Psychotic disorders, such as schizophrenia, are characterized by positive symptoms, which include hallucinations or false percepts without corresponding stimuli. According to Bayesian theory, perception results from the integration of sensory evidence, obtained from external stimuli, and prior expectations, arising from the probability of a given sensory event in a certain context. Under this framework, Friston proposed a computational model of hallucinations consisting in an excessive bias towards prior expectations resulting from an overestimation of their certainty. This hypothesis has been supported by Horga and others showing that humans with hallucinations exhibit excessive biases towards prior expectations, in the form of false alarms or distorted percepts. Importantly, deficits in the adjustment of the weight of prior expectations correlates strongly with hallucination severity and elevated DA in dorsal striatum in patients of schizophrenia. However, how excess striatal DA leads to hallucinations is still unknown. Here, we proposed to use false alarms as a proxy for hallucinations and employ signal detection tasks combined with computational modeling in humans and mice to identify the neuronal mechanisms and circuitry by which excess striatal DA induces hallucinations.

The neuromodulators acetylcholine and dopamine play important roles in learning. In the striatum cholinergic interneurons are modulated co-incident with the release of dopamine in response to unpredicted rewards and reward predicting cues and both signals have been implicated in coding prediction error signals. Whereas dopamine neurons are mostly activated by these salient events, cholinergic interneurons often show a multiphasic response with a prominent pause in activity. The time locked occurrence of both signals suggest that they are coordinated but it is still unclear whether they are regulated independently from each other or whether they mutually regulate each other. Moreover, whether their temporal co-incidence is important for learning still needs to be determined. To address this question, we combine fiberphotometry with optogenetic and genetic tools to determine how the two neurotransmitters regulate each other in the striatum and how this affects flexible learning.

Adolescence is a period of increased vulnerability for the development of psychiatric disorders, including schizophrenia. The prefrontal cortex (PFC) undergoes substantial maturation during this period, and PFC dysfunction is central to cognitive impairments in schizophrenia. As a result, impaired adolescent maturation of the PFC has been proposed as a mechanism in the etiology of the disorder and its cognitive symptoms. In adulthood, PFC function is tightly linked to its reciprocal connections with the thalamus, and acutely inhibiting thalamic inputs to the PFC produces impairments in PFC function and cognitive deficits. Here, we propose that thalamic activity is equally important during adolescence as it is required for proper PFC circuit development. To test this hypothesis we use genetic tools in combination with slice and in vivo physiology to determine how thalamic inhibition during adolescence affects prefrontal cortex function and behavior during adolescent and adulthood.