The long-term goal of our investigation is to understand how neural circuits in the prefrontal cortex support decision-making. Orbitofrontal cortex (OFC) is a key brain region for decision- making under uncertainty in humans and other animals. Our central hypothesis is that OFC represents confidence information and plays causal role in reporting decision confidence to other brain regions, thereby affecting behavior. To study this issue, we have developed quantitative psychophysical methods for rodents, adapted from human and primate work, which enables the behavioral readout of confidence in a well-controlled decision task. Briefly, in each trial the animal has to decide which of two odor components is in the majority. After moving to the corresponding choice port, the rat waits for a delayed reward that may or may not come. If it doesn't, the rat eventually leaves the port and initiates another trial. The duration rats are willing to wait for a reward can be thought of as a gamble on the outcome of the perceptual decision, and hence it provides a quantitative index for confidence. Thus in each trial there is a perceptual decision (left/right) and a post-decision confidence report (leaving decision). If OFC is causal in this leaving decision, neural activity should be predictive of how long a rat waits before leaving on a trial-by-trial basis (correlation) We will also test the necessity of OFC activity for this process using pharmacological inactivation. These results will be interpreted in a computational framework that links neural and behavioral data to decision confidence. Next we will test the hypothesis that identified subsets of OFC neurons projecting to distinct target areas carry different types of information and thus mediate distinct behavioral functions. Using retrograde viruses to deliver light-sensitive activators (ChR2) and suppressors (Halo), we will optically microstimulate or block a subset of OFC neurons defined not by spatial proximity but by projection target. In combination with electrophysiology we will identify the neural correlates of distinct projection neurons and determine whether they are necessary and sufficient for confidence reports on a trial-to-trial basis. Upon completion of these aims, we expect to establish the role of OFC in decision confidence and determine the neural circuits through which it exerts its actions. By recording from neurons belonging to different long-range projections we also expect to help explain the observed heterogeneity in OFC neural representations. Beyond these mechanistic studies, we hope to inform an improved framework for understanding how impairments in a single prefrontal brain area can lead to such a wide range of psychiatric disorders, including addiction, depression, anxiety, obsessive-compulsive disorder, schizophrenia, and autism.

Public Health Relevance

This proposal aims to identify the causal neural circuit mechanisms responsible for confidence reporting in the mammalian brain. Using a combination of viral, optogenetic, and electrophysiological tools along with a novel confidence-reporting task in rats will enable us to determine how OFC and its pathways mediate behavior. Because our studies will be conducted in rodents, we expect to gain mechanistic insights in terms of the neural circuits and pathways involved, which has the potential to generate improved strategies for treating the human neuropsychiatric disorders in which OFC disruption is strongly implicated, such as depression, obsessive-compulsive disorder, schizophrenia, addiction, and autism.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (SPC)
Program Officer
Rossi, Andrew
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Cold Spring Harbor Laboratory
Cold Spring Harbor
United States
Zip Code
Lak, Armin; Nomoto, Kensaku; Keramati, Mehdi et al. (2017) Midbrain Dopamine Neurons Signal Belief in Choice Accuracy during a Perceptual Decision. Curr Biol 27:821-832
Sanders, Joshua I; Hangya, Balázs; Kepecs, Adam (2016) Signatures of a Statistical Computation in the Human Sense of Confidence. Neuron 90:499-506
Kobak, Dmitry; Brendel, Wieland; Constantinidis, Christos et al. (2016) Demixed principal component analysis of neural population data. Elife 5:
Hangya, Balázs; Sanders, Joshua I; Kepecs, Adam (2016) A Mathematical Framework for Statistical Decision Confidence. Neural Comput 28:1840-58
Pouget, Alexandre; Drugowitsch, Jan; Kepecs, Adam (2016) Confidence and certainty: distinct probabilistic quantities for different goals. Nat Neurosci 19:366-74
Kepecs, Adam; Mensh, Brett D (2015) Emotor control: computations underlying bodily resource allocation, emotions, and confidence. Dialogues Clin Neurosci 17:391-401
Lak, Armin; Costa, Gil M; Romberg, Erin et al. (2014) Orbitofrontal cortex is required for optimal waiting based on decision confidence. Neuron 84:190-201
Sanders, Joshua I; Kepecs, Adam (2014) A low-cost programmable pulse generator for physiology and behavior. Front Neuroeng 7:43