The purpose of this research is to explore the cellular and circuit mechanisms that underlie cholinergic control of spatial attention. Patients with various psychiatric disorders, including schizophrenia and ADHD, typically exhibit dysregulation of attention and gaze control, abnormal modulation of gamma (25-60 Hz) oscillations in local field potentials, and dysfunction of cholinergic signaling. We hypothesize that the co- occurrence of these four symptomatic phenomena reflects that they are mechanistically related. We will test this hypothesis by studying the properties of cholinergic neurons that lie at the heart of the midbrain stimulus selection network, where these four phenomena converge. We will use a combination of sophisticated behavioral, in vivo electrophysiological, and in vitro slice approaches.
In Aim #1, we characterize quantitatively the causal role of these cholinergic neurons in the control of attention and gaze in chickens trained to perform selective attention tasks;
in Aim #2, we parameterize and quantify the information they encode in the context of these attention-demanding tasks;and in Aim #3, we use in vitro slice techniques to reveal the synaptic mechanisms they employ to control the power and duration of gamma oscillations. This critical, cholinergic circuit element is spatially segregated from other circuit components in bird (uniquely). Our experiments take advantage of this spatial segregation in birds, to selectively record from and manipulate this critical circuit element in vivo and in vitro. We hypothesize that the action of these neurons is essential to the generation of selection signals that are issued by the midbrain for controlling spatial attention and gaze;preliminary data support this hypothesis. The results from our experiments will illuminate the role of cholinergic mechanisms in the generation of selection signals. Discovering these mechanisms will give insight into the symptoms and causes of diseases that involve these four phenomena, as well as suggest avenues for improved diagnosis and rational treatments of those symptoms.

Public Health Relevance

The proposed research will investigate neural mechanisms that may be dysfunctional in psychiatric disorders involving atypical control of attention and gaze, such as schizophrenia, autism spectrum disorder and ADHD. The experiments will reveal the role that a specific kind of cholinergic neuron plays in controlling the locus of spatial attention and gaze, the information these neurons encode, and how they regulate the power and duration of gamma oscillations. Our findings could provide fundamental insights to cellular and circuit mechanisms that give rise to such psychiatric disorders, lead to techniques for their early diagnosis, and inform therapeutic approaches for ameliorating some of their symptoms.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Special Emphasis Panel (SPC)
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Steinmetz, Michael A
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Stanford University
Schools of Medicine
United States
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Sridharan, Devarajan; Steinmetz, Nicholas A; Moore, Tirin et al. (2017) Does the Superior Colliculus Control Perceptual Sensitivity or Choice Bias during Attention? Evidence from a Multialternative Decision Framework. J Neurosci 37:480-511
Asadollahi, Ali; Knudsen, Eric I (2016) Spatially precise visual gain control mediated by a cholinergic circuit in the midbrain attention network. Nat Commun 7:13472
Bryant, Astra S; Goddard, C Alex; Huguenard, John R et al. (2015) Cholinergic control of gamma power in the midbrain spatial attention network. J Neurosci 35:761-75
Sridharan, Devarajan; Knudsen, Eric I (2015) Gamma oscillations in the midbrain spatial attention network: linking circuits to function. Curr Opin Neurobiol 31:189-98
Sridharan, Devarajan; Ramamurthy, Deepa L; Schwarz, Jason S et al. (2014) Visuospatial selective attention in chickens. Proc Natl Acad Sci U S A 111:E2056-65
Sridharan, Devarajan; Steinmetz, Nicholas A; Moore, Tirin et al. (2014) Distinguishing bias from sensitivity effects in multialternative detection tasks. J Vis 14:
Goddard, C Alex; Huguenard, John; Knudsen, Eric (2014) Parallel midbrain microcircuits perform independent temporal transformations. J Neurosci 34:8130-8