of visual neuroscience, cognitive neuroscience and computational neuroscience. As such, our goal in this application is to provide the oculomotor science community a forum to present and hear about cutting-edge research and to interact in an intimate, informal yet scientifically rigorous setting. In 2005, we held the first oculomotor Gordon Research Conference (GRC) ever, titled Oculomotor System Biology. The success of the first meeting resulted in second, sponsored GRC in 2007. The third and so far, most successful oculomotor GRC occurred in 2011, titled Eye Movements: The Motor System that Sees the World. The topics included: Eye Movements as a Probe for Attention, Perception, and Decision Making Mechanisms, in which the speaker's explored how the oculomotor system is used as a read-out for perceptual decision-making; The Action between Eye Movements, which explored the characteristics and control mechanisms for microsaccades and Central and Peripheral Oculomotor Subsystems in Health and Disease, which evaluated new findings about the role of peripheral mechanisms in controlling eye orientation. In the meeting scheduled for 2013 we hope to capitalize on the excitement generated from the 2011 meeting and plan to explore topics such as: Rodent Models for Higher Order Oculomotor Control; In this session the recent surge in the use of small mammals that are easily manipulated genetically to explore cognition and eye movements will be the theme. Beyond Black Boxes - New Computational Approaches for Understanding Oculomotor Control; in this session the topic of applying mathematical models to the oculomotor system such as Bayesian inference will be explored. More than Pretty Pictures- Lessons Learned from Imaging the Oculomotor System; in this session, we will explore how the technique of fMRI and other imaging methods enhances our understanding of the neural circuits underlying eye movements. This proposal requests support for a conference whose objective is to bring together scientists and physicians to discuss recent work in the oculomotor system. We plan to bring together early-career and established investigators to propel forward novel research venues and collaborations.

DESCRIPTION: In this application we have one Specific Aim: To test a new model of saccade generation by the nigro-colliculus pathway by determining the influence of the inhibitory inputs from the substantia nigra pars reticulata (nigra) on identified neuronal cell types within the superior colliculus. To achieve this aim we propose two experiments using the in vitro rodent model. Each of these experiments will be performed on both projection neurons and GAD 67 GFP labeled interneurons within both the intermediate (premotor) layers and the superficial (visual) layers of the colliculus. We shall, 1) introduce hyperpolarizing current into collicular neurons to assess expression of Ih, the hyperpolarization activated cation current and use hyperpolarizing voltage steps under voltage clamp to test for Ih in collicular neurons. 2) Introduce realistic spike trains into the nigra and record from neurons in the colliculus to assess whether nigral activity invokes Ih leading to bursting in superior colliculus neurons. The work proposed here may change the current dogma regarding the role of the nigro-collicular pathway in eye movement initiation by showing that its role is active rather than a passive gating of cortical afferents. The results therefore, may provide a new understanding of how eye movement symptoms occurring in neurological and neuropsychiatric diseases involving the basal ganglia such as Parkinson's disease, Huntington's disease, Tourette syndrome, attention deficit disorder, obsessive compulsive disorder and schizophrenia arise.

DESCRIPTION (provided by applicant): In the neuroimaging literature, there is a large gap in knowledge regarding the relationship between blood oxygen level dependent signals (BOLD) that are measured and neuronal inhibition. The circuits in the basal ganglia that control the suppression and release of saccadic eye movements provide a unique opportunity to fill this gap in knowledge. We propose to study BOLD signals in response to activation of an inhibitory circuit involved in eye movement control. We will insert genes encoding the light-activated ion channel, ChR2 into an output nucleus of the basal ganglia causing them to express ChR2. A light source provided to the channel- expressing neurons will open ion channels and cause neuronal depolarization of inhibitory neurons. BOLD signals will be measured. We have one Specific Aim: to determine BOLD signals in response to activation of an inhibitory neural circuit involved in eye movement control. We will perform three experiments to achieve this aim. 1) Using the neuron-specific promoter CAG, we will express ChR2 in neurons of the substantia nigra pars reticulata (nigra) and measure BOLD responses to light activation using fMRI; 2) using inhibitory neuron-specific promoters (PV and GAD67) we will express ChR2 in inhibitory nigral neurons and measure BOLD signals in response to light activation using fMRI; 3) we will record the electrical activity (LFPs) in the super colliculus and the thalamus (targets of nigral inhibition) in response to light activation to compare BOLD responses to electrical responses. The results of these experiments will uncover critical mechanisms of neural processing of inhibition and how this fundamental neuronal activity appears in BOLD signals.

PROJECT SUMMARY Decision-making operates over vastly different temporal scales. Although perceiving a sound requires information gathered over a time span of just milliseconds, deciding whom to marry may require years. Decision- makers also change over time. As we age, our perceptual and motor processing abilities change but also our knowledge base, our motivations and our comfort with risk change, all factors that contribute to our decisions. Recent work indicates that older adults may rely more on heuristics to inform their decisions, compared to younger adults. Conversely, we recently discovered that people with Parkinson?s disease, one of several related neurodegenerative proteinopathies falling along a continuum of alpha-synuclein and tauopathy that includes Alzheimer?s disease and variants of these two diseases, are impaired in the use of previously learned information (priors or heuristics) to guide perceptual decisions. Together these results indicate that the ability to use prior information for decisions changes over the lifespan and with diseases associated with aging. It is unknown how the use of priors or heuristics for perceptual decision-making develops or changes over the lifespan. It is equally unknown how the ability to use heuristics for decision-making is impaired with aging or neurodegenerative disease. Therefore, we propose to develop a novel animal model of decision-making behavior over the lifespan to test the hypothesis that the use of heuristics for decision-making differs between young and old and those with age-related proteinopathy and neurodegeneration. The results of our proposed experiments will provide a timeline of decision-making changes in a novel animal model of aging in health and disease. The results will provide the groundwork for future experiments designed to unravel the neural circuitry and neuropharmacology underlying decision-making changes over the lifespan and with age-related proteinopathies along the synuclein- tauopahy continuum, including Alzheimer?s disease, Parkinson?s disease and variants of these diseases, and thus facilitate the development of novel treatments for cognitive impairment associated with these diseases.

ABSTRACT Perceptual decision-making is a fundamental cognitive ability that is vital to healthy, daily functioning and is impaired in many diseases. Although many brain regions are known to be involved, there is no clear brain-wide model of how perceptual decisions are formed and executed and the underlying circuit mechanisms are still largely unknown. Here, a team of investigators propose a series of experiments that will use behavioral measures, imaging, physiology, circuit dissection, and computational modeling to study how the midbrain superior colliculus (SC) participates in visual decision-making. Specifically, this new team of investigators will probe the contribution of two SC neuronal cell types, wide field vertical (WFV) cells in the visuosensory layers and predorsal bundle (PDB) cells in the motor layers. These experiments will be done in mice and tree shrews, to reveal the underlying circuits and computational principles across species and to lay the foundation for future experiments designed to dissect decision-making circuits in primates. In Aim 1, the investigators will establish and perform psychophysical experiments to assess perceptual decision-making in both species. The behavioral data will be fitted with computational models to arbitrate between different theories of decision-making. In Aim 2, two photon calcium imaging and/or physiological recording will be performed in mice and tree shrews to determine the activity of WFV and PDB neurons during the psychophysical measures established in Aim 1. In addition, WFV and PDB neurons will be silenced optogenetically during the behavioral tasks to reveal their specific roles in decision-making. In Aim 3, the investigators will use intersectional monosynaptic viral tracing techniques, multiplexed peroxidase labeling for confocal and ultrastructural analysis of synaptic connections and and optogenetics-assisted brain slice recording to investigate the intrinsic and extrinsic circuits that link WFV and PDB cells. Together, these experiments will generate novel knowledge of the synapse to circuit mechanisms underlying perceptual decision-making, and provide technical and theoretical foundations for future mechanistic studies of cognitive function in higher mammalian species directly relevant to humans.